Steroid compound as well as preparation method and application thereof

Abstract

The invention relates to a steroidal compound as well as a preparation method and application thereof. Specifically, the invention provides a compound shown as a general formula (I), a stereoisomer or pharmaceutically acceptable salt of the compound, a preparation method of the compound, a pharmaceutical composition containing the compound and application of the compound as a GABAa receptor modulator to treatment of CNS-related diseases.

Description

Steroidal compounds, preparation methods and uses thereof

[0001] This application claims priority to Chinese patent application No. 202310527779.1 filed on May 11, 2023, priority to Chinese patent application No. 202311387436.6 filed on October 25, 2023, and priority to Chinese patent application No. 202410117316.2 filed on January 29, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a steroid compound, a preparation method and use thereof. Background Art

[0003] GABA receptors are ligand-gated ionotropic receptors located primarily at the apical site of the postsynaptic membrane of neurons, triggering fast inhibitory postsynaptic potentials (IPSPs). They are heteromeric 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 large N-terminus, four hydrophobic transmembrane domains, a circular intracellular domain containing phosphorylation sites for tyrosine kinases, protein kinase A, and protein kinase C, and a short C-terminus. Most GABA receptor subunits are composed of two α, two β, and one γ (δ) subunit, forming a heteropentamer. Different subunit compositions influence the physiological and pharmacological functions of the resulting GABA receptor. In the mammalian brain, α1-β1-γ2 is the main type of GABAAR composition, and α2-β3-γ2 and α3-β3-γ2 are also common. There is a GABA recognition site on the β subunit of GABAAR. After binding to GABA, the receptor is activated. The internal Cl - The channel opens and selectively allows Cl - By entering the cell, the postsynaptic neuron membrane becomes hyperpolarized, thereby inhibiting electrical discharges and generating a postsynaptic inhibitory potential (IPSP). This inhibitory effect produced at the postsynaptic membrane reduces the excitability of nerve cells.

[0004] It is known that GABAAR membrane endocytosis and recycling are mediated by its β and γ subunits, which are activated by binding to the clathrin adaptor protein AP2. Phosphorylation of the Tyr and Ser sites on the binding sequence affects AP2 binding, thereby regulating receptor internalization and affecting the efficiency of GABAergic inhibition. Dysfunction of the inhibitory GABA / GABAAR system may increase the risk of neurological diseases.

[0005] Depression is a common neuropsychiatric disorder characterized by mood changes, primarily low mood. Globally, an estimated 5% of adults suffer from this condition. It is characterized by persistent sadness and a lack of interest or pleasure in previously rewarding or pleasurable activities. Depression is the leading cause of disability worldwide and contributes significantly to the global burden of disease.

[0006] Research results suggest that both synaptic and extrasynaptic GABA receptors may be involved in the development of depression, and that different GABA receptor subunits play distinct roles in the development of depression. Although research findings regarding changes in hippocampal GABA receptor expression during depression are inconsistent, GABA receptor activation has antidepressant and anxiolytic effects. Activation of rat hippocampal GABA receptors can reduce Glu levels and increase GABA levels, thereby exerting an antidepressant effect. This suggests that regulating Glu and GABA levels may be one of the pathways through which GABA receptors exert their antidepressant effects. Furthermore, patch-clamp electrophysiological studies have shown that GABA receptors can inhibit whole-cell currents mediated by Glu ionotropic receptors, indicating that GABA receptors also regulate the function of Glu ionotropic receptors. Therefore, GABA receptor activation has antidepressant effects, and its antidepressant pathways are closely related to both the Glu and GABAergic systems.

[0007] However, over the past two decades, there has been little innovation in the discovery and development of depression treatments. The goal of developing GABA receptor modulators is to change patients' expectations by altering treatment options for MDD. Currently, international pharmaceutical companies, including Sage Therapeutics and Marinus, are fully committed to developing GABA receptor modulators.

[0008] GABAa-targeting neurosteroids currently in development include Alfaxalone, Alfadolone, Ganaxolone, Allopregnanolone, and Sage-217. Alfaxalone, Alfadolone, Ganaxolone, and Allopregnanolone have all been clinically proven to be neurosteroidal GABAa ligands with significant therapeutic efficacy. Unfortunately, due to their high lipophilicity and rapid hepatic metabolism, these drugs have very low oral bioavailability and can only be used for parenteral administration. Sage Therapeutics' Sage-217, an oral GABAa receptor-positive allosteric modulator, has demonstrated significant, consistent, rapid, and sustained reductions in depressive symptoms (including anxiety and insomnia) in clinical development, along with acceptable tolerability and safety, and has been granted Breakthrough Therapy Designation by the US FDA. However, further studies found that Sage-217 still has many problems. For example, due to the high lipophilicity of its steroid skeleton, its solubility is poor, and the fact that it cannot be salted makes it impossible to improve its poor solubility. In clinical applications, a larger dose is required to be successful, which increases costs and reduces patient compliance. In addition, the drug is poorly absorbed, and patients need to take the drug with meals in clinical plans. Most fatally, it has serious side effects. The FDA has issued a black box warning for "excessive sedation". The patient 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 problem potentially limits its approval for MDD.

[0009] Therefore, there is an urgent need to develop a new class of steroid compounds with improved drug-forming properties, lower metabolic rate, higher in vivo exposure, while maintaining reasonable lipophilicity to ensure that they can cross the blood-brain barrier, and the maximum agonist effect on the target can also be reduced to alleviate adverse reactions, so that they can serve as safe and long-term brain excitability regulators for the prevention and treatment of CNS-related diseases.

[0010] Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a GABAa receptor modulator with a novel structure, specifically, to provide a steroid compound, a preparation method thereof, a pharmaceutical composition thereof and its use, wherein the compound has a good positive regulatory effect on the GABAa receptor (for example, with improved E max and / or EC 50 ), and / or improved pharmacokinetic properties (e.g., having a longer half-life t 1 / 2 , greater exposure AUC and higher maximum plasma concentration C max), and / or an improved safety window (for example, having a larger safe dosage range, or having a lower likelihood of side effects at the same dose), and / or improved safety (for example, having lower toxicity and / or fewer side effects), and / or improved pharmacodynamic effects (for example, having a significant anti-epileptic effect, and / or a significant anti-depressant effect).

[0012] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0013] in:

[0014] X is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5- to 10-membered heteroaryl group may be further substituted with one or more R A replaced by;

[0015] R A Halogen, hydroxyl, -NO2, -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)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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group is optionally further selected from deuterium, halogen, hydroxyl, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl or 5-10 membered heteroaryl;

[0016] R aa 、R bb and R cc are independently hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, or R aa 、R bb or R cc Any two of the atoms together with the atoms to which they are attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl ring;

[0017] L is -(CH2) n1 -、-(CH2) n1 O(CH2) n2 -、-(CH2)n1 S(CH2) n2 -、-(CH2) n1 NH(CH2) n2 -、-(CH2) n1 C(O)(CH2) n2 -、-(CH2) n1 S(O)(CH2) n2 -、-(CH2) n1 C(O)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) n1 NHS(O)2(CH2) n2 -;

[0018] R x and R y are independently hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl or 5-6 membered heteroaryl group is optionally further selected from deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 substituted by one or more substituents in a haloalkoxy group;

[0019] R1, R2, R3, R3', R5, R6 and R6' are each independently hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) n3 R dd 、-(CH2) n3 OR dd 、-(CH2) n3 SR dd 、-(CH2) n3 C(O)R dd 、-(CH2) n3 C(O)OR dd 、-(CH2) n3 S(O)R dd 、-(CH2) n3 S(O)2R dd 、-(CH2) n3 NR dd R ee 、-(CH2) n3 C(O)NR dd R ee 、- (CH2) n3 S(O)NR dd R ee 、-(CH2) n3 NR dd C(O)R ee 、-(CH2) n3 NR dd S(O)R ee or -(CH2) n3 NR dd S(O)2R ee ;

[0020] R dd and R ee are independently hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0021] R4 and R4' are each independently hydrogen, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-8 Cycloalkyl; and R4 and R4' are not hydrogen at the same time;

[0022] n is an integer from 0 to 5;

[0023] m is an integer from 0 to 5;

[0024] n1 is an integer from 0 to 3;

[0025] n2 is an integer from 0 to 3; and

[0026] n3 is an integer from 0 to 3.

[0027] In a preferred embodiment, X is hydrogen, C 1-6 Alkyl, C 6-10 Aryl or a 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S, wherein the C 1-6 Alkyl, C 6-10 The aryl group or the 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S is optionally further substituted with one or more R A substituted, preferably X is hydrogen, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 The aryl group or the 5-10 membered heteroaryl group containing 1-4 heteroatoms selected from N, O and S is optionally further substituted with one or more R A replaced.

[0028] In a preferred embodiment, the R A Halogen, -CN, -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, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, preferably halogen, -CN, -S(=O)2R aa 、-S(=O)2NR aa R bb 、-S(=O)(=NR aa )R bb 、-P(=O)R aa Rbb 、C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, more preferably halogen, -CN, -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, C 1-3 Haloalkyl or C 1-3 Alkoxy is further preferably fluorine, chlorine, -CN, methyl, trifluoromethyl, methoxy, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3) or -P(=O)(CH3)2.

[0029] In a preferred embodiment, the R aa 、R bb and R cc are each independently hydrogen or C 1-6 Alkyl, preferably hydrogen or C 1-3 Alkyl, more preferably hydrogen or methyl.

[0030] In a preferred embodiment, said 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) n1 NHS(O)2(CH2) n2 -, preferably -C(O)(CH2) n2 -、-C(O)NH(CH2) n2 -、-C(O)(CH2) n2 NH-, -(CH2) n1 NHC(O)- or -(CH2) n1 NHS(O)2-, more preferably -C(O)(CH2) n2 -or-C(O)(CH2)n2 NH-.

[0031] In a preferred embodiment, the R x and R y are independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, preferably hydrogen, deuterium, halogen, hydroxyl or C 1-6 Alkyl, more preferably hydrogen.

[0032] In a preferred embodiment, R1, R2 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -(CH2) n3 OR dd 、-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd , preferably hydrogen, deuterium, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, more preferably hydrogen or C 1-3 The alkyl group is more preferably hydrogen or methyl.

[0033] In a preferred embodiment, R3, R3', R6 and R6' are each independently hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or C 1-3 The alkyl group is more preferably hydrogen or methyl.

[0034] In a preferred embodiment, R4 and R4' are each independently hydrogen or C 1-6 Alkyl, preferably hydrogen or C 1-3 Alkyl, more preferably hydrogen or methyl; and R4 and R4' are not hydrogen at the same time;

[0035] In a preferred embodiment, the R dd and R ee Each independently is C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-3 alkyl.

[0036] In a preferred embodiment, n is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2.

[0037] In a preferred embodiment, m is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2.

[0038] In a preferred embodiment, n1 is selected from 0, 1 or 2, preferably 0 or 1.

[0039] In a preferred embodiment, n2 is selected from 0, 1 or 2, preferably 0 or 1, more preferably 1.

[0040] In a preferred embodiment, n3 is selected from 0, 1 or 2, preferably 0 or 1.

[0041] In a preferred embodiment, the general formula (I) further has a structure represented by the general formula (II):

[0042] Among them, X, L, R1, R2, R3, R x 、R y , n and m are as described above.

[0043] In a preferred embodiment, the general formula (I) further has a structure represented by the general formula (III):

[0044] Among them, X, L, R1, R2, R x 、R y , n and m are as described above.

[0045] In a preferred embodiment, the general formula (I) further has a structure represented by the general formula (IV):

[0046] in:

[0047] Z is -(CH2) n4 - or -NH(CH2) n4 -, preferably -(CH2) n4 -, more preferably -CH2-;

[0048] R1 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -(CH2) n3 OR dd 、-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd , preferably C 1-6Alkyl, more preferably C 1-3 Alkyl, more preferably methyl;

[0049] R2 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -(CH2) n3 OR dd 、-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd , preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl;

[0050] R dd C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-3 alkyl;

[0051] n4 is 0, 1 or 2, preferably 0 or 1;

[0052] X, R x 、R y , n and m are as described above.

[0053] In a preferred embodiment, the general formula (I) further has a structure represented by the general formula (V) or the general formula (VA):

[0054] in:

[0055] X is hydrogen or optionally replaced by one or more R A substituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, preferably hydrogen or optionally substituted by one or more R A a substituted 5- to 10-membered heteroaryl group containing 1 to 4 nitrogen atoms;

[0056] R A Halogen, hydroxyl, -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)Rbb 、-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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, preferably halogen, -CN, -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, C 1- 6 haloalkyl or C 1-6 Alkoxy, more preferably halogen, -CN, -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, C 1-3 Haloalkyl or C 1-3Alkoxy, further preferably fluorine, chlorine, -CN, methyl, trifluoromethyl, methoxy, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3) or -P(=O)(CH3)2;

[0057] R aa 、R bb and R cc are independently hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 The alkyl group is more preferably hydrogen or methyl.

