Salt and crystalline forms of steroid derivative modulators

Abstract

The present invention relates to steroid derivative modulators, particularly those of formula (I) TIFF2022543576000186.tif69169, its salts and crystalline forms, process for preparing same, pharmaceutical compositions containing a therapeutically effective amount of the crystalline forms, and use of GABA in the treatment of depression, convulsions, parkinsonism and nervous system disorders A and its use as a receptor modulator.

Description

[Technical Field]

[0001] The present invention is in the field of drug synthesis and particularly relates to salts of steroid derivative modulators, their crystalline forms, methods for preparing them, and their uses. [Background technology]

[0002] GABA A GABA receptors are chemically gated channels on the cell membrane and belong to the ion receptor family. A Receptors are widely distributed throughout the nervous system and bind to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), opening chloride ion channels and causing neuronal inhibition. A The receptor modulator (tetrahydroprogesterone) is a GABA A Positive modulator of the receptor. Tetrahydroprogesterone and GABA in the synapse A Binding to the receptor modulator increases the frequency of chloride ion channel opening on this receptor, increasing the inward flow of chloride ions, thereby increasing the phasic current, achieving a rapid inhibitory effect, reducing neural excitability, and achieving anxiolytic and antidepressant effects. Tetrahydroprogesterone and extrasynaptic GABA A Binding to the receptor generates a sustained chloride ion current, mediating a long-lasting inhibitory effect. Tetrahydroprogesterone also increases the content of brain-derived neurotrophic factor (BDNF), promotes the regeneration of hippocampal neurons, and exerts neuroprotective effects, thereby improving symptoms of anxiety and depression, although the specific mechanism of action remains unclear.

[0003] Major depressive disorder (MDD) is a common, chronic, relapsing illness. The burden and adverse effects caused by it are becoming increasingly severe. Over the past 40 years, significant progress has been made in the research and clinical application of antidepressants. However, most antidepressants (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram) take 2–4 weeks to take effect. Clinical treatment of MDD, especially in patients with suicidal tendencies, often requires immediate and rapid clinical treatment, so the development of fast-acting antidepressants is urgently needed.

[0004] There has been little innovation in research and development of depression treatments over the past 20 years. A The goal of developing GABA receptor modulators is to alter the treatment regimen for MDD and thereby change patient expectations. A GABA receptor modulators have the potential to be the first drugs in over 20 years to offer a truly novel mechanism of action for the treatment of depression. Currently, overseas pharmaceutical companies, including Sage Therapeutics and Marinus, are developing GABA receptor modulators. A Every effort is being made to develop receptor modulators.

[0005] GABA A Published patent applications related to receptor modulators include WO2003077919, WO2014169833, WO2016061537, WO2015180679, and WO2015027227.

[0006] GABA A Receptor modulators, as popular targets in the pharmaceutical industry, have good application prospects.

[0007] First, GABA A Receptor modulators can be applied to major depressive disorder (MDD), which has an annual incidence of about 2% in China, creating a huge potential market.

[0008] Second, conventional antidepressants take a long time to work (usually 3-4 weeks), have a high failure rate (up to 40%), and require long-term medication. A Receptor modulators can exert significant antidepressant effects within 24 hours, and the effects can last from several days to two weeks.

[0009] Third, GABA A Receptor modulators can meet the treatment needs of MDD patients with once-daily oral administration.

[0010] Jiangsu Hansoh Pharmaceutical Group Co., Ltd.'s PCT patent applications (PCT / CN2019 / 074134 and PCT / CN2019 / 074108) disclose the structures of a series of steroid derivative regulators. In subsequent research and development, in order to obtain products that can be easily processed, filtered, and dried, and that have characteristics such as convenient storage and long-term stability, the present invention is dedicated to conducting comprehensive research on the salts of the above substances and obtaining the optimal salt and crystalline form. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] WO2003077919 [Patent Document 2] WO2014169833 [Patent Document 3] WO2016061537 [Patent Document 4] WO2015180679 [Patent Document 5] WO2015027227 [Patent Document 6] PCT / CN2019 / 074134 [Patent Document 7] PCT / CN2019 / 074108 Summary of the Invention [Problem to be solved by the invention]

[0012] The clinical treatment of major depressive disorder, especially in suicidal patients, often requires immediate and rapid clinical treatment, and therefore there is an urgent need for the development of fast-acting antidepressants. [Means for solving the problem]

[0013] The object of the present invention is to provide a compound having the structure as shown in formula (Ia):

[0014] [ka]

[0015] (In the formula: X1 is selected from the group consisting of CR1 and N, preferably N; X2 is selected from the group consisting of CR2 and N; X3 is selected from the group consisting of CR3 and N; X4 is selected from the group consisting of CR4 and N; R1 and R2 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 independently selected from the group consisting of aryl, and 5-10 membered heteroaryl; R3 and R4 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 3~8 Cycloalkyl, cyano-substituted C 3~8Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n OR a , -(CH2) n SR a , -(CH2) n C(O)R a , -S(O)R a , -S(O)2R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH2) n NR a R b wherein C is independently selected from the group consisting of 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; R5 and R6 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkylthio, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n ORa , -S(O)R a , -S(O)2R a , and -(CH2) n NR a R b wherein C is independently selected from the group consisting of 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~8 Forming a cycloalkyl or 3-8 membered heterocyclyl, wherein C 3~8 The cycloalkyl and 3- to 8-membered heterocyclyl can each be optionally further substituted; R5 and R6 are not simultaneously hydrogen; R a and R b are hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, and C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, C 1~8 Deuterated alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 aryl, and 5-10 membered heteroaryl, wherein C 1~8 Alkyl, C 1~8 Deuterated alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfuric acid, dibenzoyltartaric acid. acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, D-tartaric acid, pamoic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; y is selected from the group consisting of 0, 1, 2, and 3; and n is an integer from 0 to 6.

[0016] In a preferred embodiment of the present invention, in the acid addition salt of formula (Ia): R1 and R2 are each hydrogen, cyano, halogen, or C 1~6 Alkyl and C 3~6 Cycloalkyl, preferably hydrogen, cyano, halogen, C 1~3 Alkyl and C 3~6independently selected from the group consisting of cycloalkyl; R3 and R4 are each hydrogen, cyano, halogen, nitro, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 5- or 6-membered heteroaryl, -(CH2) n SR a , -(CH2) n C(O)R a , -S(O)R a , -S(O)2R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH2) n NR a R b independently selected from the group consisting of: R5 is hydrogen, cyano, halogen, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n OR a , -S(O)2R a and -(CH2) n NR a R b wherein the 5-10 membered heteroaryl can be optionally further substituted; R6 is hydrogen, halogen, cyano, C 1~6 Alkyl and C 1~6 Haloalkyl, preferably hydrogen, halogen, cyano, C 1~3 Alkyl and C1~3 haloalkyl; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~8 Forming a cycloalkyl, where C 3~8 The cycloalkyl can be optionally further substituted; R5 and R6 are not simultaneously hydrogen; R a and R b are hydrogen, halogen, cyano, nitro, and C 1~6 independently selected from the group consisting of alkyl, 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein C 1~6 The alkyl, 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl can each be optionally further substituted; M is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, and p-toluenesulfonic acid; y is selected from the group consisting of 1 and 2; n is an integer from 0 to 3.

[0017] In a preferred embodiment of the present invention, in the acid addition salt of formula (Ia): R1 and R2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, and cyclopropyl; R3 and R4 are each hydrogen, halogen, cyano, nitro, or C 1~3 Alkyl, cyano-substituted C 1~3 Alkyl, halogen-substituted C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, oxazolyl, -C(O)R a , -SC 1~3 Alkyl, -S(O)C 1~3 Alkyl, -S(O)2C 1~3 Alkyl, -C(O)OC 1~3 Alkyl, -S(O)(=NH)C 1~3Alkyl, and -C(O)O(CH2) n N(CH3)C 1~3 Alkyl, and preferably hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl, cyclopropyl, cyano-substituted cyclopropyl, cyano-substituted isopropyl, hydroxyisopropyl, oxazolyl, -C(O)R a , -SCH3, -S(O)CH3, -S(O)2CH3, -C(O)OCH2CH3, -S(O)(=NH)CH3, and -C(O)O(CH2)2NCH3(CH3); R5 is hydrogen, halogen, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, cyano-substituted C 1~3 Alkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 3-6 membered nitrogen-containing heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 1~3 Alkylthio, -(CH2) n R a , -(CH2) n OR a , -S(O)2R a and -(CH2) n N(R a )2, and preferably hydrogen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, methoxy, cyclopropyl, cyclobutyl, methyl-substituted pyrazolyl, phenyl, -SCH3, -(CH2) n R a , —NC(CH3)2, —S(O)2C(CH3)2, and —CH2N(CH3)2; R6 is selected from the group consisting of hydrogen, fluorine, cyano, methyl, ethyl, and trifluoromethyl; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~6 forming a cycloalkyl, preferably a cyclopropyl, wherein the cyclopropyl is optionally substituted by fluorine; R a is hydrogen, nitro, C 1~3 selected from the group consisting of alkyl, azetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are each optionally substituted with halogen, preferably fluorine; M is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, nitric acid and 1,5-naphthalenedisulfonic acid, preferably methanesulfonic acid; y is 0, 1, or 2; n is selected from the group consisting of 0, 1, and 2.

[0018] In a preferred embodiment of the present invention, the acid addition salt of formula (Ia) is of formula (IIa):

[0019] [ka]

[0020] It has a structure as shown in

[0021] In a preferred embodiment of the present invention, the acid addition salt of formula (Ia) is of formula (IIIa):

[0022] [ka]

[0023] (In the formula: R7 and R8 each have a structure as shown in (independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methyl, preferably hydrogen and fluorine).

[0024] In a preferred embodiment of the present invention, the acid addition salt of formula (Ia) is of formula (IVa):

[0025] [ka]

[0026] It has a structure as shown in

[0027] In a preferred embodiment of the present invention, the acid addition salt of formula (Ia) is represented by formula (Va):

[0028] [ka]

[0029] It has a structure as shown in

[0030] In a preferred embodiment of the invention, the acid addition salt of formula (Ia) is

[0031] [ka]

[0032] [ka]

[0033] [ka]

[0034] [ka]

[0035] [ka]

[0036] It has a structure like this.

[0037] In a preferred embodiment of the present invention, the acid addition salt of formula (Ia) is of formula (VIa):

[0038] [ka]

[0039] and having a structure as shown in M is methanesulfonic acid and y is 1.

[0040] In a preferred embodiment of the invention, the compound of formula (Ia) is characterized in that the compound of formula (VIa) is amorphous.

[0041] The object of the present invention is to provide a compound of formula (I):

[0042] [ka]

[0043] (In the formula: X1 is selected from the group consisting of CR1 and N, preferably N; X2 is selected from the group consisting of CR2 and N; X3 is selected from the group consisting of CR3 and N; X4 is selected from the group consisting of CR4 and N; R1 and R2 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 independently selected from the group consisting of aryl, and 5-10 membered heteroaryl; R3 and R4 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 3~8 Cycloalkyl, cyano-substituted C 3~8Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n OR a , -(CH2) n SR a , -(CH2) n C(O)R a , -S(O)R a , -S(O)2R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH2) n NR a R b wherein C is independently selected from the group consisting of 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; R5 and R6 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkylthio, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n ORa , -S(O)R a , -S(O)2R a , and -(CH2) n NR a R b wherein C is independently selected from the group consisting of 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~8 Forming a cycloalkyl or 3-8 membered heterocyclyl, wherein C 3~8 The cycloalkyl and 3- to 8-membered heterocyclyl can each be optionally further substituted; R5 and R6 are not simultaneously hydrogen; R a and R b are hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, and C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, C 1~8 Deuterated alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 aryl, and 5-10 membered heteroaryl, wherein C 1~8 Alkyl, C 1~8 Deuterated alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfuric acid, dibenzoyltartaric acid. acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, D-tartaric acid, pamoic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; x is selected from the group consisting of 0, 1, 2, and 3; n is an integer from 0 to 6) The present invention provides a crystalline form of the compound of formula (I) having the structure as shown in

[0044] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is R1 and R2 are each hydrogen, cyano, halogen, or C 1~6 Alkyl and C 3~6 Cycloalkyl, preferably hydrogen, cyano, halogen, C 1~3Alkyl and C 3~6 independently selected from the group consisting of cycloalkyl; R3 and R4 are each hydrogen, cyano, halogen, nitro, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 5- or 6-membered heteroaryl, -(CH2) n SR a , -(CH2) n C(O)R a , -S(O)R a , -S(O)2R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH2) n NR a R b independently selected from the group consisting of: R5 is hydrogen, cyano, halogen, nitro, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n OR a , -S(O)2R a and -(CH2) n NR a R b wherein the 5-10 membered heteroaryl can be optionally further substituted; R6 is hydrogen, halogen, cyano, C 1~6 Alkyl and C 1~6 Haloalkyl, preferably hydrogen, halogen, cyano, C1~3 Alkyl and C 1~3 haloalkyl; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~8 Forming a cycloalkyl, where C 3~8 The cycloalkyl can be optionally further substituted; R5 and R6 are not simultaneously hydrogen; R a and R b are hydrogen, halogen, cyano, nitro, and C 1~6 independently selected from the group consisting of alkyl, 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein C 1~6 The alkyl, 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl can each be optionally further substituted; M is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, and p-toluenesulfonic acid; x is selected from the group consisting of 1 and 2; n is an integer from 0 to 3.

[0045] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is R1 and R2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, and cyclopropyl; R3 and R4 are each hydrogen, halogen, cyano, nitro, or C 1~3 Alkyl, cyano-substituted C 1~3 Alkyl, halogen-substituted C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, oxazolyl, -C(O)R a , -SC 1~3 Alkyl, -S(O)C 1~3 Alkyl, -S(O)C 1~3 Alkyl, -C(O)OC 1~3Alkyl, -S(O)(=NH)C 1~3 Alkyl, and -C(O)O(CH2) n N(CH3)C 1~3 Alkyl, and preferably hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl, cyclopropyl, cyano-substituted cyclopropyl, cyano-substituted isopropyl, hydroxyisopropyl, oxazolyl, -C(O)R a , -SCH3, -S(O)CH3, -S(O)2CH3, -C(O)OCH2CH3, -S(O)(=NH)CH3, and -C(O)O(CH2)2NCH3(CH3); R5 is hydrogen, halogen, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, cyano-substituted C 1~3 Alkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 3-6 membered nitrogen-containing heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 1~3 Alkylthio, -(CH2) n R a , -(CH2) n OR a , -S(O)2R a and -(CH2) n N(R a )2, and preferably hydrogen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, methoxy, cyclopropyl, cyclobutyl, methyl-substituted pyrazolyl, phenyl, -SCH3, -(CH2) n R a , —NC(CH3)2, —S(O)2C(CH3)2, and —CH2N(CH3)2; R6 is selected from the group consisting of hydrogen, fluorine, cyano, methyl, ethyl, and trifluoromethyl; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~6forming a cycloalkyl, preferably a cyclopropyl, wherein the cyclopropyl is optionally substituted with a halogen, preferably with fluorine; R a is hydrogen, nitro, C 1~3 selected from the group consisting of alkyl, azetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are each optionally substituted with halogen, preferably fluorine; M is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, nitric acid and 1,5-naphthalenedisulfonic acid, and is preferably methanesulfonic acid; x is 0, 1, or 2; n is selected from the group consisting of 0, 1, and 2.

[0046] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is of formula (II):

[0047] [ka]

[0048] It has a structure as shown in

[0049] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is of formula (III):

[0050] [ka]

[0051] (In the formula: R7 and R8 each have a structure as shown in (independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methyl, preferably hydrogen and fluorine).

[0052] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is of formula (IV):

[0053] [ka]

[0054] It has a structure as shown in

[0055] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is of formula (V):

[0056] [ka]

[0057] It has a structure as shown in

[0058] In a preferred embodiment of the present invention, in the crystalline form of the compound of formula (I), the structure of the compound is as follows:

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] [ka]

[0064] As stated above.

[0065] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (I) is of formula (VI):

[0066] [ka]

[0067] It has a structure as shown in

[0068] A further preferred embodiment of the present invention is characterized in that x is 0 and the compound of formula (VI) is in the crystalline form of the free base.

[0069] A further preferred embodiment of the present invention is characterized in that the compound of formula (VI) is a salt in crystalline form, preferably where x is selected from the group consisting of 1, 2 and 3, and preferably where x is 1.

[0070] A further preferred embodiment of the present invention is a crystalline form of the free base of the compound of formula (VI), characterized in that the compound of formula (VI) is a hydrate or an anhydrate.

[0071] It is also an object of the present invention to provide a process for preparing a crystalline form of a compound of formula (I) or a compound of formula (Ia), specifically comprising the following steps: 1) Preparation of stock solution: dissolving the free base of the compound of the general formula in an organic solvent to obtain a clear stock solution, the concentration of which is preferably 50-100 mg / mL, more preferably 100 mg / mL; 2) Preparation of counter ion acid solution: Add the counter ion acid to an organic solvent or water to obtain a clear counter ion acid solution; the organic solvent is preferably ethanol, and the concentration is preferably 1.2-2.2 mol / L; 3) Preparation of the salt of the compound: Add the stock solution to the counterion acid solution to obtain a clear salt solution, stir the salt solution overnight to precipitate a solid, then filter, and dry the filter cake in vacuum to obtain the salt of the compound of formula (I); the vacuum temperature is preferably 40°C, and the amount of the counterion acid is preferably 0.6-1.2 equivalents; Including, where: The organic solvent is selected from the group consisting of 88% acetone, methanol, ethanol, ethyl acetate, dichloromethane, acetone, toluene, acetonitrile, tetrahydrofuran, heptane, methyl tert-butyl ether, isopropyl ether, and N,N-dimethylformamide; preferably ethyl acetate and ethanol; Counter ions include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, D-tartaric acid, pamoic acid, lauryl sulfate, dibenzoyltartaric acid, ethane-1,2 1,5-naphthalenedisulfonic acid, 1,5-naphthalene-2-sulfonic acid, 2-hydroxysalicylic acid, 2-hydroxybenzoic ...

