Steroid derivative modulators, their manufacturing methods and applications

Abstract

To provide steroid derivative modulators, a method for preparing the same, and uses thereof.SOLUTION: The invention relates to steroid derivative modulators, a method for preparing the same, and uses thereof. In particular, the invention relates to a compound represented by the general formula (I), a method for preparing the same, a pharmaceutical composition containing the compound, and applications thereof as a GABAA receptor modulator in treating depression, convulsion, Parkinson's disease, and nervous system diseases, where the substituents in the general formula (I) are the same as defined in the specification.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention belongs to the field of drug synthesis and, more specifically, relates to steroid derivative modulators, methods for producing the same, and uses thereof. [Background technology]

[0002] GABA A Receptors are chemically gated channels on the cell membrane and belong to the ion channel receptor type. They are widely distributed in the nervous system and bind to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid), opening chloride ion channels and causing neuronal inhibition. The GABA receptor modulator (tetrahydroprogesterone) binds to GABA A It is a positive modulator of the receptor. Tetrahydroprogesterone and GABA in the synapse. A Binding to receptor modulators increases the frequency of opening of chloride ion channels on the receptor, thereby increasing the internal flow of chloride ions, increasing the phasic current, achieving a rapid inhibitory effect, and reducing neuronal excitability, thereby achieving anxiolytic and antidepressant effects. Binding of tetrahydroprogesterone to GABAA receptor modulators within synapses generates a sustained chloride ion current, mediating a long-lasting inhibitory effect. Tetrahydroprogesterone can also improve symptoms of anxiety and depression by increasing the content of neurotrophic factor (BDNF), promoting hippocampal neuron regeneration, and exerting neuroprotective effects, although the specific mechanism of action is not yet clear.

[0003] Major depressive disorder (MDD) is a common and chronic relapsing disorder, and the disease burden and adverse events caused by it are becoming increasingly serious. In the past 40 years, there have been great advances in the research, development and clinical use of antidepressants. However, most antidepressants (such as fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, etc.) take 2 to 4 weeks to take effect. In the clinical treatment of major depressive disorder, especially in patients with depression with suicidal tendencies, timely and rapid clinical treatment is often required. Therefore, the development of immediate-acting antidepressants is an urgent task.

[0004] In the past 20 years, there has been little innovation in the discovery and development of depression treatment, and GABA A The development goal of receptor modulators is to change patients' expectations by changing the MDD treatment plan. If the research is successful, GABA A receptor modulators may become the first drugs to truly provide a new mechanism of action for the treatment of depression within 20 years. Currently, overseas pharmaceutical companies including Sage Therapeutics and Marinus are making every effort to develop GABA A receptor modulators.

[0005] The currently disclosed patent applications for GABA A receptor modulators include WO2003077919, WO2014169833, WO2016061537, WO2015180679 and WO2015027227.

[0006] GABA A receptor modulators have good prospects for use as a popular drug target in the pharmaceutical industry.

[0007] First, GABA A receptor modulators can be applied to major depressive disorder (MDD). The annual incidence of MDD in China is about 2%, indicating huge market potential.

[0008] Secondly, conventional antidepressants have a slow onset of action, usually taking 3-4 weeks, have a high failure rate of up to 40%, and require long-term medication. GABA A Receptor modulators can exert a clear antidepressant effect within 24 hours, and the effects of the medication may last from several days to two weeks.

[0009] Third, GABA A Receptor modulators can meet the daily oral treatment needs of MDD patients. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] International Publication No. 2003077919 [Patent Document 2] International Publication No. 2014169833 [Patent Document 3] International Publication No. 2016061537 [Patent Document 4] International Publication No. 2015180679 [Patent Document 4] International Publication No. 2015027227 [Overview of the project] [Problems that the invention aims to solve]

[0011] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the structure of the compound represented by general formula (I) is as follows. [Means for solving the problem]

[0012] [ka] (In the formula, X is -CR 17 - or -N- is selected, Y is -CR 23R 24 -, -S(CH2) n1 -, -P(CH2) n1 -, -O(CH2) n1 -,-(CH2) n1 NR 22 -, [ka] Selected from, R x , R y , R z and R f These are the same or different, and each independently consists of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, mercapto group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: Alternatively, R x , R y , R z and R fAny two adjacent or non - adjacent groups among them can combine to form one cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, among which the cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group can further have deuterium atoms, alkyl groups, halogenated alkyl groups, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, -(CH2) n1 R 23 、-(CH2) n1 OR 23 、-(CH2) n1 SR 23 、-(CH2) n1 C(O)R 23 、-(CH2) n1 C(O)OR 23 、-(CH2) n1 S(O) m1 R 23 、-(CH2) n1 NR 23 R 24 、-(CH2) n1 C(O)NR 23 R 24 、-(CH2) n1 NR 23 C(O)R 24 and -(CH2) n1 NR 23 S(O) m1 R 24 may be substituted with one or more substituents selected from or, R x 、R y 、R z and R f There are no two adjacent groups among any two of them, and a double bond is formed, R 21This includes hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2)n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: X is -CR 17 -If selected from, R 17 This group is selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, hydroxyl groups, amino groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may be further substituted with one or more substituents selected from deuterium atoms, substituted or unsubstituted alkyl groups, halogens, hydroxyl groups, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups. Alternatively, R 17 R x , R y , R z and R fIt can combine with any of the following groups to form a cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group, of which the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 24 and -(CH2) n1 NR 23 S(O) m1 R 24 They may be substituted with one or more substituents selected from the following: R 22 This includes hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: R 23 , R 24 , R 25 and R 26 These are the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, hydroxyl groups, amino groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may be further substituted with one or more substituents selected from deuterium atoms, substituted or unsubstituted alkyl groups, halogens, hydroxyl groups, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups. m is an integer of 0, 1, 3, 4, 5, 6, 7, 8, 9, or 10. n is an integer, 0, 1, 2, or 3. o is an integer of 0, 1, 2, 3, 4, or 5. p is an integer, 0, 1, 2, 3, 4, 5, or 6. q is an integer of 0, 1, 2, 3, 4, 5, or 6. m1 is an integer of 0, 1, or 2, and n1 is an integer between 0, 1, 2, 3, 4, or 5.

[0013] In preferred embodiments of the present invention, the compound represented by general formula (I) is a compound represented by general formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, Y is [ka] Selected from, R 3a This is selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, mercapto groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, or alkynyl groups. R5 is selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, or alkynyl groups. R 15a This is selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, or alkynyl groups. R 16a This is selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, or alkynyl groups. Alternatively, R 15a and R 16a These atoms bond to form a cycloalkyl group or heteroalkyl group, and the cycloalkyl group or heteroalkyl group formed may be further substituted with one or more substituents selected from hydrogen atoms, deuterium atoms, alkyl groups, alkyl halides, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups. R 19This includes hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, mercapto groups, hydroxyl groups, cyano groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, and -(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 S(O)(=NR 23 )R 24 or -(CH2) n1 C(O)NR 23 R 24 Selected from, Alternatively, R5 and R 19 These atoms bond to form a cycloalkyl group or heteroalkyl group, and the cycloalkyl group or heteroalkyl group formed may be further substituted with one or more substituents selected from hydrogen atoms, deuterium atoms, alkyl groups, alkyl halides, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups. R 21 This includes hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, alkynyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26They may be substituted with one or more substituents selected from the following: R 23 , R 24 , R 25 and R 26 These are the same or different, and each is independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, hydroxyl groups, amino groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may be further substituted with one or more substituents selected from deuterium atoms, substituted or unsubstituted alkyl groups, halogens, hydroxyl groups, substituted or unsubstituted amino groups, oxo groups, nitro groups, cyano groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups. n is an integer of 1 or 2, m1 is an integer of 0, 1, or 2, and n1 is an integer between 0, 1, 2, 3, 4, or 5.

[0014] In preferred embodiments of the present invention, the compound represented by general formula (II) is a compound represented by general formula (III-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, Z is -CR 23 R 24 -, -NR 23 -,-(CH2) n1 O(CH2) n2 - or -O- is selected, preferably a methylene group, Ring C is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which alkyl groups, halogenated alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may further include deuterium atoms, alkyl groups, halogenated alkyl groups, halogens, amino groups, oxo groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, and -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: R c These are the same or different, hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n1 R 23 ,-(CH2)n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 S(O)NR 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 23 or -(CH2) n1 NR 23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: z is an integer of 0, 1, 3, 4, or 5, and R 3a , R 3b , R5, R 19 , R 23 ~R 26 n, m1, and n1 are defined as in the compound represented by general formula (II).

[0015] In preferred embodiments of the present invention, the compound represented by general formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by general formula (V-7) and general formula (V-8), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, Ring A is selected from cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, of which the alkyl groups, halogenated alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, and -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: R a These are the same or different, hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 S(O)NR 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 23 or -(CH2) n1 NR23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: R 19 This includes hydrogen atoms, alkyl groups, alkyl halides, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 S(O)NR 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 23 ,-(CH2) n1 S(O)(=NR 23 )R 24 or -(CH2) n1 NR 23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2)n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: x, m1, and n1 are as described in general formula (II).

[0016] In preferred embodiments of the present invention, the compound represented by general formula (II) is a compound represented by general formula (III-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R5 is a hydrogen atom, C 1-6 Alkyl alkyl group, C 1-6 Halogenated alkyl group or C 1-6 Selected from alkoxy groups, R 19 C is a hydrogen atom. 1-6 Alkyl alkyl group, C 1-6 Alkyl halogenated compounds, C 1-6 Alkoxy group, -(CH2) n1 Ure 23 or -(CH2) n1 SR 23 Selected from, R c is a hydrogen atom, a cyano group, or C 1-6 Selected from alkyl groups, z is an integer, and n is 0, 1, or 2.

[0017] In preferred embodiments of the present invention, the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by general formulas (IV-A) and (IV-B), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 3a C 1-6 Alkyl alkyl group, C 1-6 Halogenated alkyl group or C 1-6 Selected from alkoxy groups, R 19 is a cyano group, halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkyl halogenated compounds, C 1-6 Alkoxy group, -(CH2) n1 Ure 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 S(O)(=NR 23 )R 24 or -(CH2) n1 SR 23 Selected from, R a This includes hydrogen atoms, cyano groups, halogens, nitro groups, alkyl groups, alkoxy groups, halogenated alkyl groups, cycloalkyl groups, hydroxyalkyl groups, heterocyclyl groups, heteroaryl groups, and -(CH2) n1 CR 23 R 24 R 25 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 S(O)(=NR 23 )R 24 ,-(CH2) n1 C(O)NR 23 R 24A group is selected from the group, and the alkyl group, cycloalkyl group, heterocyclyl group, or heteroaryl group may be further substituted with one or more substituents selected from a hydrogen atom, alkyl group, halogen, cyano group, hydroxyl group, cycloalkyl group, heterocyclyl group, and heteroaryl group. x is an integer, 0, 1, or 2, and R5, m1, and n1 are as described in claim 2.

[0018] In preferred embodiments of the present invention, the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by general formula (VIII), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, Rings A, Z, R a And x are as described in general formula (III). In preferred embodiments of the present invention, the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by general formula (VI), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, Z is -CR 23 R 24 -,-(CH2) n1 NR 23 -,-(CH2) n1 O(CH2) n2 - or -O- is selected, preferably a methylene group, Ring B is selected from a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, of which the cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group may further include a deuterium atom, an alkyl group, an alkyl halide, a halogen, an amino group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: R b These are the same or different, hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n1 R 23 ,-(CH2) n1 Ure23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 S(O)NR 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 23 or -(CH2) n1 NR 23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 It may be substituted with one or more substituents selected from and y is an integer selected from 0, 1, 2, 3, or 4.

[0019] In preferred embodiments of the present invention, the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by general formula (VIII), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, R 21 This includes hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1NR 23 S(O) m1 R 24 Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: R 23 ~R 26 (m1 and n1 are as described in claim 1.)

[0020] In preferred embodiments of the present invention, the compound represented by general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof is the compound represented by general formula (X), its stereoisomer, or a pharmaceutically acceptable salt thereof. [ka] (In the formula, M is -CR 23 -or selected from oxygen atoms, Y is -S(CH2) n1 -, [ka] Selected from, R 21 This includes hydrogen atoms, deuterium atoms, alkyl groups, deuterated alkyl groups, halogenated alkyl groups, alkoxy groups, haloalkoxy groups, halogens, amino groups, nitro groups, hydroxyl groups, cyano groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, heteroaryl groups, and -(CH2) n1 R 23 ,-(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)OR 23 ,-(CH2) n1 S(O) m1 R 23 ,-(CH2) n1 NR 23 R 24 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24Selected from, of which the alkyl group, halogenated alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group may further include a deuterium atom, alkyl group, halogenated alkyl group, halogen, amino group, oxo group, nitro group, cyano group, hydroxyl group, alkenyl group, alkynyl group, alkoxy group, haloalkoxy group, hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 ,-(CH2) n1 Ure 25 ,-(CH2) n1 SR 25 ,-(CH2) n1 C(O)R 25 ,-(CH2) n1 C(O)OR 25 ,-(CH2) n1 S(O) m1 R 25 ,-(CH2) n1 NR 25 R 26 ,-(CH2) n1 C(O)NR 25 R 26 ,-(CH2) n1 C(O)NHR 25 ,-(CH2) n1 NR 25 C(O)R 26 and -(CH2) n1 NR 25 S(O) m1 R 26 They may be substituted with one or more substituents selected from the following: R 22 ~R 26 (m1 and n1 are as described in claim 1.)

[0021] In preferred embodiments of the present invention, in the compound represented by the general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, rings A, B, and C are [ka] It is selected based on the following criteria.