[0058] In a preferred embodiment, X in the general formula (Ia), general formula (I), general formula (II), general formula (III), and general formula (IV) is hydrogen or the following groups:

[0059] Preferably, hydrogen,

[0060] R A Halogen, hydroxyl, -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)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)2Rbb 、-P(=O)R aa R bb 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, preferably halogen, -CN, -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, C 1- 6 haloalkyl or C 1-6 Alkoxy, more preferably halogen, -CN, -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, C 1-3 Haloalkyl or C 1-3 Alkoxy, further preferably fluorine, chlorine, -CN, methyl, trifluoromethyl, methoxy, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3) or -P(=O)(CH3)2;

[0061] R aa 、R bb and R cc are independently hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl;

[0062] o is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1.

[0063] In a preferred embodiment of the present invention, the general formula (I) further has a structure shown by the general formula (VI):

[0064] in:

[0065] R1 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably hydrogen, deuterium or C 1-6 Alkyl, more preferably hydrogen, deuterium or C 1-3 Alkyl, further preferably hydrogen, deuterium or methyl;

[0066] X is hydrogen or optionally replaced by one or more R A substituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, preferably hydrogen or optionally substituted by one or more R A substituted 5-10 membered heteroaryl containing 1-4 nitrogen atoms, more preferably hydrogen,

[0067] R A Halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably cyano, C 1-6 Alkyl or C 1-6 Haloalkyl, more preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably cyano, methyl or trifluoromethyl;

[0068] o is selected from 0, 1 or 2, preferably 0 or 1.

[0069] In a preferred embodiment of the present invention, the general formula (VI) further has a structure represented by the general formula (VIa) or (VIb):

[0070] in:

[0071] X is hydrogen or optionally replaced by one or more R A substituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, preferably hydrogen or optionally substituted by one or more R A substituted 5-10 membered heteroaryl containing 1-4 nitrogen atoms, more preferably hydrogen,

[0072] R A Halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably cyano, C 1-6 Alkyl or C 1-6 Haloalkyl, more preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably cyano, methyl or trifluoromethyl;

[0073] o is selected from 0, 1 or 2, preferably 0 or 1.

[0074] In a preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (VII):

[0075] in:

[0076] R1 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably hydrogen, deuterium or C 1-6 Alkyl, more preferably hydrogen, deuterium or C 1-3 Alkyl, further preferably hydrogen, deuterium or methyl;

[0077] X is optionally replaced by one or more R A substituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, preferably optionally substituted with one or more R A Substituted 5-10 membered heteroaryl containing 1-4 nitrogen atoms, more preferably

[0078] R A Halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably cyano or C 1-6 Alkyl, more preferably cyano or C 1-3 Alkyl, more preferably cyano or methyl;

[0079] o is selected from 0, 1 or 2, preferably 0 or 1.

[0080] In a preferred embodiment of the present invention, the general formula (VII) further has a structure represented by the general formula (VIIa) or (VIIb):

[0081] in:

[0082] X is optionally replaced by one or more R A substituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, preferably optionally substituted with one or more R A Substituted 5-10 membered heteroaryl containing 1-4 nitrogen atoms, more preferably

[0083] R A Halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably cyano or C 1-6 Alkyl, more preferably cyano or C 1-3 Alkyl, more preferably cyano or methyl;

[0084] o is selected from 0, 1 or 2, preferably 0 or 1.

[0085] In a preferred embodiment of the present invention, the general formula (I) further has a structure represented by the general formula (VIII):

[0086] in:

[0087] R1 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl;

[0088] R3 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl;

[0089] R4 is C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl;

[0090] X is optionally replaced by one or more R A Substituted 5-membered heteroaryl containing 1 to 4 nitrogen atoms, preferably

[0091] R A Halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, preferably halogen, -CN, C 1-3 Alkyl, C1-3 Haloalkyl or C 1-3 Alkoxy, more preferably fluoro, chloro, -CN, methyl, ethyl, trifluoromethyl or methoxy;

[0092] o is selected from 0, 1 or 2.

[0093] In a preferred embodiment of the present invention, the general formula (VIII) further has a structure represented by the general formula (VIII-A) or (VIII-B):

[0094] in:

[0095] R1 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl;

[0096] R3 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl;

[0097] R4 is C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl;

[0098] R A Halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, preferably halogen, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy, more preferably fluoro, chloro, -CN, methyl, ethyl, trifluoromethyl or methoxy;

[0099] o is selected from 0, 1 or 2.

[0100] In a preferred embodiment of the present invention, the compound is selected from:

[0101] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above-mentioned general formula, its stereoisomers, its tautomers or pharmaceutically acceptable salts, and at least one pharmaceutical excipient among pharmaceutically acceptable carriers, diluents or excipients.

[0102] In some embodiments of the present invention, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or administration via an external implanted reservoir, wherein oral administration is preferred.

[0103] For oral administration, the compounds of the present application can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Carriers used in tablet formulations typically include lactose and corn starch, and lubricants such as magnesium stearate may also be added. Diluents used in capsule formulations typically include lactose and dried corn starch. Aqueous suspension formulations typically combine the active ingredient with a suitable emulsifier and suspending agent. If desired, sweeteners, flavorings, or coloring agents may be added to these oral formulations.

[0104] The present invention further provides the use of the compounds represented by the above-mentioned general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions in preparing drugs.

[0105] The present invention further provides the use of the compounds represented by the above-mentioned general formulas, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of GABAa receptor modulator drugs.

[0106] The present invention further provides the use of the compounds represented by the above-mentioned general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of drugs for treating CNS-related diseases.

[0107] The present invention further provides the use of the compounds represented by the above-mentioned general formulae, their stereoisomers, their tautomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in treating CNS-related diseases.

[0108] In some embodiments of the invention, the CNS-related disease is selected from the group consisting of 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 depressive disorder, perimenopausal depression, anxiety disorders, premenstrual dysphoric disorder, epilepsy, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, or tinnitus.

[0109] In some embodiments of the present invention, the CNS-related disease is depression.

[0110] In some embodiments of the present invention, the CNS-related disease is postpartum depression.

[0111] In some embodiments of the present invention, the CNS-related disease is major depressive disorder.

[0112] In some embodiments of the present invention, the CNS-related disease is perimenopausal depression.

[0113] In some embodiments of the present invention, the CNS-related disease is anxiety disorder.

[0114] In some embodiments of the present invention, the CNS-related disease is premenstrual dysphoric disorder.

[0115] In some embodiments of the present invention, the CNS-related disease is epilepsy.

[0116] Detailed description of the invention

[0117] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0118] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also included within the scope of the present invention. Purification and isolation of such substances can be achieved by standard techniques known in the art.

[0119] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. "Alkyl" can have 1 to 8 carbon atoms, i.e., "C1-C8 alkyl", for example, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 1-6 Alkyl, C 3-6Alkyl. Non-limiting 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 the like, or isomers thereof. The alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent may be one or more, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the like.

[0120] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted. For example, the term "C 1-8 "Alkylene" refers to an alkylene group having 1 to 8 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene or ethylpropylene, etc. The alkylene group can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available point of attachment, and the substituent can be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl, etc. "Methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc.

[0121] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 carbon atoms, i.e., "C3-C 20 Cycloalkyl", such as C 3-18 Cycloalkyl, C 3-16 Cycloalkyl, C 3-12 Cycloalkyl, C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl, C 4-8 Cycloalkyl, C 4-6 Cycloalkyl, C 5-6 Cycloalkyl, preferably C 3-8 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 3-4Cycloalkyl. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0122] The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The term includes 3-20 membered heterocyclyl groups, such as 3-18 membered heterocyclyl groups, 3-16 membered heterocyclyl groups, 3-12 membered heterocyclyl groups, 3-8 membered heterocyclyl groups, 3-6 membered heterocyclyl groups, 3-5 membered heterocyclyl groups, 3-4 membered heterocyclyl groups, 4-8 membered heterocyclyl groups, 4-6 membered heterocyclyl groups, 5-6 membered heterocyclyl groups, preferably 3-8 membered heterocyclyl groups, 3-6 membered heterocyclyl groups, 3-5 membered heterocyclyl groups, 3-4 membered heterocyclyl groups, 4-8 membered heterocyclyl groups, 4-6 membered heterocyclyl groups, 5-6 membered heterocyclyl groups, which optionally contain 1-4 heteroatoms, 1-3 heteroatoms or 1-2 heteroatoms, wherein the heteroatoms are optionally N, O, S atoms, but do not include the ring portion of -OO-, -OS- or -SS-, and 3-8 membered heterocyclyl groups containing 1-4 heteroatoms selected from N, O and S are particularly preferred. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolane, 2,2-difluoro-1,3-dioxolane or azepanyl, etc. Non-limiting examples of polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups, wherein the spirocyclic, fused ring and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent may be one or more, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl or heteroaryl.

[0123] The term "aryl" refers to a 6- to 14-membered, all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent may be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl. When the aryl group is substituted with a substituent, the substituent may not be further substituted.

[0124] The term "heteroaryl" refers to a monocyclic or fused polycyclic heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5-14 membered heteroaryl group, more preferably a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl and a 5-6 membered cycloalkyl group, a 5-6 membered heteroaryl and a C 6-10 Aryl or C 6-10 phenyl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, 5-6-membered heteroaryl, 5-6-membered cycloalkyl, 5-6-membered heteroaryl, phenyl, or phenyl-5-6-membered heteroaryl. Particularly preferred are 5-10-membered heteroaryl groups containing 1 to 4 heteroatoms selected from N, O, and S, such as pyrrolyl, imidazolyl, furyl, pyranyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienophenyl, thienopyridyl, pyrazolophenyl, pyrazolopyridyl, pyrazolocyclohexyl, pyridothiphenyl, pyridopyrrolyl, benzothienyl, indolyl, indazolyl, and the like. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent may be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl, etc. When the heteroaryl group is substituted by a substituent, the substituent may not be further substituted.

[0125] The "hetero" in the heteroaryl or heterocyclic group means that one or more ring atoms are independently selected from N, O or S(O) m (wherein m is an integer from 0 to 2) and the like, preferably wherein 1 to 4 ring atoms are selected from N, O or S, preferably 1 to 3 ring atoms are selected from N, O or S.

[0126] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, 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. When the alkoxy group is substituted with a substituent, the substituent may not be further substituted.

[0127] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. Alkylthio can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted on any available point of attachment, and the substituent can be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic radical, aryl or heteroaryl, etc. When the alkylthio is substituted by a substituent, the substituent is no longer further substituted.

[0128] The term "alkylamino" refers to -NH-(alkyl or non-substituted cycloalkyl), or -N-(alkyl or non-substituted cycloalkyl)(alkyl or non-substituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkylamino include methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like. Alkylamino may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent may be one or more, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl. When the alkylamino is substituted with a substituent, the substituent is no longer further substituted.

[0129] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0130] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl 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, dibromofluoromethyl, and the like; preferably fluoromethyl, difluoromethyl, and trifluoromethyl. Non-limiting examples of haloethyl groups include: 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, and the like; preferably 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, and 2,2-difluoroethyl.

[0131] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. Non-limiting examples of halomethoxy include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy. Non-limiting examples of haloethoxy include: 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2- Chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, etc.; preferably 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, and 2,2-difluoroethoxy.

[0132] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. The "alkenyl" group may have 2 to 6 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, etc.

[0133] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The "alkynyl" group may have 2 to 6 carbon atoms, wherein the alkynyl group may be further substituted with other related groups, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups, etc.

[0134] "Hydroxy" refers to -OH.

[0135] "Amino" refers to -NH2.

[0136] "Cyano" refers to -CN.

[0137] "Nitro" refers to -NO2.

[0138] "Carboxyl" refers to -C(O)OH.

[0139] "Oxo" refers to =0.

[0140] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0141] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0142] When the lower limit and upper limit of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0143] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0144] The expression mn used herein refers to the range from m to n and the subranges and individual point values ​​therein. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, 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, the expression "C3-C 10 ” or “C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be encompassed, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "C1-C6" or "C 1-6 " covers a range of 1-6 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, the expression "three-membered to ten-membered" should be understood to cover any subranges and each point value therein, such as three-membered to five-membered, three-membered to six-membered, three-membered to seven-membered, three-membered to eight-membered, four-membered to five-membered, four-membered to six-membered, four-membered to seven-membered, four-membered to eight-membered, five-membered to seven-membered, five-membered to eight-membered, six-membered to seven-membered, six-membered to eight-membered, nine-membered to ten-membered, etc., as well as three, four, five, six, seven, eight, nine, ten-membered, etc. Other similar expressions herein should be understood in a similar manner.