[0072] It is also an object of the present invention to provide a process for preparing a crystalline form of a compound of formula (I) or a compound of formula (Ia), specifically comprising the following steps: 1) weighing out an appropriate amount of the free base or acid addition salt obtained in claim 20, followed by adding a good solvent and heating the mixture until dissolved; 2) After stirring for several hours, adding anti-solvent dropwise until turbidity appears; 3) stirring and cooling the mixture, followed by precipitating crystals to obtain the target product; Includes; where: The good solvent is selected from the group consisting of 88% acetone, ethyl acetate, methanol, ethanol, dichloromethane, acetone, and tetrahydrofuran; preferably ethyl acetate; The organic solvent is selected from the group consisting of 88% acetone, methanol, ethanol, ethyl acetate, dichloromethane, acetone, toluene, acetonitrile, tetrahydrofuran, heptane, methyl tert-butyl ether, isopropyl ether, and N,N-dimethylformamide; tetrahydrofuran and ethanol are preferred; the good solvent and the organic solution are miscible when used; The anti-solvent is selected from the group consisting of n-heptane, methyl tert-butyl ether, and isopropyl ether; preferably, n-heptane and methyl tert-butyl ether; the anti-solvent, good solvent, and organic solution are miscible when used; in a preferred embodiment of the present invention, the crystalline form of the compound of formula (VI) is crystalline form I of the free base (crystalline form I of the free base in Example 40), where x is 0, and the crystalline form is crystalline form I of the free base, and its X-ray powder diffraction pattern shows a diffraction peak at 16.7 at 2θ (±0.2°), or a diffraction peak at 12.6 at 2θ (±0.2°), or a diffraction peak at 17 at 2θ (±0.2°). or a diffraction peak at 7.3 at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 11.9 at 2θ (±0.2°), or a diffraction peak at 11.1 at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°), or a diffraction peak at 2θ (±0.2°); preferably, any 3 to 11, 5 to 8, or 6 to 8 of the above diffraction peaks are included, and more preferably, any 3, 6, 8, 10, or 11 of the above diffraction peaks are included.

[0073] In a preferred embodiment of the invention, the X-ray powder diffraction pattern of crystalline Form I of the free base of Example 40 has diffraction peaks at 16.7, 12.6, and 17.4 2θ (±0.2°), and optionally further includes one or more diffraction peaks at 7.3, 20.2, 20.6, 11.9, 11.1, 23.9, 21.9, and 38.4 2θ (±0.2°).

[0074] Preferably, the X-ray powder diffraction pattern of the crystalline form has diffraction peaks at 16.7, 12.6, 17.4, 7.3, 20.2 and 20.6 2θ (±0.2°).

[0075] More preferably, the X-ray powder diffraction pattern of the crystalline form has diffraction peaks at 16.7, 12.6, 17.4, 7.3, 20.2, 20.6, 11.9 and 11.1 in degrees 2θ (±0.2°).

[0076] Even more preferably, the X-ray powder diffraction pattern of the crystalline form has diffraction peaks in degrees 2θ (±0.2°) at 16.7, 12.6, 17.4, 7.3, 20.2, 20.6, 11.9, 11.1, 23.9 and 21.9.

[0077] Even more preferably, the crystalline form has an X-ray powder diffraction pattern with diffraction peaks at 16.7, 12.6, 17.4, 7.3, 20.2, 20.6, 11.9, 11.1, 23.9, 21.9 and 38.4 in degrees 2θ (±0.2°).

[0078] In a preferred embodiment of the present invention, the crystalline form of the compound of formula (VI) is crystalline form I of the free base (i.e., crystalline form I of the free base of Example 40), and its X-ray powder diffraction pattern has diffraction peaks at 16.7, 12.6, and 14.6 2θ (±0.2°), preferably at 7.3, 13.2, 17.4, 19.4, 20.2, and 20.6 2θ (±0.2°), and more preferably at 9.2, 11.1, 11.9, 19.6, 22.3, and 25.5 2θ (±0.2°).

[0079] Table 1 shows the characteristic X-ray diffraction peaks expressed by the 2θ angle and the d-spacing value using Cu-Kα radiation.

[0080] [Table 1]

[0081] The compound of formula (VI) of the present invention is crystalline form I of the free base compound (i.e., crystalline form I of the free base of Example 40), and its X-ray powder diffraction pattern is substantially as shown in FIG.

[0082] The compound of formula (VI) of the present invention is crystalline form I of the free base compound (i.e., crystalline form I of the free base of Example 40), and its DSC spectrum has an endothermic peak at 151.4±0.5°C, and its TGA spectrum shows a mass loss of 0.36% from 40 to 150°C, indicating little residual solvent. Its DSC spectrum shows no heat effect before 120°C, and its TGA spectrum shows no mass loss before 120°C, indicating the absence of water of crystallization in crystalline form I of the free base. Specifically, its TGA-DSC spectrum is substantially as shown in FIG. 2.

[0083] The compound of formula (VI) of the present invention is crystalline form I of the free base compound (ie, crystalline form I of the free base of Example 40), and its DVS spectrum is substantially as shown in FIG.

[0084] In a preferred embodiment of the present invention, the acid addition salt of the compound of formula (VI), and hydrate forms, stereoisomers, pharmaceutically acceptable salts, and crystalline forms thereof, wherein x is 0, is crystalline Form II of the free base (i.e., crystalline Form II of the free base of Example 40), having an X-ray powder diffraction pattern with diffraction peaks at 11.7, 13.4, 13.6, 16.6, and 18.9 2θ (±0.2°), and further with diffraction peaks at 9.5, 10.1, 14.7, 19.3 2θ (±0.2°), and further with diffraction peaks at 19.6, 20.6, 20.9, 21.6, 22.1, 22.5, 22.7, and 24.4 2θ (±0.2°).

[0085] The compound of formula (VI) of the present invention is crystalline form II of the free base (i.e., crystalline form II of the free base of Example 40), and its characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacing values, are shown in Table 2 using Cu-Kα radiation.

[0086] [Table 2]

[0087] The compound of formula (VI) of the present invention is crystalline form II of the free base (ie, crystalline form II of the free base of Example 40), and its X-ray powder diffraction pattern is substantially as shown in FIG.

[0088] The compound of formula (VI) of the present invention is crystalline form II of the free base (i.e., crystalline form II of the free base of Example 40), and its DSC spectrum has an endothermic peak at 193.5±0.5°C, and its TGA spectrum shows a mass loss of 0.32% from 40 to 150°C, indicating little residual solvent. Its DSC spectrum shows no thermal effect before 120°C, and its TGA spectrum shows no mass loss before 120°C, indicating the absence of water of crystallization in crystalline form II of the free base. Specifically, its TGA-DSC spectrum is substantially as shown in FIG. 4.

[0089] The compound of formula (VI) of the present invention is crystalline form II of the free base (ie, crystalline form II of the free base of Example 40), and its DVS spectrum is substantially as shown in FIG.

[0090] In a preferred embodiment of the present invention, the acid addition salt of the compound of formula (VI), and hydrate forms, stereoisomers, pharmaceutically acceptable salts, and crystalline forms thereof, wherein x is 0, is crystalline Form III of the free base (i.e., crystalline Form III of the free base of Example 40), having an X-ray powder diffraction pattern with diffraction peaks at 10.0, 11.7, 13.7, 16.6, 18.9, and 19.2 2θ (±0.2°), and further with diffraction peaks at 9.5, 10.1, 14.7, 19.3 2θ (±0.2°), and further with diffraction peaks at 13.4, 19.6, 20.6, 20.9, 22.0, 22.7, 23.4, and 25.6 2θ (±0.2°).

[0091] The compound of formula (I) of the present invention is crystalline form III of the free base (i.e., crystalline form III of the free base of Example 40), and its characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacing values, are shown in Table 3 using Cu-Kα radiation.

[0092] [Table 3]

[0093] The compound of formula (VI) of the present invention is crystalline form III of the free base (ie, crystalline form III of the free base of Example 40), and its X-ray powder diffraction pattern is substantially as shown in FIG.

[0094] The compound of formula (VI) of the present invention is crystalline form III of the free base (i.e., crystalline form III of the free base of Example 40), and its DSC spectrum has an endothermic peak at 206.4±0.5°C, and its TGA spectrum shows a mass loss of 0.29% from 40 to 150°C, indicating little residual solvent. The DSC spectrum shows no thermal effect before 120°C, and the TGA spectrum shows no mass loss before 120°C, indicating the absence of water of crystallization in crystalline form III of the free base. The TGA-DSC spectrum is substantially as shown in Figure 6.

[0095] The compound of formula (VI) of the present invention is crystalline form III of the free base (ie, crystalline form III of the free base of Example 40), and its DVS spectrum is substantially as shown in FIG.

[0096] In a preferred embodiment of the present invention, the acid addition salt of the compound of formula (VI), and hydrate forms, stereoisomers, pharmaceutically acceptable salts, and crystalline forms thereof, wherein M is methanesulfonic acid and x is 1, is a crystalline form of mesylate (i.e., the crystalline form of mesylate of Example 40), having an X-ray powder diffraction pattern having diffraction peaks at 112.5, 13.5, 19.4, and 19.9 2θ (±0.2°), and further having diffraction peaks at 15.1, 15.8, 16.5, 17.3, 18.7, and 23.1 2θ (±0.2°), and further having diffraction peaks at 11.1, 11.5, 13.9, 18.5, 21.3, 21.7, 26.5, and 28.9 2θ (±0.2°).

[0097] The compound of formula (VI) of the present invention is a mesylate (i.e., the mesylate of Example 40), and its characteristic X-ray diffraction peaks, expressed as 2θ angles and d-spacing values, are shown in Table 4 using Cu-Kα radiation.

[0098] [Table 4]

[0099] The compound of formula (VI) of the present invention is a mesylate (ie, the mesylate of Example 40), and its X-ray powder diffraction pattern is substantially as shown in FIG.

[0100] It is also an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of an acid addition salt of formula (Ia) and one or more pharmaceutically acceptable carriers.

[0101] The object of the present invention is also to provide a method for the preparation of GABA A The present invention provides the use of a compound of formula (Ia) or a pharmaceutical composition comprising the same in the preparation of a receptor modulator medicament.

[0102] It is also an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound of formula (I) and one or more pharmaceutically acceptable carriers.

[0103] The object of the present invention is also to provide a compound of formula (I),

[0104] [ka]

[0105] (In the formula: X1 is selected from the group consisting of CR1 and N, preferably N; X2 is selected from the group consisting of CR2 and N; X3 is selected from the group consisting of CR3 and N; X4 is selected from the group consisting of CR4 and N; R1 and R2 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10independently selected from the group consisting of aryl, and 5-10 membered heteroaryl; R3 and R4 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 1~8 Haloalkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n OR a , -(CH2) n SR a , -(CH2) n C(O)R a , -S(O)R a , -S(O)2R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH2) n NR a R b wherein C is independently selected from the group consisting of 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; R5 and R6 are each hydrogen, deuterium, cyano, halogen, nitro, amino, or C 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8Alkoxy, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkylthio, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n OR a , -S(O)R a , -S(O)2R a , and -(CH2) n NR a R b wherein C is independently selected from the group consisting of 1~8 Alkyl, C 2~8 Alkenyl, C 2~8 Alkynyl, C 1~8 Haloalkyl, C 1~8 Hydroxyalkyl, cyano-substituted C 1~8 Alkyl, C 1~8 Alkoxy, C 3~8 Cycloalkyl, cyano-substituted C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~8 Forming a cycloalkyl or 3-8 membered heterocyclyl, wherein C 3~8 The cycloalkyl and 3- to 8-membered heterocyclyl can each be optionally further substituted; R5 and R6 are not simultaneously hydrogen; R a and R b are hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, and C 1~8 Alkyl, C 1~8 Alkoxy, C 1~8 Hydroxyalkyl, C 1~8 Deuterated alkyl, C 1~8 Haloalkyl, C 3~8Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 aryl, and 5-10 membered heteroaryl, wherein C 1~8 Alkyl, C 1~8 Deuterated alkyl, C 1~8 Haloalkyl, C 3~8 Cycloalkyl, 3-8 membered heterocyclyl, C 6~10 The aryl and 5- to 10-membered heteroaryl can each be optionally further substituted; M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfuric acid, dibenzoyltartaric acid. acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, D-tartaric acid, pamoic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid and L-malic acid; x is selected from the group consisting of 0, 1, 2, and 3; n is an integer from 0 to 6) and providing a pharmaceutical composition comprising the compound of formula (I).

[0106] In a preferred embodiment of the present invention, the pharmaceutical composition comprises: R1 and R2 are each hydrogen, cyano, halogen, or C 1~6 Alkyl and C 3~6 Cycloalkyl, preferably hydrogen, cyano, halogen, C 1~3 Alkyl and C 3~6 independently selected from the group consisting of cycloalkyl; R3 and R4 are each hydrogen, cyano, halogen, nitro, or C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 5- or 6-membered heteroaryl, -(CH2) n SR a , -(CH2) n C(O)R a , -S(O)R a , -S(O)2R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH2) n NR a R b independently selected from the group consisting of: R5 is hydrogen, cyano, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, cyano-substituted C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkylthio, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 3-6 membered heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, -(CH2) n R a , -(CH2) n OR a , -S(O)2R aand -(CH2) n NR a R b wherein the 5-10 membered heteroaryl can be optionally further substituted; R6 is hydrogen, halogen, cyano, C 1~6 Alkyl and C 1~6 Haloalkyl, preferably hydrogen, halogen, cyano, C 1~3 Alkyl and C 1~3 haloalkyl; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~8 Forming a cycloalkyl, where C 3~8 The cycloalkyl can be optionally further substituted; R5 and R6 are not simultaneously hydrogen; R a and R b are hydrogen, halogen, cyano, nitro, and C 1~6 independently selected from the group consisting of alkyl, 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl, wherein C 1~6 The alkyl, 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl can each be optionally further substituted; M is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, and p-toluenesulfonic acid; x is selected from the group consisting of 1 and 2; n is an integer from 0 to 3.

[0107] In a preferred embodiment of the present invention, R1 and R2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, and cyclopropyl; R3 and R4 are each hydrogen, halogen, cyano, nitro, or C 1~3 Alkyl, cyano-substituted C 1~3 Alkyl, halogen-substituted C 1~3 Alkyl, C 1~3 Hydroxyalkyl, C 3~6Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, oxazolyl, -C(O)R a , -SC 1~3 Alkyl, -S(O)C 1~3 Alkyl, -S(O)C 1~3 Alkyl, -C(O)OC 1~3 Alkyl, -S(O)(=NH)C 1~3 Alkyl, and -C(O)O(CH2) n N(CH3)C 1~3 Alkyl, and preferably hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl, cyclopropyl, cyano-substituted cyclopropyl, cyano-substituted isopropyl, hydroxyisopropyl, oxazolyl, -C(O)R a , -SCH3, -S(O)CH3, -S(O)2CH3, -C(O)OCH2CH3, -S(O)(=NH)CH3, and -C(O)O(CH2)2NCH3(CH3); R5 is hydrogen, halogen, cyano, C 1~3 Alkyl, C 1~3 Haloalkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, cyano-substituted C 1~3 Alkyl, C 3~6 Cycloalkyl, cyano-substituted C 3~6 Cycloalkyl, 3-6 membered nitrogen-containing heterocyclyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 1~3 Alkylthio, -(CH2) n R a , -(CH2) n OR a , -S(O)2R a and -(CH2) n N(R a )2, and preferably hydrogen, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, methoxy, cyclopropyl, cyclobutyl, methyl-substituted pyrazolyl, phenyl, -SCH3, -(CH2) n R a, —NC(CH3)2, —S(O)2C(CH3)2, and —CH2N(CH3)2; R6 is selected from the group consisting of hydrogen, fluorine, cyano, methyl, ethyl, and trifluoromethyl; Or, R5 and R6 together with the carbon atom to which they are attached form C 3~6 forming a cycloalkyl, preferably a cyclopropyl, wherein the cyclopropyl is optionally substituted with a halogen, preferably with fluorine; R a is hydrogen, nitro, C 1~3 selected from the group consisting of alkyl, azetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are each optionally substituted with halogen, preferably fluorine; M is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, nitric acid and 1,5-naphthalenedisulfonic acid, and preferably methanesulfonic acid; x is 0, 1, or 2; n is selected from the group consisting of 0, 1, and 2.

[0108] In a preferred embodiment of the present invention, the structure of the compound of formula (I) is formula (II):

[0109] [ka]

[0110] It is as shown in the figure.

[0111] In a preferred embodiment of the present invention, the structure of the compound of formula (I) is formula (III):

[0112] [ka]

[0113] wherein R7 and R8 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine and methyl, preferably hydrogen and fluorine. It is as shown in the figure.

[0114] In a preferred embodiment of the present invention, the structure of the compound of formula (I) is formula (IV):

[0115] [ka]

[0116] It is as shown in the figure.

[0117] In a preferred embodiment of the present invention, the structure of the compound of formula (I) is formula (V):

[0118] [ka]

[0119] It is as shown in the figure.

[0120] In a preferred embodiment of the invention, the compound of formula (I) is

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] is selected from the group consisting of:

[0127] In a preferred embodiment of the present invention, it has formula (VI):

[0128] [ka]

[0129] wherein x is selected from the group consisting of 0, 1, and 2.

[0130] In a preferred embodiment of the invention, the pharmaceutical composition is an injectable or oral preparation, preferably a tablet or capsule.

[0131] In a preferred embodiment of the present invention, the unit dose is 1 to 200 mg, preferably 5 to 200 mg, further preferably 10 to 100 mg, and even more preferably 10 to 50 mg.

[0132] In a preferred embodiment of the present invention, the unit dose may be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 150 mg, etc., preferably 1-50 mg, or preferably 1-30 mg.

[0133] The object of the present invention is also to provide a method for the preparation of GABA A The present invention provides a use of a crystalline form of the compound of formula (I) or a pharmaceutical composition according to claim 29 in the preparation of a receptor modulator medicament.

[0134] It is also an object of the present invention to provide a crystalline form of the compound of formula (VI), and one or more pharmaceutically acceptable carriers.