[0022] In preferred embodiments of the present invention, in a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, The aforementioned R a , R b and R c C is a hydrogen atom, a cyano group, a halogen, a nitro group, and 1-6 Alkyl alkyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkyl halogenated compounds, C 3-6 Cycloalkyl groups, C 1-6 Hydroxyalkyl group, 5-10 membered heterocyclyl group, 5-10 membered heteroaryl group, -(CH2) n1 Ure 23 ,-(CH2) n1 SR 23 ,-(CH2) n1 C(O)R 23 ,-(CH2) n1 C(O)NR 23 R 24 ,-(CH2) n1 C(O)OR 23 or -(CH2) n1 S(O) m1 R 23 Selected from, of which C 1-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Alkyl halogenated compounds, C 3-6 Cycloalkyl groups, C 1-6 Hydroxyalkyl groups, 5-10 membered heterocyclyl groups, and 5-10 membered heteroaryl groups further contain hydrogen atoms, C 1-6 Alkynyl group, halogen, cyano group, hydroxyl group, C 3-6 Cycloalkyl groups, C 1-6 It may be substituted with one or more substituents selected from hydroxyalkyl groups, 5-10 membered heterocyclyl groups, and 5-10 membered heteroaryl groups. The aforementioned R 23 and R 24 These are, independently, hydrogen atoms and C 1-6It is selected from an alkyl group or a 3- to 8-membered heterocyclyl group.

[0023] In a preferred embodiment of the present invention, in the compound represented by the general formula (I), its stereoisomer or its pharmacologically acceptable salt, Z is selected from -CH2-, -CH2NH-, -CH2O-, -CH2-, -NH- or -NHSO2-, R 3a is a C 1-6 alkyl group, a C 1-6 halogenated alkyl group or a C 1-6 alkoxy group, preferably a C 1-3 alkyl group or a C 1-3 alkoxy group, more preferably a methyl group or a methoxymethyl group, R5 is a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 halogenated alkyl group or a C 1-6 alkoxy group, preferably a hydrogen atom and a C 1-3 alkyl group, R 19 is a cyano group, a halogen, a C 1-6 alkyl group, a C 1-6 halogenated alkyl group, a C 1-6 alkoxy group, -(CH2) n1 OR 23 、-(CH2) n1 S(O) m1 R 23 、-(CH2) n1 S(O)(=NR 23 )R 24 or -(CH2) n1 SR 23 selected from, preferably a cyano group, a halogen, a C 1-3 alkoxy group, a C 1-3 halogenated alkyl group, -(CH2) n1 SR 23 、-(CH2) n1 S(O) m1 R[[ID=​​​​​​and more preferably a halogen, or any two adjacent groups of R5 and R 19 can form a C 3-6 cycloalkyl group, preferably forming a cyclopropyl group.

[0024] In a preferred embodiment of the present invention, [[ID=Is]]

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0025] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), its stereoisomer or its pharmacologically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0026] The present invention further relates to the use of any compound represented by the general formula (I), its stereoisomer or its pharmacologically acceptable salt, or the pharmaceutical composition, in the manufacture of a GABA A receptor modulator.

[0027] The present invention further relates to the use of a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a drug for treating a CNS-related disorder, wherein the CNS-related disorder is selected from sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disorders, substance abuse disorders and / or withdrawal syndromes, or tinnitus.

[0028] The present invention further relates to a method for treating CNS-related diseases with a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0029] The present invention further relates to a method for the prevention and / or treatment of CNS-related diseases, comprising administering to a patient a therapeutically effective amount of a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [Modes for carrying out the invention]

[0030] Unless otherwise stated, terms used in the specification and claims have the following meanings.

[0031] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a linear or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl This includes the n-octyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.The alkyl group may be substituted or not, and if substituted, the substituent may be substituted at any available bond point, and the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups, and in the present invention, preferably, methyl groups, ethyl groups, isopropyl groups, tert-butyl groups, halogenated alkyl groups, deuterated alkyl groups, alkyl groups substituted with alkoxy groups, and alkyl groups substituted with hydroxyl groups.

[0032] The term "alkylene group" refers to an alkyl group in which one hydrogen atom is further substituted. For example, a "methylene group" is -CH2-, an "ethylene group" is -(CH2)2-, a "propylene group" is -(CH2)3-, and a "butylidene group" is -(CH2)4-. The term "alkenyl group" refers to the alkyl group defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, or a 1-, 2-, or 3-butenyl group. The alkenyl group may be substituted or not. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0033] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents. A cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups. Polycyclic cycloalkyl groups include spiro rings, fused rings, and bridged ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl groups.

[0034] The term "spirocycloalkyl group" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5 to 20 membered monocyclic rings and may contain one or more double bonds, but lacks rings with a fully conjugated π-electron system. Preferably, it has 6 to 14 members, and more preferably, 7 to 10 members. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups can be classified as monocyclic spirocycloalkyl groups, bicyclic spirocycloalkyl groups, or polycyclic spirocycloalkyl groups, but preferably monocyclic and bicyclic spirocycloalkyl groups. More preferably, it is a 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member monocyclic spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes, Furthermore, this also includes spirocycloalkyl groups in which monocyclic spirocycloalkyl groups and heterocycloalkyl groups share a spiro atom, and non-limiting examples include: [ka] Includes.

[0035] The term "condensed cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, and one or more rings may contain one or more double bonds, but there are no rings with a fully conjugated π-electron system. Preferably, it is 6-14 member, and more preferably 7-10 member. Depending on the number of constituent rings, it can be classified as a dicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl group, but preferably it is a dicyclic or tricyclic, and more preferably a 5-member / 5-member or 5-member / 6-member bicycloalkyl group. Non-limiting examples of condensed cycloalkyl groups are: [ka] Includes.

[0036] The term "bridged cycloalkyl group" refers to a 5-20 member all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly bonded, may contain one or more double bonds, but does not have a ring with a fully conjugated π-electron system. Preferably, it has 6-14 members, and more preferably, 7-10 members. Depending on the number of rings that make up the group, it can be classified as a dicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, but preferably it is dicyclic, tricyclic, or tetracyclic, and more preferably dicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka] Includes. The cycloalkyl ring may be condensed with an aryl group, a heteroaryl group, or a heterocycloalkyl ring, the ring bonded to the parent structure being a cycloalkyl group, and non-limiting examples include an indanyl group, a tetrahydronaphthyl group, a benzocycloheptane group, and the like. The alkynyl group may be optionally substituted or unsubstituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0037] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which are nitrogen, oxygen, or S(O). mThe heteroatom is selected from (where m is an integer from 0 to 2), but does not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 8 ring atoms, and most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl group, imidazolidinyl group, tetrahydrofuranyl group, tetrahydrothienyl group, dihydroimidazolyl group, dihydrofuranyl group, dihydropyrrole group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, pyranyl group, and 1,4-diazacyclo group, and preferably tetrahydrofuranyl group, pyrazolidinyl group, morpholinyl group, 1,4-diazacyclo group, piperazinyl group, and pyranyl group. Polycyclic heterocyclyl groups include spiro-ring, fused-ring, and bridged-ring heterocyclyl groups, which may be connected to other groups via single bonds or further connected in parallel rings to other cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups via any two or more atoms on the ring.

[0038] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group in which one atom (called a spiro atom) is shared between 5-20 membered monocyclic rings, and one or more ring atoms are nitrogen, oxygen, or S(O). mThe heteroatom is selected from (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but there are no rings with a fully conjugated π-electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of spiroatoms shared by the rings, the spiroheterocyclyl group can be divided into monocyclic spiroheterocyclyl groups, bicyclic spiroheterocyclyl groups, or polycyclic spiroheterocyclyl groups, preferably monocyclic and bicyclic spiroheterocyclyl groups. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monocyclic spiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0039] The term "condensed heterocyclyl group" refers to a 5-20 member polycyclic heterocyclyl group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, and one or more rings may contain one or more double bonds, but there are no rings with a fully conjugated π-electron system, and one or more ring atoms are nitrogen, oxygen, or S(O). m A heteroatom selected from (where m is an integer from 0 to 2), and the remaining ring atom is carbon. Preferably, it has 6 to 14 members, and more preferably, 7 to 10 members. Depending on the number of rings that make up the group, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl group, but preferably it is bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0040] The term "bridged ring heterocyclyl group" refers to a 5-14 member polycyclic heterocyclyl group in which any two rings share two carbon atoms that are not directly bonded, may contain one or more double bonds, but does not have a ring with a fully conjugated π-electron system, and one or more ring atoms are nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) is a heteroatom selected from the above, and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that make up the group, it can be divided into dicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl groups, but preferably it is dicyclic, tricyclic, or tetracyclic, more preferably dicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0041] The heterocyclic ring may be condensed with an aryl group, a heteroaryl group, or a cycloalkyl ring, the ring bonded to the parent structure being a heterocyclyl group, and non-limiting examples include: [ka] This includes, among others.

[0042] The heterocyclyl group may be optionally substituted or not substituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, or carboxylic acid ester groups.

[0043] The term "aryl group" refers to a 6-14 membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6-10 membered, such as a phenyl group and a naphthyl group. More preferably a phenyl group. The aryl ring may be fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, the ring bonded to the parent structure being an aryl ring, and non-limiting examples include: [ka] Includes.

[0044] The aryl group may or may not be substituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0045] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, with the heteroatoms selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, and is, for example, an imidazolyl group, furyl group, thienyl group, thiazolyl group, pyrazolyl group, oxazolyl group, pyrrolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, thiadiazole, pyrazinyl group, and is preferably a triazolyl group, tetrazolyl group, thienyl group, imidazolyl group, pyrazolyl group, pyridazine group, pyrimidinyl group, thiazolyl group, oxazolyl group, isoxazolyl group, or pyrimidinyl group, and is more preferably a triazolyl group, tetrazolyl group, pyrazolyl group, pyridyl group, pyridazine group, pyrimidinyl group, thiazolyl group, oxazolyl group, isoxazolyl group, or imidazolyl group. The heteroaryl ring may be condensed with an aryl group, a heterocyclyl group, or a cycloalkyl ring, the ring bonded to the parent structure being an aryl ring, and non-limiting examples include: [ka] Includes.

[0046] The heteroaryl group may be optionally substituted or not substituted. If substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0047] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), and the definition of alkyl group is as described above. Non-limiting examples of alkoxy groups include methoxy group, ethoxy group, propoxy group, butoxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, and cyclohexyloxy group. Alkoxy groups may or may not be substituted, and if substituted, the substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0048] A "halogenated alkyl group" refers to an alkyl group substituted with one or more halogens, and an alkyl group is as defined above.

[0049] A "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, and an alkoxy group is as defined above.

[0050] A "hydroxyalkyl group" refers to an alkyl group substituted with a hydroxyl group, and alkyl groups are defined as described above.

[0051] "Alkenyl group" refers to an olefin called an alkene, and the alkenyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0052] "Alkynyl group" refers to (CH≡C-), and the alkynyl group may be further substituted with other related groups, such as alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, or carboxylic acid ester groups.

[0053] The term "hydroxyl group" refers to the -OH group.

[0054] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0055] The term "amino group" refers to -NH2.

[0056] The term "cyano group" refers to -CN.

[0057] The term "nitro group" refers to -NO2.

[0058] The term "carboxyl group" refers to -C(O)OH.

[0059] "THF" refers to tetrahydrofuran.

[0060] "ELISA" refers to ethyl acetate.

[0061] "MeOH" refers to methanol.

[0062] "DMF" refers to N,N-dimethylformamide.

[0063] "DIPEA" refers to diisopropylethylamine.

[0064] "TFA" refers to trifluoroacetic acid.

[0065] "MeCN" refers to acetonitrile.

[0066] "DMA" refers to N,N-dimethylacetamide.

[0067] "Et2O" refers to ethyl ether.

[0068] "DCE" refers to 1,2-dichloroethane.

[0069] "DIPEA" refers to N,N-diisopropylethylamine.

[0070] "NBS" refers to N-bromosuccinimide.

[0071] "NIS" refers to N-iodosuccinimide.

[0072] "Cbz-Cl" refers to benzyl chloroformate.

[0073] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0074] "Dppf" refers to 1,1′-bis(diphenylphosphin)ferrocene.

[0075] "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.

[0076] "KHMDS" refers to potassium hexamethyldisilazide.

[0077] "LiHMDS" refers to lithium bis(trimethylsilyl)amide.

[0078] "MeLi" refers to methyllithium.

[0079] "nBuLi" refers to n-butyllithium.

[0080] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0081] The different terms "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all have the same meaning, indicating that X may be one or more of A, B, or C.

[0082] The hydrogen atoms in the present invention may all be substituted with their isotope, deuterium, and one of the hydrogen atoms in any of the compounds according to the examples of the present invention may be substituted with a deuterium atom.

[0083] "May" or "may" means that the situation or environment described later may occur, but is not necessarily so, and the description includes cases where the situation or environment occurs or does not occur. For example, "preferably a heterocyclic group substituted with an alkyl group" indicates that an alkyl group may be present, but is not necessarily so, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0084] "Substitutive" means that one or more hydrogen atoms in the group, preferably up to five, more preferably one to three, are independently substituted with a corresponding number of substituents. Needless to say, substituents are only present in possible chemical sites, and those skilled in the art can determine possible or impossible substitutions without effort (by experiment or theory). For example, instability may occur when an amino group or hydroxyl group with free hydrogen is bonded to a carbon atom with an unsaturated (e.g., ethylenically) bond.

[0085] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to exert physiological activity by promoting administration to a living organism and facilitating the absorption of the active ingredient.

[0086] "Pharmacologically acceptable salt" means a salt of the compound of the present invention, which is safe and effective when administered into the body of a mammal and has the desired biological activity. Modes for carrying out the invention

[0087] The present invention will be further described below with reference to examples, but these examples do not limit the scope of the present invention.

[0088] Examples The structure of the compounds of the present invention is determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is expressed in parts per million (ppm). For NMR measurements, a Bruker AVANCE-400 nuclear magnetometer is used, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0089] For measurements using liquid chromatography-mass spectrometry (LC-MS), an Agilent 1200 Infinity Series mass spectrometer is used. For measurements using HPLC, an Agilent 1200DAD high-performance liquid chromatography system (Sunfire C18 150×4.6mm chromatography column) and a Waters 2695-2996 high-performance liquid chromatography system (Gimini C18 150×4.6mm chromatography column) are used.

[0090] Thin-layer chromatography uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used in TLC are typically 0.15 mm to 0.20 mm in size, while those used for separating and purifying products by thin-layer chromatography are typically 0.4 mm to 0.5 mm in size. Column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200 to 300 as the support.

[0091] The starting materials for the examples of the present invention are known and can be purchased from the market or synthesized according to methods known in the art.

[0092] Unless otherwise specified, all reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, using a dry solvent, and the reaction temperature is measured in degrees Celsius.