[0145] As used herein, different expressions 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 convey the same meaning, that is, X can be any one or more of A, B, and C.

[0146] The expression "-(CY1Y2) n -", means that each Y1 or Y2 connected to C can be the same or different, that is, each Y1 can be a different group, each Y2 can be a different group, each Y1 can also be the same group, each Y2 can also be the same group.

[0147] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes both the case where the cycloalkyl is substituted with alkyl and the case where the cycloalkyl is not substituted with alkyl.

[0148] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom being replaced by a selection from the designated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When a substituent is described as not being present, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When each carbon atom in a group is described as optionally substituted by a heteroatom, the proviso is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

[0149] If a substituent is described as "optionally substituted with," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced with independently selected, optional substituents. When a substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced. Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0150] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0151] When any variable (e.g., R), as well as variables with labels (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. 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 four R substituents, and the options for each R substituent at each occurrence are independent of each other.

[0152] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0153] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0154] The term "pharmaceutical composition" refers to a composition containing one or more compounds described herein, or physiologically or pharmaceutically acceptable salts thereof, and other components such as physiologically or pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0155] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0156] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0157] As used herein, the term "treating" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.

[0158] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition. The term "neuropsychiatric disorder" refers to a general term encompassing neurological and / or psychiatric disorders.

[0159] With respect to a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0160] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0161] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses. Beneficial effects

[0162] The compounds of the present invention exhibit good binding ability to GABAa receptors and have anti-neuropsychiatric activity. They also possess good drug-forming properties, a low metabolic rate, and suitable lipophilicity, ensuring that they can cross the blood-brain barrier and have therapeutic or preventive effects on neuropsychiatric diseases. Clinically, they will have better patient compliance.

[0163] In some embodiments, the compounds of the present invention have a good positive regulatory effect on GABAa receptors (e.g., with improved E max and / or EC 50 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 improved safety windows (e.g., a larger safe dosage 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 , greater exposure AUC and higher maximum plasma concentration C max In some embodiments, the compounds of the present invention have improved pharmacodynamic effects (e.g., significant anti-epileptic effects and / or significant anti-depressant effects). In some embodiments, the compounds of the present invention have better drug properties such as good patient compliance and / or less tolerance.

[0164] Specifically, the results of the in vitro GABAa receptor cell activity test of the present disclosure show that the compound of the present invention is an effective GABAa receptor positive modulator with excellent positive regulatory effect. It has a lower Emax (i.e., a lower upper limit of action at high concentrations), indicating potential smaller side effects in vivo; combined with a lower EC 50 (i.e., a lower onset dose), showing the potential for a larger therapeutic window. The results of in vivo efficacy experiments on PTZ-induced mouse epilepsy models showed that the compounds of the present invention can prolong the survival rate of PTZ-induced convulsive mice, have a protective effect on acute epileptic seizures in mice, and some compounds still show partial protective effects at extremely low doses. In addition, some compounds can also significantly prolong the latency and number of clonic seizures and generalized tonic-clonic seizures, and have significant anti-epileptic effects. The results of in vivo efficacy experiments on forced swimming and sucrose preference in mice showed that the compounds of the present invention can significantly reduce the immobility time of C57 mice in the forced swimming test, and significantly increase the sucrose preference of C57 mice in the sucrose preference test, and have significant antidepressant effects. The results of in vivo pharmacokinetic experiments in mice showed that the compounds of the present invention have a longer half-life t 1 / 2 , greater exposure AUC and higher maximum plasma concentration C max , showing good metabolic properties. The results of acute toxicity experiments and side effect observations in mice showed that the compound of the present invention has a higher maximum tolerated dose (MTD), better safety and weaker side effects, and is worthy of further clinical development. DETAILED DESCRIPTION

[0165] The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will appreciate that the following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention. Where specific conditions are not specified in the examples, the methods are carried out according to conventional conditions or the conditions recommended by the manufacturer. Where the reagents or instruments used are not specified by manufacturer, they are all conventional products that can be obtained commercially. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0166] Example

[0167] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0168] NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed on an AVANCE III 600 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0169] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu LCMS2020 mass spectrometer, and HPLC was performed using a Shimadzu LC20A liquid chromatograph.

[0170] The thin layer chromatography silica gel plate used was Yantai Jiangyou silica gel plate, the specification used for TLC was 0.2mm±0.03mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm~0.5mm.

[0171] Example 1

[0172] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethan-1-one

[0173] Synthesis scheme:

[0174] Step 1: Preparation of (2S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-17-hydroxy-2,13-dimethylhexahydro-3H-cyclopentadienyl[a]phenanthrene-3-one

[0175] (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-cyclopentadien[a]phenanthrene-3-one (5.00 g, 17.3 mmol) was dissolved in pyridine (60.0 mL). 10% wet palladium on carbon (340 mg) was added to displace the hydrogen atmosphere. The reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered and the organic phase was concentrated to obtain a crude product (6.60 g, 100% yield, crude product), which was used directly in the next reaction.

[0176] Step 2: Preparation of (2S, 5R, 8R, 9R, 10S, 13S, 14S)-2,13-dimethyltetradecahydro-3H-cyclopentadienyl[a]phenanthrene-3,17(2H)-dione

[0177] (2S,5R,8R,9R,10S,13S,14S,17S)-17-hydroxy-2,13-dimethylhexahydro-3H-cyclopentadien[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 reaction was stirred at room temperature for 2 hours. The reaction solution was filtered and the organic phase was concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 3 / 1) and purified to give (2S,5R,8R,9R,10S,13S,14S)-2,13-dimethyltetradecahydro-3H-cyclopentadien[a]phenanthrene-3,17(2H)-dione (5.50 g, yield: 84.0%).

[0178] 1 H NMR (400MHz, CDCl3) δ2.62(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).

[0179] Step 3: Preparation of (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-2,3,13-trimethylhexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one

[0180] (2S,5R,8R,9R,10S,13S,14S)-2,13-dimethyltetradecahydro-3H-cyclopentadien[a]phenanthrene-3,17(2H)-dione (5.50 g, 18.9 mmol) was dissolved in dry toluene (200 mL). The system was purged with nitrogen and cooled to -78°C. A 0.4 M solution of methylaluminum bis(2,6-di-tert-butyl-4-anisole) (142 mL, 56.8 mmol) was slowly added, and the reaction system was stirred at -78°C for 30 minutes. 3.0 M methylmagnesium bromide (20 mL, 60.0 mmol) was slowly added dropwise, and the reaction system was stirred at -78°C for 3 hours. TLC indicated the reaction was complete, and the reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The reaction mixture was filtered and dried, and the crude product was separated by column chromatography (rinsed with petroleum ether: ethyl acetate = 2:1) to give (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-2,3,13-trimethylhexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one (4.90 g, yield: 84.0%).

[0181] 1H NMR (400MHz, CDCl3) δ2.47–2.40(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).

[0182] 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-cyclopentadienyl[a]phenanthrene-3-ol

[0183] A dry 100 mL round-bottom flask was charged with 2.0 M lithium diisopropylamide (32.2 mL, 64.4 mmol). The atmosphere was purged with nitrogen and cooled to -78°C. (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethylhexahydro-17H-cyclopentadien[a]phenanthrene-17-one (4.90 g, 16.1 mmol) was dissolved in 35 mL of anhydrous tetrahydrofuran and slowly added dropwise to the reaction system. The reaction was stirred for 1 hour. Trimethylsilyl chloride (3.50 mL, 40.3 mmol) was then added to the reaction system. The reaction mixture was stirred at -78°C for 2 hours and then stirred at 0°C for 15 minutes. TLC indicated the reaction was complete. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and dried to give a 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-cyclopentadien[a]phenanthrene-3-ol (6.06 g, yield: 100%), which was used directly in the next reaction.

[0184] 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-cyclopentadienyl[a]phenanthrene-17-one

[0185] (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-cyclopentadien[a]phenanthrene-3-ol (6.06 g, 16.1 mmol) was dissolved in anhydrous dichloromethane (120 mL) and anhydrous acetonitrile (40.0 mL), the atmosphere was replaced with nitrogen, palladium acetate (3.50 g, 9.17 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction solution was filtered, the organic phase was concentrated, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 5 / 1) to give (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-cyclopentadien[a]phenanthrene-17-one (2.20 g, yield: 45.0%).

[0186] 1 H NMR (400MHz, CDCl3) δ7.52 (dd, J=6.0, 1.1Hz, 1H), 6.02 (dd, J=6.0, 3.2Hz, 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=6.7Hz,3H).

[0187] Step 6: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,3,13,15-tetramethylhexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one

[0188] A dry 100 mL round-bottom flask was charged with 3.0 M methylmagnesium bromide (9.69 mL, 29.1 mmol). The atmosphere was purged with nitrogen and cooled to zero degrees Celsius. Cuprous iodide (4.16 g, 21.8 mmol) was added to the reaction system, and the reaction was stirred at 0°C for 1 hour. (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-cyclopenta[a]phenanthrene-17-one (2.20 g, 7.27 mmol) was dissolved in 25 mL of anhydrous tetrahydrofuran and slowly added dropwise to the reaction system. The reaction was stirred for 2 hours. TLC indicated the reaction was complete. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The reaction mixture was filtered and dried, and the crude product was separated by column chromatography (rinsed with petroleum ether: ethyl acetate = 3:1) to give (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R)-3-hydroxy-2,3,13,15-tetramethylhexahydro-17H-cyclopentadien[a]phenanthrene-17-one (1.50 g, yield: 65.0%).

[0189] 1 H NMR (400MHz, CDCl3) δ2.50–2.40(m,2H),2.24(d,J=17.6Hz,1H),1.91–1.09(m,25H),1.03(s,3H),0.87(d,J=6.7Hz,3H).

[0190] Step 7: Preparation of (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile

[0191] Potassium tert-butoxide (5.29 g, 47.2 mmol) and tert-butanol (30.0 mL) were added to a dry 100 mL round-bottom flask, and the atmosphere was purged with nitrogen. (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,3,13,15-tetramethylhexahydro-17H-cyclopentadien[a]phenanthrene-17-one (1.50 g, 4.71 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and slowly added dropwise to the reaction system. The reaction was stirred for 30 minutes. p-Toluenesulfonylmethyl isocyanide (1.84 g, 9.46 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and slowly added dropwise to the reaction system. The reaction was stirred at room temperature overnight. TLC showed that the reaction was complete, and water (50 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product which was separated by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 3 / 1) and purified to give (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile (0.95 g, yield: 61.3%).

[0192] 1 H NMR (400MHz, CDCl3) δ2.51–2.48(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=7.4Hz,3H),0.87(d,J=6.7Hz,3H).

[0193] Step 8: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethane-1-one

[0194] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile (950 mg, 2.88 mmol) was dissolved in dry tetrahydrofuran (100 mL). The system was purged with nitrogen and 3.0 M methylmagnesium bromide (28.5 mL, 85.5 mmol) was slowly added dropwise. The reaction system was stirred at 80°C for 7 hours. TLC showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The reaction mixture was filtered and dried, and the crude product was separated by column chromatography (rinsed with petroleum ether: ethyl acetate = 4:1) to give 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)ethan-1-one (540 mg, yield: 54.0%).

[0195] 1 H NMR(400MHz, CDCl3)δ2.49(dd,J=10.4,8.6Hz,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=7.2Hz,3H),0.87(d,J=6.7Hz,3H),0.77(s,3H).

[0196] Example 2

[0197] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0198] Synthesis scheme:

[0199] Step 1: Preparation of 2-bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethan-1-one

[0200] Dissolve 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)ethan-1-one (150 mg, 0.43 mmol) in methanol (5 mL). Add one drop of hydrogen bromide and then liquid bromine (75.6 mg, 0.48 mmol). Stir the reaction at room temperature for 3 hours. Add water (20.0 mL), extract the aqueous phase with ethyl acetate (20.0 mL x 2), and combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product (150 mg, crude product) that is used directly in the next reaction.

[0201] Step 2: Preparation of 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0202] 2-Bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethan-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) were dissolved in anhydrous tetrahydrofuran (5.00 mL) and N, N-dimethylformamide (1.00 mL) was added, the reaction was stirred at room temperature overnight, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated by high performance liquid chromatography to give 1-(2-((2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (51.0 mg, yield: 33.0%).

[0203] 1 H NMR (400MHz, CDCl3) δ7.86 (s, 1H), 7.81 (s, 1H), 5.03–4.88 (m, 2H), 2.55 (dd, J = 10.2, 8.4Hz,1H),2.27–2.10(m,2H),2.03–1.81(m,5H),1.75–1.25(m,11H),1.1 7–1.03(m,7H),0.98(d,J=7.0Hz,3H),0.87(d,J=6.7Hz,3H),0.83(s,3H).