[0135] The object of the present invention is also to provide a method for the preparation of GABA A The present invention provides a use of a crystalline form of the compound of formula (VI) or a pharmaceutical composition according to claim 31 in the preparation of a receptor modulator medicament.

[0136] In a preferred embodiment of the present invention, GABA A The pharmaceutical composition of the receptor modulator medicament is used to treat a central nervous system (CNS)-related disorder, wherein the CNS-related disorder is selected from the group consisting of a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus. [Brief explanation of the drawings]

[0137] [Figure 1] FIG. 1 is an XRPD pattern of crystalline Form I of the free base of Formula (VI) (i.e., crystalline Form I of the free base of Example 40). [Figure 2] FIG. 1 is a TGA-DSC spectrum of crystalline Form I of the free base of Formula (VI) (i.e., crystalline Form I of the free base of Example 40). [Figure 3] FIG. 1 is an XRPD pattern of crystalline Form II of the free base of Formula (VI) (i.e., crystalline Form II of the free base of Example 40). [Figure 4] FIG. 1 is a TGA-DSC spectrum of crystalline Form II of the free base of Formula (VI) (i.e., crystalline Form II of the free base of Example 40). [Figure 5] FIG. 1 is an XRPD pattern of crystalline Form III of the free base of Formula (VI) (i.e., crystalline Form III of the free base of Example 40). [Figure 6] 1 is a TGA-DSC spectrum of crystalline Form III of the free base of Formula (VI) (i.e., crystalline Form III of the free base of Example 40). [Figure 7] 1 is an XRPD pattern of the mesylate of formula (VI) (i.e., the mesylate of Example 40). [Figure 8]FIG. 1 is a DVS spectrum of crystalline Form I of the free base of Formula (VI) (i.e., crystalline Form I of the free base of Example 40). [Figure 9] FIG. 1 is a DVS spectrum of crystalline Form II of the free base of Formula (VI) (i.e., crystalline Form II of the free base of Example 40). [Figure 10] FIG. 1 is a DVS spectrum of crystalline Form III of the free base of Formula (VI) (i.e., crystalline Form III of the free base of Example 40). [Figure 11] FIG. 1 is a schematic representation of the single crystal structure of crystalline Form I of the free base of formula (VI) (i.e., crystalline Form I of the free base of Example 40). DETAILED DESCRIPTION OF THE INVENTION

[0138] Unless otherwise specified, terms used in the specification and claims have the meanings set forth below.

[0139] The term "alkyl" refers to a saturated aliphatic hydrocarbon group that is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl containing 1 to 8 carbon atoms, more preferably an alkyl containing 1 to 6 carbon atoms, and most preferably an alkyl containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 Examples of alkyl groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available point of attachment.The substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl. The alkyl of the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.

[0140] The term "alkylene" refers to an alkyl further substituted with a hydrogen atom; for example, "methylene" refers to -CH-, "ethylene" refers to -(CH)-, "propylene" refers to -(CH)-, "butylene" refers to -(CH)-, etc. The above substituents can be attached to different carbon atoms to form a carbon chain or to a single carbon atom to form a cycloalkyl. The term "alkenyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. Alkenyl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocyclylthio.

[0141] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent having 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyls include cycloalkyls having spirocyclic, fused, or bridged rings. Cycloalkyls are preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0142] The term "heterocyclyl" refers to a 3- to 20-membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, in which one or more ring atoms are selected from N, O, and S(O). m(m is an integer of 0 to 2), with the proviso that, except for -OO-, -OS-, or -SS-, the remaining ring atoms in the ring are carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, with 1 to 4 ring atoms, more preferably 3 to 8 ring atoms, and most preferably 3 to 8 ring atoms being heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., with tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclyls include heterocyclyls having spiro rings, fused rings, or bridged rings. Heterocyclyls having spiro, fused, or bridged rings are optionally bonded to other groups through a single bond or further bonded to other cycloalkyls, heterocyclyls, aryls, and heteroaryls through any two or more atoms on the ring. Heterocyclyls can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy, and alkoxycarbonyl.

[0143] The term "aryl" refers to a 6-14 membered all-carbon monocyclic or polycyclic fused ring (i.e., each ring in the system shares adjacent pairs of carbon atoms with another ring in the system) having a conjugated π electron system, preferably a 6-10 membered aryl, such as phenyl and naphthyl. An aryl is more preferably phenyl. An aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring. Non-limiting examples include:

[0144] [ka]

[0145] Examples include:

[0146] Aryl can be substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0147] The term "heteroaryl" refers to a 5-14 membered heteroaromatic system having 1-4 heteroatoms selected from the group consisting of O, S, and N. Heteroaryl is preferably a 5-10 membered heteroaryl, more preferably a 5- or 6-membered heteroaryl, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl, and more preferably triazolyl, pyrrolyl, thienyl, thiazolyl, and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, with the ring attached to the parent structure being a heteroaryl ring. Non-limiting examples include:

[0148] [ka]

[0149] Examples include:

[0150] Heteroaryl can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0151] The term "alkoxy" refers to an -O-(alkyl) or -O-(unsubstituted cycloalkyl) group, where alkyl is as defined above. Alkoxy is preferably an alkoxy having 1 to 8 carbon atoms, more preferably an alkoxy having 1 to 6 carbon atoms, and most preferably an alkoxy having 1 to 3 carbon atoms. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted. If substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, and alkoxycarbonyl.

[0152] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is defined above.

[0153] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is defined above.

[0154] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy, where alkyl is as defined above.

[0155] "Alkenyl" refers to an alkenyl chain, also known as an alkene group, which is preferably an alkenyl having 2 to 8 carbon atoms, more preferably an alkenyl having 2 to 6 carbon atoms, and most preferably an alkenyl having 2 to 3 carbon atoms. The alkenyl can be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0156] "Alkynyl" refers to (CH≡C-), which is preferably an alkynyl having from 2 to 8 carbon atoms, more preferably an alkynyl having from 2 to 6 carbon atoms, and most preferably an alkynyl having from 2 to 3 carbon atoms. Alkynyl can be further substituted with other related groups such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy, or alkoxycarbonyl.

[0157] "Hydroxy" refers to the group --OH.

[0158] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0159] "Amino" refers to the group -NH2.

[0160] "Cyano" refers to the radical -CN.

[0161] "Nitro" refers to the -NO2 group.

[0162] "Carboxy" refers to the group --C(O)OH.

[0163] By way of example, various phrases such as "X is selected from the group consisting of A, B, or C," "X is selected from the group consisting of A, B, and C," "X is A, B, or C," and "X is A, B, and C" convey the same meaning, i.e., X can be any one or more of A, B, and C.

[0164] "Optional" or "optionally" means that a subsequently described event or circumstance may occur, but need not occur, and such description includes situations in which the event or circumstance occurs or does not occur.

[0165] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3, independently substituted with a corresponding number of substituents. Obviously, substituents exist only at feasible chemical positions. Those skilled in the art can determine whether a substitution is possible or not by experiment or theory without undue effort. For example, the combination of an amino or hydroxyl group having free hydrogen with a carbon atom having an unsaturated bond (such as an olefin) may be unstable.

[0166] "Stereoisomerism" includes geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0167] Any hydrogen atom in the compounds of the present invention may be substituted with its deuterium isotope. Any hydrogen atom in the compounds of the examples of the present invention may be substituted with a deuterium atom.

[0168] A "pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components and other ingredients, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, thereby facilitating absorption of the active ingredient so that it exerts its biological activity.

[0169] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective in mammals and that possesses the desired biological activity.

[0170] "TGA" refers to thermogravimetric analysis (TGA) testing.

[0171] "DSC" refers to differential scanning calorimetry (DSC) testing.

[0172] "DVS" refers to Dynamic Vapor Sorption (DVS) testing.

[0173] "XRPD" refers to X-ray powder diffraction (XRPD) testing.

[0174] "HPLC" refers to high performance liquid chromatography (HPLC) testing.

[0175] "PK" refers to pharmacokinetic (PK) studies.

[0176] The present invention is further described with reference to the following examples, which should not be construed as limiting the scope of the invention.

[0177] 1.1 Experimental equipment 1.1.1 Some parameters of physical and chemical testing equipment

[0178] [Table 5]

[0179] 1.2 Instrumentation and liquid phase analysis conditions 1.2.1 Equipment and Devices

[0180] [Table 6]

[0181] 1.2.2 Chromatographic conditions Chromatography column: Agilent ZORBAX® Bonus-RP (3.5 μm, 4.6*150 mm) Flow rate: 1.0mL / min Column temperature: 40℃ Detection wavelength: 230 nm Injection volume: 10.0μL Run Time: 30 minutes Diluent: methanol-water (v / v, 3:1) Mobile phase: A: Water (0.05% trifluoroacetic acid); B: Acetonitrile (0.05% trifluoroacetic acid)

[0182] [Table 7]

[0183] Preparation of the free base [Example]

[0184] Example 1 Preparation of 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0185] [ka]

[0186] Step 1: Preparation of 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethan-1-one

[0187] [ka]

[0188] 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethan-1-one (70 mg, 0.21 mmol) was dissolved in methanol (3 mL). One drop of hydrogen bromide was added to the solution, followed by liquid bromine (41 mg, 0.25 mmol), and the reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (87 mg, yield: 100%, crude), which was used directly in the next step.

[0189] Step 2: Preparation of 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0190] [ka]

[0191] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (87 mg, 0.21 mmol), 1H-pyrazole-4-carbonitrile (59 mg, 0.64 mmol), and potassium carbonate (145 mg, 1.05 mmol) were dissolved in tetrahydrofuran (2 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high-performance liquid chromatography to obtain 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (33 mg, yield: 37%). MS m / z (ESI): 404.2 [M-HO+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.82 (s, 1H), 5.24-5.13 (m, 2H), 2.84 (d, J = 2.7 Hz, 1H), 1.98 - 1.92 (m, 1H), 1.87 - 1.77 (m, 4H), 1.76 - 1.66 (m, 3H), 1.57 - 1.51 (m, 1H), 1.46 - 1.24 (m, 15H), 1.12 - 1.02 (m, 1H), 1.00 - 0.96 (m, 1H), 0.78 (s, 3H), 0.54 - 0.46 (m, 1H).

[0192] Example 2 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0193] [ka]

[0194] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (80 mg, 0.19 mmol), 1H-pyrazole-3-carbonitrile (55 mg, 0.58 mmol), and potassium carbonate (131 mg, 0.95 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high-performance liquid chromatography to obtain 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (34.7 mg, yield: 42%). MS m / z (ESI): 404.2 [M-HO+H] + 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.29 - 5.13 (m, 2H), 2.83 (d, J = 2.9 Hz, 1H), 1.97 - 1.92 (m, 1H), 1.86 - 1.79 (m, 4H), 1.73 - 1.64 (m, 3H), 1.58 - 1.52 (m, 1H), 1.43 - 1.27 (m, 15H), 1.12 - 0.96 (m, 2H), 0.79 (s, 3H), 0.53 - 0.44 (m, 1H).

[0195] Example 3 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0196] [ka]

[0197] Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0198] [ka]

[0199] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (60 mg, 0.15 mmol), 4-(trifluoromethyl)-1H-pyrazole (60 mg, 0.44 mmol), and potassium carbonate (104 mg, 0.75 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high-performance liquid chromatography to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (22.2 mg, yield: 33%). MS m / z (ESI): 465.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.73 (s, 1H), 5.25 - 5.09 (m, 2H), 2.83 (d, J = 3.6 Hz, 1H), 2.00 - 1.91 (m, 1H), 1.89 - 1.79 (m, 4H), 1.78 - 1.65 (m, 3H), 1.58 - 1.52 (m, 1H), 1.47 - 1.22 (m, 15H), 1.15 - 0.95 (m, 2H), 0.79 (s, 3H), 0.52 - 0.44 (m, 1H).

[0200] Example 4 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0201] [ka]

[0202] Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0203] [ka]

[0204] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (80 mg, 0.2 mmol), 3-(trifluoromethyl)-1H-pyrazole (80 mg, 0.6 mmol), and potassium carbonate (138 mg, 1.0 mmol) were dissolved in tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high-performance liquid chromatography to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (17 mg, yield: 18%). MS m / z (ESI): 447.3 [M-HO+H] + . 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 1.9 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 5.27 - 5.13 (m, 2H), 2.83 (d, J = 3.7 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.89 - 1.76 (m, 4H), 1.75 - 1.61 (m, 3H), 1.58 - 1.50 (m, 1H), 1.50 - 1.21 (m, 15H), 1.13 - 0.96 (m, 2H), 0.79 (s, 3H), 0.52 - 0.45 (m, 1H).

[0205] Examples 5 and 6 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (5) 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (6)

[0206] [ka]

[0207] Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (5) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (6)

[0208] [ka]

[0209] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (80 mg, 0.19 mmol), 1H-1,2,3-triazole (40 mg, 0.58 mmol), and potassium carbonate (131 mg, 0.95 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high-performance liquid chromatography to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (5) (9 0.2 mg, yield: 12%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (6) (17.8 mg, yield: 23%) were obtained. Example 5: MS m / z (ESI): 380.3 [M-HO+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 5.55 - 5.36 (m, 2H), 2.82 (d, J = 4.1 Hz, 1H), 1.99 - 1.92 (m, 1H), 1.87 - 1.74 (m, 4H), 1.73 - 1.52 (m, 5H), 1.47 - 1.26 (m, 14H), 1.14 - 0.98 (m, 2H), 0.84 (s, 3H), 0.52 - 0.43 (m, 1H). Example 6: MS m / z (ESI): 398.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.66 (s, 1H), 5.52 - 5.35 (m, 2H), 2.87 (d, J = 3.9 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.89 - 1.78 (m, 4H), 1.76 - 1.65 (m, 3H), 1.59 - 1.52 (m, 1H), 1.48 - 1.23 (m, 15H), 1.15 - 0.98 (m, 2H), 0.80 (s, 3H), 0.56 - 0.45 (m, 1H).

[0210] Examples 7 and 8 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (7) 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (8)

[0211] [ka]

[0212] Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (7) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (8)

[0213] [ka]

[0214] 2-Bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (50 mg, 0.12 mmol), 1H-tetrazole (26 mg, 0.37 mmol), and potassium carbonate (83 mg, 0.6 mmol) were dissolved in tetrahydrofuran (3 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high-performance liquid chromatography to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (7) (1 1.6 mg, yield: 24%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (8) (4.4 mg, yield: 9%) were obtained. Example 7: MS m / z (ESI): 381.2 [M-HO+H] + 1 H NMR (400 MHz, CDCl3) δ8.58 (s, 1H), 5.74 - 5.62 (m, 2H), 2.88 (d, J = 3.8 Hz, 1H), 1.97 - 1.91 (m, 1H), 1.87 - 1.79 (m, 4H), 1.75 - 1.64 (m, 3H), 1.58 - 1.55 (m, 1H), 1.45 - 1.35 (m, 7H), 1.34 - 1.24 (m, 8H), 1.14 - 1.01 (m, 2H), 0.85 (s, 3H), 0.56 - 0.48 (m, 1H). Example 8: MS m / z (ESI): 399.3 [M+H] + 1 H NMR (400 MHz, CDCl3) δ8.77 (s, 1H), 5.57 - 5.39 (m, 2H), 2.90 (s, 1H), 2.00 - 1.91 (m, 1H), 1.88 - 1.79 (m, 4H), 1.76 - 1.65 (m, 3H), 1.59 - 1.56 (m, 1H), 1.46 - 1.37 (m, 7H), 1.35 - 1.24 (m, 8H), 1.13 - 0.99 (m, 2H), 0.79 (s, 3H), 0.58 - 0.49 (m, 1H).

[0215] Example 9 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0216] [ka]

[0217] Step 1: (3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

[0218] [ka]

[0219] 3.0 M methylmagnesium bromide (8.5 mL, 25.5 mmol) and 20 mL of anhydrous tetrahydrofuran were added to a dry 100 mL round-bottom flask. The reaction was purged with nitrogen and cooled to 0 °C. Cuprous iodide (3.94 g, 20.7 mmol) was added, and the reaction solution was then stirred at 0 °C for 1 h. (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (2 g, 6.9 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and the resulting solution was slowly added dropwise to the reaction. The reaction was stirred for 3 h, and TLC showed the reaction was complete. The reaction was quenched by the addition of saturated ammonium chloride solution, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give (3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.56 g, yield: 75%). 1 H NMR (400 MHz, CDCl3) δ 2.51-2.42 (m, 2H), 2.24 (d, J = 17.6 Hz, 1H), 1.89-1.63 (m, 7H), 1.54-1.18 (m, 16H), 1.10 (d, J = 7.6 Hz, 3H), 1.03 (s, 3H).

[0220] Step 2: (3R,5R,8R,9R,10S,13S,14S,15R,E)-17-ethylidene-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0221] [ka]

[0222] Ethyltriphenylphosphonium bromide (18.5 g, 505 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL) and the reaction system was purged with nitrogen. Sodium hydride (2.0 g, 50 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.52 g, 5 mmol) was added, and the reaction solution was stirred at 100 °C overnight. The reaction solution was cooled to room temperature. Water (200 mL) was added to the reaction solution to quench the reaction, and the aqueous phase was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 3 / 1) to obtain (3R,5R,8R,9R,10S,13S,14S,15R,E)-17-ethylidene-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.37 g, yield: 86%).

[0223] Step 3: (3R,5R,8R,9R,10S,13S,14S,15R,17S)-17-((R)-1-hydroxyethyl)-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0224] [ka]

[0225] (3R,5R,8R,9R,10S,13S,14S,15R,E)-17-ethylidene-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.37 g, 4.33 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). The solution was cooled to 0 °C, and then BH3 / THF (43 mL, 43 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC indicated the reaction was complete. After cooling the reaction solution to 0 °C, 3M aqueous NaOH (40 mL) was slowly added, followed by H2O2 (30 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC indicated the reaction was complete. After adding ethyl acetate (50 mL), the reaction solution was washed successively with saturated aqueous Na2S2O3 (30 mL) and water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product (1.37 g) which was used directly in the next step.