[0093] Example 1 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Step 1: (8S,9S,10S,13S,14S)-10-fluoro-13-methyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-diketone [ka] (8R,9S,13S,14S)-3-hydroxyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthrene-17-ketone (2.7 g, 10 mmol) and acetonitrile (100 mL) were added in sequence to a 100 mL three-necked flask. 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo2,2,2-octanbis(tetrafluoroboric acid) salt (3.6 g, 10 mmol) was added while stirring. The mixture was heated in an oil bath to 45°C and reacted for 5 hours. After cooling to room temperature, the reaction mixture was concentrated, dissolved in dichloromethane (100 mL), washed with saturated brine (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to obtain (8S,9S,10S,13S,14S)-10-fluoro-13-methyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-diketone (1.8g, pale yellow solid, yield: 62.5%).

[0094] MS m / z (ESI): 289.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.12-7.05 (m, 1 H), 6.30-6.19 (m, 1H), 6.04 (s, 1H), 2.70-2.60 (m, 1H), 2.52-2.45 (m, 2H), 2.16-1.86 (m, 7H), 1.65-1.18 (m, 5H), 0.98 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -165.20. Step 2: (5R,8S,9S,10R,13S,14S)-10-fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-diketone [ka] (8S,9S,10S,13S,14S)-10-fluoro-13-methyl-7,8,9,10,11,12,13,14,15,16-decahydro-3H-cyclopenta[a]phenanthrene-3,17(6H)-diketone (1.8g, 6.25 mmol) was added to a 100 mL single-neck flask and dissolved in ethanol (50 mL). The mixture was stirred at room temperature for 2-3 minutes, then palladium-barium sulfate catalyst (300 mg) was added. After the addition was complete, the mixture was stirred at room temperature under a hydrogen gas atmosphere for 5 hours. The reaction mixture was filtered, dissolved in 20 mL of dichloromethane, and a white solid precipitated. This was filtered, and the filtrate was spin-dried. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to obtain (5R,8S,9S,10R,13S,14S)-10-fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-diketone (600 mg, white solid, yield: 32.9%).

[0095] 1 H NMR (400 MHz, CDCl3) δ 2.63-2.45 (m, 2H), 2.43-2.33 (m, 3H), 2.30-1.80 (m, 8H),1.75-1.55 (m, 5H), 1.45-1.35 (m, 3H), 1.25-1.18 (m, 1H), 0.94 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -159.89 . Step 3: (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-ketone [ka] 2,6-di-tert-butyl-4-methylphenol (1.45 g, 6.6 mmol) was added to a 100 mL three-necked flask and dissolved in anhydrous toluene (15 mL). The mixture was cooled to 0-5°C in an ice bath, and trimethylaluminum (1.7 mL, 2 M, 3.3 mmol) was added dropwise under nitrogen gas protection. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 1 hour. The reaction mixture was cooled to -78°C, and a solution of (5R,8S,9S,10R,13S,14S)-10-fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-diketone (320 mg, 1.1 mmol) in toluene (5 mL) was added dropwise to the reaction mixture. The reaction mixture was allowed to react at -78°C for 1 hour. Subsequently, methylmagnesium bromide (1.0 mL, 3 M, 3 mmol) was added dropwise, and the reaction mixture was allowed to react at -78°C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20 mL), and a large amount of white solid precipitated. The mixture was filtered, the filtrate was separated into layers, the organic phase was dried over anhydrous sodium sulfate, spin-dried, separated and purified by column chromatography (petroleum ether / ethyl acetate: 2 / 1) to obtain (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-ketone (250 mg, white solid, yield: 74.0%).

[0096] 1 H NMR (400 MHz, CDCl3) δ 2.46 (dd, J = 19.3, 8.7 Hz, 1H), 2.17 - 1.72 (m, 8H), 1.71 - 1.44 (m, 10H), 1.38 (s, 3H), 1.34 - 1.11 (m, 3H), 0.90 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -158.16 . Step 4: (3R,5R,8S,10R,13S,14S)-17-ethylene-10-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol [ka] Potassium t-butoxide (500 mg, 4.5 mmol) and tetrahydrofuran (15 mL) were added in sequence to a 100 mL three-necked flask. The reaction mixture was cooled to 0°C, and ethyltriphenylphosphonium bromide (1.82 g, 4.8 mmol) was added in several portions. The reaction mixture was stirred at 60°C for 2 hours. (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-ketone (250 mg, 0.75 mmol) was added to the reaction mixture, and the reaction mixture was allowed to react at 60°C for 8 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (20 mL), washed with saturated brine (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, spin-dried, and separated by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain (3R,5R,8S,10R,13S,14S)-17-ethylene-10-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (110 mg, white solid, yield 42%).

[0097] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.08 (m, 1H), 2.40-1.80 (m, 8H), 1.65 - 1.45 (m, 13H), 1.36 (s, 3H), 1.31 - 1.05 (m, 4H), 0.89 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -157.91 . Step 5: (3R,5R,8S,10R,13S,14S)-10-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol [ka] (3R,5R,8S,10R,13S,14S)-17-ethylene-10-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (110 mg, 0.35 mmol) was dissolved in dry tetrahydrofuran (5 mL), and borane-tetrahydrofuran complex (1.1 mL, 1 M, 1.05 mmol) was added at room temperature. After the addition was complete, the mixture was stirred for 1 hour. The reaction mixture was cooled in an ice bath, and NaOH (10%, 1.5 mL) was gradually added dropwise, releasing a large amount of gas. Then, hydrogen peroxide solution (30%, 2 mL) was gradually added dropwise, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was extracted with ethyl acetate (10 mL x 2), washed with 10% sodium thiosulfate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (3R,5R,8S,10R,13S,14S)-10-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (100 mg, white solid).

[0098] Step 6: 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] (3R,5R,8S,10R,13S,14S)-10-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (100 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), pyridinium chlorochromate (130 mg, 0.6 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate: 5 / 1) to obtain 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (80 mg, white solid, yield: 81%). 1 H NMR (400 MHz, CDCl3) δ 2.53 (t, J = 9.0 Hz, 1H), 2.23-2.16 (m, 1H), 2.12 (s, 3H), 2.10 - 1.83 (m, 5H), 1.73 - 1.42 (m, 12H), 1.38 (s, 3H), 1.35 - 1.02 (m, 4H), 0.64 (s, 3H).

[0099] Example 2 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile [ka] Step 1: 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (80 mg, 0.25 mmol) was dissolved in methanol (5 mL), 3 drops of hydrogen bromide and 3 drops of liquid bromine were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added to ice water and extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (80 mg, 81%), which was then used directly in the next reaction.

[0100] Step 2: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile [ka] 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and 4-cyanopyrazole (46 mg, 0.5 mmol) and potassium carbonate (84 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered, concentrated, and separated by prep-HPLC to obtain the product (25 mg, white solid, yield 30.3%).

[0101] MS m / z (ESI): 428.3[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.81 (s, 1H), 5.10-4.83 (m, 2H), 2.60 (t, J = 8.8 Hz, 1H), 2.28-2.18 (m, 1H), 2.15-2.07 (m, 2H), 2.05 -~ 1.75 (m, 5H), 1.69 - 1.45 (m, 10H), 1.38 (s, 3H), 1.35 - 1.23 (m, 3H), 1.19 - 1.07 (m, 1H), 0.70 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -158.28 .

[0102] Examples 3 and 4 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonitrile(3) 1-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonitrile(4) [ka] 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (80 mg, 0.2 mmol) was dissolved in tetrahydrofuran (5 mL), and 3-cyanopyrazole (46 mg, 0.5 mmol) and potassium carbonate (84 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was filtered, concentrated, and separated by prep-HPLC to obtain product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonitrile(3)(18mg, white A colored solid (yield 21.9%) and product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonitrile (4) (5 mg, white solid, yield 6.0%) were obtained.

[0103] Example 3: MS m / z (ESI): 428.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J =2.4 Hz, 1H), 6.74 (d, J =2.4 Hz, 1H), 5.15-4.85 (m, 2H), 2.60 (t, J = 8.9 Hz, 1H), 2.26-2.16 (m, 1H), 2.05-1.90 (m, 2H), 1.85 - 1.73 (m, 3H), 1.67 - 1.43 (m, 12H), 1.38 (s, 3H), 1.38 - 1.25 (m, 3H), 1.18 - 1.06 (m, 1H), 0.71 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -158.21 .

[0104] Example 4: MS m / z (ESI): 428.1[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J =2.4 Hz, 1H), 6.76 (d, J =2.4 Hz, 1H), 5.15-4.85 (m, 2H), 2.78 (dd, J = 8.0,2.8 Hz, 1H), 2.10-1.73 (m, 7H), 1.70 - 1.36 (m, 11H), 1.35 (s, 3H), 1.32 - 1.10(m, 4H), 0.98 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -158.42 .

[0105] Examples 5 and 6 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone(5) 1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone(6) [ka] Using 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)-2-(1H-tetrazole-1-yl)ethane-1-ketone (5) (35.5 mg, white solid, yield 43%) and 1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone (6) (12.3 mg, white solid, yield 14.9%) were obtained.

[0106] Example 5: MS m / z (ESI): 471.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 6.59 (d, J = 2.1 Hz, 1H), 5.05-4.92 (m, 2H), 2.59 (t, J = 8.8 Hz, 1H), 2.25-2.15 (m, 1H), 2.15-2.05 (m, 2H), 2.03 - 1.69 (m, 5H), 1.70 - 1.41 (m, 12H), 1.38 (s, 3H), 1.06 (m, 4H), 0.71 (s, 3H).

[0107] Example 6: MS m / z (ESI): 471.3[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 1.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 5.07-4.90 (m, 2H), 2.77 (dd, J = 7.9, 3.0 Hz, 1H), 2.12 - 1.72 (m, 9H), 1.72 - 1.38 (m, 11H), 1.34(s, 3H), 1.33-1.04(m, 4H), 0.96 (s, 3H). Examples 7 and 8 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone(7) 1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone(8) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2 -(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone (7) (22 mg, white solid, yield 32.9%) and product 1-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone (8) (8 mg, white solid, yield 11.5%) were obtained.

[0108] Example 7: MS m / z (ESI): 471.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.72 (s, 2H), 5.05 - 4.85(m, 2H), 2.60 (t, J = 8.0 Hz, 1H), 2.30-2.15 (m, 1H), 2.15-2.05 (m, 2H), 2.01 - 1.93 (m, 2H), 1.92 - 1.83 (m, 1H), 1.81 - 1.71 (m, 2H),1.71 - 1.43 (m, 10H), 1.38 (s, 3H), 1.35 - 1.25 (m, 3H), 1.19 - 1.10 (m, 1H), 0.71 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -56.44, -158.26 .

[0109] Example 8: MS m / z (ESI): 471.3[M+H]+ . 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.73 (s, 1H), 5.29 - 5.19 (m, 2H), 2.79 (dd, J = 7.9,2.7 Hz, 1H), 2.10-2.03 (m, 1H), 1.95-1.75 (m, 6H), 1.65 - 1.25 (m, 17H), 1.19 - 1.10 (m, 1H), 0.98 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -56.42, -158.43 .

[0110] Examples 9 and 10 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-ketone(9) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazole-2-yl)ethane-1-ketone(10) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 6, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17 The product obtained was -yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-ketone (9) (32 mg, white solid, yield 32.9%) and product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazole-2-yl)ethane-1-ketone (10) (20 mg, white solid, yield 20.5%).

[0111] Example 9: MS m / z (ESI): 404.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (s, 1H), 5.30 - 5.13 (m, 2H), 2.65 (t, J = 8.0 Hz, 1H), 2.25-2.15 (m, 1H), 2.13-2.03 (m, 2H), 2.05 - 1.75 (m, 5H), 1.68 - 1.43 (m, 10H), 1.38 (s, 3H), 1.35 - 1.25 (m, 3H), 1.19 - 1.10 (m, 1H), 0.71 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -158.26 .

[0112] Example 10: MS m / z (ESI): 404.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 2H), 5.24 (s, 2H), 2.57 (t, J = 8.0 Hz, 1H), 2.27-2.16 (m, 1H), 2.15-2.07 (m, 2H), 2.05 - 1.75 (m, 5H), 1.68 - 1.43 (m, 10H), 1.38 (s, 3H), 1.35 - 1.25 (m, 3H), 1.19 - 1.05 (m, 1H), 0.74 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -158.24 .

[0113] Example 11 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 8 of Example 6, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-methyl-1H-pyrazole-1-yl)ethane-1-ketone (11) (24 mg, white solid, yield 29%) was obtained.

[0114] MS m / z (ESI): 417.3[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.18 (s, 1H), 4.90-4.79 (m, 2H), 2.56 (t, J = 8.9 Hz, 1H), 2.27-2.13 (m, 1H), 2.11 (s, 3H), 2.06-1.80 (m, 4H), 1.80-1.40 (m, 11H), 1.38 (s, 3H), 1.35- 1.19 (m, 5H), 1.18 - 1.03 (m, 1H), 0.71 (s, 3H).

[0115] Examples 12 and 13 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(2H-tetrazole-2-yl)ethane-1-ketone(12) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(1H-tetrazole-1-yl)ethane-1-ketone(13) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, Product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a] Phenanthren-17-yl)-2-(2H-tetrazole-2-yl)ethane-1-ketone (12) (12 mg, white solid, yield 16%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-tetrazole-1-yl)ethane-1-ketone (13) (9 mg, white solid, yield 12%) were obtained.

[0116] Example 12: MS m / z (ESI): 405.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 5.46 (s, 2H), 2.64 (t, J = 8.0 Hz, 1H), 2.28-2.19 (m, 1H), 2.18-2.07 (m, 2H), 2.05 - 1.75 (m, 4H), 1.71 - 1.43 (m, 11H), 1.38 (s, 3H), 1.34 - 1.26 (m, 3H), 1.21 - 1.11 (m, 1H), 0.75 (s, 3H).

[0117] Example 13: MS m / z (ESI): 405.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 5.35 - 5.15 (m, 2H), 2.67 (t, J = 8.0 Hz, 1H), 2.30-2.19 (m, 1H), 2.15-2.07 (m, 1H), 2.05 - 1.75 (m, 4H), 1.68 - 1.45 (m, 11H), 1.39 (s, 3H), 1.35 - 1.25 (m, 4H), 1.20 - 1.10 (m, 1H), 0.71 (s, 3H).