[0204] 13 C NMR (101MHz, CDCl3) δ201.98,142.38,136.01,113.23,93.17,74.11,61.69,61.40,57.43,45.52,43.08,41.2 9,41.22,39.41,39.26,35.94,35.09,34.09,33.53,31.32,30.25,26.09,25.21,20.47,18.25,16.81,15.13.

[0205] LC-MS m / z(ESI):420.25[M+H-18] + .

[0206] Example 3

[0207] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0208] Synthesis scheme

[0209] The synthesis method is the same as that of Example 2, except that 1H-pyrazole-4-carbonitrile in the second step is replaced by 1H-pyrazole-3-carbonitrile.

[0210] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=2.4Hz,1H),6.73(d,J=2.4Hz,1H),5.04–4.90(m,2H),2.55(dd,J=10.3,8.3Hz,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=7.1Hz,3H),0.88(d,J=6.7Hz,3H),0.83(s,3H).

[0211] 13C NMR (101MHz, CDCl3) δ202.16,132.19,125.17,113.89,111.96,74.12,62.08,61.36,57.42,45.52,43.09,41. 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.

[0212] LC-MS m / z(ESI):420.20[M+H-18] + .

[0213] Example 4

[0214] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0215] Synthesis scheme

[0216] The synthesis method is the same as that of Example 2, except that 1H-pyrazole-4-carbonitrile in the second step is replaced by 3-(trifluoromethyl)-1H-pyrazole.

[0217] 1 H NMR (400MHz, CDCl3) δ7.47(dt,J=2.0,1.0Hz,1H),6.59(d,J=2.4Hz,1H),4.97(d,J=4.6Hz,2H),2.54(dd,J=10.5,8.1H z,1H),2.29–2.10(m,2H),1.97(m,1H),1.92–1.05(m,20H),0.98(d,J=7.0Hz,3H),0.88(d,J=6.7Hz,3H),0.84(s,3H).

[0218] 13 C NMR(101MHz,CDCl3)δ202.58,142.57(q,J C-F =38.0Hz),132.26,122.71(q,J C-F=145.0Hz),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.

[0219] MS m / z(ESI):479.2[MH] - .

[0220] Example 5

[0221] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0222] Synthesis scheme

[0223] The synthesis method is the same as that of Example 2, except that 1H-pyrazole-4-carbonitrile in the second step is replaced by 1H-pyrazole-3,5-dicarbonitrile.

[0224] 1 H NMR (400MHz, CDCl3) δ7.21 (s, 1H), 5.16 (d, J = 1.6Hz, 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=6.8Hz,3H),0.88–0.86(m,6H).

[0225] 13 C NMR (101MHz, CDCl3) δ200.10,125.91,118.36,118.13,111.80,108.72,74.13,61.95,61.33,57.51,45.86,43. 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.

[0226] MS m / z(ESI):461.15[MH] - .

[0227] Example 6

[0228] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one

[0229] Synthesis scheme

[0230] The synthesis method is the same as that of Example 2, except that 1H-pyrazole-4-carbonitrile in the second step is replaced by 1H-1,2,4-triazole.

[0231] 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.96(s,1H),5.04–4.91(m,2H),2.59–2.55(m,1H),2.26–2.13(m,2 H),2.00–1.84(m,4H),1.76–1.04(m,19H),0.98(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H),0.84(s,3H).

[0232] 13 C NMR (101MHz, CDCl3) δ201.99,151.82,144.53,74.11,61.38,58.76,57.42,45.47,43.10,41.27,41.2 2,39.42,39.27,35.96,35.10,34.10,33.56,31.33,30.25,26.09,25.22,20.45,18.26,16.80,15.13.

[0233] MS m / z(ESI):414.40[M+H] + .

[0234] Example 7

[0235] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one

[0236] Example 8

[0237] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

[0238] Synthesis scheme

[0239] The synthesis method was the same as that in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced by 1H-1,2,3-triazole, and finally product 1 (compound 7) and product 2 (compound 8) were separated by column chromatography.

[0240] Compound 7:

[0241] 1 H NMR (400MHz, CDCl3) δ7.69(s,2H),5.24(d,J=1.2Hz,2H),2.52(dd,J=10.5,8.1Hz,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=7.1Hz,3H),0.89–0.85(m,6H).

[0242] 13 C NMR (101MHz, CDCl3) δ202.61,135.03,74.13,63.87,60.88,57.37,45.34,43.11,41.23,41.14 ,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.

[0243] MS m / z(ESI):414.3[M+H] + .

[0244] Compound 8:

[0245] 1H NMR (400MHz, CDCl3) δ7.76(d,J=1.0Hz,1H),7.65(d,J=1.1Hz,1H),5.29–5.11(m,2H),2.60(dd,J=10.5,8.1Hz,1H),2.31–2.1 2(m,2H),2.07–1.97(m,1H),1.93–1.83(m,3H),1.79–1.12(m,16H),0.98(d,J=7.0Hz,3H),0.88(d,J=6.8Hz,3H),0.84(s,3H).

[0246] 13 C NMR (101MHz, CDCl3) δ201.69,134.01,125.04,74.14,61.46,58.89,57.40,45.52,43.08,41.25,41.2 1,39.41,39.26,35.96,35.09,34.09,33.56,31.33,30.26,26.08,25.21,20.42,18.26,16.79,15.11.

[0247] MS m / z(ESI):396.2[M+H-H2O] + .

[0248] Example 9

[0249] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0250] Example 10

[0251] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)-2-(1H-tetrazol-1-yl)ethan-1-one

[0252] Synthesis scheme

[0253] The synthesis method was the same as that in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced by 1H-tetrazole, and finally product 1 (Compound 9) and product 2 (Compound 10) were separated by column chromatography.

[0254] Compound 9:

[0255] 1 H NMR (400MHz, CDCl3) δ8.57(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=6.8Hz,3H),0.91–0.86(m,6H).

[0256] 13 C NMR (101MHz, CDCl3) δ200.10,153.22,74.12,61.42,61.34,57.43,45.58,43.11,41.23,41.19,39 .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.

[0257] MS m / z(ESI):413.15[MH] - .

[0258] Compound 10:

[0259] 1 H NMR(400MHz, CDCl3)δ8.74(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=6.8Hz,3H),0.88(d,J=6.4Hz,3H),0.84(s,3H).

[0260] 13 C NMR (101MHz, CDCl3) δ200.07,143.63,74.11,61.70,57.46,56.74,45.71,43.07,41.31,41.21,39 .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.

[0261] MS m / z(ESI):413.15[MH] - .

[0262] Example 11

[0263] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0264] Example 12

[0265] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one

[0266] Synthesis scheme

[0267] The synthesis method was the same as that in Example 2, except that 1H-pyrazole-4-carbonitrile in the second step was replaced by 5-methyl-1H-tetrazole, and finally product 1 (Compound 11) and product 2 (Compound 12) were separated by column chromatography.

[0268] Compound 11:

[0269] 1 H NMR (400MHz, CDCl3) δ5.35(s,2H),2.57(s,3H),2.30–2.12(m,2H),2.00(m,1H)1.95~1.05(m,23H),0.98(d,J=6.9Hz,3H),0.92–0.84(m,6H).

[0270] 13 C NMR (101MHz, CDCl3) δ200.42,163.38,77.34,77.02,76.71,74.13,61.27,57.39,45.51,43.09,41.22 ,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.

[0271] MS m / z(ESI):429.3[M+H] + .

[0272] Compound 12:

[0273] 1H NMR(400MHz, CDCl3)δ5.19–5.02(m,2H),2.61(dd,J=10.4,8.0Hz,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=7.0Hz,3H),0.93–0.81(m,6H).

[0274] 13 C NMR (101MHz, CDCl3) δ200.60,152.42,74.11,61.41,57.46,56.08,46.35,43.72,41.19,39.85,39.2 4,35.93,35.07,34.08,33.51,31.30,30.70,30.27,26.89,25.23,20.48,18.23,16.84,15.12,8.91.

[0275] MS m / z(ESI):429.3[M+H] + .

[0276] Example 13

[0277] 2-((1,3,4-thiazol-2-yl)amino)-1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)ethan-1-one

[0278] Synthesis scheme

[0279] The synthesis method is the same as that of Example 2, except that 1H-pyrazole-4-carbonitrile in the second step is replaced by 1,3,4-thiadiazole-2-amino.

[0280] 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),7.66(s,1H),4.78(s,2H),2.57(dd,J=10.5,8.0Hz,1H ),2.29–1.20(m,17H),1.10(d,J=9.5Hz,6H),0.97(d,J=7.0Hz,3H),0.87(dd,J=6.8,3.1 Hz,3H),0.84(s,3H).

[0281] 13C NMR (101MHz, CDCl3) δ203.75,161.72,133.15,74.14,60.91,57.43,57.34,45.22,43.15,41.27,41.01,39.4 2,39.30,39.28,35.98,35.15,34.13,33.50,31.38,30.24,26.13,25.27,20.39,18.29,16.61,16.46,15.12.

[0282] MS m / z(ESI):446.2[M+H] + .

[0283] Example 14

[0284] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0285] Synthesis scheme

[0286] Step 1: Preparation of (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-2,13-dimethylhexahydro-17H-cyclopenta[a]phenanthrene-17-one

[0287] (2S, 5R, 8R, 9R, 10S, 13S, 14S)-2,13-dimethyltetradecahydro-3H-cyclopentadienyl[a]phenanthrene-3,17 (2H)-dione (20.0 g, 69.4 mmol) was dissolved in tetrahydrofuran (1000 mL). The temperature was lowered to -70 °C, and lithium tri-tert-butoxyaluminum hydride (31.4 g, 123.5 mmol) dissolved in tetrahydrofuran (400 mL) was added. The temperature was raised to -50 °C for 3 hours. The reaction was quenched by adding aqueous ammonium chloride. After extraction with ethyl acetate, the mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a column (DCM / EA = 0-30%) to give (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-2,13-dimethylhexahydro-17H-cyclopenta[a]phenanthrene-17-one product (9.0 g, yield 45%).

[0288] 1H NMR (400MHz, CDCl3) δ3.20–3.14(m,1H),2.61–2.34(m,2H),2.10–0.92(m,24H),0.86(s,3H).

[0289] Step 2: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-16-(phenylsulfinyl)hexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one

[0290] (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-2,13-dimethylhexahydro-17H-cyclopenta[a]phenanthrene-17-one (9.0 g, 31.0 mmol) was added to a solution of potassium tert-butoxide (6.9 g, 61.6 mmol) in tetrahydrofuran (180 mL), and the mixture was stirred at room temperature for 10 minutes under nitrogen protection, and then methyl benzenesulfite (9.6 g, 61.6 mmol) was added. 5mmol), continued stirring at room temperature for 1 hour, water was added to quench the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated, and then passed through a column (DCM / EA=0-30%) to obtain (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-2,13-dimethyl-16-(phenylsulfinyl) hexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one product (7.8 g, yield 60%).

[0291] MS m / z(ESI):415[M+H] +

[0292] 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-cyclopentadienyl[a]phenanthrene-17-one

[0293] (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,13-dimethyl-16-(phenylsulfinyl)hexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one (7.8 g, 18.8 mmol) was dissolved in xylene (124 mL), anhydrous sodium carbonate (29.0 g, 27.4 mmol) was added, and the mixture was stirred at 125 °C for 24 h. After filtering off the sodium carbonate, the mixture was concentrated through a column (DCM / EA=0-30%) to give (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-cyclopentadienyl[a]phenanthrene-17-one product (2.6 g, yield 48%).

[0294] 1 H NMR (400MHz, CDCl3) δ7.53–7.51(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=6.4Hz,3H).

[0295] Step 4: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,13,15-trimethylhexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one

[0296] Under ice bath, cuprous iodide (4.9 g, 25.7 mmol) was added to a 3 M solution of methyl Grignard reagent (11.46 mL) in tetrahydrofuran and stirred at 0°C for 1 hour. Then (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-cyclopentadien[a]phenanthrene 1 dissolved in tetrahydrofuran (32 mL) was added. 7-ketone (2.6 g, 9.02 mmol) was stirred under ice bath for 2 hours before the reaction was complete. An aqueous ammonium chloride solution was added to quench the reaction. After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated and passed through a column (DCM / EA = 0-30%) to give (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R)-3-hydroxy-2,13,15-trimethylhexahydro-17H-cyclopentadienyl[a]phenanthrene-17-one product (2.3 g, yield 84%).

[0297] 1H NMR (400MHz, CDCl3) δ3.21–3.15(m,1H),2.50–2.38(m,2H),2.30–2.22(m,1H), 1.90–1.18(m,19H),1.10(d,J=7.2Hz,3H),1.03(s,3H),0.97(d,J=6.4Hz,3H).