[0226] Step 4: 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethan-1-one

[0227] [ka]

[0228] (3R,5R,8R,9R,10S,13S,14S,15R,17S)-17-((R)-1-hydroxyethyl)-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.37 g, crude) was dissolved in dichloromethane (30 mL). PCC (1.8 g, 8.66 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and the organic phase was concentrated. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate: 1 / 1) to give 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (780 mg, two-step yield: 54.3%). 1 H NMR (400 MHz, CDCl3) δ 2.49 (dd, J = 8.8, 10.4 Hz, 1H), 2.14-2.03 (m, 5H), 1.95-1.79 (m, 5H), 1.69-1.06 (m, 18H), 0.96 (d, J = 7.2 Hz, 3H), 0.78 (s, 3H).

[0229] Step 5: 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethan-1-one

[0230] [ka]

[0231] 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethan-1-one (333 mg, 1 mmol) was dissolved in methanol (10 mL). One drop of hydrogen bromide was added to the solution, followed by liquid bromine (176 mg, 1.1 mmol), and the reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (413 mg, crude), which was used directly in the next step.

[0232] Step 6: 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0233] [ka]

[0234] 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (82 mg, 0.2 mmol), 1H-pyrazole-4-carbonitrile (28 mg, 0.3 mmol), and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The obtained crude product was purified by high performance liquid chromatography to obtain 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (41 mg, yield: 48%). 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.01 (d, J = 17.9 Hz, 1H), 4.90 (d, J = 17.9 Hz, 1H), 2.62-2.48 (m, 1H), 2.30-2.06 (m, 3H), 2.04-1.75 (m, 7H), 1.75-1.04 (m, 15H), 0.99 (d, J = 7.1 Hz, 3H), 0.84 (s, 3H). MS m / z (ESI): 424.6 [M+H] + .

[0235] Example 14 2-(4-chloro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

[0236] [ka]

[0237] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-chloro-1H-pyrazole were used as starting materials, thus obtaining 2-(4-chloro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (21.9 mg, yield: 26%). MS m / z (ESI): 431.2 [M+H] + MS m / z (ESI): 431.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ7.45 (d, J = 11.8 Hz, 2H), 5.17 - 5.01 (m, 2H), 2.81 (d, J = 3.5 Hz, 1H), 1.99 - 1.91 (m, 1H), 1.86 - 1.79 (m, 3H), 1.77 - 1.62 (m, 3H), 1.57 - 1.49 (m, 3H), 1.44 - 1.20 (m, 14H), 1.12 - 0.96 (m, 2H), 0.78 (s, 3H), 0.51 - 0.44 (m, 1H).

[0238] Examples 24 and 25 3-Cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (24) 5-Cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (25)

[0239] [ka]

[0240] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethan-1-one and 5-cyclopropyl-1H-pyrazole-4-carbonitrile were used as starting materials, thus obtaining 3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethan-1-one. Cyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (24) (19.2 mg, yield: 21%) and 5-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (25) (3.0 mg, yield: 3.3%) were obtained. Example 24: MS m / z (ESI): 462.3 [M+H] + 1 H NMR (400 MHz, CDCl3) δ7.73 (s, 1H), 5.14 - 4.98 (m, 2H), 2.80 (d, J = 2.2 Hz, 1H), 2.05 - 1.89 (m, 2H), 1.86 - 1.78 (m, 4H), 1.75 - 1.64 (m, 3H), 1.58 - 1.52 (m, 2H), 1.46 - 1.33 (m, 7H), 1.33 - 1.20 (m, 7H), 1.14 - 0.92 (m, 6H), 0.76 (s, 3H), 0.53 - 0.43 (m, 1H). Example 25: MS m / z (ESI): 462.3 [M+H] + 1H NMR (400 MHz, CDCl3) δ7.69 (s, 1H), 5.33 - 5.13 (m, 2H), 2.85 (d, J = 3.8 Hz, 1H), 2.00 - 1.92 (m, 1H), 1.86 - 1.79 (m, 3H), 1.76 - 1.62 (m, 4H), 1.60 - 1.51 (m, 2H), 1.45 - 1.34 (m, 7H), 1.34 - 1.22 (m, 7H), 1.17 - 0.94 (m, 7H), 0.81 (s, 3H), 0.54 - 0.45 (m, 1H).

[0241] Examples 28 and 29 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (28) 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (29)

[0242] [ka]

[0243] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 3-methyl-1H-pyrazole-4-carbonitrile were used as starting materials, thus obtaining a mixture of Example 28 and Example 29 (approximately 3:1) (25.9 mg, white solid, yield: 39.3%). The mixture was further separated by preparative chromatography to give 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (28) and 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (29). Example 37A MS m / z (ESI): 436.3[M+H] + Example 37B MS m / z (ESI): 436.3[M+H] +

[0244] Example 30 2-(4-Fluoro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

[0245] [ka]

[0246] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-fluoropyrazole were used as starting materials, thus obtaining 2-(4-fluoro-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (6.2 mg, white solid, yield: 7.7%). MS m / z (ESI): 415.2[M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 4.0 Hz, 1H), 7.32 (d, J = 4.0 Hz, 1H), 5.03 (d, J = 3.6 Hz, 2H), 2.80 (d, J = 3.6 Hz, 1H), 2.01-1.93 (m, 2H), 1.85-1.80 (m, 3H), 1.73-1.61 (m, 6H), 1.41-1.32 (m, 9H), 1.27 (s, 3H), 1.12-1.02 (m, 2H), 0.99-0.96 (m, 1H), 0.78 (s, 3H), 0.50-0.44 (m, 1H).

[0247] Example 35 Ethyl 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carboxylate

[0248] [ka]

[0249] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethan-1-one and ethyl 1H-pyrazole-4-carboxylate were used as starting materials, thus Ethyl 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carboxylate (29.6 mg, white solid, yield: 43%) was obtained. MS m / z (ESI): 469.3 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 2H), 5.32 - 4.99 (m, 2H), 4.36 - 4.24 (m, 2H), 2.83 (s, 1H), 1.99 - 1.92 (m, 1H), 1.87 - 1.79 (m, 3H), 1.72 - 1.52 (m, 6H), 1.49 - 1.16 (m, 17H), 1.14 - 0.96 (m, 2H), 0.83 (s, 3H), 0.53 - 0.44 (m, 1H).

[0250] Example 39 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trifluorohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0251] [ka]

[0252] 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (82 mg, 0.2 mmol), 4-(trifluoromethyl)-1H-pyrazole (41 mg, 0.3 mmol), and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to obtain 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trifluorohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (24.6 mg, yield: 26%). 1 H NMR (400 MHz, CDCl3) δ 7.72 (s, 2H), 5.00 (d, J = 16 Hz, 1H), 4.90 (d, J = 16 Hz, 1H), 2.58-2.54 (m, 1H), 1.88-1.83 (m, 2H), 1.69-1.58 (m, 5H), 1.50-1.25 (m, 19H), 0.98 (d, J = 8.0 Hz, 3H), 0.85 (s, 3H). MS m / z (ESI): 467.3 [M+H] +

[0253] Example 40 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0254] [ka]

[0255] Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0256] [ka]

[0257] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (12.5 mg, yield: 20.2%). MS m / z (ESI): 424.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.07 - 4.84 (m, 2H), 2.55 (t, J = 8.1 Hz, 1H), 2.33 - 1.06 (m, 25H), 0.98 (d, J = 7.0 Hz, 3H), 0.84 (s, 3H).

[0258] Examples 41 and 42 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (41) 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (42)

[0259] [ka]

[0260] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

[0261] [ka]

[0262] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (9.5 mg, yield: 16.3%) and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (13 mg, yield: 22.3%) were obtained. Example 41: MS m / z (ESI): 400.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.29 - 5.15 (m, 2H), 2.52 (t, J = 8.0 Hz, 1H), 2.17 - 1.29 (m, 24H), 1.15 - 1.05 (m, 1H), 0.97 (d, J = 7.0 Hz, 3H), 0.87 (s, 3H). Example 42: MS m / z (ESI): 400.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ7.77 (s, 1H), 7.65 (s, 1H), 5.32 - 5.02 (m, 2H), 2.60 (t, J = 9.1 Hz, 1H), 2.30 - 2.12 (m, 2H), 1.99 - 1.27 (m, 22H), 1.17 - 1.06 (m, 1H), 0.99 (d, J = 6.9 Hz, 3H), 0.84 (s, 3H)

[0263] Example 43 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0264] [ka]

[0265] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0266] [ka]

[0267] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (4.7 mg, yield: 7%). MS m / z (ESI): 415.3[M+H] + 1H NMR (400 MHz, CDCl3) δ 5.36 (s, 2H), 2.57 (s, 3H), 2.27 - 2.11 (m, 2H), 2.00 -198 (m, 1H), 1.87 - 1.83 (m, 5H), 1.77 - 1.57 (m, 6H), 1.52 - 1.30 (m, 12H), 1.11 (s, 2H), 0.98 (d, J = 7.0 Hz, 3H), 0.88 (s, 3H).

[0268] Example 44 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0269] [ka]

[0270] 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (82 mg, 0.2 mmol), 2H-tetrazole (21 mg, 0.3 mmol), and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high-performance liquid chromatography to obtain 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (15.7 mg, yield: 20%). MS m / z (ESI): 401.3 [M+H] + 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 4.46 (s, 2H), 2.62-2.58 (m, 1H), 1.89-1.84 (m, 2H), 1.70-1.26 (m, 23H), 0.99 (d, J = 8.0 Hz, 3H), 0.88 (s, 3H).

[0271] Example 47 3-Cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0272] [ka]

[0273] Step 1: Preparation of 3-cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0274] [ka]

[0275] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 3-cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (30 mg, yield: 41%). MS m / z (ESI): 464.3[M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 4.82 (q, J = 17.9 Hz, 2H), 2.51 - 2.46 (m, 1H), 2.27 - 2.18 (m, 1H), 2.19 - 2.08 (m, 1H), 2.04 - 1.91 (m, 2H), 1.90 - 1.80 (m, 4H), 1.68 - 1.60 (m, 4H), 1.57 (s, 3H), 1.51 - 1.29 (m, 8H), 1.18 - 1.03 (m, 3H), 1.02 - 0.95 (m, 7H), 0.82 (s, 3H).

[0276] Example 48 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0277] [ka]

[0278] Step 1: (3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

[0279] [ka]

[0280] 1.0 M cyclopropylmagnesium bromide (12.7 mL, 12.7 mmol) and 20 mL of anhydrous tetrahydrofuran were added to a dry 100 mL round-bottom flask. The reaction was purged with nitrogen and cooled to 0 °C. Cuprous iodide (1.97 g, 10.4 mmol) was added, and the reaction solution was then stirred at 0 °C for 1 h. (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (1 g, 3.5 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and the resulting solution was slowly added dropwise to the reaction. The reaction was stirred for 3 h, and TLC indicated the reaction was complete. The reaction was quenched by the addition of saturated ammonium chloride solution, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give (3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.11 g, 96%). 1H NMR (400 MHz, CDCl3) δ 2.45-2.30 (m, 2H), 1.85-1.76 (m, 9H), 1.59-1.52 (m, 5H), 1.59-1.27 (m, 12H), 1.11-0.98 (m, 1H), 0.67-0.64 (m, 1H), 0.47-0.43 (m, 1H), 0.22-0.18 (m, 1H), 0.09-0.07 (m, 1H).

[0281] Step 2: (3R,5R,8R,9R,10S,13S,14S,15S,E)-15-cyclopropyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0282] [ka]

[0283] Ethyltriphenylphosphonium bromide (12.5 g, 33 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 mL) and the reaction system was purged with nitrogen. Sodium hydride (1.32 g, 33 mmol) was added, and the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.1 g, 3.3 mmol) was added, and the reaction solution was stirred at 60 °C overnight. The reaction solution was cooled to room temperature. Water (200 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate: 50 / 1 to 3 / 1) to obtain (3R,5R,8R,9R,10S,13S,14S,15S,E)-15-cyclopropyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.67 g, yield: 59%). 1H NMR (400 MHz, CDCl3) δ 5.15-5.09 (m, 1H), 2.45-2.38 (m, 1H), 2.38-2.18 (m, 2H), 1.90-1.07 (m, 28H), 0.86-0.78 (m, 1H), 0.56-0.50 (m, 1H), 0.38-0.32 (m, 1H), 0.12-0.02 (m, 2H).

[0284] Step 3: (3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-17-((R)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0285] [ka]

[0286] (3R,5R,8R,9R,10S,13S,14S,15S,E)-15-Cyclopropyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.67 g, 1.96 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The solution was cooled to 0 °C, and then BH3 / THF (9.8 mL, 9.8 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC indicated the reaction was complete. After cooling the reaction solution to 0 °C, 3M aqueous NaOH (10 mL) was slowly added, followed by 30% hydrogen peroxide (8 mL). The reaction solution was stirred at room temperature for 2 hours, and TLC indicated the reaction was complete. Ethyl acetate (50 mL) was added, and the reaction solution was washed successively with saturated aqueous Na2S2O3 (30 mL) and water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product (0.71 g) which was used directly in the next step.

[0287] Step 4: 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0288] [ka]

[0289] (3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-Cyclopropyl-17-((R)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.71 g, crude) was dissolved in dichloromethane (20 mL). Pyridinium chlorochromate (1.27 g, 5.88 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and the organic phase was concentrated. The obtained crude product was purified by column chromatography (petroleum ether / ethyl acetate: 1 / 1) to give 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (480 mg, two-step yield: 68.3%). 1 H NMR (400 MHz, CDCl3) δ 2.45-2.40 (m, 1H), 2.18-2.10 (m, 4H), 1.99-1.03 (m, 24H), 0.84-0.79 (m, 4H), 0.60-0.53 (m, 1H), 0.43-0.38 (m, 1H), 0.14-0.02 (m, 2H).

[0290] Step 5: 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0291] [ka]

[0292] 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (107 mg, 0.3 mmol) was dissolved in methanol (5 mL). One drop of hydrogen bromide was added to the solution, followed by liquid bromine (56 mg, 0.35 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (120 mg, crude), which was used directly in the next step.

[0293] Step 6: 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0294] [ka]

[0295] 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (60 mg, 0.14 mmol), 1H-pyrazole-4-carbonitrile (28 mg, 0.3 mmol), and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The obtained crude product was purified by high performance liquid chromatography to obtain 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (31 mg, yield: 49%). MS m / z (ESI): 450.3 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.92 (d, J = 16.0 Hz, 1H), 2.51-2.47 (m, 1H), 2.09-1.71 (m, 9H), 1.48-1.10 (m, 16H), 0.90 (s, 3H), 0.83-0.79 (m, 1H), 0.62-0.58 (m, 1H), 0.45-0.40 (m, 1H), 0.14-0.11 (m, 1H), 0.05-0.02 (m, 1H).

[0296] Example 49 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0297] [ka]

[0298] Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0299] [ka]

[0300] According to Example 3, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (20 mg, 20% yield). MS m / z (ESI): 432.2 [M-HO +H] + 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 4.98 (dd, J = 40.0, 17.8 Hz, 2H), 2.52 - 2.45 (m, 1H), 2.24 - 2.13 (m, 1H), 2.11 - 2.03 (m, 1H), 2.04 - 1.95 (m, 2H), 1.90 - 1.82 (m, 2H), 1.75 - 1.66 (m, 2H), 1.54 - 1.23 (m, 16H), 1.18 - 1.05 (m, 2H), 0.93 - 0.79 (m, 4H), 0.63 - 0.55 (m, 1H), 0.45 - 0.37 (m, 1H), 0.18 - 0.09 (m, 1H), 0.08 - 0.01 (m, 1H).

[0301] Examples 50 and 51 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (50) 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (51)

[0302] [ka]

[0303] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one and 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

[0304] [ka]

[0305] According to Example 3, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (7.6 mg, yield: 7.8%) and 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (11.6 mg, yield: 11.9%) were obtained. Example 50: MS m / z (ESI): 408.3 [M-HO + H] + 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.24 (s, 2H), 2.49 - 2.42 (m, 1H), 2.23 - 2.14 (m, 1H), 2.10 - 1.94 (m, 3H), 1.91 - 1.81 (m, 3H), 1.75 - 1.66 (m, 2H), 1.48 - 1.24 (m, 15H), 1.17 - 1.04 (m, 2H), 0.94 (s, 3H), 0.86 - 0.76 (m, 1H), 0.63 - 0.54 (m, 1H), 0.45 - 0.38 (m, 1H), 0.14 - 0.01 (m, 2H). Example 51: MS m / z (ESI): 426.3[M +H] + 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.67 (s, 1H), 5.22 (dd, J = 47.1, 17.8 Hz, 2H), 2.59 - 2.50 (m, 1H), 2.25 - 2.15 (m, 1H), 2.14 - 1.98 (m, 2H), 1.96 - 1.79 (m, 3H), 1.76 - 1.58 (m, 6H), 1.56 - 1.25 (m, 12H), 1.22 - 1.04 (m, 2H), 0.91 (s, 3H), 0.87 - 0.77 (m, 1H), 0.62 - 0.55 (m, 1H), 0.47 - 0.36 (m, 1H), 0.18 - 0.02 (m, 2H).

[0306] Example 52 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0307] [ka]

[0308] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0309] [ka]

[0310] According to Example 3, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (8.5 mg, yield: 9%). MS m / z (ESI): 441.3[M +H] + 1 H NMR (400 MHz, CDCl3) δ 5.36 (s, 2H), 2.57 (s, 3H), 2.54 - 2.47 (m, 1H), 2.25 - 2.15 (m, 1H), 2.13 - 1.95 (m, 3H), 1.92 - 1.79 (m, 3H), 1.77 - 1.66 (m, 2H), 1.50 - 1.24 (m, 15H), 1.18 - 1.05 (m, 2H), 0.94 (s, 3H), 0.87 - 0.78 (m, 1H), 0.63 - 0.55 (m, 1H), 0.45 - 0.37 (m, 1H), 0.17 - 0.02 (m, 2H).