[0118] Examples 14 and 15 2-(2H-benzo[d][1,2,3]triazole-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone(15) 2-(1H-benzo[d][1,2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone(16) [ka] Using 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 8 of Example 6, the product 2-(2H-benzo[d][1,2,3]triazole-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13- Dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (14) (11 mg, yield 14%) and 2-(1H-benzo[d][1,2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (15) (31 mg, yield 41%) were obtained.

[0119] Example 14: MS m / z (ESI): 453.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 6.6, 3.0 Hz, 2H), 7.40 (dd, J = 6.6, 3.0 Hz, 2H), 5.53 (t, J = 4.7 Hz, 2H), 2.64 (t, J = 8.9 Hz, 1H), 2.34 - 1.41 (m, 16H), 1.38 (s, 3H), 1.35 - 0.97 (m, 6H), 0.78 (s, 3H).

[0120] Example 15: MS m / z (ESI): 453.3[M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.46 -~ 7.30 (m, 2H), 5.42 (s, 2H), 2.70 (t, J = 8.5 Hz, 1H), 2.35 - 1.42 (m, 16H), 1.38 (s, 3H), 1.35 - 1.01 (m, 6H), 0.77 (s, 3H).

[0121] Examples 16 and 17 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(2H-pyrazolo[3,4-c]pyridyl-2-yl)ethane-1-ketone(16) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(1H-pyrazolo[3,4-c]pyridyl-1-yl)ethane-1-ketone(17) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 6, product 1-((3R,5R,8S,9 is prepared. We obtained phenanthren-17-yl)-2-(1H-tetrazole-1-yl)ethane-1-ketone (16) (9.2 mg, white solid, yield 10.5%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazole-2-yl)ethane-1-ketone (17) (16 mg, white solid, yield 18.3%).

[0122] Example 16: MS m / z (ESI): 454.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.72 (s, 1H), 5.42 - 5.25 (m, 2H), 2.70 (t, J = 8.0 Hz, 1H), 2.30-2.10 (m, 3H), 2.05-1.85 (m, 8H), 1.70 - 1.45 (m, 7H), 1.39 (s, 3H), 1.32 - 1.25 (m, 3H), 0.90-0.85 (m, 1H), 0.75 (s, 3H).

[0123] Example 17: MS m / z (ESI): 454.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 5.32 - 5.25 (m, 2H), 2.69 (t, J = 8.0 Hz, 1H), 2.25-2.10 (m, 3H), 2.05-1.75 (m, 5H), 1.70 - 1.45 (m, 10H), 1.39 (s, 3H), 1.35 - 1.25 (m, 3H), 1.20-1.10 (m, 1H), 0.76 (s, 3H).

[0124] Examples 18, 19, and 20 2-(5-fluoro-2H-benzo[d][1,2,3]triazole-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone(18) 2-(6-fluoro-1H-benzo[d][1,2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone(19) 2-(5-fluoro-1H-benzo[d][1,2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone(20) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, 2-(5-fluoro-2H-benzo[d][1,2,3]triazole-2-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (18) (20 mg, white solid, yield 14.9%), 2-(6-fluoro-1H-benzo[d][1 [2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (19) (18 mg, white solid, yield 13.1%) and 2-(5-fluoro-1H-benzo[d][1,2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (20) (19 mg, white solid, yield 13.9%) were obtained.

[0125] Example 18: MS m / z (ESI): 472.3[M+H] + . 11H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 9.3, 4.7 Hz, 1H), 7.47 (dd, J = 8.7, 1.9 Hz, 1H), 7.21 (m, 1H), 5.55 - 5.45 (m, 2H), 2.65 (t, J = 8.8 Hz, 1H), 2.32 - 2.08 (m, 3H), 2.04 - 1.45 (m, 15H), 1.38 (s, 3H), 1.35 - 1.23 (m, 3H), 1.20 - 1.10 (m, 1H), 0.78 (s, 3H).

[0126] Example 19: MS m / z (ESI): 472.3[M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J = 8.9, 4.4 Hz, 1H), 7.20 - 7.10 (m, 1H), 6.99 (d, J = 7.6 Hz, 1H), 5.45 - 5.35 (m, 2H), 2.69 (d, J = 8.7 Hz, 1H), 2.31 - 2.08 (m, 3H), 2.04 - 1.45 (m, 15H), 1.39 (s, 3H), 1.35 - 1.25 (m, 3H), 1.20 - 1.10 (m, 1H), 0.76 (s, 3H).

[0127] Example 20: MS m / z (ESI): 472.3[M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.9 Hz, 1H), 7.35 - 7.28 (m, 2H), 5.45 - 5.35 (m, 2H), 2.69 (d, J = 8.7 Hz, 1H), 2.31 - 2.08 (m, 3H), 2.04 - 1.45 (m, 15H), 1.39 (s, 3H), 1.35 - 1.25 (m, 3H), 1.20 - 1.10 (m, 1H), 0.76 (s, 3H).

[0128] Examples 21 and 22 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4,5,6,7-tetrahydro-2H-indazole-2-yl)ethane-1-ketone(21) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4,5,6,7-tetrahydro-1H-indazole-1-yl)ethane-1-ketone(22) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 6, 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4, 5,6,7-tetrahydro-2H-indazole-2-yl)ethane-1-ketone (21) (15.0 mg, white solid, yield 27.2%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4,5,6,7-tetrahydro-1H-indazole-1-yl)ethane-1-ketone (22) (8.0 mg, white solid, yield 12.1%) were obtained.

[0129] Example 21: MS m / z (ESI): 457.2[M+H] + . 11H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 4.90 - 4.85 (m, 2H), 2.72-2.66 (m, 2H), 2.62-2.52 (m, 3H), 2.25-1.40 (m, 22H), 1.37 (s, 3H), 1.33 - 1.23 (m, 3H), 1.17-1.07 (m, 1H), 0.71 (s, 3H).

[0130] Example 22: MS m / z (ESI): 457.2[M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 7.31 (s, 1H), 4.85 -~ 4.75 (m, 2H), 2.60-2.50 (m, 3H), 2.45-2.39 (m, 2H), 2.25-1.40 (m, 22H), 1.37 (s, 3H), 1.33 - 1.23 (m, 3H), 1.15-1.05 (m, 1H), 0.71 (s, 3H).

[0131] Example 23 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((4-fluorophenyl)amino)ethan-1-one [Chemical formula] Dissolve 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.2 mmol) in tetrahydrofuran (5 mL), and add 4-fluoroaniline (42 mg, 0.4 mmol) and triethylamine (60 mg, 0.6 mmol). Stir the reaction solution at room temperature for 5 h. Concentrate the reaction solution and separate it by prep-HPLC to obtain the product (18 mg, white solid, yield 21%).

[0132] MS m / z (ESI): 446.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.94-6.88 (m, 2H), 6.58 - 6.53(m, 2H), 3.96 -~ 3.85(m, 2H), 2.57 (t, J = 8.0 Hz, 1H), 2.30-2.20 (m, 1H), 2.15-2.06 (m, 1H), 2.05 -~ 1.71 (m, 6H), 1.68 - 1.43 (m, 10H), 1.38 (s, 3H), 1.34 - 1.20 (m, 3H), 1.18 - 1.07 (m, 1H), 0.68 (s, 3H).

[0133] Example 24 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((2-fluorophenyl)amino)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to Example 23, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((2-fluorophenyl)amino)ethane-1-ketone (11 mg, white solid, yield 20.5%) was obtained.

[0134] MS m / z (ESI): 446.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.04 - 6.92 (m, 2H), 6.71 - 6.61 (m, 1H), 6.60 - 6.52 (m, 1H), 4.03 - 3.86 (m, 2H), 2.58 (t, J = 8.8 Hz, 1H), 2.33 -~ 1.44 (m, 18H), 1.38 (s, 3H), 1.33 - 1.05 (m, 4H), 0.69 (s, 3H).

[0135] Example 25 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((3-fluorophenyl)amino)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to Example 23, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((3-fluorophenyl)amino)ethane-1-ketone (4.5 mg, white solid, yield 7.0%) was obtained.

[0136] MS m / z (ESI): 446.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.15 - 7.07 (m, 1H), 6.51 - 6.38 (m, 2H), 6.30 (d, J = 11.4 Hz, 1H), 3.98 - 3.85 (m, 2H), 2.57 (t, J = 8.8 Hz, 1H), 2.12 - 1.64 (m, 18H), 1.38 (s, 3H), 1.30 - 1.26 (m, 3H), 1.18 - 1.11 (m, 1H), 0.68 (s, 3H).

[0137] Example 26 2-((2,4-difluorophenyl)amino)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (80 mg, 0.193 mmol) was dissolved in tetrahydrofuran (3 mL), and 2,4-difluoroaniline (37 mg, 0.289 mmol) and potassium carbonate (53 mg, 0.438 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water (15 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with saturated brine (15 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated by preparative chromatography to obtain a white solid 2-((2,4-difluorophenyl)amino)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (7 mg, yield: 7.8%).

[0138] MS m / z (ESI): 464.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.84 - 6.70 (m, 2H), 6.50-6.45 (m, 1H), 3.98-3.88 (m, 2H), 2.57 (t, J = 8.9 Hz, 1H), 2.31 - 2.19 (m, 1H), 2.10 (m, 1H), 2.04 - 1.74 (m, 7H), 1.51 - 1.44 (m, 5H), 1.38 (s, 3H), 1.37 - 1.20 (m, 8H), 1.13 (m, 2H), 0.69 (s, 3H).

[0139] Example 27 5-Fluoro-2-((2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)amino)benzonitrile [ka] Dissolve 2-amino-5-fluorobenzonitrile (147 mg, 1.08 mmol) in tetrahydrofuran (5 mL) at 0°C, then add sodium hydride (29 mg, 0.72 mmol) and stir at 0°C for 40 minutes. Then, stir the mixed solution of 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (150 mg, 0.36 mmol) and tetrahydrofuran (2 mL) at 0°C for 30 minutes, and add water to the reaction mixture. (20 mL) was added, followed by extraction with ethyl acetate (20 mL x 3), the organic phase was combined and washed with saturated saline solution (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and then separated and purified by preparative chromatography to obtain 5-fluoro-2-((2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-carbonylethyl)amino)benzonitrile (10 mg, white solid, yield: 6%).

[0140] MS m / z (ESI): 471.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 9.6, 3.0 Hz, 1H), 7.10 -~ 7.01 (m, 1H), 6.62 (dd, J = 9.1, 4.5 Hz, 1H), 4.90 - 4.73 (m, 2H), 2.58 (t, J = 8.8 Hz, 1H), 2.28-1.78 (m, 9H), 1.65-1.58 (m, 3H), 1.61-1.44 (m, 4H),1.38(s, 3H), 1.31-1.26 (m, 4H), 1.15-1.09 (m, 2H), 0.90-0.86 (m, 2H), 0.73 (s, 3H).

[0141] Example 28 1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((3-fluoropyridine-4-yl)amino)ethane-1-ketone [ka] 4-amino-3-fluoropyridine (32.4 mg, 0.28 mmol) and 2-bromo-1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (60 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (5 mL), triethylamine (42.5 mg, 0.42 mmol) was added, and the mixture was stirred overnight at room temperature. 5 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed once with saturated saline solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated by prep-HPLC to obtain product 1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((3-fluoropyridine-4-yl)amino)ethane-1-ketone (6.1 mg, white solid, yield 9.7%).

[0142] MS m / z (ESI): 447.2[M+H] + .

[0143] Example 29 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(pyridazine-4-oxy)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(pyridazine-4-oxy)ethane-1-ketone (19 mg, white solid, yield 30.5%) was obtained.

[0144] MS m / z (ESI): 431.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.72 (s, 1H), 6.60 (s, 1H), 4.99 - 4.73 (m, 2H), 2.67 - 2.54 (m, 1H), 2.32 - 1.49 (m, 18H), 1.38 (s, 3H), 1.31 - 1.01 (m, 4H), 0.71 (s, 3H).

[0145] Examples 30 and 32 5-Fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile(30) 5-Fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile(32) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, the product 5-fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)-2-carbonylethoxy)benzonitrile (30) (14.5 mg, white solid, yield 21.2%) and 5-fluoro-2-(2-((3R,5R,8S,9S,10R,13S,14S,17R)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-carbonylethoxy)benzonitrile (32) (13.5 mg, white solid, yield 19.8%) were obtained.

[0146] Example 30: 1 H NMR (400 MHz, CDCl3) δ 7.31 (dd, J = 7.4, 3.1 Hz, 1H), 7.25 - 7.18 (m, 1H), 6.74 (dd, J = 9.3, 4.0 Hz, 1H), 4.69 - 4.53 (m, 2H), 2.90 (t, J = 8.7 Hz, 1H), 2.32 - 1.43 (m, 18H), 1.37 (s, 3H), 1.31 - 1.03 (m, 4H), 0.70 (s, 3H). Example 32: 1 H NMR (400 MHz, CDCl3) δ 7.37 - 7.32 (m, 1H), 7.25 - 7.17 (m, 2H), 5.67 - 5.40 (m, 2H), 3.40 (t, J = 8.9 Hz, 1H), 2.44 - 1.08 (m, 25H), 0.73 (s, 3H).

[0147] Example 31 3-Fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, the product 3-fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-carbonylethoxy)benzonitrile (13 mg, white solid, yield 19.0%) was obtained.

[0148] 1 H NMR (400 MHz, CDCl3) δ 7.50 - 7.34 (m, 2H), 6.86 (t, J = 8.4 Hz, 1H), 4.76 - 4.59 (m, 2H), 2.79 (t, J = 8.9 Hz, 1H), 2.29 - 1.42 (m, 17H), 1.38 (s, 3H), 1.34 - 1.07 (m, 5H), 0.70 (s, 3H).

[0149] Example 33 4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile (27.5 mg, white solid, yield 41.9%) was obtained.

[0150] 1 H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.65 - 4.52 (m, 2H), 2.77 (t, J = 8.7 Hz, 1H), 2.24 - 1.49 (m, 18H), 1.38 (s, 3H), 1.32 - 1.25 (m, 3H), 1.18 -1.06 (m, 1H), 0.71 (s, 3H).