[0298] Step 5: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile

[0299] Potassium tert-butoxide (8 g, 71.29 mmol) and tert-butanol (46 mL) were added to a dry 100 mL round-bottom flask, and the atmosphere was purged with nitrogen. (2S,3S,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-2,13,15-trimethylhexahydro-17H-cyclopentadien[a]phenanthrene-17-one (2.3 g, 7.6 mmol) was dissolved in ethylene glycol dimethyl ether (12 mL) and slowly added dropwise to the reaction system. The reaction was stirred for 30 minutes. p-Toluenesulfonylmethyl isocyanide (2.8 g, 14.4 mmol) was dissolved in ethylene glycol dimethyl ether (12 mL) and slowly added dropwise to the reaction system. The reaction was stirred at room temperature overnight. TLC showed that the reaction was complete, and water was added to quench the reaction. After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated and passed through a column (DCM / EA = 0-30%) to give (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile product (2.0 g, yield 84%).

[0300] 1 H NMR (400MHz, CDCl3) δ3.21–3.15(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).

[0301] Step 6: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethane-1-one

[0302] (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile (2.0 g, 6.3 mmol) was dissolved in dry tetrahydrofuran (250 mL) solution, the system was replaced with nitrogen and 3.0 M methylmagnesium bromide (60 mL) was slowly added dropwise, and the reaction system was stirred at 80 ° C for 7 hours. TLC showed that the reaction was complete, and the reaction was quenched with saturated ammonium chloride. After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated and passed through a column (DCM / EA = 0-30%) to give 1-((2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)ethane-1-one product (1.3 g, yield 62%).

[0303] 1 H NMR (400MHz, CDCl3) δ3.22–3.15(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).

[0304] Step 7: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-acetyl-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate

[0305] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)ethan-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 and the reaction was stirred at room temperature for 2 hours. The reaction solution was washed with water and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to give a crude product of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-acetyl-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate (338 mg), which was used directly in the next step.

[0306] Step 8: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-bromoacetyl)-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate

[0307] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-acetyl-2,13,15-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl acetate (338 mg, 0.9 mmol) was dissolved in methanol (5.0 mL). One drop of hydrogen bromide was added, followed by liquid bromine (0.15 mL). The reaction was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium sulfite solution. After extraction with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated to afford the crude product (408 mg) of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-bromoacetyl)-2,13,15-trimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl acetate, which was used directly in the next step.

[0308] Step 9: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate

[0309] (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-bromoacetyl)-2,13,15-trimethylhexahydro-1H-cyclopentadien[a]phenanthren-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) were dissolved in anhydrous tetrahydrofuran (15.0 mL) and N,N-dimethylformamide. The reaction was stirred at room temperature overnight. The reaction solution was filtered, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 15R, 17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate crude product (418 mg) which was used directly in the next step.

[0310] Step 10: Preparation of 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0311] The crude product of (2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-2,13,15-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-3-yl acetate (418 mg, 0.9 mmol) and potassium carbonate (373 mg, 2.7 mmol) were dissolved in methanol (10.0 mL) and reacted at 400 °C. The reaction mixture was stirred at room temperature for 3 hours, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated by high performance liquid chromatography to give 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (160 mg, yield: 42.0%).

[0312] 1 H NMR (400MHz, CDCl3) δ7.86(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).

[0313] 13 C NMR (101MHz, CDCl3) δ202.02,142.40,136.05,113.25,93.16,77.15,61.70,61.40,57.40,45.54,41.27,4 0.98,39.80,39.47,36.20,36.04,35.39,33.65,33.53,31.28,30.26,26.15,25.10,18.57,18.25,16.81.

[0314] MS m / z(ESI):406[M+H-18] + .

[0315] Example 15

[0316] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one

[0317] Example 16

[0318] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

[0319] The synthesis method was the same as that of Example 14, except that 1H-pyrazole-4-carbonitrile in the ninth step was replaced by 1H-1,2,3-triazole, and finally product 1 (Compound 15) and product 2 (Compound 16) were obtained by column chromatography.

[0320] Compound 15:

[0321] 1 H NMR (400MHz, CDCl3) δ7.68(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).

[0322] 13 C NMR (101MHz, CDCl3) δ202.63,135.04,77.20,63.87,60.90,57.35,45.36,41.15,41.00,39.83 ,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.

[0323] MS m / z(ESI):382[M+H-18] + .

[0324] Compound 16:

[0325] 1H NMR(400MHz, CDCl3)δ7.76(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).

[0326] 13 C NMR (101MHz, CDCl3) δ201.66,133.99,125.10,77.18,61.48,58.94,57.40,45.55,41.26,40.9 9,39.81,39.49,36.22,36.06,35.39,33.67,33.57,31.30,30.28,26.16,25.10,18.57,18.26, 16.82.

[0327] MS m / z(ESI):400[M+H] + .

[0328] Example 17

[0329] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0330] Example 18

[0331] 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-Hydroxy-2,13,15-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(1H-tetrazol-1-yl)ethan-1-one

[0332] The synthesis method was the same as that of Example 14, except that 1H-pyrazole-4-carbonitrile in the ninth step was replaced by 1H-tetrazole, and finally product 1 (Compound 17) and product 2 (Compound 18) were obtained by column chromatography.

[0333] Compound 17:

[0334] 1H NMR (400MHz, CDCl3) δ8.57(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).

[0335] 13 C NMR (101MHz, CDCl3) δ200.06,153.23,77.16,61.42,61.33,57.39,45.60,41.19,40.98,39.80 ,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.

[0336] MS m / z(ESI):401[M+H] + .

[0337] Compound 18:

[0338] 1 H NMR(400MHz, CDCl3)δ8.75(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).

[0339] 13 C NMR (101MHz, CDCl3) δ200.06,143.63,77.14,61.69,57.43,56.75,45.73,41.30,40.96,39.79 ,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.

[0340] MS m / z(ESI):401[M+H] + .

[0341] Example 19

[0342] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0343] Synthesis scheme

[0344] Step 1: Preparation of (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile

[0345] Potassium tert-butoxide (4.06 g, 36.2 mmol) and tert-butanol (24.0 mL) were added to a dry 100 mL round-bottom flask, and the atmosphere was purged with nitrogen. (2S,3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-2,3,13-trimethylhexahydro-17H-cyclopentadien[a]phenanthrene-17-one (1.1 g, 3.62 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and slowly added dropwise to the reaction system. The reaction was stirred for 30 minutes. p-Toluenesulfonylmethyl isocyanide (1.41 g, 7.24 mmol) was dissolved in 15 mL of ethylene glycol dimethyl ether and slowly added dropwise to the reaction system. The reaction was stirred at room temperature overnight. TLC showed that the reaction was complete, and water (50 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1-3 / 1) to obtain (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile (0.65 g, yield: 57.1%).

[0346] Step 2: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethane-1-one

[0347] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-carbonitrile (650 mg, 2.06 mmol) was dissolved in dry tetrahydrofuran (75 mL). The atmosphere was purged with nitrogen and 3.0 M methylmagnesium bromide (20 mL, 61.8 mmol) was slowly added dropwise. The reaction was stirred at 80°C for 7 hours. TLC indicated the reaction was complete. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The reaction mixture was filtered and dried, and the crude product was separated by column chromatography (rinsed with petroleum ether: ethyl acetate = 3:1) to give 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)ethan-1-one (520 mg, yield: 76.0%).

[0348] Step 3: Preparation of 2-bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethane-1-one

[0349] Dissolve 1-((2S,3S,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-2,3,13,15-tetramethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)ethan-1-one (520 mg, 1.5 mmol) in methanol (20 mL). Add one drop of hydrogen bromide and then liquid bromine (230 mg, 1.65 mmol). Stir the reaction at room temperature for 3 hours. Add water (50.0 mL), extract the aqueous phase with ethyl acetate (50.0 mL x 2), and combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product (520 mg), which is used directly in the next reaction.

[0350] Step 4: Preparation of 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0351] 2-Bromo-1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethan-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) were dissolved in anhydrous tetrahydrofuran (7.00 mL) and N, N-dimethylformamide (1.40 mL) was added, the reaction was stirred at room temperature overnight, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated by high performance liquid chromatography to give 1-(2-((2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-3-hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (120 mg, yield: 52.6%).

[0352] 1 H NMR(400MHz, CDCl3)δ7.86(s,1H),7.81(s,1H),5.06–4.79(m,2H),2.60(t,J=8.8Hz,1H),2.23–2.16(m,1H),2.06–2.00(m,1H),1.8 2(d,J=7.5Hz,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=6.7Hz,3H),0.67(s,3H).

[0353] 13 C NMR (101MHz, CDCl3) δ202.31,142.58,136.23,113.42,93.32,74.34,61.84,61.31,56.11,45.63,43.10,4 1.86,41.21,39.37,38.73,36.15,35.14,34.21,31.40,26.26,25.95,24.51,23.28,20.64,15.33,14.00.

[0354] MS m / z(ESI):422.1[MH] - .

[0355] Example 20

[0356] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0357] Example 21

[0358] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)-2-(1H-tetrazol-1-yl)ethan-1-one

[0359] Synthesis scheme

[0360] The synthesis method was the same as that of Example 19, except that 1H-pyrazole-4-carbonitrile in the fourth step was replaced by 1H-tetrazole, and finally product 1 (Compound 20) and product 2 (Compound 21) were obtained by column chromatography.

[0361] Product 1 (Compound 20):

[0362] 1 H NMR (400MHz, CDCl3) δ8.57(s,1H),5.45(s,2H),2.64(t,J=8.9Hz,1H),2.28–2.14(m,1H),2.08(dt,J=12.1 ,3.4Hz,1H),1.91–1.68(m,8H),1.63–1.38(m,10H),1.33–1.24(m,6H),0.87(d,J=6.7Hz,3H),0.71(s,3H).

[0363] 13 C NMR (101MHz, CDCl3) δ200.38,153.39,74.34,61.56,61.25,56.08,45.69,43.09,41.85,41.20 ,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.

[0364] MS m / z(ESI):399.1[MH] - .

[0365] Product 2 (Compound 21):

[0366] 1 H NMR(400MHz, DMSO-d6)δ9.31(s,1H),5.69-5.44(m,2H),4.06(s,1H),2.81(t,J=8.9Hz,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=6.7Hz,3H),0.60(s,3H).

[0367] 13 C NMR (101MHz, CDCl3) δ202.45,145.21,72.00,59.92,56.81,55.25,44.63,42.97,41.31,40.78 ,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.

[0368] MS m / z(ESI):399.1[MH] - .

[0369] Example 22

[0370] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-one

[0371] Synthesis scheme

[0372] The synthesis method is the same as that of Example 19, except that 1H-pyrazole-4-carbonitrile in the fourth step is replaced by 1H-1,2,4-triazole.

[0373] 1 H NMR (400MHz, CDCl3) δ8.14(s,1H),7.95(s,1H),5.04-4.91(m,2H),2.62(t,J=8.6Hz,1H),2.20(q,J=10.8,10.0Hz,1 H),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=6.7Hz,3H),0.68(s,3H).

[0374] 13 C NMR (101MHz, CDCl3) δ202.26,152.00,74.31,61.27,58.89,56.07,45.55,43.07,41.83,41.18,39 .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.

[0375] MS m / z(ESI):400.2[M+H] + .

[0376] Example 23

[0377] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0378] Example 24

[0379] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-Hydroxy-2,3,13-trimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one

[0380] Synthesis scheme

[0381] The synthesis method was the same as that of Example 19, except that 1H-pyrazole-4-carbonitrile in the fourth step was replaced by 5-methyl-1H-tetrazole, and finally product 1 (Compound 23) and product 2 (Compound 24) were obtained by column chromatography.

[0382] Compound 23:

[0383] 1 H NMR (400MHz, CDCl3) δ5.35(s,2H),2.62(t,J=8.7Hz,1H),2.56(s,3H),2.28–2.14(m,1H),2.07(dt,J=12.2 ,3.4Hz,1H),1.83–1.74(m,7H),1.59–1.40(m,10H),1.34–1.26(m,7H),0.88(d,J=6.6Hz,3H),0.71(s,3H).

[0384] 13 C NMR (101MHz, CDCl3) δ200.69,163.55,74.30,61.41,61.18,56.07,45.61,43.09,41.84,41.20,39 .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.

[0385] MS m / z(ESI):413.1[MH] - .

[0386] Compound 24:

[0387] 1 H NMR(400MHz, CDCl3)δ5.10(q,J=18.1Hz,2H),2.66(t,J=8.7Hz,1H),2.47(s,3H),2.24–2.19(m,1H),2.07(t, J=12.0Hz,1H),1.84–1.72(m,7H),1.63–1.41(m,10H),1.37–1.26(m,7H),0.88(d,J=6.7Hz,3H),0.68(s,3H).