[0311] Example 59 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0312] [ka]

[0313] Step 1: (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

[0314] [ka]

[0315] Tetrahydrofuran (15 mL) was added to a 100 mL three-neck flask, and then ethylmagnesium bromide (10 mL, 1 M, 10 mmol) was added at 0 °C under a nitrogen atmosphere, followed by cuprous iodide (1.6 g, 8.4 mmol). The reaction solution was stirred at 0 °C for 1 hour. (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (800 mg, 2.8 mmol) was dissolved in tetrahydrofuran (5 mL), and the resulting solution was slowly added dropwise to the reaction solution, followed by stirring at 0 °C for 4 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, and the reaction solution was extracted with ethyl acetate (20 mL). The organic phase was washed with water and brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness by rotary evaporation. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to give (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (750 mg, yield: 84.9%). 1 H NMR (400 MHz, CDCl3) δ 2.37 - 2.30 (m, 1H), 2.15 - 2.02 (m, 2H), 1.91 - 1.31 (m, 17H), 1.27 (s, 3H), 1.24 - 1.03 (m, 4H), 0.98 (s, 3H), 0.90 (t, J = 7.3 Hz, 3H).

[0316] Step 2: (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0317] [ka]

[0318] Dimethyl sulfoxide (20 mL) was added to a 100 mL three-neck flask, followed by the addition of ethyltriphenylphosphonium bromide (8.7 g, 23.5 mmol) under a nitrogen atmosphere. Sodium hydride (60%) (940 mg, 23.5 mmol) was added in batches, and the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (750 mg, 2.35 mmol) was dissolved in dimethyl sulfoxide (5 mL), and the resulting solution was slowly added dropwise to the reaction solution. The mixture was then stirred at 80°C under a nitrogen atmosphere for 5 hours. The reaction solution was cooled to room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution, and the reaction solution was extracted with ethyl acetate (50 mL). The organic phase was washed with water and brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness by rotary evaporation. The crude product was purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to give (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (580 mg, yield: 71.7%). 1 H NMR (400 MHz, CDCl3) δ 5.22 - 5.06 (m, 1H), 2.54 - 2.39 (m, 1H), 2.28 - 2.09 (m, 2H), 1.96 - 1.80 (m, 4H), 1.78 - 1.59 (m, 6H), 1.55 - 1.33 (m, 11H), 1.26 (s, 3H), 1.20 - 1.08 (m, 3H), 1.05 (s, 3H), 0.82 (t, J = 7.3 Hz, 3H).

[0319] Step 3: (3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

[0320] [ka]

[0321] According to step 3 of Example 71, (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol was used as the starting material, thus obtaining (3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (600 mg, yield: 98.1%).

[0322] Step 4: 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0323] [ka]

[0324] According to step 4 of Example 71, (3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, yield: 83.8%). 1H NMR (400 MHz, CDCl3) δ 2.51 (t, J = 8.0 Hz, 1H), 2.12 (s, 3H), 2.00 - 1.30 (m, 20H), 1.28 (s, 3H), 1.25 - 1.00 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H), 0.73 (s, 3H).

[0325] Step 5: 2-Bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0326] [ka]

[0327] According to step 5 of Example 71, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, yield: 81.4%).

[0328] Step 6: 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0329] [ka]

[0330] According to step 6 of Example 71, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (24 mg, yield: 38.8%). MS m / z (ESI): 438.2[M+H]+. 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.08 - 4.78 (m, 2H), 2.58 (t, J = 8.0 Hz, 1H), 2.07 - 1.29 (m, 20H), 1.28 (s, 3H), 1.27 - 1.06 (m, 4H), 0.85 (t, J = 7.3 Hz, 3H), 0.79 (s, 3H).

[0331] Example 68 2-(4-chloro-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0332] [ka]

[0333] Step 1: Preparation of 2-(4-chloro-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0334] [ka]

[0335] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 2-(4-chloro-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (10 mg, yield: 14%). MS m / z (ESI): 433.3[M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.41 (s, 1H), 4.86 (q, J = 17.9 Hz, 2H), 2.61 - 2.44 (m, 1H), 2.30 - 2.07 (m, 2H), 2.02 - 1.91 (m, 1H), 1.86 - 1.80 (m, 4H), 1.76 - 1.57 (m, 4H), 1.51 - 1.38 (m, 6H), 1.37 - 1.20 (m, 6H), 1.20 - 1.03 (m, 2H), 0.98 (d, J = 7.1 Hz, 3H), 0.83 (s, 3H).

[0336] Example 69 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

[0337] [ka]

[0338] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-methylpyrazole were used as starting materials, thus obtaining 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one (12.6 mg, white solid, yield: 15.7%). MS m / z (ESI): 411.3[M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.26 (s, 1H), 5.23( m, 2H), 2.83 (d, J = 4.4 Hz, 1H), 2.13 (s, 3H), 1.98-1.85 (m, 2H), 1.83-1.69 (m, 9H), 1.60-1.56 (m, 1H), 1.40-1.27 (m, 12H), 1.09-1.01 (m, 2H), 0.80 (s, 3H), 0.48-0.45 (m, 1H).

[0339] Example 70 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-imidazol-1-yl)ethan-1-one

[0340] [ka]

[0341] According to Example 63, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)ethan-1-one and imidazole were used as starting materials, thus obtaining 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-yl)-2-(1H-imidazol-1-yl)ethan-1-one (23.3 mg, white solid, yield: 34.4%). MS m / z (ESI): 397.2[M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.12 (s, 1H), 6.88 (s, 1H), 4.98-4.87 (m, 2H), 2.82 (d, J = 2.8 Hz, 1H), 1.94-1.91(m, 1H), 1.85-1.81( m, 4H), 1.70-1.53 (m, 10H), 1.41-1.28 (m, 9H), 1.13-0.95 (m, 2H), 0.78 (s, 3H), 0.52-0.46 (m, 1H).

[0342] Example 71 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one

[0343] [ka]

[0344] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 5-methyl-1H-4-tetrazole were used as starting materials, thus 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethan-1-one (19 mg, white solid, yield: 23.5%) was obtained. MS m / z (ESI): 413.2[M+H] + 1 H NMR (400 MHz, CDCl3) δ 5.58 (dd, J1= 17.6 Hz, J2= 7.6 Hz, 2H), 2.86 (d, J = 4.0 Hz, 1H), 2.57 (s, 3H), 1.96-1.93 (m, 1H), 1.89-1.61 (m, 8H), 1.55-1.22 (m, 14H), 1.14-0.97 (m, 3H), 0.84 (s, 3H), 0.47-0.53 (m, 1H).

[0345] Example 72 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one

[0346] [ka]

[0347] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and azetidin-1-yl(1H-pyrazol-4-yl)methanone were used as starting materials, but As a result, 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (10.0 mg, yield: 14.3%) was obtained. MS m / z (ESI): 480.3 [M+H] + 1H NMR (400 MHz, CDCl3) δ 7.85 - 7.80 (m, 1H), 7.80 - 7.74 (m, 1H), 5.20 - 5.05 (m, 2H), 4.53 - 4.10 (m, 4H), 2.82 (d, J = 3.3 Hz, 1H), 2.44 - 2.31 (m, 2H), 1.98 - 1.90 (m, 1H), 1.86 - 1.79 (m, 3H), 1.74 - 1.64 (m, 3H), 1.57 - 1.53 (m, 2H), 1.44 - 1.24 (m, 15H), 1.13 - 0.97 (m, 2H), 0.79 (s, 3H), 0.51 - 0.44 (m, 1H).

[0348] Example 73 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-nitro-1H-pyrazol-1-yl)ethan-1-one

[0349] [ka]

[0350] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-nitro-1H-pyrazole were used as starting materials, thus obtaining 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-nitro-1H-pyrazol-1-yl)ethan-1-one (32.5 mg, yield: 60%). MS m / z (ESI): 424.2 [M+H-HO] + 1 H NMR (400 MHz, CDCl3) δ8.20 (s, 1H), 8.09 (s, 1H), 5.26 - 5.09 (m, 2H), 2.85 (s, 1H), 1.98 - 1.91 (m, 1H), 1.87 - 1.79 (m, 4H), 1.74 - 1.65 (m, 3H), 1.56 - 1.52 (m, 2H), 1.47 - 1.35 (m, 7H), 1.34 - 1.24 (m, 7H), 1.13 - 0.97 (m, 2H), 0.79 (s, 3H), 0.55 - 0.47 (m, 1H).

[0351] Example 80 3-Cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0352] [ka]

[0353] Step 1: Preparation of 3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0354] [ka]

[0355] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, thus obtaining 3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (19.2 mg, yield: 21%). MS m / z (ESI): 462.3 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 5.13 - 4.95 (m, 2H), 2.80 (d, J = 2.2 Hz, 1H), 2.04 - 1.89 (m, 2H), 1.86 - 1.79 (m, 3H), 1.76 - 1.63 (m, 3H), 1.58 - 1.49 (m, 3H), 1.46 - 1.21 (m, 14H), 1.12 - 0.93 (m, 6H), 0.76 (s, 3H), 0.51 - 0.43 (m, 1H).

[0356] Example 81 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one

[0357] [ka]

[0358] Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one

[0359] [ka]

[0360] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, thus obtaining 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (8.7 mg, yield: 16%). MS m / z (ESI): 443.2 [M+H] + 1 H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.45 (s, 1H), 5.17 - 5.00 (m, 2H), 2.81 (d, J = 3.8 Hz, 1H), 2.35 (s, 3H), 1.99 - 1.91 (m, 1H), 1.88 - 1.76 (m, 4H), 1.73 - 1.63 (m, 3H), 1.55 - 1.50 (m, 1H), 1.43 - 1.18 (m, 15H), 1.12 - 0.97 (m, 2H), 0.79 (s, 3H), 0.50 - 0.41 (m, 1H).

[0361] Examples 82 and 83 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one (82) 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one (83)

[0362] [ka]

[0363] Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one

[0364] [ka]

[0365] 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (80 mg, 0.18 mmol) was dissolved in dichloromethane (10 mL) and the solution was cooled to −78 °C. m-Chloroperoxybenzoic acid (55 mg, 0.27 mmol) was added and the reaction solution was stirred for 1 h. Water (10 mL) was added, and the reaction solution was then washed with saturated aqueous sodium bicarbonate (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness by rotary evaporation. The obtained crude product was purified by high performance liquid chromatography to obtain 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one (1 7.2 mg, yield: 20%) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one (20.4 mg, yield: 25%) were obtained. Example 82: MS m / z (ESI): 441.3 [M-HO+H] + 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.83 (s, 1H), 5.30 - 5.09 (m, 2H), 2.91 (s, 3H), 2.85 - 2.82 (m, 1H), 1.98 - 1.90 (m, 1H), 1.87 - 1.78 (m, 3H), 1.75 - 1.50 (m, 8H), 1.47 - 1.21 (m, 12H), 1.13 - 0.96 (m, 2H), 0.79 (s, 3H), 0.54 - 0.45 (m, 1H). Example 83: MS m / z (ESI): 457.2 [M-HO+H] + 1 H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.87 (s, 1H), 5.26 - 5.10 (m, 2H), 3.14 (s, 3H), 2.85 (d, J = 2.7 Hz, 1H), 1.98 - 1.91 (m, 1H), 1.87 - 1.79 (m, 3H), 1.76 - 1.64 (m, 3H), 1.59 - 1.52 (m, 1H), 1.50 - 1.18 (m, 16H), 1.15 - 0.96 (m, 2H), 0.79 (s, 3H), 0.55 - 0.46 (m, 1H).

[0366] Example 84 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0367] [ka]

[0368] Step 1: Preparation of 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0369] [ka]

[0370] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, thus obtaining 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (18.0 mg, yield: 31.8%). MS m / z (ESI): 429.2 [M-HO+H] + 1 H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 5.38 (q, J = 18.0 Hz, 2H), 2.87 (d, J = 3.0 Hz, 1H), 1.97 - 1.91 (m, 1H), 1.88 - 1.75 (m, 4H), 1.76 - 1.64 (m, 3H), 1.58 - 1.51 (m, 1H), 1.48 - 1.26 (m, 15H), 1.15 - 0.99 (m, 2H), 0.83 (s, 3H), 0.58 - 0.48 (m, 1H).

[0371] Example 85 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one

[0372] [ka]

[0373] Step 1: Preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one

[0374] [ka]

[0375] According to Example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one was used as the starting material, thus obtaining 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one (16.0 mg, yield: 14%). MS m / z (ESI): 464.3 [M +H] + 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 7.13 (s, 1H), 5.27 - 5.13 (m, 2H), 2.85 (d, J = 4.0 Hz, 1H), 2.01 - 1.93 (m, 1H), 1.87 - 1.65 (m, 11H), 1.58 - 1.50 (m, 1H), 1.44 - 1.22 (m, 11H), 1.14 - 0.98 (m, 2H), 0.81 (s, 3H), 0.53 - 0.44 (m, 1H).

[0376] Example 86 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trifluorohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0377] [ka]

[0378] Step 1: 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trifluorohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0379] [ka]

[0380] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trifluorohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (20.5 mg, yield: 30.1%). MS m / z (ESI): 467.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.49 - 7.43 (m, 1H), 6.59 (d, J = 2.4 Hz, 1H), 5.14 - 4.85 (m, 2H), 2.54 (t, J = 8.1 Hz, 1H), 2.26 - 2.08 (m, 2H), 2.02 - 1.93 (m, 1H), 1.90 - 1.79 (m, 4H), 1.74 -1.59 (m, 3H), 1.57 - 1.19 (m, 14H), 1.21 - 1.04 (m, 1H), 0.98 (d, J = 7.0 Hz, 3H), 0.84 (s, 3H).

[0381] Example 87 2-(4-(Azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0382] [ka]

[0383] Step 1: Preparation of 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

[0384] [ka]

[0385] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (12.0 mg, yield: 21%). MS m / z (ESI): 482.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 2H), 5.00 - 4.77 (m, 2H), 4.38-4.25 (m, 4H), 2.54 (t, J = 7.6 Hz, 1H), 2.43 - 2.32 (m, 2H), 2.26 - 2.08 (m, 2H), 1.98-1.96 (m, 1H), 1.88-1.83 (m, 3H), 1.69-1.62(m, 5H), 1.48-1.42 (m, 4H), 1.38-1.26 (m, 9H), 1.16-1.07 (m, 2H), 0.98 (d, J = 7.0 Hz, 3H), 0.84 (s, 3H).

[0386] Example 88 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0387] [ka]

[0388] Step 1: Preparation of 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0389] [ka]

[0390] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining the product 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (37 mg, yield: 55.3%). MS m / z (ESI): 456.2[MH]-. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 5.03 - 4.75 (m, 2H), 2.54 (t, J = 8.0 Hz, 1H), 2.31 - 2.13 (m, 2H), 1.93 - 1.06 (m, 23H), 0.99 (d, J = 7.1 Hz, 3H), 0.83 (s, 3H).

[0391] Example 89 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0392] [ka]

[0393] Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0394] [ka]

[0395] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining the product 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (18 mg, yield 27.5%). MS m / z (ESI): 447.2[MH] - . 1 H NMR (400 MHz, CDCl3) δ7.20 (s, 1H), 5.23 - 5.07 (m, 2H), 2.68 - 2.52 (m, 1H), 2.28 - 1.36 (m, 21H), 1.28 (s, 3H), 1.18 - 1.08 (m, 1H), 1.00 (d, J = 6.9 Hz, 3H), 0.88 (s, 3H).

[0396] Example 90 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0397] [ka]

[0398] Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

[0399] [ka]

[0400] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining the product 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (16 mg, yield: 25.9%). MS m / z (ESI): 438.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 2.5 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.22 - 4.78 (m, 2H), 2.57 (t, J = 8.0 Hz, 1H), 2.15 - 1.30 (m, 20H), 1.28 (s, 3H), 1.16 - 1.03 (m, 4H), 0.84 (t, J= 7.3 Hz, 3H), 0.79 (s, 3H).

[0401] Example 91 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0402] [ka]

[0403] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0404] [ka]

[0405] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining the product 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (23 mg, yield: 33.9%). MS m / z (ESI): 481.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J =4.0Hz, 1H), 6.59 (d, J = 4.0 Hz 1H), 5.07 - 4.89 (m, 2H), 2.56 (t, J = 9.3 Hz, 1H), 2.20 - 1.29 (m, 20H),1.28 (s, 3H), 1.27 - 1.03 (m, 4H),0.84 (t, J = 7.3 Hz, 3H), 0.80 (s, 3H).

[0406] Example 92 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0407] [ka]

[0408] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one

[0409] [ka]

[0410] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining the product 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (13.5 mg, yield: 22.3%). MS m / z (ESI): 429.3[M+H] + . 1H NMR (400 MHz, CDCl3) δ 5.39 - 5.29 (m, 2H), 2.63 - 2.57 (m, 1H), 2.56 (s, 3H), 2.10 - 1.30 (m, 20H), 1.28 (s, 3H), 1.27 - 1.05 (m, 4H), 0.87 - 0.81 (m, 6H).

[0411] Examples 93 and 94 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (93) 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (94)

[0412] [ka]

[0413] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one

[0414] [ka]

[0415] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, and thus the product 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was obtained. 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (17 mg, yield: 29.1%) and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (9.2 mg, yield: 15.7%) were obtained. Example 93: MS m / z (ESI): 414.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.67 (s, 1H), 5.37 - 5.09 (m, 2H), 2.62 (t, J = 9.2 Hz, 1H), 2.28 - 1.20 (m, 25H), 1.16 - 1.05 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H), 0.80 (s, 3H). Example 94: MS m / z (ESI): 414.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.28 - 5.20 (m, 2H), 2.54 (t, J = 8.0 Hz, 1H), 1.99 - 1.23 (m, 25H), 1.13 - 1.06 (m, 2H), 0.88 - 0.78 (m, 6H).

[0416] Example 95 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0417] [ka]

[0418] Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0419] [ka]

[0420] According to Example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining the product 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (5 mg, yield: 9.2%). MS m / z (ESI): 463.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 5.29 - 5.02 (m, 2H), 2.61 (t, J = 9.3 Hz, 1H), 2.24 - 1.34 (m, 19H), 1.28 (s, 3H), 1.26 - 1.02 (m, 5H), 0.92 - 0.76 (m, 6H).