[0151] Example 34 4-Fluoro-3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, the product 4-fluoro-3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile (32 mg, white solid, yield 46.9%) was obtained.

[0152] 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 1H), 7.20 (dd, J = 10.6, 8.4 Hz, 1H), 7.11 (dd, J = 7.6, 1.9 Hz, 1H), 4.76 - 4.51 (m, 2H), 2.77 (t, J = 8.9 Hz, 1H), 2.24 - 1.51 (m, 18H), 1.38 (s,3H), 1.32 - 1.23 (m, 3H), 1.19 - 1.06 (m, 1H), 0.71 (s, 3H).

[0153] Example 35 2-Fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)benzonitrile [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, the product 2-fluoro-4-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-carbonylethoxy)benzonitrile (23 mg, white solid, yield 33.7%) was obtained.

[0154] 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.27 (m, 1H), 7.20 (dd, J = 10.6, 8.4 Hz, 1H), 7.11 (dd, J = 7.6, 1.9 Hz, 1H), 4.76 - 4.51 (m, 2H), 2.77 (t, J = 8.9 Hz, 1H), 2.24 - 1.51 (m, 18H), 1.38 (s,3H), 1.32 - 1.23 (m, 3H), 1.19 - 1.06 (m, 1H), 0.71 (s, 3H).

[0155] Example 36 2-(2,4-difluorophenoxy)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxyl-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, the product 2-(2,4-difluorophenoxy)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (16.4 mg, white solid, yield 24.4%) was obtained.

[0156] 1 H NMR (400 MHz, Chloroform-d) δ 6.95 - 6.83 (m, 2H), 6.82 - 6.69 (m, 1H), 4.67 - 4.45 (m, 2H), 2.81 (t, J = 8.8 Hz, 1H), 2.36 - 2.16 (m, 1H), 2.14 - 2.04 (m, 1H), 2.03 - 1.78 (m, 4H), 1.76 - 1.69 (m, 1H), 1.65 - 1.44 (m, 11H), 1.37 (s, 3H), 1.32 - 1.21 (m, 3H), 1.19 - 0.99 (m, 1H), 0.69 (s, 3H).

[0157] Example 37 2-(4-chloro-1H-pyrazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 2-(4-chloro-1H-pyrazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (22 mg, white solid, yield 34.9%) was obtained.

[0158] MS m / z (ESI): 437.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.42 (s, 1H), 5.04-4.62 (m, 2H), 2.57 (t, J = 8.8 Hz, 1H), 2.31-1.45 (m, 18H), 1.38 (s, 3H), 1.33-1.23 (m, 3H), 1.18-1.05 (m, 1H), 0.70 (s, 3H).

[0159] Examples 38 and 39 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-3-methyl-1H-pyrazole-4-carbonitrile(38) 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-5-methyl-1H-pyrazole-4-carbonitrile(39) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl) is prepared as a starting material. (38)-2-carbonylethyl)-3-methyl-1H-pyrazole-4-carbonitrile (38) (16.5 mg, white solid, yield 19.5%) and 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-5-methyl-1H-pyrazole-4-carbonitrile (39) (9.5 mg, white solid, yield 11%) were obtained.

[0160] Example 38: MS m / z (ESI): 442.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 4.96 -~ 4.79 (m, 2H), 2.65 - 2.54 (m, 1H), 2.38 (s, 3H), 2.17 - 1.58 (m, 18H), 1.38 (s, 3H), 1.33 - 1.24 (m, 3H), 1.18 - 1.06 (m, 1H), 0.70 (s, 3H).

[0161] Example 39: MS m / z (ESI): 442.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 4.86 - 4.80 (m, 2H), 2.61 - 2.54 (m, 1H), 2.33 (s, 3H), 2.23 - 1.55 (m, 18H), 1.38 (s, 3H), 1.30 - 1.27 (m, 3H), 1.15 - 1.11 (m, 1H), 0.71 (s, 3H).

[0162] Example 40 3-Cyclopropyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-Fluoro-3-Hydroxyl-3,13-Dimethylhexadecahydro-1H-Cyclopenta[a]phenanthrene-17-yl)-2-Carbonylethyl)-1H-Pyrazole-4-Carbonitrile [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, the product 3-cyclopropyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitol (15 mg, white solid, yield 22.2%) was obtained.

[0163] MS m / z (ESI): 468.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 4.92 - 4.72 (m, 2H), 2.57 (t, J = 8.8 Hz, 1H), 2.26 - 1.40 (m, 19H), 1.38 (s, 3H), 1.37 - 1.05 (m, 4H), 1.05 - 0.91 (m, 4H), 0.69 (s, 3H).

[0164] Examples 41 and 42 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazole-2-yl)ethane-1-ketone(41) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazole-1-yl)ethane-1-ketone(42) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, Product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-1 7-yl)-2-(5-methyl-2H-tetrazole-2-yl)ethane-1-ketone (41) (23 mg, white solid, yield 22.8%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazole-1-yl)ethane-1-ketone (42) (6.5 mg, white solid, yield 6.5%) were obtained.

[0165] Example 41: MS m / z (ESI): 419.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 5.46 - 5.27 (m, 2H), 2.63 (d, J = 8.5 Hz, 1H), 2.57 (s, 3H), 2.31 - 1.46 (m, 18H), 1.38 (s, 3H), 1.35 - 1.03 (m, 4H), 0.75 (s, 3H).

[0166] Example 42: MS m / z (ESI): 419.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 5.19 - 5.02 (m, 2H), 2.66 (t, J = 8.5 Hz, 1H), 2.48 (s, 3H), 2.30 - 1.48 (m, 18H), 1.39 (s, 3H), 1.33 - 1.07 (m, 4H), 0.72 (s, 3H).

[0167] Example 43 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(thiazolyl-2-ylamino)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(thiazolyl-2-ylamino)ethane-1-ketone (13 mg, white solid, yield 20.7%) was obtained.

[0168] MS m / z (ESI): 435.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.37 (d, J = 4.9 Hz, 1H), 5.92 (d, J = 4.9 Hz, 1H), 4.70 - 4.46 (m, 2H), 2.68 (t, J = 8.9 Hz, 1H), 2.32 - 1.46 (m, 17H), 1.37 (s, 3H), 1.35 - 1.20 (m, 4H), 1.16 - 1.06 (m, 1H), 0.70 (s, 3H).

[0169] Example 44 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((1-methyl-1H-pyrazole-4-yl)amino)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to Example 23, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((1-methyl-1H-pyrazole-4-yl)amino)ethane-1-ketone (8.2 mg, white solid, yield 13.2%) was obtained.

[0170] MS m / z (ESI): 432.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 7.26 (s, 1H), 3.94 -~ 3.88 (m, 2H), 3.83 (s, 3H), 2.52 (t, J = 8.7 Hz, 1H), 2.27 - 1.46 (m, 16H), 1.37 (s, 3H), 1.33 - 1.05 (m, 6H), 0.65 (s, 3H).

[0171] Example 45 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(isothiazole-4-ylamino)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(isothiazole-4-ylamino)ethane-1-ketone (8.5 mg, white solid, yield 14.0%) was obtained.

[0172] MS m / z (ESI): 419.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.91 (s, 1H), 3.85 - 3.65 (m, 2H), 2.53 (t, J = 8.7 Hz, 1H), 2.23 - 1.72 (m, 8H), 1.51 - 1.13 (m, 17H), 0.67 (s, 3H).

[0173] Examples 46, 47, and 48 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)ethane-1-ketone(46) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)ethane-1-ketone(47) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)ethane-1-ketone(48) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazole-2-yl)ethane-1-ketone (46) (13.5 mg, white solid, yield 11.6%), 1-((3R,5R,8S,9S,10R ,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)ethane-1-ketone (47) (14 mg, white solid, yield 12.0%) and 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazole-1-yl)ethane-1-ketone (48) (14 mg, white solid, yield 12.0%) were obtained.

[0174] Example 46: MS m / z (ESI): 484.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.75 - 7.70 (m, 1H), 7.11 - 7.04 (m, 2H), 5.49 - 5.40 (m, 2H), 3.88 (s, 3H), 2.62 (t, J = 8.8 Hz, 1H), 2.30 - 1.46 (m, 18H), 1.38 (s, 3H), 1.34 - 1.10 (m, 4H), 0.78 (s, 3H).

[0175] Example 47: MS m / z (ESI): 484.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 9.0 Hz, 1H), 7.15 (dd, J = 9.0, 2.2 Hz, 1H), 5.39 - 5.35 (m, 2H), 3.90 (s, 3H), 2.70 - 2.64 (m, 1H), 2.26 - 1.45 (m, 18H), 1.38 (s, 3H), 1.32 - 1.12 (m, 4H), 0.76 (s, 3H).

[0176] Example 48: MS m / z (ESI): 484.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 9.1 Hz, 1H), 7.01 (dd, J = 9.1, 2.2 Hz, 1H), 6.60 (d, J = 2.2 Hz, 1H), 5.35 - 5.31 (m, 2H), 3.87 (s, 3H), 2.73 - 2.65 (m, 1H), 2.26 - 1.46 (m, 18H), 1.38 (s, 3H), 1.34 - 1.10 (m, 4H), 0.77 (s, 3H).

[0177] Example 49 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(pyrimidine-5-oxy)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(pyrimidine-5-oxy)ethane-1-ketone (10.3 mg, white solid, yield 20.0%) was obtained.

[0178] MS m / z (ESI): 431.2[M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.44 (s, 2H), 4.78 - 4.63 (m, 2H), 2.75-2.70 (m, 1H), 2.29-2.20 (m, 1H), 2.15-2.05 (m, 3H), 2.02-1.93 (m, 3H), 1.92 - 1.82 (m, 1H), 1.81-1.73 (m, 2H), 1.62-1.60 (m, 2H), 1.59 - 1.43 (m, 6H), 1.38 (s, 3H), 1.35-1.25 (m, 3H), 1.20-1.07 (m, 1H), 0.72 (s, 3H).

[0179] Example 50 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3,5-dicarbonitrile [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3,5-dicarbonitride (26 mg, white solid, yield 39.7%) was obtained.

[0180] MS m / z (ESI): 451.2[MH] - . 1 H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 5.19 - 5.14 (m, 2H), 2.63 (t, J = 8.9 Hz, 1H), 2.29 - 1.49 (m, 18H), 1.38 (s, 3H), 1.32 - 1.30 (m, 3H), 1.20 - 1.10 (m, 1H), 0.75 (s, 3H).

[0181] Example 51 3-Chloro-1-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 3-chloro-1-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile (12 mg, white solid, yield: 22%).

[0182] MS m / z (ESI): 462.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 4.98-4.85 (m, 2H), 2.58 (t, J = 8.5 Hz, 1H), 2.26-2.18 (m, 1H), 2.15 - 1.75 (m, 7H), 1.66 - 1.45 (m, 10H), 1.40 - 1.25 (m, 7H), 1.15-1.09 (m, 1H), 0.70 (s, 3H).

[0183] Example 52 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(oxazolyl-2-yl)-1H-pyrazole-1-yl)ethane-1-ketone [ka] Step 1: Preparation of 2-(1H-pyrazole-4-yl)oxazolyl [ka] A mixture of 1H-pyrazole-4-carbaldehyde (0.8 g, 8.33 mmol), 1-((isocyanomethyl)sulfonyl)-4-toluene (1.79 g, 9.16 mmol), potassium carbonate (2.53 g, 18.33 mmol), and methanol (20 mL) was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to dryness, separated and purified by column chromatography (dichloromethane / methanol = 10:1) to obtain a white solid 2-(1H-pyrazole-4-yl)oxazolyl (160 mg, yield: 14%).

[0184] MS m / z (ESI): 136.2[M+H] + . 1 H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 8.30 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.26 (s, 1H). Step 2: 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(oxazolyl-2-yl)-1H-pyrazole-1-yl)ethane-1-ketone [ka] A mixture of 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (60 mg, 0.14 mmol), 2-(1H-pyrazole-4-yl)oxazolyl (28 mg, 0.21 mmol), potassium carbonate (39 mg, 0.28 mmol), and tetrahydrofuran (3 mL). The mixture was stirred at room temperature for 16 hours, the reaction solution was concentrated to dryness under reduced pressure, separated and purified by preparative chromatography to obtain 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(oxazolyl-2-yl)-1H-pyrazole-1-yl)ethane-1-ketone (13 mg, white solid, yield: 20%).

[0185] MS m / z (ESI): 470.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.13 (s, 1H), 4.99-4.89 (m, 2H), 2.61 (t, J = 8.8 Hz, 1H), 2.28 - 2.18 (m, 1H), 2.15 - 2.08 (m, 2H), 2.03 - 1.82 (m, 4H), 1.78-1.76(m, 2H), 1.64-1.62 (m, 3H), 1.52 - 1.43 (m, 5H), 1.38 (s, 3H), 1.31-1.26 (m, 4H), 1.16-1.11 (m, 2H), 0.73 (s, 3H).

[0186] Examples 53 and 54 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazole-1-yl)ethane-1-ketone(53) 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(5-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazole-1-yl)ethane-1-ketone(54) [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(6-(2-hydroxypropane (53) (20 mg, white solid, yield 27.1%) and (54) (15 mg, white solid, yield 20.3%) were obtained.

[0187] Example 53: MS m / z (ESI): 511.3[M+H] + . 1H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.87 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 4.96 - 4.84 (m, 2H), 2.64 (t, J = 8.7 Hz, 1H), 2.31 - 2.17 (m, 1H), 2.16 -~ 2.06 (m, 2H), 2.04 - 1.93 (m, 2H), 1.92 -~ 1.75 (m, 2H), 1.71 - 1.43 (m, 15H), 1.39 (s, 3H), 1.35 - 1.20 (m, 5H), 1.18 - 1.05 (m, 1H), 0.75 (s, 3H).

[0188] Example 54: MS m / z (ESI): 511.3[M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J = 8.1 Hz, 1H), 5.12 - 4.89 (m, 2H), 2.68 (t, J = 8.2 Hz, 1H), 2.31 - 2.06 (m, 7H), 2.04 - 1.47 (m, 15H), 1.38 (s, 3H), 1.35 - 1.21 (m, 5H), 1.20 - 1.02 (m, 1H), 0.75 (s, 3H).