[0388] 13 C NMR (101MHz, CDCl3) δ200.47,152.92,74.29,61.31,56.18,56.12,45.77,43.06,41.83,41.17,3 9.42,38.69,36.12,35.10,34.17,31.35,26.22,25.93,24.48,23.26,20.63,15.30,14.02,9.08.

[0389] MS m / z(ESI):415.1[M+H] + .

[0390] Example 25

[0391] 1-(2-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0392] Synthesis scheme

[0393] Step 1: Preparation of (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile

[0394] Potassium tert-butoxide (3.48 g, 34.4 mmol) and tert-butanol (20.0 mL) were added to a dry 100 mL round-bottom flask, and nitrogen was replaced in the system. (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S)-3-hydroxy-2,13-dimethylhexahydro-17H-cyclopenta[a]phenanthrene-17-one (1.00 g, 3.44 mmol) was dissolved in 10 mL of ethylene glycol dimethyl ether and slowly added dropwise to the reaction system. The reaction was stirred for 30 minutes. p-Toluenesulfonylmethyl isocyanide (1.21 g, 6.88 mmol) was dissolved in 10 mL of ethylene glycol dimethyl ether. The reaction system was slowly added dropwise to dimethyl ether, and the reaction was stirred at room temperature overnight. TLC showed that the reaction was complete, and water (50 mL) was added to quench the reaction. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1-3 / 1) to give (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile (0.6 g, yield: 57.8%).

[0395] Step 2: Preparation of 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)ethane-1-one

[0396] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-carbonitrile (1.10 g, 3.65 mmol) was dissolved in dry tetrahydrofuran (124 mL). The system was purged with nitrogen and 3.0 M methylmagnesium bromide (36.6 mL, 11.0 mmol) was slowly added dropwise. The reaction system was stirred at 80°C for 7 hours. TLC showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The reaction mixture was filtered and dried, and the crude product was separated by column chromatography (rinsed with petroleum ether: ethyl acetate = 4:1) to give 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadien[a]phenanthrene-17-yl)ethan-1-one (600 mg, yield: 51.8%).

[0397] Step 3: Preparation of (2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-17-acetyl-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate

[0398] 1-((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethan-1-one (500 mg, 1.57 mmol) was dissolved in dichloromethane (25.0 mL). DMAP (20.0 mg, 2.36 mmol), pyridine (2.00 mL), and acetic anhydride (1.25 mL) were added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the organic phase was concentrated to obtain crude (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-acetyl-2,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-3-yl acetate (566 mg, crude).

[0399] Step 4: Preparation of (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-bromoacetyl)-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate

[0400] Dissolve (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-acetyl-2,13-dimethylhexahydro-1H-cyclopentadien[a]phenanthrene-3-yl acetate (566 mg, 1.57 mmol) in methanol (6.00 mL). Add one drop of hydrogen bromide and then liquid bromine (0.25 mL, 4.88 mmol). Stir the reaction at room temperature for 3 hours. Add water (20.0 mL), extract the aqueous phase with ethyl acetate (20.0 mL x 2), and combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product (680 mg, crude product) that is used directly in the next reaction.

[0401] Step 5: Preparation of ((2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate

[0402] (2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-bromoacetyl)-2,13-dimethylhexahydro-1H-cyclopentadien[a]phenanthrene-3-yl acetate (680 mg, crude), 1H-pyrazole-4-carbonitrile (480.0 mg, 5.20 mmol) and potassium carbonate (725 mg, 5.20 mmol) were dissolved in anhydrous Tetrahydrofuran (10.0 mL) was added, the reaction was stirred at room temperature overnight, the reaction solution was filtered, and the filtrate was concentrated to give ((2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-3-yl acetate (600 mg, crude).

[0403] Step 6: Preparation of 1-(2-(((2S,3S,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0404] (((2S,3S,5R,8R,9R,10S,13S,14S,17S)-17-(2-(4-cyano-1H-pyrazol-1-yl)acetyl)-2,13-dimethylhexahydro-1H-cyclopentadien[a]phenanthrene-3-yl acetate (600 mg, crude) and potassium carbonate (725 mg, 5.20 mmol) were dissolved in methanol (10.00 mL) and the reaction was carried out at room temperature. The mixture was stirred for 3 hours, the reaction solution was filtered, the filtrate was concentrated, and the crude product was separated by high performance liquid chromatography to give (1-(2-(((2S, 3S, 5R, 8R, 9R, 10S, 13S, 14S, 17S)-3-hydroxy-2,13-dimethylhexahydro-1H-cyclopentadienyl[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (172 mg, yield: 31.6%).

[0405] 1 H NMR (400MHz, CDCl3) δ7.86 (s, 1H), 7.81 (s, 1H), 5.05–4.87 (m, 2H), 3.18 (dt, J = 10.3, 5.1Hz, 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=6.3Hz,3H),0.67(s,3H).

[0406] 13 C NMR (101MHz, CDCl3) δ202.11,142.39,136.04,113.23,93.16,77.20,61.65,61.11,55.89,45.46,41.7 2,40.80,39.16,39.07,36.03,35.92,35.28,33.66,31.16,26.16,25.64,24.33,23.09,18.59,13.81.

[0407] MS m / z(ESI):392[M+H-18] + .

[0408] The following target compounds 26-68 were synthesized using a similar synthesis method to Examples 1 and 2:

[0409] Biological test evaluation

[0410] The following further describes the present invention in conjunction with test examples, but these are not intended to limit the scope of the present invention.

[0411] The structure of compound Sage-217 is as follows:

[0412] It was prepared by referring to the preparation method of Example 20 of patent CN105339381B.

[0413] Test Example 1: Positive regulatory effect of the compounds of the present invention on GABAa receptors

[0414] 1. Experimental methods:

[0415] 1.1 Cell culture

[0416] The cells used in this experiment were derived from a CHO cell line stably expressing normal GABA receptor function after transfection with human GABA receptor α1, β2, and γ2 subunit cDNAs. This cell line was established by B'sys GmbH. Cells were cultured in a medium containing the following ingredients (purchased from Invitrogen): Dulbecco's Membrane Medium (DMEM); 10% (v / v) inactivated fetal bovine serum; 5 μg / ml Puromycin; 250 μg / ml Hygromycin B; and 100 μg / ml Zeocin. Cells were grown in culture dishes containing this medium and incubated at 37°C in a 5% CO2 incubator. Twelve to 24 hours prior to electrophysiological experiments, cells were transferred to circular glass slides placed in culture dishes and grown in the same medium and conditions. The cell density per slide was such that the majority of cells were isolated and single.

[0417] 1.2 Electrophysiological recording system

[0418] Whole-cell current recordings were performed using a manual patch-clamp system, the HEKA EPC10 USB signal amplifier and digitizer (purchased from HEKA Electronics, Germany). A circular glass slide containing CHO GABAa cells (see the Cell Culture and Requirements section above) was removed from the culture dish and placed in an electrophysiological recording chamber under an inverted microscope. Extracellular solution was continuously perfused into the recording chamber (approximately 1 to 2 ml per minute). Whole-cell current recordings were used to record chloride currents from GABAa channels. 1 μM GABA was used to activate the chloride current of the GABAa channel in each cell as an initial control (the GABA concentration used was 1 μM because it is the concentration at which the GABAa channel agonist, GABA, produces an effective activation of between 10% and 20% in the cells used in this experiment). Unless otherwise noted, experiments were performed at room temperature (~25°C), and only cells meeting the electrophysiological recording criteria were used. Cells were ruptured, sealed, and clamped at -80 mV after entering the whole-cell state. 1 μM GABA was applied to cells via a drug perfusion system for approximately 4 seconds to induce a chloride current through the GABAa channel. This current served as the initial control value. Subsequently, the test compound concentration was perfused and incubated for 3 minutes. A mixture of 1 μM GABA and the corresponding test compound concentration was then applied to the cells to induce a chloride current. The enhancement of the 1 μM GABA-induced current by the test compound was then observed. Once the cells were stable, the test compound was applied to the same cells at increasing concentrations. To avoid current reduction due to desensitization of the GABAa channel, the interval between application of the test compound to the cells via the drug perfusion system was at least 180 seconds.

[0419] 2. Data Analysis

[0420] The experimental data were analyzed using data analysis software provided by HEKA Patchmaster, Microsoft Excel, and Graphpad Prism.

[0421] 3. Experimental Results

[0422] Table 1-1 In vitro GABAa receptor (α1β2γ2) cell activity test results of the compounds of the present invention (single concentration) [1]

[0423] Table 1-2 Results of in vitro GABAa receptor (α1β2γ2) cell activity test of the compounds of the present invention

[0424] [1] The single concentration is 0.1 μM.

[0425] [2] The agonist ratio is the enhancement of GABAa receptor currents induced by 1 μM GABA, expressed as a percentage.

[0426] [3] The tested compounds acted as positive modulators to enhance the EC of GABAa receptor (chloride channel) currents induced by 1 μM GABA. 50 (half-maximal effect concentration) value.

[0427] [4]E max E is the maximum enhancement of GABAa receptor current induced by 1 μM GABA, expressed as a percentage. max and its corresponding test compound concentration value is determined by EC 50 Estimated from the fitted curve.

[0428] 4. Experimental Conclusion

[0429] As shown in Table 1, the compounds of the present invention have excellent positive regulatory effects on GABAa receptors. Among them, Examples 2, 9 and 20 showed lower E max , indicating potentially smaller side effects in vivo; combined with lower EC 50 , showing the potential for a larger therapeutic window.

[0430] Test Example 2: In vivo efficacy experiment in PTZ-induced mouse epilepsy model

[0431] 1. Test methods

[0432] 1.1 Experimental animals

[0433] Male C57 mice were purchased from SPIEF (Suzhou) Biotechnology Co., Ltd.

[0434] 1.2 Test compounds

[0435] All test compounds were stored in a refrigerator at 4°C.

[0436] The test sample information is shown in the following table:

[0437] 1.3 Test equipment

[0438] 1) 1mL Kangdeli sterile disposable syringe with needle

[0439] 2) 100-1000 μL pipette

[0440] 3) Vortex-Genie2 Multifunctional Vortex Mixer

[0441] 4) CNC ultrasonic cleaning machine

[0442] 5) MSA series magnetic stirrer

[0443] 6) Sartorius SQP electronic balance

[0444] 7) Liping Precision Electronic Scale

[0445] 8) Organic glass box, the adjacent space side walls are light-proof design (customized);

[0446] 1.4 Experimental Animal Grouping

[0447] Note: ① Vehicle: 5% DMSO + 5% HS-15 + 90% 20% hydroxypropyl β-cyclodextrin (10 mL / kg, po);

[0448] 1.5 Solvent preparation: 20% hydroxypropyl β-cyclodextrin

[0449] Accurately weigh 20.4082 g of hydroxypropyl-β-cyclodextrin (purity calculated as 98%) and add it to a 100 mL solvent bottle. Add 60 mL of double-distilled water and vortex for 3-5 minutes. Place it on a magnetic stirrer and stir and mix for 1 hour to obtain a homogeneous clear solution. Then add double-distilled water to make the volume to 100 mL. After vortexing, stir and mix with a magnetic stirrer for 10 minutes to obtain a homogeneous clear solution.

[0450] 1.6 Preparation of test compounds

[0451] 1) PTZ: Prepare a 120 mg / kg PTZ solution using normal saline (dosage volume: 10 mL / kg);

[0452] 2) Test compound: Using the vehicle described in 1.4 as the solvent, prepare solutions of the test compound at 3, 1, and 0.3 mg / kg, respectively (dosing volume: 10 mL / kg);

[0453] 1.7 Test operation

[0454] a) 1 hour before testing, transfer the experimental animals to the operating room to acclimate to the environment;

[0455] b) Randomly group, label, and weigh mice, with 10 mice per group. 60 minutes before PTZ administration, the test compound and vehicle were orally administered.

[0456] c) PTZ solution was administered subcutaneously before the experimental observation, and this time point was recorded as the starting point of the observation;

[0457] d) Immediately after PTZ administration, the animals were placed in an observation box and observed for 30 minutes.

[0458] I. Number of animal deaths;

[0459] II.1) Latency to the first clonic seizure, 2) Latency to the first generalized tonic-clonic seizure, 3) Number of clonic seizures, 4) Number of generalized tonic-clonic seizures. If the animal did not experience a seizure during the 30-min observation period, the latency was recorded as 1800 s and the number of seizures was recorded as 0.

[0460] ◆Clonic seizure: The animal has whole-body myoclonus that lasts for more than 3 seconds and is accompanied by falling;

[0461] ◆Tonic seizure: The limbs are straightened and form a 90-degree angle with the body.