[0421] Example 96 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0422] [ka]

[0423] Step 1: Preparation of 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile

[0424] [ka]

[0425] According to Example 3, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (19.6 mg, yield: 18%). MS m / z (ESI): 473.2[M- H] - 1 H NMR (400 MHz, CDCl3) δ 7.20 (s, 1H), 5.24 - 5.09 (m, 2H), 2.58 - 2.50 (m, 1H), 2.26 - 2.07 (m, 2H), 2.06 - 1.95 (m, 2H), 1.90 - 1.80 (m, 2H), 1.78 - 1.66 (m, 2H), 1.58 - 1.22 (m, 16H), 1.19 - 1.06 (m, 2H), 0.94 (s, 3H), 0.87 - 0.78 (m, 1H), 0.64 - 0.56 (m, 1H), 0.45 - 0.39 (m, 1H), 0.18 - 0.02 (m, 2H).

[0426] Example 97 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0427] [ka]

[0428] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

[0429] [ka]

[0430] According to Example 3, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (18.0 mg, yield: 23%). MS m / z (ESI): 491.3[M- H] - 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 2.0 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 5.08 - 4.90 (m, 2H), 2.53 - 2.42 (m, 1H), 2.24 - 1.94 (m, 4H), 1.91 - 1.79 (m, 3H), 1.78 - 1.66 (m, 2H), 1.52 - 1.22 (m, 15H), 1.18 - 1.02 (m, 2H), 0.91 (s, 3H), 0.88 - 0.76 (m, 1H), 0.65 - 0.54 (m, 1H), 0.48 - 0.36 (m, 1H), 0.18 - 0.00 (m, 2H).

[0431] Example 98 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0432] [ka]

[0433] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0434] [ka]

[0435] According to Example 3, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (12.9 mg, yield: 13.2%). MS m / z (ESI): 409.3 [M-HO+ H] + 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 5.46 (s, 2H), 2.58 - 2.47 (m, 1H), 2.24 - 1.94 (m, 4H), 1.93 - 1.80 (m, 3H), 1.77 - 1.66 (m, 2H), 1.50 - 1.21 (m, 15H), 1.18 - 1.06 (m, 2H), 0.95 (s, 3H), 0.87 - 0.78 (m, 1H), 0.64 - 0.55 (m, 1H), 0.46 - 0.38 (m, 1H), 0.17 - 0.01 (m, 2H).

[0436] Example 99 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0437] [ka]

[0438] Step 1: Preparation of 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

[0439] [ka]

[0440] According to Example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (13.5 mg, yield: 17.4%). MS m / z (ESI): 482.2[M- H] - 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 5.01 - 4.76 (m, 2H), 2.55 - 2.41 (m, 1H), 2.22 - 1.94 (m, 4H), 1.91 - 1.77 (m, 3H), 1.76 - 1.66 (m, 2H), 1.56 - 1.24 (m, 15H), 1.18 - 1.04 (m, 2H), 0.90 (s, 3H), 0.87 - 0.75 (m, 1H), 0.64 - 0.53 (m, 1H), 0.46 - 0.38 (m, 1H), 0.17 - 0.02 (m, 2H).

[0441] Example 100 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0442] [ka]

[0443] Step 1: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one

[0444] [ka]

[0445] According to Example 3, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one was used as the starting material, thus obtaining the product 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (11 mg, white solid, yield: 18.8%). MS m / z (ESI): 397.2 [M-HO+H] + 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 5.50 - 5.41 (m, 2H), 2.62 (t, J = 8.5 Hz, 1H), 2.29 - 1.30 (m, 20H), 1.28 (s, 3H), 1.27 - 1.05 (m, 4H), 0.85 - 0.82 (m, 6H).

[0446] (Example 103) (3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-Hydroxy-3,13-dimethyl-17-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile

[0447] [ka]

[0448] Step 1: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-bromoacetyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile

[0449] [ka]

[0450] (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (120 mg, 0.349 mmol) was dissolved in methanol (3 mL). Liquid bromine (83 mg, 0.524 mmol) and hydrogen bromide drops were added, and the reaction solution was stirred at room temperature for 5 hours. Water (30 mL) was added, and the reaction solution was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-bromoacetyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (140 mg, crude product).

[0451] Step 2: Preparation of (3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-hydroxy-3,13-dimethyl-17-(2-(4-(trifluoromethyl)-1H-pyrazol)-1-yl)acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile

[0452] [ka]

[0453] A mixture of (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-bromoacetyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (100 mg, 0.23 mmol), 4-(trifluoromethyl)-1H-pyrazole (63 mg, 0.46 mmol), potassium carbonate (95 mg, 0.69 mmol), and tetrahydrofuran (5 mL) was stirred at room temperature for 16 hours. After adding water (20 mL), the reaction mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure, and the resulting crude product was purified by high-performance liquid chromatography to give (3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-hydroxy-3,13-dimethyl-17-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (25 mg, yield: 23%). MS m / z (ESI): 478.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.74 (s, 1H), 5.01 (dd, J = 77.6, 18.0 Hz, 2H), 3.65 - 3.36 (m, 1H), 2.96 (d, J = 8.7 Hz, 1H), 2.18 - 2.04 (m, 2H), 1.89 - 1.71 (m, 5H), 1.69-1.60 (m, 5H), 1.46-1.39 (m, 5H), 1.32-1.25 (m, 5H), 1.24 - 1.03 (m, 3H), 0.65 (s, 3H).

[0454] Biological Assays and Evaluation of Compounds The present invention is further described below in conjunction with the following test examples, which are not intended to limit the scope of the invention.

[0455] 1. GABA of the Compounds of the Present Invention A Receptor binding assay 1.1 Experimental Objective: The objective of this example is to measure the ability of compounds to allosterically inhibit the binding of an ion channel blocker (tert-butylbicyclophosphorothionate (TBPS)) to GABA-A receptors.

[0456] [Table 8]

[0457] 1.2 Experimental Procedure 1.2.1 Extraction of cerebral cortex cell membranes: 1. The cerebral cortex was isolated from male Sprague-Dawley rats. 2. Pre-chilled 0.32 M sucrose solution (containing one protease inhibitor tablet per 100 mL) was added to the cerebral cortices (the volume of the sucrose solution was 10 times the volume of the cerebral cortices). The mixture was pulverized in batches using a 50 mL glass tissue homogenizer and mixed thoroughly. 3. The mixture was centrifuged at 1,500 g and 4°C for 10 minutes, and the supernatant was collected. 4. The mixture was centrifuged at 20,000 g for 30 minutes at 4°C, and the supernatant was discarded. 5. The pellet was resuspended in pre-chilled phosphate buffered saline (PBS) (one protease inhibitor tablet per 100 mL). An average of 4 mL of PBS was added per rat, and the mixture was thoroughly mixed using a glass tissue homogenizer. 6. The mixture was centrifuged at 10,000 g for 10 minutes at 4°C, and the supernatant was discarded. 7. Steps 5 and 6 were repeated three times. 8. Finally, the precipitate was resuspended in four volumes of PBS. The resulting solution was aliquoted, frozen in liquid nitrogen, and stored at -80°C. 9. Protein concentration was measured by the bicinchoninic acid (BCA) method.

[0458] 1.2.2 35S-TBPS binding assay 1. 230 μL of PBS was added to each well of a 1.1 mL volume well plate. 2. 60 μL of cerebral cortical cell membrane (5 μg / μL) solution was added to each well, and the mixture was mixed well. 3. Test compound (3 μL per well) was added and the plate was incubated at 25° C. for 5 minutes. DMSO concentration was 1%. The initial compound concentration was 1 μM, and 3-fold dilutions were performed in the gradient, resulting in a total of 8 gradients and 2 replicates. 1% DMSO was used as a negative control, and 10 μM P026-2 was used as a positive control. 4. GABA was added to a final concentration of 5 μM and incubated for 5 minutes at 25° C. A 1 mM GABA solution was formulated and 1.5 μL of the solution was added to each well. 5. 35S-TBPS was added to a final concentration of 2 nM. The concentration of the isotope stock solution was 9.7 μM. After diluting 100 times with PBS, 6 μL of the diluted isotope solution was added to each well. 6. The plates were incubated at 4°C for 20 hours. 7. FilterMate GF / C plates were pretreated with 0.5% PEI and incubated at 4°C for 1 hour. 8. The FilterMate GF / C plates were washed twice with 50 mL PBS in the Universal Harvester. 9. The reaction solution was transferred to a GF / C plate, and each well was washed four times with 900 μL of PBS. 10. The washed GF / C plates were placed at 55°C and allowed to dry for 10 minutes. 11. 40 μL of scintillation fluid was added to each well and the CPM values were read on a TopCount.

[0459] 1.2.3 Experimental data processing method: In the experiment, the CPM (counts per minute) values were read on a TopCount. According to the measurements of the high control (DMSO) and low control (10 μM positive compound) experimental groups, the % inhibition was calculated based on the following formula: % Inhibition = 100 × (CPM 高対照 -CPM 試料 ) / (CPM 高対照 -CPM 低対照 ) Compound IC 50 was calculated according to the following four-parameter nonlinear logistic formula: Y=Lower limit+(Upper limit-Lower limit) / (1+10^((LogIC50-X)*Hill slope)), During the ceremony, X represents the logarithm of the compound concentration, Y represents % inhibition.

[0460] The effect of the compounds of the present invention on TBPS binding activity was determined by the above test and the measured IC 50 The values are shown in Table 5.

[0461] [Table 9]

[0462] Conclusion The compounds of the examples of the present invention have significant inhibitory effects on TBPS binding activity.

[0463] 2. Pharmacokinetic assay in Balb / C mice 2.1 Test Objective: Balb / C mice were used as test animals. The compounds of Examples 1-4, 7, 9, 39-41, 44, 48-52, 59, 73, 88-91, 93-94, 96 and 98 were orally administered at a dose of 5 mg / kg to study the pharmacokinetic behavior in mice (plasma and brain tissue).

[0464] 2.2 Test Scheme 2.2.1 Test Compounds: The compounds of Examples 1-4, 7, 9, 39-41, 44, 48-52, 59, 73, 88-90, 93-94, 96 and 98 of the present invention prepared by the applicant.

[0465] 2.2.2 Test animals: Male Balb / C mice were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD with certificate number: SCXK (Shanghai) 2013-0006 No. 311620400001794.

[0466] 2.2.3 Administration Each group contained 24 male Balb / C mice. After overnight fasting, Balb / C mice were administered po with test compounds at a dose of 5 mg / kg and a volume of 10 mL / kg.

[0467] 2.2.4 Sample Collection: 0.2 ml of blood was collected from the heart before administration and at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The samples were stored in EDTA-K2 tubes and centrifuged at 6000 rpm for 6 minutes at 4°C to separate the plasma. Plasma samples were stored at -80°C. Mice were sacrificed with CO2, and whole brain tissue was removed, weighed, placed in 2 mL centrifuge tubes, and stored at -80°C.

[0468] 2.2.5 Sample Process: 1) After precipitation by adding 160 μL of acetonitrile to 40 μL of plasma sample, the mixture was centrifuged at 3500 × g for 5–20 min. 2) 90 μL of acetonitrile containing an internal standard (100 ng / mL) was added to 30 μL of plasma and brain homogenate samples to precipitate, and the mixture was then centrifuged at 13,000 rpm for 8 minutes. 3) 70 μL of the treated supernatant was taken and added to 70 μL of water, and mixed by vortexing for 10 minutes. 20 μL of the mixture was taken and analyzed for the concentration of the test compound by LC / MS / MS. LC / MS / MS analysis equipment: AB Sciex API 4000 Qtrap.

[0469] 2.2.6 Liquid Chromatography Analysis Liquid chromatography conditions: Shimadzu LC-20AD pump Chromatography column: Agilent ZORBAX XDB-C18 (50 x 2.1 mm, 3.5 μm) Mobile phase: Eluent A was 0.1% formic acid in water, and Eluent B was acetonitrile. ·Flow rate: 0.4mL / min Elution time: 0 to 4.0 minutes, eluent:

[0470] [Table 10]

[0471] 2.3. Test Results and Analysis The main pharmacokinetic parameters were calculated by WinNonlin 6.1. The results of the pharmacokinetic experiments in mice are shown in Table 6 below:

[0472] [Table 11A]

[0473] [Table 11B]

[0474] From the results of the pharmacokinetic experiments in mice shown in the table, the compounds of the examples of the present invention exhibited good metabolic properties, and the exposure AUC and maximum blood drug concentration C max It can be seen that both of these compounds performed well. Compared with the existing compound SAGE-217, the compounds of the present invention can significantly increase exposure in mice, but the maximum tolerated dose is equal to or greater than that of SAGE-217. Therefore, the compounds of the present invention have good tolerance, a wide safety window, and high safety.

[0475] 3. In vivo pharmacodynamic experiments in the forced swimming model in mice 3.1 Experimental Objectives: The antidepressant effects of the compounds were evaluated by the forced swimming model in mice.

[0476] 3.2 Main equipment and reagents for the experiment 3.2.1 Equipment Forced swimming device (LBehv-FSC-4, Shanghai Jiliang Software Technology Co., Ltd.).

[0477] 3.2.2 Reagents Sodium carboxymethylcellulose (CMC-Na, SLBV9664, Sigma) Tween 80 (BCBV8843, Sigma)

[0478] 3.2.3 Test Compounds The compounds of Examples 1 to 3, Example 9, Example 40, Example 41, Examples 48 to 52, Example 90 and Example 98 of the present invention prepared by the applicant.

[0479] 3.3 Experimental procedure 3.3.1 Adaptation: Male ICR mice (25–35 g) were adapted to the experimental environment for 3 days before the forced swimming test.

[0480] 3.3.2 Grouping and Management: According to the experimental design, mice are randomly divided into groups according to body weight on the day before the experiment, and each group contains 12 mice.Before the test, each example compound is intragastrically administered according to its Tmax in the brain in the pharmacokinetics experiment of mice.

[0481] each: 1) Model group (0.5% CMC-Na-1% Tween 80 solution, oral, 10 mL / kg); 2) Compounds of Examples 1 to 3, 40, 41, 48 to 51, 90 and 98 (10 mg / kg, po, 10 mL / kg); Example 9 and Example 52 (5 mg / kg, po, 5 mL / kg).

[0482] When administered, each example compound was suspended in 0.5% CMC-Na+1% Tween 80 solution to the desired concentration.

[0483] 3.3.2 Forced swim test: 0.5 to 1 hour after administration, ICR mice were placed in a forced swimming apparatus (a transparent glass drum (18 cm deep, 25-26°C water temperature, one mouse per tank) and forced to swim for 6 minutes. The swimming time of the ICR mice was recorded throughout the 6 minutes, and the data from the last 4 minutes were used for data analysis. Immediately after the swimming experiment, the mice were removed, wiped dry, and returned to their original cages.

[0484] NOTE: The criteria for immobility time is that the mouse does not struggle in the water, remains floating, and only small limbs move to keep the head above the water surface.

[0485] 3.4 Data analysis Float time percentage = 100 * Float time / 240 seconds.

[0486] 3.5 Test Data:

[0487] [Table 12]

[0488] 3.6 Experimental results From the above results, it is clear that the compounds of the Examples of the present application significantly shorten the cumulative immobility time of the forced swimming mice and have significant antidepressant effects.

[0489] The immobility time for the last 4 minutes of the compounds of Example 2, Example 40, Example 41, Example 49, Example 50, Example 90 and Example 98 was significantly different from that of the model group.

[0490] 4. In vivo pharmacodynamic testing in a PTZ-induced epilepsy model in mice 4.1 Test Objective: A PTZ-induced epilepsy model in CD-1 mice was established and used to evaluate the antiepileptic effects of the compounds of Example 2, Example 40, Example 41 and Example 52.

[0491] 4.2 Test Method 4.2.1 Test animals Fifty male CD-1 mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The test animals were adapted for 7 days prior to the experiment in the animal room of Building 3 of Shanghai ChemPartner Co., Ltd. The average weight of the animals on the day of the experiment was 32.2±0.2 grams. The breeding environment was 5 mice per cage, room temperature 23±2°C, 12 / 12 hour light / dark cycle, food and water available ad libitum. Mice were randomly assigned to groups on the day of the experiment.

[0492] 4.2.2 Test Compounds Compounds of Example 2, Example 40, Example 41 and Example 52 (prepared by the applicant) Test compounds were stored in a refrigerator at 4°C.

[0493] [Table 13]

[0494] 4.2.3 Test equipment 1ml sterile disposable syringe with needle (purchased from Zhejiang Kangdelai Medical Devices Co., Ltd.) Pipette: Eppendorf Research Plus (100-1000 μL) Vortex mixer: Kylin-Bell Vortex 5 Ultrasonic equipment: JL-360 ultrasonic cleaner Balance: METTLER TOLEDO XS204 precision balance Balance: METTLER TOLEDO XS6002S electronic balance Plexiglass box: 25cm long x 15cm wide x 15cm high, one side wall is opaque, custom-made by Suzhou Fengshi Laboratory Animal Equipment Co., Ltd. 3-Channel Timer: Oregon / Model No. WB-388

[0495] 4.2.4 Test Animal Grouping 1) Vehicle / PTZ: 0.5% CMC-Na+1% Tween-80 (10 ml / kg, po), administered 0.5 h before PTZ administration, PTZ (120 ml / kg, sc), administered before the experiment; 2) 3 mg / kg Example Compounds / PTZ: Compounds of Examples 2, 40, 41, and 52 (3 mg / kg, 10 ml / kg, po) were administered 0.5 hours before PTZ administration. PTZ (120 ml / kg, sc) was administered before the experiment.