[0189] Example 55 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(methylthio)-1H-pyrazole-1-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(methylthio)-1H-pyrazole-1-yl)ethane-1-ketone (25 mg, white solid, yield 38%) was obtained.

[0190] MS m / z (ESI): 449.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.43 (s, 1H), 4.95-4.85 (m, 2H), 2.58 (t, J = 8.9 Hz, 1H), 2.35 (s, 3H), 2.25-2.17 (m, 1H), 2.10 (d, J = 11.4 Hz, 2H), 2.02 - 1.82 (m, 4H), 1.77-1.74 (m, 2H), 1.68 - 1.42 (m, 9H), 1.38 (s, 3H), 1.35 - 1.21 (m, 4H), 1.17 - 1.04 (m, 1H), 0.71 (s, 3H).

[0191] Example 56 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(methylsulfinyl<sulfinyl>)-1H-pyrazole-1-yl)ethane-1-ketone [ka] Dissolve 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylthio)-1H-pyrazole-1-yl)ethane-1-ketone (35 mg, 0.078 mmol) in dichloromethane (3 mL), then add metachloroperbenzoic acid (17 mg, 0.0858 mmol), stir at -78°C for 2 hours, quench with saturated sodium sulfite solution, and extract with ethyl acetate (20 mL x 3). The phases were combined and washed with saturated saline solution (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then separated and purified by preparative chromatography to obtain a white solid 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylsulfinyl<sulfinyl>)-1H-pyrazole-1-yl)ethane-1-ketone (25 mg, white solid, yield: 69%). MS m / z (ESI): 465.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 4.6 Hz, 2H), 4.96-4.85 (m, 2H), 2.90 (s, 3H), 2.61 (t, J = 8.7 Hz, 1H), 2.27 - 2.17 (m, 1H), 2.13-2.07 (m, 2H), 2.04 - 1.73 (m, 4H), 1.66-1.62 (m, 4H), 1.50-1.48 (m, 5H), 1.38 (s, 3H), 1.33 - 1.22 (m, 5H), 1.14-1.11(m, 2H), 0.71 (s, 3H).

[0192] Example 57 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-(methanesulfonyl)-1H-pyrazole-1-yl)ethane-1-ketone [ka] Dissolve 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methylthio)-1H-pyrazole-1-yl)ethane-1-ketone (15 mg, 0.033 mmol) in dichloromethane (3 mL), then add metachloroperbenzoic acid (17 mg, 0.1 mmol) and heat at room temperature for 6 The mixture was stirred for a certain amount of time, concentrated under reduced pressure to dryness, separated and purified by preparative chromatography to obtain 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(methanesulfonyl)-1H-pyrazole-1-yl)ethane-1-ketone (10 mg, white solid, yield: 63%).

[0193] MS m / z (ESI): 481.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (s, 1H), 4.99-4.90 (m, 2H), 3.13 (s, 3H), 2.62 (t, J = 8.7 Hz, 1H), 2.24-2.20 (m, 1H), 2.12-2.09 (m, 2H), 2.03 - 1.74 (m, 5H), 1.66-1.63 (m, 4H), 1.53 - 1.42 (m, 6H), 1.38 (s, 3H), 1.28 -1.26(m, 3H), 1.15 (m, 1H), 0.89-0.86 (m, 1H), 0.71 (s, 3H).

[0194] Example 58 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(4-nitro-1H-pyrazole-1-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-nitro-1H-pyrazole-1-yl)ethane-1-ketone (39 mg, white solid, yield: 60.3%) was obtained.

[0195] MS m / z (ESI): 448.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.08 (s, 1H), 5.08 - 4.81 (m, 2H), 2.62 (t, J = 8.7 Hz, 1H), 2.30 - 1.46 (m, 16H), 1.38 (s, 3H), 1.34 - 1.04 (m, 6H), 0.71 (s, 3H).

[0196] Example 59 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carboxylate ethyl ester [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carboxylate ethyl ester (32 mg, white solid, yield 46.6%) was obtained. MS m / z (ESI): 475.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.92 (s, 1H), 5.04 - 4.80 (m, 2H), 4.38 - 4.19 (m, 2H), 2.60 (t, J = 8.7 Hz, 1H), 2.27 - 1.45 (m, 21H), 1.38 (s, 3H), 1.37 - 1.25 (m, 3H), 1.20 - 1.07 (m, 1H), 0.71 (s, 3H).

[0197] Example 60 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide (10 mg, white solid, yield 14.6%) was obtained.

[0198] MS m / z (ESI): 474.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H), 5.09 - 4.82 (m, 2H), 3.16 (s, 6H), 2.69 - 2.53 (m, 1H), 2.30 - 1.45 (m, 18H), 1.38 (s, 3H), 1.32 - 1.05 (m, 4H), 0.72 (s, 3H).

[0199] Example 61 N-ethyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-N-methyl-1H-pyrazole-4-carboxamide [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, the product N-ethyl-1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-N-methyl-1H-pyrazole-4-carboxamide (14 mg, white solid, yield 19.8%) was obtained by referring to step 2 of Example 2.

[0200] MS m / z (ESI): 488.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.73 (s, 1H), 5.02 - 4.80 (m, 2H), 3.66 - 3.44 (m, 2H), 3.28 - 2.93 (m, 3H), 2.60 (t, J = 8.6 Hz, 1H), 2.30 - 1.45 (m, 18H), 1.38 (s, 3H), 1.34 - 1.06 (m, 7H), 0.71 (s, 3H).

[0201] Example 62 2-(4-(azetidine-1-carbonyl)-1H-pyrazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 2-(4-(azetidine-1-carbonyl)-1H-pyrazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (12 mg, white solid, yield: 17.1%) was obtained.

[0202] MS m / z (ESI): 486.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.76 (s, 1H), 5.02 - 4.82 (m, 2H), 4.39 - 4.21 (m, 4H), 2.59 (t, J = 8.5 Hz, 1H), 2.46 - 1.59 (m, 20H), 1.38 (s, 3H), 1.34 - 1.19 (m, 3H), 1.17 - 1.05 (m, 1H), 0.71 (s, 3H).

[0203] Examples 63 and 64 2-(4-Cyclopropyl-2H-1,2,3-Triazol-2-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone(63) 2-(4-Cyclopropyl-1H-1,2,3-Triazole-1-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-Fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone(64) [ka] Step 1: Preparation of 4,5-dibromo-2H-1,2,3-triazole [ka] Liquid bromine (3 mL) was gradually added dropwise to a solution of 2H-1,2,3-triazole (3 g, 43.43 mmol) in water (30 mL) at 0°C, causing a pale yellow solid to precipitate. The mixture was then stirred at room temperature for 16 hours, the reaction solution was filtered, the cake was washed with water (20 mL), and the cake was dried. Without further purification, the cake was used directly in the next step to obtain 4,5-dibromo-2H-1,2,3-triazole (5.7 g, white solid, yield: 58%).

[0204] MS m / z (ESI): 227.2[M+H] + . Step 2: Preparation of 4-bromo-2H-1,2,3-triazole [ka] 4,5-dibromo-2H-1,2,3-triazole (5.7 g, 25.13 mmol) was suspended in water (50 mL), then sodium sulfite (9.5 g, 75.38 mmol) was added and the mixture was stirred at 100°C for 3 days. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (30 mL x 6). The organic phases were combined and washed with saturated saline solution (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 4-bromo-2H-1,2,3-triazole (3 g, white solid, yield: 81%).

[0205] MS m / z (ESI): 148.2 [M+H] + , 150.2 [M+2+H] + . Step 3: Preparation of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole [ka] 4-bromo-2H-1,2,3-triazole (2 g, 13.51 mmol) at 0°C was added gradually to tetrahydrofuran (20 mL) with sodium hydride (760 mg, 18.9 mmol), then stirred at 0°C for 0.5 hours, followed by dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.48 g, 14.86 mmol). After the addition was complete, the mixture was stirred at room temperature for 2 hours, water (50 mL) was added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was separated and purified by column chromatography to obtain 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (1.4 g, white solid, yield: 38%).

[0206] MS m / z (ESI): 278.2 [M+H] + , 280.2 [M+2+H] + . Step 4: Preparation of 4-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole [ka] 4-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (0.5 g, 1.79 mmol) and potassium cyclopropyltrifluoroborate (530 mg, 3.58 mmol) were dissolved in 1,4-dioxane (10 mL), then [1,1'-bis(diphenylphosphine)ferrocene]palladium chloride (0.5 g, 1.79 mmol) and sodium carbonate (0.5 g, 1.79 mmol) were added, and after purging with nitrogen gas three times, the mixture was stirred at 100°C for 16 hours under nitrogen gas protection. The mixture was filtered over soil, the filtrate was concentrated under reduced pressure to obtain a residue, water (30 mL) was added to the residue, and then extracted with ethyl acetate (30 mL x 3). The organic phase was combined and washed with saturated brine (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to dryness, separated and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain 4-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (70 mg, pale yellow oily substance, yield: 16%).

[0207] MS m / z (ESI): 240.2 [M+H] + . Step 5: Preparation of 4-cyclopropyl-2H-1,2,3-triazole [ka] 4-Cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (50 mg, 0.208 mmol) was dissolved in dichloromethane (1 mL), then trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction mixture, and saturated sodium carbonate solution was added to adjust the pH to 8. The mixture was then extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with saturated saline solution (50 mL), the organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 4-Cyclopropyl-2H-1,2,3-triazole (35 mg, white solid, crude product).

[0208] MS m / z (ESI): 110.2 [M+H] + . Step 6: Preparation of 2-(4-cyclopropyl-2H-1,2,3-triazole-2-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (63) and 2-(4-cyclopropyl-1H-1,2,3-triazole-1-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (64) [ka] A mixed solution of 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (80 mg, 0.193 mmol) and tetrahydrofuran (3 mL) was added to potassium carbonate (80 mg, 0.579 mmol), then stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (30 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Separation and purification were performed by preparative chromatography to obtain a white solid 2-(4-cyclopro Pyr-2H-1,2,3-triazole-2-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (63) (34 mg, white solid, yield 39.8%) and white solid 2-(4-cyclopropyl-1H-1,2,3-triazole-1-yl)-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (64) (14 mg, white solid, yield 16.4%) were obtained.

[0209] Example 63: MS m / z (ESI): 444.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 5.15-5.05 (m, 2H), 3.91 (d, J = 3.0 Hz, 1H), 2.61 - 2.47 (m, 1H), 2.25-2.08 (m, 4H), 2.04 - 1.81 (m, 5H), 1.78-1.71 (m, 2H), 1.54 - 1.42 (m, 6H), 1.37 (s, 3H), 1.33 - 1.20 (m, 4H), 1.18 - 1.04 (m, 2H), 0.99-0.96 (m, 2H), 0.80 - 0.75 (m, 2H), 0.73 (s, 3H).

[0210] Example 64: MS m / z (ESI): 444.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 5.16-5.06 (m, 2H), 3.91 (d, J = 3.0 Hz, 1H), 2.54 (t, J = 8.8 Hz, 1H), 2.24-2.09 (m, 4H), 2.04 - 1.81 (m, 5H), 1.78-1.70 (m, 2H), 1.54- 1.42 (m, 6H), 1.37 (s, 3H), 1.31-1.22 (m, 4H), 1.18 - 1.04 (m, 2H), 0.99 - 0.96 (m, 2H), 0.80-0.76(m, 2H), 0.73 (s, 3H).

[0211] Example 66 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-((2-(trifluoromethyl)pyrimidine-5-yl)oxo)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidine-5-yl)oxo)ethane-1-ketone (39.2 mg, white solid, yield 65.5%) was obtained.

[0212] MS m / z (ESI): 499.2[M+H] + . 1 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 2H), 4.84 - 4.70 (m, 2H), 2.68 (t, J = 8.9 Hz, 1H), 2.23 (m, 1H), 2.09 (d, J = 10.8 Hz, 1H), 1.98 (t, J = 12.6 Hz, 3H), 1.91 - 1.83 (m, 1H), 1.79 (t, J = 8.4 Hz, 2H), 1.60 - 1.52 (m, 4H), 1.48 (dd, J = 19.5, 12.9 Hz, 5H), 1.38 (s, 3H), 1.35 - 1.21 (m, 4H), 1.20 - 1.05 (m, 1H), 0.73 (s, 3H). Example 67 3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)thiazolidined-2,4-diketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 3-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)thiazolidinedione-2,4-diketone (18.5 mg, white solid, yield 28.3%) was obtained.

[0213] 1 H NMR (400 MHz, CDCl3) δ 4.43 - 4.32 (m, 2H), 4.03 (s, 2H), 2.56 (t, J = 8.7 Hz, 1H), 2.21 - 1.54 (m, 18H), 1.37 (s, 3H), 1.32 - 1.25 (m, 3H), 1.17 - 1.08 (m, 1H), 0.68 (s, 3H).

[0214] Example 68 (1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-2-azabicyclo[3.1.0]hexane-3-carbonyl [ka] Step 1: Preparation of tert-butyl(1R,3R,5R)-3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylic acid ester [ka] To a suspension of tert-butyl(1R,3R,5R)-3-carbamyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid (2g, 8.85 mmol) and pyridyl (25 mL) at -20°C, trifluoroacetic anhydride (5 mL, 35.3 mmol) was gradually added dropwise, the mixture was stirred at -20°C for 1 hour, then the temperature was raised to room temperature and stirred for 8 hours, the reaction mixture was quenched by adding ice water, and then extracted with ethyl acetate (3 (0 mL x 3) The organic phases were combined and washed with dilute hydrochloric acid (10%), then washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Separation and purification were performed by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain tert-butyl(1R,3R,5R)-3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylic acid ester (1.5 g, white solid, yield: 83%).

[0215] 1 H NMR (400 MHz, CDCl3) δ 4.71 (dd, J = 41.1, 9.6 Hz, 1H), 3.58 (d, J = 33.8 Hz, 1H), 2.63 - 2.47 (m, 1H), 2.35 (d, J = 12.7 Hz, 1H), 1.70-1.60 (m, 1H), 1.52 (s, 9H), 1.02 (s, 1H), 0.90-0.81 (m, 1H). Step 2: Preparation of (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carbonitrile [ka] 0.8 g, 3.85 mmol of tert-butyl(1R,3R,5R)-3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylic acid ester was dissolved in 2 mL of dioxane, then 8 mL of hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried to dryness. 50 mL of water was added to the residue, and then the mixture was extracted with (dichloromethane / methanol = 10:1). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and dried to dryness to obtain (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carbonitrile (0.5 g, brown oily substance, crude product).