[0462] 2. Data Analysis

[0463] All measurement data were expressed as mean ± standard error (SEM), and Prism 8.0 statistical software was used for test and analysis.

[0464] 3. Experimental results and conclusions

[0465] Table 2-1 Statistics of mouse survival rate

[0466] Conclusion: As shown in Table 2-1, compared to the blank control group, the compounds in each example in this experiment prolonged the survival rate of mice with PTZ-induced seizures and demonstrated a protective effect against acute epileptic seizures in mice. Examples 5, 6, 9, and 20, as well as Sage-217, showed significant protective effects at a low dose (1 mpk), while Examples 5, 9, and 20 exhibited partial protective effects at an extremely low dose (0.3 mpk).

[0467] Table 2-2 Statistics of paroxysmal and tonic seizures in mice

[0468] Conclusion: As shown in Table 2-2, compared with the blank group, the compounds of each example in this experiment significantly prolonged the latency period of clonic seizures and generalized tonic-clonic seizures and significantly reduced the number of seizures, and had significant anti-epileptic effects.

[0469] Test Example 3: In vivo drug efficacy experiment on mice with forced swimming and sugar water preference

[0470] 1. Purpose of the test:

[0471] The core manifestations of depression are despair, helplessness and anhedonia. The forced swimming test is commonly used to evaluate despair-like behavior. The test is to place the animal in an unpleasant and inescapable environment (water tank). At first, the animal shows active behavior (swimming or struggling), and then the animal begins to show an immobile state, and the immobility time gradually increases. Anhedonia means losing interest in things that were once pleasurable. In rodents, it is usually manifested as a reduced preference for sweets (sucrose). Therefore, the in vivo efficacy of the compounds of the present invention on mice can be evaluated by forced swimming and sugar water preference experiments.

[0472] 2. Experimental Materials

[0473] 2.1 Experimental animals

[0474] Female / male C57 mice were purchased from SPIEF (Suzhou) Biotechnology Co., Ltd.

[0475] 2.2 Test compounds

[0476] All test compounds were stored in a refrigerator at 4°C.

[0477] The test sample information is shown in the following table:

[0478] 2.3 Test equipment

[0479] 2.4 Experimental Animal Grouping

[0480] Note: ① Vehicle: 5% DMSO + 5% HS-15 + 90% 20% hydroxypropyl β-cyclodextrin (10 mL / kg, po);

[0481] 2.5 Test sample configuration

[0482] When preparing the test sample, take a certain amount of sample, add solvent and perform ultrasound.

[0483] Dilution of test sample: Take a certain volume of stock solution and add the required volume of solvent according to the dilution ratio. Label the prepared solution and set aside.

[0484] Calculation formula: Theoretical concentration (mg / mL) = dose (mg / kg) / administration volume (mL / kg)

[0485] Theoretical sample weight (mg) = [preparation volume (mL) × theoretical concentration of test sample (mg / mL) × salt coefficient] / purity

[0486] 2.6 Test operation

[0487] Forced swimming: 1 hour after administration of vehicle or drug, the animals were placed in a plexiglass tank at 25°C and 20 cm deep. The animals' swimming state in the water was recorded by video, and the immobility time of the animals in the floating state in the water and stopping struggling was recorded and analyzed for 2-6 minutes.

[0488] Sugar water preference: Day 1: 1% sugar water administered bilaterally; Days 2 / 3: Drinking water administered to one side and 1% sugar water administered to the other side; Day 4: Food and water deprivation; Day 5: Sugar water preference test. Chronic stressed mice were administered drugs according to experimental groups. Following drug administration, weighed sugar water and drinking water were administered on Days 2 / 3. The animals were allowed free access to water in the dark for 2 hours, with the sugar water and drinking water sides switched for 1 hour.

[0489] 3. Data Processing

[0490] Experimental data One-way analysis of variance was used for the data, and Dunnett's multiple comparisons tests were used for pairwise comparisons. The floating time, swimming time, and struggling time were calculated.

[0491] Sugar water preference (%) = sugar water consumption / (sugar water consumption + pure water consumption) × 100%.

[0492] 4. Experimental results and conclusions

[0493] Table 3-1 Statistical results of immobility time of 2-6 minutes in the forced swimming test of mice

[0494] Table 3-2 Results of sugar water preference in the mouse sugar water preference experiment

[0495] From the above results, it can be seen that compared with the blank group, the compound of Example 9 of the present invention can significantly reduce the immobility time of C57 mice in the forced swimming test, and significantly increase the sugar water preference of C57 mice in the sugar water preference test, and has a significant antidepressant effect, and has certain advantages over Sage-217.

[0496] Test Example 4: Pharmacokinetics of the Compounds of the Invention in Mice

[0497] 1. Purpose of the test:

[0498] The compound of the present invention was administered orally orally to male ICR mice, the blood concentration of the compound of the present invention in the mice was measured, the PK parameters were calculated, and the pharmacokinetic evaluation of the compound of the present invention was performed.

[0499] 2. Test materials:

[0500] (1) Test sample: Compounds of the present invention, homemade.

[0501] (2) Experimental animals: ICR mice, SPF grade, male, Shanghai Lingchang Biotechnology Co., Ltd.

[0502] (3) Main test instruments:

[0503] 3. Experimental plan:

[0504] (1) Dosage information:

[0505] Drug preparation: Calculate the preparation volume based on the weight of the drug, add 5% DMSO and 5% HS-15 in sequence, and after the drug is fully dissolved, add 90% of a 20% β-cyclodextrin aqueous solution and mix thoroughly for later use.

[0506] Route of administration: Oral gavage, oral dosage is 10 mg / kg.

[0507] Frequency and duration of administration: Single dose.

[0508] (2) Test method:

[0509] ICR mice were stratified by weight and randomly divided into groups of 9 mice per group. All mice were fasted overnight before the experiment. The drug was administered orally by gavage. At 0, 0.167, 0.333, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours, 50 μL of blood was collected from the fundus vein of the mice into a sample tube containing sodium heparin, an anticoagulant, and placed on wet ice. The tube was rotated at 4000 rpm. -1 The cells were centrifuged for 10 min to separate the plasma, which was then frozen and stored in a -80°C refrigerator until testing.

[0510] 4. Test results and analysis:

[0511] The concentration of plasma samples was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The retention time of compounds and internal standards, chromatographic acquisition and chromatographic integration were processed using Analyst (AB SCIEX) software, and data statistics were processed using Microsoft Office software. WinNonlin TM Plasma concentrations were calculated using a non-compartmental model using the pharmacokinetic software Version 6.3 (Pharsight, Mountain View, CA). Pharmacokinetic parameters were calculated using the linear-log trapezoidal method. The results are shown in Table 3.

[0512] Table 4 Results of mouse pharmacokinetic experiments

[0513] 5. Test conclusion:

[0514] From the results of the mouse pharmacokinetic experiment in the table, it can be seen that the compound of the present invention has a longer half-life t 1 / 2 , greater exposure AUC and higher maximum plasma concentration C max , showing good metabolic properties. This result also clearly reflects that this type of compound with a lower Emax, due to its longer half-life and greater exposure, shows better in vivo efficacy than Sage-217.

[0515] Test Example 5: Acute toxicity test and side effect observation of the compound of the present invention in mice

[0516] 1. Purpose of the study

[0517] Evaluate the acute toxicity of the test compound in ICR mice after a single oral gavage; observe the recovery of ICR mice within 14 days after administration; and determine the maximum tolerated dose of the test compound.

[0518] 2. Test methods

[0519] 2.1 Experimental animals

[0520] Sixty-five male and female ICR mice were purchased from Shanghai Jihui Laboratory Animal Breeding Co., Ltd. Experiments were conducted after the animals had acclimated for 4–5 days. The animals were housed 5 per cage at 23 ± 2°C, with a 12 / 12 hr light / dark cycle and free access to food and water.

[0521] 2.2 Sample storage

[0522] All test compounds were stored in a refrigerator at 4°C.

[0523] Table 5-1: Test sample information

[0524] 2.3 Test equipment

[0525] 1mL Kangdeli sterile disposable syringe with needle

[0526] 100-1000 μL pipette

[0527] Vortex-Genie2 Multi-function Vortex Mixer

[0528] CNC ultrasonic cleaner

[0529] MSA Series Magnetic Stirrers

[0530] Sartorius SQP electronic balance

[0531] Liping Precision Electronic Scale

[0532] 2.4 Experimental Animal Grouping

[0533] Table 5-2: Animal grouping information

[0534] Note: ① Vehicle: 5% DMSO + 5% HS-15 + 90% 20% hydroxypropyl β-cyclodextrin (10 mL / kg, po).

[0535] 3 Test steps

[0536] 3.1 Solvent preparation: 20% hydroxypropyl β-cyclodextrin

[0537] Accurately weigh 20.4082 g of hydroxypropyl-β-cyclodextrin (purity calculated as 98%) and add it to a 100 mL solvent bottle. Add 60 mL of double-distilled water and vortex for 3-5 minutes. Place it on a magnetic stirrer and stir and mix for 1 hour to obtain a homogeneous clear solution. Then add double-distilled water to make the volume to 100 mL. After vortexing, stir and mix with a magnetic stirrer for 10 minutes to obtain a homogeneous clear solution.

[0538] 3.2 Preparation of test compounds

[0539] Based on the Vehicle in 2.4, weigh a certain weight of the test compound, first add 5% of the total volume of DMSO liquid, vortex and shake. After the drug is completely dissolved, add 5% of the total volume of HS-15 liquid, mix again and vortex and shake. Finally, add the remaining volume of 20% hydroxypropyl β-cyclodextrin solution to form a clear, homogeneous solution of 2 mg / mL. Then, dilute the solution in a proportional gradient to concentrations of 1, 0.5, and 0.25 mg / mL (dosing volume is 10 mL / kg).

[0540] 3.3 Test operation

[0541] a. Approximately 12 to 18 hours before testing, the animals were weighed and divided into groups and fasted overnight (without water restriction).

[0542] b. The next day, the mice were re-weighed according to their groups. Ten mice in each group (5 males and 5 females per dose) were orally gavaged with the test compound and vehicle. The dosing date was designated as Day 1.

[0543] c. According to the acute toxicity test experimental procedures, cage-side observation of each group was conducted 0.5-1 hour and 4-8 hours after administration on Day 1, and cage-side observation was conducted once a day from Day 2 to Day 14;

[0544] d. Observation time from Day 2 to Day 14 is: 9:00 to 12:00.

[0545] 4. Record Metrics

[0546] (1) Record the clinical symptoms and mortality of each group of ICR mice after administration to determine the maximum tolerated dose;

[0547] (2) Record the symptom relief and recovery of each group of ICR mice after administration.

[0548] 5. Experimental Results

[0549] (1) No deaths occurred in any group within 0.5 to 1 h after administration;

[0550] (2) 4 to 8 hours after administration, one male rat and two female rats died in the 20 mpk Sage-217 group, and the surviving rats still showed prone symptoms. There was no death in all the dose groups of Examples 9 and 20, among which the 20 mpk group of Example 9 was only accompanied by unstable gait. The following dose groups all recovered to normal.

[0551] (3) All other mice survived until Day 14.

[0552] Specific cage-side observation results for some doses on the first day are shown in Table 4-3.

[0553] Table 5-3 Cage-side observation statistics on the first day of 10mpk

[0554] a “*” indicates the severity of a single side effect, with * indicating mild, ** indicating moderate, and *** indicating severe;

[0555] bProneness and hypoactivity often coincide;

[0556] c. Unstable gait / prone / loss of righting reflex, which can be understood as the gradual severity of side effects;

[0557] d Ataxia includes unsteady gait and loss of balance.

[0558] 6. Experimental Conclusion

[0559] Under the conditions of this experiment, ICR mice were given a single oral gavage of 2.5, 5, 10, and 20 mg / kg of Sage-217. Deaths occurred in both males and females in the 20 mg / kg group, and the maximum tolerated dose (MTD) was 10 mg / kg. Cage-side observations in each dose group mainly showed ataxia that worsened with increasing dose, and high doses were accompanied by severe loss of righting reflex. For Example 9, all animals were well tolerated, the MTD was 20 mg / kg, and there was potential for further dose increases. The main adverse reactions were only prone position and mild loss of righting reflex in some mice at high doses. For Example 20, all animals were well tolerated, the MTD was 20 mg / kg, and ataxia that worsened with increasing dose was the main symptom, but no mice died.

[0560] In summary, the safety of the compounds of the present invention is significantly better than that of Sage-217, and the side effects of GABAa agonists are weakened, which makes them worthy of further clinical development.