[0496] 4.3 Experimental procedure 4.3.1 Solvent Blend 1) 0.5% CMC-NA + 1% Tween-80 (administration volume: 10 mL / kg): One gram of sodium carboxymethylcellulose was accurately weighed and added to a 250 mL solvent bottle, followed by 150 mL of double-distilled water. The mixture was stirred with a magnetic stirrer at room temperature for 4 hours to obtain a homogeneous, clear solution. 2 mL of Tween-80 was slowly added, and the mixture was stirred at room temperature for 3 hours to obtain a homogeneous, clear solution. The solution was slowly transferred to a 200 mL volumetric flask and double-distilled water was added to a constant volume of 200 mL. The solution was transferred to a 250 mL solvent bottle and stirred with a magnetic stirrer for 1 hour to obtain a homogeneous, clear solution. 2) 30% hydroxypropyl-β-cyclodextrin Accurately weigh 30.6122 g of hydroxypropyl-β-cyclodextrin (purity: 98%) into a 100 mL solvent bottle, then add 60 mL of double-distilled water. The mixture was vortexed for 3 minutes and sonicated at room temperature for 15 minutes to obtain a homogeneous, clear solution. Double-distilled water was added to a constant volume of 100 mL, vortexed for 1 minute, and sonicated at room temperature for 5 minutes to obtain a homogeneous, clear solution.

[0497] 4.3.2 Test Compound Formulation 1) 12 mg / mL PTZ (dose: 120 mg / kg, administration volume: 10 mL / kg): 248 mg of PTZ was accurately weighed into a 40 mL brown flask, followed by 20.667 mL of saline. The mixture was vortexed for 2 minutes and sonicated at room temperature for 2 minutes to obtain a homogeneous, clear solution (concentration: 12 mg / mL). 2) 0.3 mg / mL of the compound of Example 5 or Example 23 (dose: 3 mg / kg; administration volume: 10 mL / kg): A certain amount of 0.5% CMC-Na+1% Tween-80 was taken and added to a flask containing a certain amount of the compound of Example 5 or Example 23. The mixture was vortexed for 3 minutes and sonicated at room temperature for 15 minutes to obtain a uniform suspension (concentration: 0.3 mg / mL).

[0498] 4.3.3 Test method 1) The test animals were transferred to the operating room 1 hour before the test to allow them to adapt to the environment. 2) Animals were randomly grouped, marked, and weighed; 3) The compounds of Example 2, Example 40, Example 41, and Example 52 were each administered 1 hour before PTZ administration, or 0.5% CMC-Na+1% Tween-80, the compounds of Example 2, Example 40, Example 41, and Example 52 were each administered 0.5 hour before PTZ administration. 4) PTZ (120 mg / kg) was administered subcutaneously before the experimental observation, and this time point was recorded as the starting point of the observation. 5) After PTZ administration, the animals were immediately placed in an observation box and observed for 30 minutes. The following were recorded: a) the latency period until the first clonic seizure, b) the latency period until the first generalized tonic-clonic seizure, c) the number of clonic seizures, d) the number of generalized tonic-clonic seizures, and e) the time when the animals died. 6) If the animals did not have a seizure during the 30-minute observation period, the latency period was recorded as 1800 seconds and the number of seizures was recorded as 0. · Clonic seizures: generalized clonic seizures in animals lasting longer than 3 seconds and accompanied by falling; Tonic-clonic seizures: limbs are straightened at a 90-degree angle to the body. 6) Possible side effects caused by the drug after administration are observed and recorded, which can be divided into four levels: None: Normal Mild sedation Moderate sedation Heavy sedation 7) The test was conducted from 12:00 AM to 4:30 PM.

[0499] 4.4 Adaptation to the environment The test animals were transferred to the operating room for 1 hour before testing to allow them to adapt to the environment.

[0500] 4.5 Grouping and Dosing: 2) Mice were randomly divided into groups, marked, and weighed; 10 mice per group. Test compounds were orally administered at a dose of 10 mL / kg 30-60 minutes before PTZ administration.

[0501] 4.6 PTZ Modeling and Testing Before the experimental observation, PTZ (120 mg / kg) was administered subcutaneously, and this time point was recorded as the starting point of observation. After PTZ administration, the animals were immediately placed in the observation box and observed for 30 minutes. The following were recorded: a) the latency to the first clonic seizure, b) the latency to the first generalized tonic-clonic seizure, c) the number of clonic seizures, d) the number of generalized tonic-clonic seizures, and e) the time the animal died. If the animal did not experience a seizure during the 30-minute observation period, the latency was recorded as 1800 seconds, and the number of seizures was recorded as 0.

[0502] 4.7 Data Analysis All measurement data were expressed as mean ± SEM and analyzed with Prism 6.0 statistical software.

[0503] 4.8 Test Data:

[0504] [Table 14]

[0505] 4.9 Experimental results The compounds of the examples significantly prolonged the latency period of clonic seizures and generalized tonic-clonic seizures, and reduced the frequency of clonic seizures and generalized tonic-clonic seizures compared to the control group. The compounds of the examples protected 60% to 100% of the animals from death, significantly prolonged the latency period of death, and may have good antiepileptic effects.

[0506] 5. GABA A Positive modulatory effect of the compounds of the present invention on the receptor 5.1 Experimental Objectives: The purpose of this test example is to measure the GABA receptor agonist activity by electrophysiological manual patch clamping. A The objective is to determine the positive modulatory effect of the compound on the receptor.

[0507] 5.2 Experimental equipment Manual patch clamp system HEKA EPC10 USB signal amplifier and digital conversion system (purchased from HEKA Electronics, Germany), centrifuge (Eppendorf, etc.), carbon dioxide incubator (purchased from Thermo, etc.), biological safety cabinet (Thermo, etc.), pipette (purchased from Eppendorf, etc.).

[0508] 5.3 Experimental Method: The cells used in this experiment were human GABA A Normal GABA receptors were transfected with α1, β2, and γ2 subunit cDNAs. A The cells were derived from a HEK293T cell line that stably exhibited receptor function. The cells were grown in culture dishes containing DMEM medium (purchased from Invitrogen) and cultured in an incubator at 37°C with 5% CO2. Prior to electrophysiological experiments, the cells were transferred to round glass slides placed on the culture dishes and grown in the same medium and under the same culture conditions as above. The cell density on each round glass slide was required to ensure that most cells were isolated and distinct.

[0509] Each test compound was diluted with DMSO to obtain a stock solution, which was then diluted 1,000-fold with extracellular solution to obtain the final test concentration. The final concentration of DMSO in each compound solution was 0.1%. In the experiment, whole-cell currents were recorded using a manual patch clamp system, HEKA EPC10 USB signal amplifier and digital conversion system. HEK293T GABA receptors were attached to the surface. A The round glass slide on which the cells were grown was removed from the culture dish and placed in an electrophysiological recording tank under an inverted microscope. The recording tank was continuously perfused with extracellular solution. During the experiment, GABA signals were recorded using whole-cell current recording techniques. A The chloride current of the channel was recorded. A Use GABA in each cell as an initial control. A 1 μM GAB activated the chloride current of the channel. A GABA acts on cells via a drug perfusion system. AA chloride current was induced in the channel, with an action time of approximately 3-5 seconds, and the current value was used as the initial control value. A test concentration of compound was perfused and incubated for 2-5 minutes. A 1 μM GABA solution (mixed with the test concentration of compound) was then applied to the cells to observe the enhancing effect of the test compound on the current induced by 1 μM GABA. Once the cell condition was stable, the test compound was applied to the same cells at low to high concentrations, and the enhancing effect on the induced current was recorded.

[0510] 5.4 Experimental data processing method: The experimental data were analyzed by data analysis software provided by HEKA Patchmaster, Microsoft Excel, and Graphpad Prism.

[0511] 5.5 Experimental conclusions: The biological activities of the compounds of the present invention in the in vitro cell activity test obtained according to the above scheme are shown in Table 10:

[0512] [Table 15]

[0513] Conclusion The compounds of the examples of the present invention have a clear positive modulatory effect on GABA-A current.

[0514] Screening studies on salts and crystalline forms of compounds 1. Preparation of different crystalline forms of the free base of formula (VI) 1.1 Preparation of Crystalline Form I of the Free Base 20.5 g of the free base compound of Example 40 (purity: approximately 95%) was dissolved in 125 mL of ethyl acetate, and the resulting solution was refluxed to clarify. 125 mL of n-heptane was added dropwise, and a granular solid precipitated during the addition process. The mixture was allowed to cool to 20°C in an oil bath and then stirred at 10-20°C for 1 hour. The mixture was filtered, and the filter cake was dried to obtain 16.7 g of a white solid. After detection and analysis, the solid was identified as crystalline Form I of the free base, with the XRPD pattern shown in Figure 1, the TGA-DSC spectrum shown in Figure 2, and the DVS spectrum shown in Figure 8.

[0515] 1.2 Preparation of Crystalline Form II of the Free Base 0.2 g of crystalline Form I of the free base of Example 40 was added to a 20 mL dry, clean glass flask and heated to 160° C. for 5 minutes, and a sample was taken. After detection and analysis, the sample was determined to be crystalline Form II of the free base, with the XRPD pattern shown in FIG. 3, the TGA-DSC spectrum shown in FIG. 4, and the DVS spectrum shown in FIG. 9.

[0516] 1.3 Preparation of Crystalline Form III of the Free Base 17.5 g of the free base compound of Example 40 (purity: approximately 86%) was dissolved in 96 mL of ethyl acetate, and the resulting solution was refluxed to clarify. 96 mL of n-heptane was added dropwise. A coagulable solid precipitated during the addition process, and the precipitation rate was rapid. The mixture was allowed to cool to 20°C in an oil bath and then stirred at 10-20°C for 1 hour. The mixture was filtered, and the filter cake was dried to obtain 12.1 g of a white coagulable solid. After detection and analysis, the solid was identified as crystalline Form III of the free base, with the XRPD pattern shown in Figure 5, the TGA spectrum shown in Figure 6, and the DSC spectrum shown in Figure 10.

[0517] 2. Screening of crystalline forms of complex salt forms 2.1 Experimental Objectives: The salts with different crystalline forms were prepared using different counter ion acids by crystallization methods such as natural evaporation, solution crystallization, and antisolvent crystallization.

[0518] 2.2 Experimental equipment

[0519] [Table 16]

[0520] 2.3 Screening of salt forms of compounds of formula (VI) 0.5 mL of a good solvent was added to 50 mg of the free base of Example 40 (using a 1 mL pipette), and the resulting mixture was subjected to ultrasonic waves to obtain a solution of the free base (concentration: 100 mg / mL). The corresponding counter ion acid was weighed (1 to 1.2 equivalents of counter ion acid) and dissolved in 200 μL of the same good solvent (using a 1 mL pipette). The counter ion acid was added to the suspension of the free base with stirring, and the mixture was stirred overnight. If no precipitate was observed, a poor solvent was added to induce precipitation. The mixture was centrifuged at high speed, the supernatant was removed, and the resulting solid precipitate was dried under vacuum at 40 °C to obtain the corresponding salt of the compound.

[0521] The good solvent was selected from the group consisting of methanol, ethanol, acetone, tetrahydrofuran, dichloromethane, and 1,4-dioxane, and preferably ethyl acetate and ethanol.

[0522] The anti-solvent was selected from the group consisting of heptane, methyl tert-butyl ether, toluene, isopropyl ether, and ethyl acetate, preferably methyl tert-butyl ether and isopropyl ether.

[0523] When used, the good and poor solvents were miscible.

[0524] [Table 17]

[0525] 3. Solubility Experiments 3.1 Experimental Objectives: Comparison of the aqueous solubility of the compound's free base and salts in fasted-state simulated gastric fluid (FaSGF), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) provides a basis for assessing the druggability of crystalline forms and salts.

[0526] 3.2 Experimental scheme: Approximately 2-3 mg of crystalline Forms I, II, and III of the free base of Example 40 were weighed and suspended in 1 mL of fasted-state simulated gastric fluid (FaSSGF), fasted-state simulated intestinal fluid (FaSSIF), fed-state simulated intestinal fluid (FeSSIF), and pure water, respectively, and shaken for 24 hours. The thermodynamic solubility of the compound at 37°C was determined using HPLC with an external standard method.

[0527] 3.3 Experimental results 3.3.1 The solubility results for crystalline Forms I, II, and III of the free base of Example 40 are as shown in Table 11 below.

[0528] [Table 18]

[0529] The solubility results of crystalline forms I, II, and III of the free base of Example 40 in the four media showed that the three crystalline forms of the free base of Example 40 had low solubilities, with crystalline form I of the free base having the lowest solubility, indicating that crystalline form I of the free base is the most stable crystalline form under the current temperature conditions.

[0530] 4. Hygroscopicity Experiment 4.1 Experimental Objectives: The hygroscopicity of crystalline Forms I, II, and III of the free base of Example 40 under different relative humidity conditions was investigated to provide a basis for screening, manufacturing, and storage of crystalline forms and salts of the compound.

[0531] 4.2 Experimental scheme: 10-15 mg of the free base of Example 40 was placed in the sample chamber of the DVS. DVS was performed while simultaneously recording the vapor sorption mass gain percentage of the compound at 80% RH.

[0532] 4.3 Equipment parameters: The DVS experimental parameters are as follows:

[0533] [Table 19]

[0534] 4.4 Experimental results 4.4.1 The hygroscopicity results for crystalline Forms I, II, and III of the free base of Example 40 are as shown in Table 12 below:

[0535] [Table 20]

[0536] Crystalline Forms I, II, and III of the free base of Example 40 were not hygroscopic.

[0537] 5. Competition experiments with different crystalline forms of the free base 5.1 Experimental Objectives: To select a stable crystalline form, the stability among crystalline forms I, II and III of the free base of Example 40 was investigated.

[0538] 5.2 Experimental scheme: Portions of approximately 20 mg of crystalline Forms I, II, and III of the free base of Example 40 were accurately weighed and mixed in equal pairs. Methyl tert-butyl ether and n-heptane were added, respectively, and the resulting mixture was stirred at 40° C. for 7 days. The mixture was centrifuged at high speed, the supernatant removed, and the resulting solid precipitate was dried in an oven under vacuum at 40° C. and characterized by XRPD.

[0539] 5.3 Experimental results 4.4.1 The competition results for crystalline Forms I, II and III of the free base of Example 40 are as shown in Table 13 below:

[0540] [Table 21]

[0541] The results in the table show that crystalline forms I, II, and III of the free base of Example 40 were almost insoluble in n-heptane, and no crystalline form conversion occurred; in methyl tert-butyl ether, the other two crystalline forms were eventually converted to crystalline form I, indicating that crystalline form I of the free base is a stable crystalline form.

[0542] 6. Solid-state stability experiments 6.1 Experimental Objectives: The physicochemical stability of candidate crystalline Forms I, II and III of the free base of Example 40 under influencing factors such as high temperature, high humidity and strong light was investigated to provide a basis for the manufacture and storage of the compounds.

[0543] 6.2 Experimental scheme: Approximately 5 mg of crystalline Form I of the free base of Example 40 was accurately weighed and placed in a 60°C oven (closed) or a light box (5000±500 lux, closed), or placed at room temperature / 90% RH (saturated aqueous KNO solution, open) or at high temperature and humidity (50°C / 75% RH, saturated aqueous sodium chloride solution, open) for 5 and 10 days, respectively. The related substance changes of the free base were calculated by the chromatographic peak area normalization method.

[0544] 6.3 Experimental results 1) The physicochemical stability results of crystalline Form I of the free base of Example 40 are shown in Table 14 below:

[0545] [Table 22]

[0546] After the free base crystalline form I was exposed to the influences of high temperature, high humidity, and light for 10 days, no impurities increased, indicating that the free base crystalline form I has good physicochemical stability.

[0547] 7. Crystal morphology stability experiment 7.1 Experimental Objectives: The stability of the crystalline form I of the free base of Example 40 under the influence of factors such as high temperature, high humidity, and strong light was investigated.

[0548] 7.2 Experimental scheme: Approximately 5 mg of crystalline Form I of the free base of Example 40 was accurately weighed and placed under the influence of light, 40°C, 60°C, 25°C / RH75%, or 25°C / RH90% for 5, 10, and 30 days, respectively. X-ray powder diffraction assays were performed, and the obtained data were compared with the initial data.

[0549] 7.3 Experimental results 1) The crystal form stability results for crystalline Form I of the free base of Example 40 are shown in Table 15 below:

[0550] [Table 23]

[0551] The results show that the X-ray powder diffraction assay data is consistent with the initial data under various influencing factors. No crystal form transformation occurred, indicating that crystalline form I of the free base is stable. It should be emphasized that those skilled in the art will know that the typical diffraction angle error of crystalline forms is within the range of ±0.2°. Individual peaks of crystalline forms that are not within the scope of the present invention do not mean that such crystalline forms are new crystalline forms. Those skilled in the art will know that if there are differences in individual peaks, the crystalline form still belongs to the crystalline forms of the present invention.

[0552] 8. Single Crystal Culture 8.1 Experimental Objectives: A single crystal was grown to elucidate the structure of the free base of Example 40.

[0553] 8.2 Experimental scheme: Approximately 20 mg of the free base of Example 40 was placed in a 1.5 mL glass flask and 1 mL of toluene was added. The mixture was heated to 50°C to dissolve the compound and then filtered through a 0.45 μm organic nylon membrane. The resulting filtrate was placed in a clean glass flask preheated to 50°C and slowly cooled to room temperature. After approximately one day, colorless crystalline particles, i.e., single crystals of crystalline Form I of the free base of Example 40, precipitated.

[0554] 8.3 Experimental results Single crystal data for crystalline Form I of the free base of Example 40 is shown in Table 16 below.

[0555] [Table 24]

[0556] Single crystal results show that:

[0557] The unit cell structure of the single crystal of crystalline Form I of the free base of Example 40 is orthogonal, with each unit cell containing four molecules, and the chiral molecular configuration optimized by single crystal characterization is consistent with the theoretical structure from chemical synthesis. The XRD pattern fitted from the single crystal data is consistent with that of crystalline Form I of the free base of Example 40, indicating that the single crystal of Example 40 formed at room temperature is crystalline Form I of the free base. The specific structure is shown in Figure 11.