[0216] Step 3: Preparation of (1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-2-azabicyclo[3.1.0]hexane-3-carbonilite [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, the product (1R,3R,5R)-2-(2-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-2-azabicyclo[3.1.0]hexane-3-carbonyl (12 mg, white solid, yield: 23%) was obtained.

[0217] MS m / z (ESI): 443.2 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 4.08 (s, 2H), 3.70 (s, 2H), 2.49 (t, J = 8.7 Hz, 1H), 2.24 - 2.16 (m, 2H), 2.12 - 1.82 (m, 11H), 1.74-1.70(m, 2H), 1.60-1.48(m, 6H), 1.37 (s, 3H), 1.31-1.25 (m, 6H), 1.12-1.07 (m, 1H), 0.65 (s, 3H).

[0218] Example 69 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((1-methyl-1H-pyrazole-4-yl)oxo)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((1-methyl-1H-pyrazole-4-yl)oxo)ethane-1-ketone (20 mg, white solid, yield 32.0%) was obtained.

[0219] MS m / z (ESI): 433.3[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.08 (s, 1H), 4.48 - 4.28 (m, 2H), 3.82 (s, 3H), 2.74 (t, J = 8.9 Hz, 1H), 2.22 - 1.50 (m, 18H), 1.37 (s, 3H), 1.30 - 1.10 (m, 4H), 0.68 (s, 3H).

[0220] Example 70 7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)quinoline-1-nitrogen oxide [ka] Step 1: Preparation of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-(quinoline-7-oxy)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(quinoline-7-oxy)ethane-1-ketone (60.0 mg, white solid, yield 52.1%) was obtained.

[0221] MS m / z (ESI): 480.2[M+H] + . Step 2: Preparation of 7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethoxy)quinoline-1-nitrogen oxide [ka] 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(quinoline-7-oxy)ethane-1-ketone (60 mg, 0.125 mmol) and dichloromethane (10 ml) were added to a 100 ml single-neck flask, followed by the addition of metachloroperbenzoic acid (78 mg, 0.313 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution and then concentrated. The concentrated crude product was purified by prep-HPLC to obtain 7-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-carbonylethoxy)quinoline-1-nitrogen oxide (29.2 mg, white solid, yield 47.1%).

[0222] MS m / z (ESI): 496.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.43 (dd, J = 9.0, 2.4 Hz, 1H), 7.26 - 7.20 (m, 1H), 4.87 - 4.73 (m, 2H), 2.83-2.75 (m, 1H), 2.33-2.21 (m, 1H), 2.13-2.07 (m, 1H), 2.06-1.95 (m, 4H), 1.94-1.84 (m, 2H), 1.82-1.74 (m, 2H), 1.62-1.42 (m, 8H), 1.38 (s, 3H), 1.35 - 1.25 (m, 3H), 1.20-1.06 (m, 1H), 0.75 (s, 3H).

[0223] Example 71 N-(2-((3S,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)benzenesulfonamide [ka] Benzenesulfonamide (28 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (7.2 mg, 0.18 mmol) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. 2-bromo-1-((3S,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (50 mg, 0.12 mmol) was added at 0°C, and the mixture was stirred overnight at room temperature. 5 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). After washing once with saturated saline (20 mL), the organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated by prep-HPLC to obtain the product (7.1 mg, white solid, yield 12%).

[0224] 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 5.48 (s, 1H), 3.87 - 3.68 (m, 2H), 2.36 (t, J = 8.9 Hz, 1H), 2.06-2.08 (m, 2H), 1.94-1.97 (m, 2H), 1.90-1.80 (m, 1H), 1.71 - 1.62 (m, 4H), 1.52 - 1.39 (m, 6H), 1.37 (s, 3H), 1.34 - 1.25 (m, 4H), 1.24 - 1.01 (m, 3H), 0.38 (s, 3H).

[0225] Example 72 (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-N-(4-fluorophenyl)-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide [ka] Step 1: Preparation of (3R,5R,8S,9S,10R,13S,14S)-10-fluoro-3,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol [ka] Potassium tert-butoxide (4.36 g, 38.961 mmol) was added to a solution of methyltriphenylphosphonium bromide (13.9 g, 38.961 mmol) and tetrahydrofuran (50 mL), and the mixture was stirred at 65°C for 1 hour. A mixed solution of (3R,5R,8S,9S,10R,13S,14S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-ketone (2 g, 6.494 mmol) and tetrahydrofuran (30 mL) was then added dropwise, and the mixture was stirred at 65°C for 1 hour. The reaction mixture was cooled to room temperature, water was added to quench it, and then extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Separation and purification were performed by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain (3R,5R,8S,9S,10R,13S,14S)-10-fluoro-3,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (1.8 g, white solid, yield: 90%).

[0226] Step 2: Preparation of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-17-(hydroxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol [ka] (3R,5R,8S,9S,10R,13S,14S)-10-fluoro-3,13-dimethyl-17-methylenehexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (0.5 g, 1.634 mmol) is dissolved in tetrahydrofuran (8 mL), then borane-tetrahydrofuran (8.2 mL, 8.169 mmol) is added dropwise, the mixture is stirred at room temperature for 1.5 hours, then cooled to 0°C, and a solution of sodium hydroxide (327 mg, 8.169 mmol) in water (3 mL) is added dropwise, followed by a solution of hydrogen peroxide (3 mL) 30%) was gradually added dropwise, followed by stirring at room temperature for 1.5 hours. Water (50 mL) was added to the reaction mixture, then extracted with ethyl acetate (50 mL x 3). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-17-(hydroxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (600 mg, crude product).

[0227] Step 3: Preparation of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid [ka] (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-17-(hydroxymethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (400 mg, 1.234 mmol), N,N-dimethylformamide (15 mL), and water (1 mL) are mixed with pyridinium dichromate (4.6 g, 12.34 mmol), and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then mixed with saturated sodium sulfite solution (50 The mixture was quenched with (40 mL x 3) added, then extracted with ethyl acetate, washed with saturated brine after combining the organic phases, dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated the filtrate under reduced pressure to dryness to obtain a pale yellow solid (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid (400 mg, pale yellow solid, crude product).

[0228] 1 H NMR (400 MHz, DMSO) δ 11.92 (s, 1H), 4.38 (s, 1H), 2.90-2.70 (m, 2H), 2.05 - 1.52 (m, 9H), 1.39-1.19(m, 15H), 0.61 (s, 3H). Step 4: Preparation of (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-N-(4-fluorophenyl)-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide [ka] A mixture of 3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxylic acid (200 mg, 0.592 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate (270 mg, 0.71 mmol), triethylamine (119 mg, 1.18 mmol), and dichloromethane (5 mL) was stirred at room temperature for 30 minutes, and then 4-fluoroaniline (79 mg, 0.71 mmol) was added. l) was added and stirred at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture, and then it was extracted with dichloromethane (40 mL x 3). The organic phases were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Separation and purification were performed by preparative chromatography to obtain (3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-N-(4-fluorophenyl)-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-carboxamide (25 mg, white solid, yield: 10%).

[0229] MS m / z (ESI): 432.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.51 - 7.41 (m, 2H), 7.05-6.95 (m, 2H), 2.43 - 2.17 (m, 2H), 2.14 - 1.80 (m, 8H), 1.72-1.69 (m, 3H), 1.51 - 1.11 (m, 15H), 0.93 (s, 3H).

[0230] Example 73 2-((4-fluoro-2-methoxyphenyl)amino)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material, and referring to Example 23, the product 2-((4-fluoro-2-methoxyphenyl)amino)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (29 mg, white solid, yield 42.2%) was obtained.

[0231] MS m / z (ESI): 476.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 6.61 - 6.49 (m, 2H), 6.40 - 6.31 (m, 1H), 3.91 (d, J = 6.3 Hz, 2H), 3.87 - 3.82 (m, 3H), 2.58 (t, J = 8.8 Hz, 1H), 2.31 - 1.42 (m, 18H), 1.38 (s, 3H), 1.35 - 1.03 (m, 4H), 0.69 (s, 3H).

[0232] Example 79A 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-(fluoromethyl)-3-hydroxyl-3,13-dimethylhexahydrodecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] This embodiment 79A is synthesized according to the following specific embodiment. [ka]

[0233] Example 82A 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-(difluoromethyl)-3-hydroxyl-3,13-dimethylhexahydrodecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] This embodiment 82A is synthesized according to the following specific embodiment.

[0234] [ka]

[0235] Example 90 1-(2-((2R,4aR,4bS,6aS,8bS,8cR,10aR)-2-hydroxylmethyl-4a-(methoxymethyl)-2,6a-dimethylhexadecahydrocyclopentadiene[4,5]cyclopenta[1,2-α]phenanthrene-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] This embodiment 90 is synthesized according to the following specific embodiment. [ka] MS m / z (ESI): 465.3 [M] + .

[0236] Example 91 1-(2-((2R,4aR,4bS,6aS,8bS,8cR,10aR)-2-hydroxylmethyl-4a-(methoxymethyl)-2,6a-dimethylhexadecahydrocyclopentadiene[4,5]cyclopenta[1,2-α]phenanthrene-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile [ka] MS m / z (ESI): 465.3 [M] + .

[0237] Example 92 1-(2-((2R,4aR,4bS,6aS,8bS,8cR,10aR)-2-thiomethyl-4a-(methoxymethyl)-2,6a-dimethylhexadecahydrocyclopentadiene[4,5]cyclopenta[1,2-α]phenanthrene-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] This embodiment 92 is synthesized by the following specific embodiment. [ka] MS m / z (ESI): 469.3 [M] + .

[0238] Example 93 2-(5-chloro-1H-benzo[d][1,2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-((methylthio)methyl)hexahydrodecahydro-1H-cyclopenta[a]phenanthren-17-yl)eth-1-ketone [ka] MS m / z (ESI): 529.3 [M] + .

[0239] Example 94 2-(4,5-difluoro-1H-benzo[d][1,2,3]triazole-1-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxyl-3,13-dimethyl-10-((methylthio)methyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethanol-1-ketone [ka] MS m / z (ESI): 531.3 [M] + .

[0240] Example 95 2-(3H-[1,2,3]triazolo[4,5-b]pyridyl-3-yl)-1-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxyl-3,13-dimethyl-10-((methylthio)methyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethanol-1-ketone [ka] MS m / z (ESI): 496.3 [M] + .

[0241] Example 96 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxyl-3,13-dimethyl-10-((methylsulfonyl)methyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] MS m / z (ESI): 501.3 [M] + .

[0242] Example 97 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-3-hydroxyl-3,13-dimethyl-10-((S-methylsulfonimidoyl)methyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile [ka] MS m / z (ESI): 500.3 [M] + . MS m / z (ESI): 456.3 [M] + .

[0243] Example 114 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile [ka] Step 1: (5R,8S,10R,13S,14S)-10-fluoro-13-methyltetradecahydrospiro[cyclopenta[a]phenanthr-3,2'-oxyranyl]-17(2H)-ketone [ka] Trimethylsulfoxonium iodide (2.65 g, 12 mmol) and tetrahydrofuran (50 mL) were added sequentially to a 100 mL three-necked flask, and potassium t-butoxide (1.35 g, 12 mmol) was added while stirring. The reaction mixture was stirred at room temperature for 0.5 hours. (5R,8S,9S,10R,13S,14S)-10-fluoro-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-diketone (3.0 g, 10 mmol) was added to the reaction mixture, and the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL), washed with brine (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to obtain (5R,8S,10R,13S,14S)-10-fluoro-13-methyltetradecahydrospiro[cyclopenta[a]phenanthro-3,2'-oxyranyl]-17(2H)-ketone (2.5g, pale yellow solid, yield: 79.5%).

[0244] 1 H NMR (400 MHz, CDCl3) δ 2.72 - 2.67 (m, 2H), 2.52 - 2.43 (m, 1H), 2.31 - 1.06 (m, 21H), 0.92 (s, 3H). Step 2: (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-ketone [ka] (5R,8S,10R,13S,14S)-10-fluoro-13-methyltetradecahydrospiro[cyclopenta[a]phenanthr-3,2'-oxyranyl]-17(2H)-ketone (2.5 g, 7.5 mmol) was added to a 100 mL single-neck flask and dissolved in methanol (50 mL). The mixture was stirred at room temperature for 2-3 minutes, then sodium methoxide (1.25 g, 22.5 mmol) was added. After the addition was complete, the mixture was stirred at 60 °C for 5 hours. The reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate (30 mL), washed with saline solution (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate: 3 / 1) to obtain (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-ketone (1.6 g, pale yellow solid, yield: 57.9%).

[0245] 1 H NMR (400 MHz, CDCl3) δ 3.39 (s, 3H), 3.21 (s, 2H), 2.51 - 2.40 (m, 1H), 2.37 - 1.04 (m, 21H), 0.90 (s, 3H). Step 3: (3R,5R,8S,10R,13S,14S)-17-ethylene-10-fluoro-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol [ka] Using (3R,5R,8S,10R,13S,14S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-ketone as a starting material, the product (3R,5R,8S,10R,13S,14S)-17-ethylene-10-fluoro-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (600 mg, white solid, yield 36.2%) was obtained by referring to step 4 of Example 1.

[0246] 1 H NMR (400 MHz, CDCl3) δ 5.18 - 4.96 (m, 1H), 3.39 (s, 3H), 3.20 (s, 2H), 2.44 - 0.99 (m, 25H), 0.90 (s, 3H). Step 4: (3R,5R,8S,10R,13S,14S,17R)-10-fluoro-17-(1-hydroxyethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol [ka] Using (3R,5R,8S,10R,13S,14S)-17-ethylene-10-fluoro-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol as a starting material, the product (3R,5R,8S,10R,13S,14S,17R)-10-fluoro-17-(1-hydroxyethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol (600 mg, white solid, yield 95.1%) was obtained by referring to step 5 of Example 1.