[0561] Although the specific embodiments of the present invention have been described in detail, based on all the teachings disclosed, those skilled in the art may make various modifications and substitutions to the details of the technical solution of the present invention, and such modifications are within the scope of protection of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: X is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 The aryl or 5- to 10-membered heteroaryl group may be further substituted with one or more R A replaced by; R A Halogen, hydroxyl, -NO2, -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)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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl; R aa , R bb and R cc are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, or R aa , R bb or R cc Any two of the atoms together with the atoms to which they are attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl ring; L is -(CH2) n1 -, -(CH2) n1 O(CH2) n2 -, -(CH2) n1 S(CH2) n2 -, -(CH2) n1 NH(CH2) n2 -, -(CH2) n1 C(O)(CH2) n2 -, -(CH2) n1 S(O)(CH2) n2 -, -(CH2) n1 C(O)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) n1 NHS(O)2(CH2) n2 -; R x and R y are independently hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 Aryl or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 The aryl or 5-6 membered heteroaryl group is optionally further selected from deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkoxy group; R1, R2, R3, R3', R5, R6 and R6' are each independently hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) n3 R dd 、-(CH2) n3 OR dd 、-(CH2) n3 SR dd 、-(CH2) n3 C(O)R dd 、-(CH2) n3 C(O)OR dd 、-(CH2) n3 S(O)R dd 、-(CH2) n3 S(O)2R dd 、-(CH2) n3 NR dd R ee 、-(CH2) n3 C(O)NR dd R ee 、-(CH2) n3 S(O)NR dd R ee 、-(CH2) n3 NR dd C(O)R ee 、-(CH2) n3 NR dd S(O)R ee or -(CH2) n3 NR dd S(O)2R ee ; R dd and R ee are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R4 and R4' are each independently hydrogen, halogen, hydroxyl, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-8 Cycloalkyl; and R4 and R4' are not hydrogen at the same time; n is an integer from 0 to 5; m is an integer from 0 to 5; n1 is an integer from 0 to 3; n2 is an integer from 0 to 3; and n3 is an integer from 0 to 3.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) X is hydrogen, C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 6-10 The aryl or 5- to 10-membered heteroaryl group may be further substituted with one or more R A substituted, preferably X is hydrogen, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 The aryl or 5- to 10-membered heteroaryl group may be further substituted with one or more R A replaced by; (2)R A Halogen, -CN, -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, C 1-6 Haloalkyl, C 1- 6 alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, preferably halogen, -CN, -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, C 1-6 Haloalkyl or C 1-6 Alkoxy, more preferably halogen, -CN, -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, C 1-3 Haloalkyl or C 1-3 Alkoxy, further preferably fluorine, chlorine, -CN, methyl, trifluoromethyl, methoxy, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3) or -P(=O)(CH3)2; (3)R aa , R bb and R cc are independently hydrogen or C 1-6 Alkyl, preferably hydrogen or C 1-3 Alkyl, more preferably hydrogen or methyl; (4) 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) n1 NHS(O)2(CH2) n2 -, preferably -C(O)(CH2) n2 -、-C(O)NH(CH2) n2 -、-C(O)(CH2) n2 NH-, -(CH2) n1 NHC(O)- or -(CH2) n1 NHS(O)2-, more preferably -C(O)(CH2) n2 -or-C(O)(CH2) n2 NH-; (5)R x and R y are independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, preferably hydrogen, deuterium, halogen, hydroxyl or C 1-6 Alkyl, more preferably hydrogen; (6) R1, R2 and R5 are each independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -(CH2) n3 OR dd 、-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd , preferably hydrogen, deuterium, C 1-3 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl; (7)R dd and R ee are independently hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably hydrogen or C 1-3 alkyl; (8) R3, R3', R6 and R6' are each independently hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl; (9) R4 and R4' are each independently hydrogen or C 1-6 Alkyl, preferably hydrogen or C 1-3 Alkyl, more preferably hydrogen or methyl; and R4 and R4' are not hydrogen at the same time; (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.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure shown in the general formula (II): in: X, L, R x , R y , R1, R2, R3, n and m are as described in claim 1 or 2.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure shown by the general formula (III): in: X is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 The aryl or 5- to 10-membered heteroaryl group may be further substituted with one or more R A replaced by; R A Halogen, hydroxyl, -NO2, -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)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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 The cycloalkyl or 3-8 membered heterocyclic group is optionally further selected from deuterium, halogen, hydroxy, amino, mercapto, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl; R aa , R bb and R cc are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, or R aa , R bb or R cc Any two of the atoms together with the atoms to which they are attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl ring; L is -(CH2) n1 -, -(CH2) n1 O(CH2) n2 -, -(CH2) n1 S(CH2) n2 -, -(CH2) n1 NH(CH2) n2 -, -(CH2) n1 C(O)(CH2) n2 -, -(CH2) n1 S(O)(CH2) n2 -, -(CH2) n1 C(O)O(CH2) n2 -, -(CH2) n1 S(O)2(CH2) n2 -, -(CH2) n1 C(O)NH(CH2) n2 -, -(CH2) n1 NHC(O)(CH2) n2 - or -(CH2) n1 NHS(O)2(CH2) n2 -; R x and R y are independently hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 Aryl or 5- to 6-membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 The aryl or 5-6 membered heteroaryl group is optionally further selected from deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 is substituted by one or more substituents in a haloalkoxy group; R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, thiol, nitro, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(CH2) n3 R dd 、-(CH2) n3 OR dd 、-(CH2) n3 SR dd 、-(CH2) n3 C(O)R dd 、-(CH2) n3 C(O)OR dd 、-(CH2) n3 S(O)R dd 、-(CH2) n3 S(O)2R dd 、-(CH2) n3 NR dd R ee 、-(CH2) n3 C(O)NR dd R ee 、-(CH2) n3 S(O)NR dd R ee 、-(CH2) n3 NR dd C(O)R ee 、-(CH2) n3 NR dd S(O)R ee or -(CH2) n3 NR dd S(O)2R ee ; R dd and R ee are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; n is an integer from 0 to 5; m is an integer from 0 to 5; n1 is an integer from 0 to 3; n2 is an integer from 0 to 3; and n3 is an integer from 0 to 3.

5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) X is hydrogen, C 1-6 Alkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 6-10 The aryl or 5- to 10-membered heteroaryl group may be further substituted with one or more R A substituted, preferably X is hydrogen, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the C 6-10 The aryl or 5- to 10-membered heteroaryl group may be further substituted with one or more R A replaced by; (2)R A Halogen, -CN, -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, C 1-6 Haloalkyl, C 1- 6 alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, preferably halogen, -CN, -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, C 1-6 Haloalkyl or C 1-6 Alkoxy, more preferably halogen, -CN, -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, C 1-3 Haloalkyl or C 1-3 Alkoxy, further preferably fluorine, chlorine, -CN, methyl, trifluoromethyl, methoxy, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3) or -P(=O)(CH3)2; (3)R aa , R bb and R cc are independently hydrogen or C 1-6 Alkyl, preferably hydrogen or C 1-3 Alkyl, more preferably hydrogen or methyl; (4) 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 NHC(O)(CH2) n2 -or-(CH2) n1 NHS(O)2(CH2) n2 -, preferably -C(O)(CH2) n2 -、-C(O)NH(CH2) n2 -、-(CH2) n1 NHC(O)- or -(CH2) n1 NHS(O)2-, more preferably -C(O)(CH2) n2 -; (5)R x and R y are independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, preferably hydrogen, deuterium, halogen, hydroxyl or C 1-6 Alkyl, more preferably hydrogen; (6) R1 and R2 are each independently hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -(CH2) n3 OR dd 、-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd , preferably hydrogen, deuterium, C 1-3 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl; (7)R dd and R ee Each independently is C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-3 alkyl; (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.

6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The general formula (I) further has a structure shown in the general formula (IV): in: Z is -(CH2) n4 - or -NH(CH2) n4 -, preferably -(CH2) n4 -, more preferably -CH2-; R1 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -(CH2) n3 OR dd 、-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd , preferably C 1-6 Alkyl, more preferably C 1-3 Alkyl, more preferably methyl; R2 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -(CH2) n3 OR dd 、-(CH2) n3 SR dd or -(CH2) n3 C(O)R dd , preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl; R dd C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably C 1-3 alkyl; 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.

7. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: The general formula (I) further has a structure shown in the general formula (V): in: X is hydrogen or optionally substituted by one or more R A substituted 5-10 membered heteroaryl, preferably hydrogen or optionally substituted with one or more R A Substituted 5- to 10-membered heteroaryl groups containing 1 to 4 nitrogen atoms; R A Halogen, hydroxyl, -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)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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, preferably halogen, -CN, -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, C 1- 6 haloalkyl or C 1-6 Alkoxy, more preferably halogen, -CN, -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, C 1-3 Haloalkyl or C 1-3 Alkoxy, further preferably fluorine, chlorine, -CN, methyl, trifluoromethyl, methoxy, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3) or -P(=O)(CH3)2; R aa , R bb and R cc are independently hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 The alkyl group is more preferably hydrogen or methyl.

8. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: The X is hydrogen or the following group: Preferably, hydrogen, R A Halogen, hydroxyl, -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)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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, preferably halogen, -CN, -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, C 1- 6 haloalkyl or C 1-6 Alkoxy, more preferably halogen, -CN, -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, C 1-3 Haloalkyl or C 1-3 Alkoxy, further preferably fluorine, chlorine, -CN, methyl, trifluoromethyl, methoxy, -SO2CH3, -SO2NH2, -SCH3(=O)(=NH), -SCH3(=O)(=NCH3) or -P(=O)(CH3)2; R aa , R bb and R cc are independently hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl, preferably hydrogen or C 1-6 Alkyl, more preferably hydrogen or C 1-3 Alkyl, further preferably hydrogen or methyl; o is selected from 0, 1, 2, 3 or 4, preferably 0 or 1.

9. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: The general formula (I) further has a structure shown in the general formula (VI): in: R1 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably hydrogen, deuterium or C 1-6 Alkyl, more preferably hydrogen, deuterium or C 1-3 Alkyl, further preferably hydrogen, deuterium or methyl; X is hydrogen or optionally substituted by one or more R A substituted 5-10 membered heteroaryl, preferably hydrogen or optionally substituted with one or more R A substituted 5-10 membered heteroaryl containing 1-4 nitrogen atoms, more preferably hydrogen, R A For halogen, hydroxyl, cyano, C 1-6 Alkyl, C2 - 6-alkenyl, C 2- 6 alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably cyano, C 1-6 Alkyl or C 1-6 haloalkyl, more preferably cyano, C 1-3 Alkyl or C 1-3 Haloalkyl, more preferably cyano, methyl or trifluoromethyl; o is selected from 0, 1 or 2, preferably 0 or 1.

10. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure shown in the general formula (VII): in: R1 is hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, preferably hydrogen, deuterium or C 1-6 Alkyl, more preferably hydrogen, deuterium or C 1-3 Alkyl, further preferably hydrogen, deuterium or methyl; X is optionally replaced by one or more R A The 5- to 10-membered heteroaryl group is preferably optionally substituted with one or more R A Replaced with 5- to 10-membered heteroaryl groups having 1 to 4 nitrogen atoms, more preferably R A For halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably cyano or C 1-6 Alkyl, more preferably cyano or C 1-3 Alkyl, more preferably cyano or methyl; o is selected from 0, 1 or 2, preferably 0 or 1.

11. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure represented by the general formula (VIII): in: R1 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl; R3 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl; R4 is C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl; X is optionally replaced by one or more R A Substituted 5-membered heteroaryl containing 1 to 4 nitrogen atoms, preferably R A Halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, preferably halogen, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy, more preferably fluorine, chlorine, -CN, methyl, ethyl, trifluoromethyl or methoxy; o is selected from 0, 1 or 2.

12. The compound according to any one of claims 1, 2 or 11, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) further has a structure represented by the general formula (VIII-A) or (VIII-B): in: R1 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl; R3 is hydrogen, deuterium or C 1-6 Alkyl, preferably hydrogen, deuterium or C 1-3 Alkyl, more preferably hydrogen or methyl; R4 is C 1-6 Alkyl, preferably C 1-3 Alkyl, more preferably methyl; R A Halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 3-8 Cycloalkyl, preferably halogen, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy, more preferably fluorine, chlorine, -CN, methyl, ethyl, trifluoromethyl or methoxy; o is selected from 0, 1 or 2.

13. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient selected from pharmaceutically acceptable carriers, diluents or excipients.

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

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 preparation of a medicament for treating a CNS-related disease; preferably, the CNS-related disease is: sleep disorder, mood disorder, premenstrual dysphoric disorder, schizophrenia spectrum disorder, spastic disorder, memory disorder and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, depression, postpartum depression, major depressive disorder, perimenopausal depression, anxiety disorder, premenstrual dysphoric disorder, epilepsy, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome or tinnitus; more preferably, depression, postpartum depression, major depressive disorder, perimenopausal depression, anxiety disorder, premenstrual dysphoric disorder or epilepsy.

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