Claims

1. The following structure: 【Chemical 1】 (In the formula: X 1 is CR 1 and N; X 2 is CR 2 and N; X 3 is CR 3 and N; X 4 is CR 4 and N; R 1 and R 2 are hydrogen, deuterium, cyano, halogen, nitro, amino, and C, respectively. 1～8 Alkyl, C 1～8 Haloalkyl, C 1～8 Alkoxy, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 independently selected from the group consisting of aryl, and 5-10 membered heteroaryl; R 3 and R 4 are hydrogen, deuterium, cyano, halogen, nitro, amino, and C, respectively. 1～8 Alkyl, C 1～8 Haloalkyl, C 1～8 Alkoxy, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -(CH 2 ) n SR a , -(CH 2 ) n C(O)R a , -S(O)R a , -S(O) 2 R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH 2 ) n NR a R b wherein C is independently selected from the group consisting of 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, C 1～8 Haloalkyl, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 1～8 Alkoxy, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 The aryl and 5-10 membered heteroaryl can each be optionally further substituted; R 5 Deuterium, cyano, halogen, nitro, amino, C 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, C 1～8 Haloalkyl, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 1～8 Alkoxy, C 1～8 Alkylthio, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -S(O)R a , -S(O) 2 R a , and -(CH 2 ) n NR a R b wherein C is independently selected from the group consisting of 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, C 1～8 Haloalkyl, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 1～8 Alkoxy, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 Each of the aryl and 5- to 10-membered heteroaryl can be optionally further substituted; R 6 is hydrogen; Or R 5 and R 6 together with the carbon atoms to which they are attached, form C 3～8 forming a cycloalkyl or a 3- to 8-membered heterocyclyl, where C 3～8 The cycloalkyl and 3- to 8-membered heterocyclyl can each be optionally further substituted; R 5 and R 6 is not hydrogen at the same time; R a and R b are hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, and C 1～8 Alkyl, C 1～8 Alkoxy, C 1～8 Hydroxyalkyl, C 1～8 Deuterated alkyl, C 1～8 Haloalkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 aryl, and 5- to 10-membered heteroaryl, wherein C 1～8 Alkyl, C 1～8 Deuterated alkyl, C 1～8 Haloalkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 The aryl and 5-10 membered heteroaryl can each be optionally further substituted; M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfuric acid, dibenzoyl benzoate, benzoic acid ... ethanolic acid, ... y is selected from the group consisting of 1, 2, and 3; and n is an integer from 0 to 6.

2. During the ceremony: R 1 and R 2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, and cyclopropyl; R 3 and R 4 are hydrogen, halogen, cyano, nitro, and C 1～3 Alkyl, cyano-substituted C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, C 1～3 Hydroxyalkyl, C 3～6 Cycloalkyl, cyano-substituted C 3～6 Cycloalkyl, oxazolyl, -C(O)R a , -SC 1～3 Alkyl, -S(O)C 1～3 Alkyl, -S(O) 2 C 1～3 Alkyl, -C(O)OC 1～3 Alkyl, -S(O)(=NH)C 1～3 Alkyl, and -C(O)O(CH 2 ) n N(CH 3 )C 1～3 independently selected from the group consisting of alkyl; R 5 is halogen, cyano, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy, C 1～3 Hydroxyalkyl, cyano-substituted C 1～3 Alkyl, C 3～6 Cycloalkyl, cyano-substituted C 3～6 Cycloalkyl, 3- to 6-membered nitrogen-containing heterocyclyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 1～3 Alkylthio, -(CH 2 ) n R a , -(CH 2 ) n OR a , -S(O) 2 R a and -(CH 2 ) n N(R a ) 2 selected from the group consisting of: R 6 is hydrogen; Or R 5 and R 6 together with the carbon atoms to which they are attached, form C 3～6 forming a cycloalkyl; R a is hydrogen, nitro, C 1～3 selected from the group consisting of alkyl, azetidinyl, and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are each optionally substituted with halogen; M is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, nitric acid, and 1,5-naphthalenedisulfonic acid; y is 1 or 2; 2. The acid addition salt of claim 1, wherein n is independently selected from the group consisting of 0, 1, and 2.

3. During the ceremony: R 1 and R 2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, and cyclopropyl; R 3 and R 4 are hydrogen, fluorine, chlorine, cyano, nitro, methyl, trifluoromethyl, cyclopropyl, cyano-substituted cyclopropyl, cyano-substituted isopropyl, hydroxyisopropyl, oxazolyl, and -C(O)R, respectively. a , -SCH 3 , -S(O)CH 3 , -S(O) 2 CH 3 , -C(O)OCH 2 CH 3 , -S(O)(=NH)CH 3 and -C(O)O(CH 2 ) 2 NCH 3 (CH 3 ) independently selected from the group consisting of: R 5 is fluorine, methyl, ethyl, isopropyl, fluoromethyl, methoxy, cyclopropyl, cyclobutyl, methyl-substituted pyrazolyl, phenyl, -SCH 3 , -(CH 2 ) n R a , -NC(CH 3 ) 2 , -S(O) 2 C(CH 3 ) 2 and -CH 2 N(CH 3 ) 2 selected from the group consisting of: R 6 is hydrogen; Or R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropyl, wherein the cyclopropyl is optionally substituted with halogen; R a is hydrogen, nitro, C 1～3 selected from the group consisting of alkyl, azetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are each optionally substituted with fluorine; M is methanesulfonic acid; y is 1 or 2; 2. The acid addition salt of claim 1, wherein n is independently selected from the group consisting of 0, 1, and 2.

4. Formula (IIa): 【Chemistry 2】 having the structure shown in or formula (IIIa): 【Chemistry 3】 (In the formula: R 7 and R 8 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and methyl; or formula (IVa): 【Chemistry 4】 having the structure shown in or formula (Va): 【Chemistry 5】 2. The acid addition salt of claim 1 having the structure shown in

5. Its structure is: 【Chemistry 6A】 【Chemistry 6B】 【Chemistry 6C】 【6D】 【Chemistry 6E】 5. Acid addition salt according to any one of claims 1 to 4, characterized in that it is as follows:

6. 6. Acid addition salt according to any one of claims 1 to 5, characterized in that it is crystalline or amorphous.

7. The following structure: 【Chemistry 7】 (In the formula: X 1 is CR 1 and N; X 2 is CR 2 and N; X 3 is CR 3 and N; X 4 is CR 4 and N; R 1 and R 2 are hydrogen, deuterium, cyano, halogen, nitro, amino, and C, respectively. 1～8 Alkyl, C 1～8 Haloalkyl, C 1～8 Alkoxy, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 independently selected from the group consisting of aryl, and 5-10 membered heteroaryl; R 3 and R 4 are hydrogen, deuterium, cyano, halogen, nitro, amino, and C, respectively. 1～8 Alkyl, C 1～8 Haloalkyl, C 1～8 Alkoxy, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -(CH 2 ) n SR a , -(CH 2 ) n C(O)R a , -S(O)R a , -S(O) 2 R a , -S(O)(=NH)R a , -C(O)OR a and -C(O)O(CH 2 ) n NR a R b wherein C is independently selected from the group consisting of 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, C 1～8 Haloalkyl, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 1～8 Alkoxy, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 The aryl and 5-10 membered heteroaryl can each be optionally further substituted; R 5 Deuterium, cyano, halogen, nitro, amino, C 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, C 1～8 Haloalkyl, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 1～8 Alkoxy, C 1～8 Alkylthio, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 Aryl, 5- to 10-membered heteroaryl, -(CH 2 ) n R a , -(CH 2 ) n OR a , -S(O)R a , -S(O) 2 R a , and -(CH 2 ) n NR a R b wherein C is independently selected from the group consisting of 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, C 1～8 Haloalkyl, C 1～8 Hydroxyalkyl, cyano-substituted C 1～8 Alkyl, C 1～8 Alkoxy, C 3～8 Cycloalkyl, cyano-substituted C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 The aryl and 5-10 membered heteroaryl can each be optionally further substituted; R 6 is hydrogen; Or R 5 and R 6 together with the carbon atoms to which they are attached, form C 3～8 forming a cycloalkyl or a 3- to 8-membered heterocyclyl, where C 3～8 The cycloalkyl and 3- to 8-membered heterocyclyl can each be optionally further substituted; R 5 and R 6 is not hydrogen at the same time; R a and R b are hydrogen, deuterium, halogen, cyano, hydroxy, amino, nitro, and C 1～8 Alkyl, C 1～8 Alkoxy, C 1～8 Hydroxyalkyl, C 1～8 Deuterated alkyl, C 1～8 Haloalkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 aryl, and 5- to 10-membered heteroaryl, wherein C 1～8 Alkyl, C 1～8 Deuterated alkyl, C 1～8 Haloalkyl, C 3～8 Cycloalkyl, 3- to 8-membered heterocyclyl, C 6～10 The aryl and 5-10 membered heteroaryl can each be optionally further substituted; M is an inorganic acid or an organic acid, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and phosphoric acid, and the organic acid is selected from the group consisting of 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfuric acid, selected from the group consisting of dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, maleic acid, malonic acid, D-tartaric acid, pamoic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, embonic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, undecylenic acid, trifluoroacetic acid, p-toluenesulfonic acid, and L-malic acid; x is selected from the group consisting of 0, 1, 2, and 3; wherein n is an integer from 0 to 6.

8. During the ceremony: R 1 and R 2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, and cyclopropyl; R 3 and R 4 are hydrogen, halogen, cyano, nitro, and C 1～3 Alkyl, cyano-substituted C 1～3 Alkyl, halogen-substituted C 1～3 Alkyl, C 1～3 Hydroxyalkyl, C 3～6 Cycloalkyl, cyano-substituted C 3～6 Cycloalkyl, oxazolyl, -C(O)R a , -SC 1～3 Alkyl, -S(O)C 1～3 Alkyl, -S(O) 2 C 1～3 Alkyl, -C(O)OC 1～3 Alkyl, -S(O)(=NH)C 1～3 Alkyl, and -C(O)O(CH 2 ) n N(CH 3 )C 1～3 independently selected from the group consisting of alkyl; R 5 is halogen, cyano, C 1～3 Alkyl, C 1～3 Haloalkyl, C 1～3 Alkoxy, C 1～3 Hydroxyalkyl, cyano-substituted C 1～3 Alkyl, C 3～6 Cycloalkyl, cyano-substituted C 3～6 Cycloalkyl, 3- to 6-membered nitrogen-containing heterocyclyl, C 6～10 Aryl, 5-10 membered heteroaryl, C 1～3 Alkylthio, -(CH 2 ) n R a , -(CH 2 ) n OR a , -S(O) 2 R a and -(CH 2 ) n N(R a ) 2 selected from the group consisting of: R 6 is hydrogen; Or R 5 and R 6 together with the carbon atoms to which they are attached, form C 3～6 forming a cycloalkyl; R a is hydrogen, nitro, C 1～3 selected from the group consisting of alkyl, azetidinyl, and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are each optionally substituted with halogen; M is selected from the group consisting of hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrobromic acid, nitric acid, and 1,5-naphthalenedisulfonic acid; x is 0, 1, or 2; 8. The crystal of claim 7, wherein n is selected from the group consisting of 0, 1, and 2.

9. During the ceremony, R 1 and R 2 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, cyano, methyl, and cyclopropyl; R 3 and R 4 are hydrogen, fluorine, chlorine, cyano, nitro, methyl, trifluoromethyl, cyclopropyl, cyano-substituted cyclopropyl, cyano-substituted isopropyl, hydroxyisopropyl, oxazolyl, and -C(O)R, respectively. a , -SCH 3 , -S(O)CH 3 , -S(O) 2 CH 3 , -C(O)OCH 2 CH 3 , -S(O)(=NH)CH 3 and -C(O)O(CH 2 ) 2 NCH 3 (CH 3 ) independently selected from the group consisting of: R 5 is fluorine, methyl, ethyl, isopropyl, fluoromethyl, methoxy, cyclopropyl, cyclobutyl, methyl-substituted pyrazolyl, phenyl, -SCH 3 , -(CH 2 ) n R a , -NC(CH 3 ) 2 , -S(O) 2 C(CH 3 ) 2 and -CH 2 N(CH 3 ) 2 selected from the group consisting of: R 6 is hydrogen, Or R 5 and R 6 together with the carbon atom to which they are attached form a cyclopropyl, wherein the cyclopropyl is optionally substituted with halogen; R a is hydrogen, nitro, C 1～3 selected from the group consisting of alkyl, azetidinyl and pyrrolidinyl, wherein azetidinyl and pyrrolidinyl are each optionally substituted with fluorine; M is methanesulfonic acid; x is 1 or 2; 8. The crystal of claim 7, wherein n is selected from the group consisting of 0, 1, and 2.

10. The structure of the compound is represented by formula (II): 【Chemistry 8】 as shown in; Or the structure of the compound is of formula (III): 【Chemistry 9】 (In the formula: R 7 and R 8 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, and methyl; Or the structure of the compound is of formula (IV): 【Chemistry 10】 as shown in; Or the structure of the compound is of formula (V): 【Chemistry 11】 The crystal according to claim 7, characterized in that it is shown in

11. The compound has the following structure: 【Chemical 12A】 【Chemistry 12B】 【Chemical 12C】 【12D】 【Chemistry 12E】 The crystal according to any one of claims 7 to 10, characterized in that it is as follows:

12. The structure of the compound is represented by formula (VI): 【Chemistry 13】 12. The crystal according to any one of claims 7 to 11, characterized in that it is as shown in

13. 13. The crystal according to claim 12, wherein x is 0 or x is selected from the group consisting of 1, 2 and 3.

14. 14. The crystal according to claim 12 or 13, wherein the compound of formula (VI) is a hydrate or anhydrous.

15. The structure of the compound is represented by formula (VI): 【Chemistry 14】 and 12. The crystal of any one of claims 7 to 11, wherein x is 0 and the crystal is Crystal I of the free base, characterized in that its X-ray powder diffraction pattern has diffraction peaks at 16.7, 12.6 and 17.4 2θ (±0.2°), and optionally further includes one or more diffraction peaks at 7.3, 20.2, 20.6, 11.9, 11.1, 23.9, 21.9 and 38.4 2θ (±0.2°).

16. 16. The crystal of claim 15, wherein crystalline I of the free base has diffraction peaks at 2θ (±0.2°) of 16.7, 12.6, 17.4, 7.3, 20.2, and 20.

6.

17. 16. The crystal of claim 15, wherein crystalline I of the free base has diffraction peaks at 2θ (±0.2°) of 16.7, 12.6, 17.4, 7.3, 20.2, 20.6, 11.9, and 11.

1.

18. The compound of claim 1, wherein the structure of the compound is represented by formula (VI): 【Chemistry 15】 and 12. The crystal according to claim 7, wherein x is 0, the crystal is crystalline II of the free base, and its X-ray powder diffraction pattern has diffraction peaks at 11.7, 13.4, 13.6, 16.6, and 18.9 2θ (±0.2°).

19. The compound of claim 1, wherein the structure of the compound is represented by formula (VI): 【Chemistry 16】 and 12. The crystal according to claim 7, wherein x is 0, and the crystal is crystalline III of the free base, characterized in that the X-ray powder diffraction pattern has diffraction peaks at 10.0, 11.7, 13.7, 16.6, 18.9, and 19.2 2θ (±0.2°).

20. The compound of claim 1, wherein the structure of the compound is represented by formula (VI): 【Chemistry 17】 wherein M is methanesulfonic acid and x is 1, and the X-ray powder diffraction pattern has diffraction peaks at 12.5, 13.5, 19.4, and 19.9 2θ (±0.2°).

21. The compound of claim 20, wherein the structure of the compound is represented by formula (VI): 【Chemistry 18】 wherein x is 0, and the crystal is crystalline I of the free base, and its X-ray powder diffraction pattern has diffraction peaks at 16.7, 12.6, and 14.6 2θ (±0.2°).

22. The crystal of claim 21, wherein crystalline I of the free base further has diffraction peaks at 7.3, 13.2, 17.4, 19.4, 20.2 and 20.6 at 2θ (±0.2°).

23. The crystal of claim 21, wherein crystalline I of the free base further has diffraction peaks at 9.2, 11.1, 11.9, 19.6, 22.3 and 25.5 at 2θ (±0.2°).

24. The crystal according to any one of claims 7 to 11, characterized in that the DSC spectrum of the crystal has an endothermic peak at 151.4 ± 0.5 ° C.

25. A method for preparing a crystal of a compound according to any one of claims 7 to 24, specifically comprising the steps of: 1) weighing out an appropriate amount of the free base according to any one of claims 15 to 19 and 21 to 24 or the acid addition salt obtained according to any one of claims 1 to 6, followed by adding a good solvent and heating the mixture until dissolution; 2) After stirring for several hours, adding anti-solvent dropwise until turbidity appears; 3) stirring and cooling the mixture, followed by precipitating crystals to obtain the target product; A method comprising:

26. The good solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, dichloromethane, acetone, toluene, acetonitrile, tetrahydrofuran, n-heptane, methyl tert-butyl ether, isopropyl ether, and N,N-dimethylformamide; 26. The method of claim 25, wherein the anti-solvent is selected from the group consisting of n-heptane, methyl tert-butyl ether, and isopropyl ether.

27. The good solvent is selected from the group consisting of 88% acetone, tetrahydrofuran, and ethanol; the anti-solvent is selected from the group consisting of n-heptane and methyl tert-butyl ether; 26. The method of claim 25.

28. 25. A pharmaceutical composition comprising a therapeutically effective amount of an acid addition salt of formula (Ia) according to any one of claims 1 to 6 or a therapeutically effective amount of a crystalline compound of formula (I) according to any one of claims 7 to 24, and one or more pharmaceutically acceptable carriers.

29. 29. Pharmaceutical composition according to claim 28, characterized in that it is an injection or oral preparation.

30. 29. Pharmaceutical composition according to claim 28, characterized in that it is a tablet or capsule.

31. 29. The pharmaceutical composition of claim 28, wherein the unit dose is 1 to 200 mg.

32. GABA A Use of an acid addition salt of a compound of formula (Ia) according to any one of claims 1 to 6, a crystal of a compound of formula (I) according to any one of claims 7 to 24 or a pharmaceutical composition according to any one of claims 28 to 31 in the preparation of a medicament for treating a related disease mediated by a receptor modulator.

33. GABA A 33. The use of claim 32, wherein the associated disorder mediated by the receptor modulator is a central nervous system (CNS) associated disorder; said CNS associated disorder is selected from the group consisting of sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory disorders, cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and / or withdrawal syndromes, or tinnitus.

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