[0247] Step 5: 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Using (3R,5R,8S,10R,13S,14S,17R)-10-fluoro-17-(1-hydroxyethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-phenol as a starting material, and referring to step 6 of Example 1, product 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (500 mg, white solid, yield 83.7%) was obtained.

[0248] 1 H NMR (400 MHz, CDCl3) δ 3.40 (s, 3H), 3.21 (s, 2H), 2.56 - 2.47 (m, 1H), 2.39 - 2.16 (m, 4H), 2.12 (s, 3H), 2.07 - 0.98 (m, 18H), 0.65 (s, 3H). Step 6: 2-Bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Using 1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material and referring to Step 1 of Example 2, product 2-bromo-1-((3R,5R,8S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone (500 mg, white solid, yield 82.2%) was obtained.

[0249] Step 7: 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile [ka] Using 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material and referring to step 2 of Example 2, product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile (11 mg, white solid, yield 17.8%) was obtained.

[0250] MS m / z (ESI): 458.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.82 (s, 1H), 5.04 - 4.90 (m, 2H), 3.40 (s, 3H), 3.22 (s, 2H), 2.58 (t, J = 8.9 Hz, 1H), 2.22 - 1.01 (m, 22H), 0.71 (s, 3H).

[0251] Example 115 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane-1-ketone as a starting material and referring to step 2 of Example 2, product 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone (25 mg, white solid, yield 37.0%) was obtained. MS m / z (ESI): 501.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.74 (s, 2H), 5.05 - 4.82 (m, 2H), 3.40 (s, 3H), 3.22 (s, 2H), 2.59 (t, J = 8.6 Hz, 1H), 2.45 - 1.05 (m, 22H), 0.72 (s, 3H).

[0252] Example 116 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonitrile [ka] Using 2-bromo-1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material and referring to step 2 of Example 2, product 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-fluoro-3-hydroxyl-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonylnitrile (19 mg, white solid, yield 30.8%) was obtained. MS m / z (ESI): 458.3[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.4 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 5.03 - 4.88 (m, 2H), 3.39 (s, 3H), 3.22 (s, 2H), 2.59 (t, J = 8.8 Hz, 1H), 2.38 - 1.05 (m, 22H), 0.71 (s, 3H).

[0253] Example 117 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile [ka] Step 1: ((8R,9S,10S,13S,14S)-13-methyl-3,17-dicarbonyl-1,2,3,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-10H-cyclopenta[a]phenanthrene-10-yl)methyl 4-methylbenzene sulfonate [ka] Pyridyl (20 mL) and (8R,9S,10S,13S,14S)-10-(hydroxymethyl)-13-methyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-diketone (6.0 g, 20 mmol) were added sequentially to a 100 mL three-necked flask, and 4-methylbenzenesulfonyl chloride (11.4 g, 60 mmol) was obtained while stirring. After stirring at room temperature for 12 hours, the mixture was placed in an ice bath, and a white solid precipitated. The solid was filtered, washed with water, and dried to obtain the product ((8R,9S,10S,13S,14S)-13-methyl-3,17-dicarbonyl-1,2,3,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-10H-cyclopenta[a]phenanthrene-10-yl)methyl 4-methylbenzenesulfonate (8.0 g, white solid, yield: 88%).

[0254] MS m / z (ESI): 457.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 5.87 (s, 1H), 4.39-4.23 (m, 2H), 2.52-2.47 (m, 1H), 2.46 (s, 3H), 2.38-2.25 (m, 5H), 2.12-1.70 (m, 7H), 1.65-1.40 (m, 2H), 1.30-1.05 (m, 4H),0.89 (s,3H). Step 2: (5S,8R,9S,10S,13S,14S)-13-methyldodecahydro-17H-5,10-methylenecyclopenta[a]phenanthrene-3,17(4H)-diketone [ka] ((8R,9S,10S,13S,14S)-13-methyl-3,17-dicarbonyl-1,2,3,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-10H-cyclopenta[a]phenanthren-10-yl)methyl 4-methylbenzenesulfonate (7.1 g, 15.5 mmol), acetic acid (300 mL), and water (300 mL) were added to a 100 mL single-neck flask. The mixture was stirred at room temperature for 2-3 minutes, then zinc powder (35 g, 538 mmol) was added. After the addition was complete, the mixture was reacted at 120°C for 1.5 hours. The reaction mixture was filtered, the filtrate was spin-dried, and the crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate: 35 / 1) to obtain (5S,8R,9S,10S,13S,14S)-13-methyldodecahydro-17H-5,10-methylenecyclopenta[a]phenanthrene-3,17(4H)-diketone (2.5 g, white solid, yield: 56%).

[0255] 1 H NMR (400 MHz, CDCl3) δ 2.56-2.53 (m, 2 H), 2.49-2.27 (m, 2H), 2.14-1.70 (m, 9H),1.55-0.90 (m, 8H), 0.89 (s, 3H),0.55 (d, J = 6.0 Hz, 1H), 0.45 (d, J = 6.0 Hz, 1H). Step 3: (3R,5S,8R,9S,10S,13S,14S)-3-hydroxyl-3,13-dimethyltetradecahydro-17H-5,10-methylenecyclopenta[a]phenanthrene-17-ketone [ka] Using (5S,8R,9S,10S,13S,14S)-13-methyldodecahydro-17H-5,10-methylenecyclopenta[a]phenanthrene-3,17(4H)-diketone as a starting material, and referring to step 3 of Example 1, the product (3R,5S,8R,9S,10S,13S,14S)-3-hydroxyl-3,13-dimethyltetradecahydro-17H-5,10-methylenecyclopenta[a]phenanthrene-17-ketone (white solid, yield 52%) was obtained.

[0256] 1 H NMR (400 MHz, CDCl3) δ 2.47-2.39 (m, 1H), 2.10 - 1.25 (m, 16H), 1.19 (s, 3H), 1.15 - 0.85 (m, 4H), 0.86 (s, 3H), 0.42 (s, 2H). Step 4: (3R,5S,8S,9S,10S,13S,14S)-17-ethylene-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-3-phenol [ka] Using (3R,5S,8R,9S,10S,13S,14S)-3-hydroxyl-3,13-dimethyltetradecahydro-17H-5,10-methylenecyclopenta[a]phenanthrene-17-ketone as a starting material, and referring to step 4 of Example 1, the product (3R,5S,8S,9S,10S,13S,14S)-17-ethylene-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-3-phenol (white solid, yield: 61.5%) was obtained.

[0257] 1 H NMR (400 MHz, CDCl3) δ 5.15-5.08 (m, 1H), 2.40-1.20 (m, 18H), 1.19 (s, 3H), 1.16- 0.87(m, 6H), 086 (s, 3H), 0.43 (d, J = 4.4 Hz, 1H), 0.35(d, J = 4.4 Hz, 1H). Step 5: (3R,5S,8S,9S,10S,13S,14S)-17-(1-hydroxyethyl)-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-3-phenol [ka] (3R,5S,8S,9S,10S,13S,14S)-17-ethylene-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-3-phenol was used as a starting material, and the product (3R,5S,8S,9S,10S,13S,14S)-17-(1-hydroxyethyl)-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-3-phenol (white solid, 100% yield) was obtained by referring to step 5 of Example 1.

[0258] Step 6: 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] (3R,5S,8S,9S,10S,13S,14S)-17-(1-hydroxyethyl)-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-3-phenol was used as a starting material, and following the procedure in step 6 of Example 1, product 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (white solid, yield: 71%) was obtained.

[0259] 1H NMR (400 MHz, CDCl3) δ 2.54 (t, J = 8.0 Hz, 1H), 2.12 (s, 3H), 2.10 - 1.25 (m, 17H), 1.19 (s, 3H), 1.15 - 0.72 (m, 4H), 0.60 (s, 3H), 0.41 (d, J = 4.4 Hz, 1H), 0.36(d, J = 4.4 Hz, 1H). Step 7: 2-Bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone [ka] Using 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 7 of Example 1, the product 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone (white solid, yield: 100%) was obtained.

[0260] Step 8: 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile [ka] Using 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material and referring to step 8 of Example 1, product 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-4-carbonitrile (18 mg, white solid, yield: 21.9%) was obtained.

[0261] MS m / z (ESI): 404.2 [M-17] + . 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.05-4.85 (m, 2H), 2.61 (t, J = 8.8 Hz, 1H), 2.25-2.15 (m, 1H), 2.10-1.95 (m, 2H), 1.90-1.25 (m, 15H), 1.19 (s, 3H), 1.15 - 1.05 (m, 1H), 0.90 - 0.80 (m, 2H), 0.66 (s, 3H), 0.43-0.38 (m, 2H).

[0262] Example 118 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonitrile [ka] Using 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material and referring to step 2 of Example 2, product 1-(2-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-carbonylethyl)-1H-pyrazole-3-carbonitrile (10.5 mg, white solid, yield 15.4%) was obtained.

[0263] MS m / z (ESI): 404.2 [M-H2O+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H) 5.10-4.85 (m, 2H), 2.61 (t, J = 8.9 Hz, 1H), 2.24-1.98 (m, 3H), 1.90 - 1.25 (m, 15H), 1.16(s, 3H), 1.15 - 1.05 (m, 1H), 0.90 - 0.80 (m, 2H), 0.67 (s, 3H), 0.43-0.37 (m, 2H).

[0264] Example 119 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone [ka] Using 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material and referring to step 2 of Example 2, product 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazole-1-yl)ethane-1-ketone (10.5 mg, white solid, yield: 15.4%) was obtained.

[0265] MS m / z (ESI): 465.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.72 (s, 2H), 5.10-4.85 (m, 2H), 2.61 (t, J = 8.9 Hz, 1H), 2.26-1.98 (m, 3H), 1.90 - 1.25 (m, 15H), 1.19(s, 3H), 1.15 - 1.05 (m, 1H), 0.90 - 0.80 (m, 2H), 0.67 (s, 3H), 0.43-0.37 (m, 2H).

[0266] Examples 120 and 121 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-ketone(120) 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-ketone(121) [ka] Using 2-bromo-1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)ethane-1-ketone as a starting material, and referring to step 8 of Example 6, product 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene- 17-yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-ketone (120) (7.2 mg, white solid, yield 12.2%) and 1-((3R,5S,8S,9S,10S,13S,14S,17S)-3-hydroxyl-3,13-dimethyltetradecahydro-6H-5,10-methylenecyclopenta[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazole-1-yl)ethane-1-ketone (121) (10 mg, white solid, yield 17.1%) were obtained.

[0267] Example 120: MS m / z (ESI): 398.2[M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.68 (s, 2H), 5.26-5.20 (m, 2H), 2.59 (t, J = 8.0 Hz, 1H), 2.24-1.95 (m, 3H), 1.90 - 1.25 (m, 15H), 1.19(s, 3H), 1.15 - 1.05 (m, 1H), 0.90 - 0.80 (m, 2H), 0.70 (s, 3H), 0.43-0.37 (m, 2H).

[0268] Example 121: MS m / z (ESI): 398.2[M+H] + . 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (s, 1H),5.35-5.10 (m, 2H), 2.66 (t, J = 8.0 Hz, 1H), 2.25-1.97 (m, 3H), 1.90 - 1.25 (m, 15H), 1.20(s, 3H), 1.13 - 1.05 (m, 1H), 0.90 - 0.80 (m, 2H), 0.67 (s, 3H), 0.43-0.36 (m, 2H).

[0269] Biological Test Evaluation The present invention will be further explained and interpreted below with reference to test examples, but these examples are not intended to limit the scope of the present invention.

[0270] 1. GABA of the compound according to the present invention A Measurement of receptor binding capacity

[0271] 1.1 Experimental Objective: This test aims to measure the inhibitory ability of a compound to inhibit the binding of allosteric ion channel inhibitors (TBPS) to GABA-A receptors. Laboratory equipment: [Table 1]

[0272] 1.2 Experimental Steps

[0273] 1.2.1 Extraction of cerebral cortical cell membranes: 1. The cerebral cortex of a male Sprague-Dawley Rat was isolated. 2. A pre-cooled 0.32 M sucrose solution (with one protease inhibitor per 100 ml) equivalent to 10 times the volume of rat cerebral cortex was added, and the mixture was homogenized in several batches using a 50 ml glass tissue homogenizer until uniform. 3. 4 for 1500g o The mixture was centrifuged in C for 10 minutes, and the supernatant was collected. 4. 20000g oThe mixture was centrifuged in C for 30 minutes, and the supernatant was discarded. 5. The precipitate was resuspended in pre-cooled PBS (with one protease inhibitor added per 100 ml), and an average of 4 ml of PBS was added per rat, which was then homogenized using a glass tissue homogenizer. 6. 4 o The mixture was centrifuged in C for 10 minutes, and the supernatant was discarded. 7. Repeat steps 5-6 three times. 8. Finally, resuspend the precipitate in four times its volume of PBS, dispense, and quench with liquid nitrogen at -80°C. o Saved in C. 9. Protein concentration was measured using the BCA method.

[0274] 1.2.2 35S-TBPS binding assay 1. 230 μL of PBS was added to each well of a 1.1 ml deep-well plate. 2. 60 μL of cerebral cortical cell membrane (5 μg / μL) solution was added to each well and mixed uniformly. 3. The test compound (3 μL per well) was added and incubated at 25°C for 5 minutes. The DMSO concentration was 1%, and the initial concentration of the compound was 1 μM. Two replicates were created by serial dilution in 8 steps of 3-fold increments, with 1% DMSO used as the negative control and 10 μM P026-2 used as the positive control. 4. GABA was added to a final concentration of 5 μM, and incubated at 25°C for 5 minutes. A 1 mM GABA solution was prepared and 1.5 μL was added to each well. 5. 35S-TBPS was added to achieve a final concentration of 2 nM, and the isotope mother liquor concentration was set to 9.7 μM. After diluting 100-fold with PBS, 6 μL of the diluted isotope solution was added to each well. 6. 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 plate was washed twice with a Universal Harvester, using 50 ml of PBS each time. 9. After transferring the reaction mixture to a GF / C plate, each well was washed four times with 900 μL of PBS. 10. The washed GF / C plates were dried at 55°C for 10 minutes. 11. 40 μL of scintillation solution was added to each well, and the CPM value was read using TopCount.

[0275] 1.2.3 Experimental data processing method: In the experiment, the CPM (counts per minute) value was read using TopCount, and based on the readings for the High control (DMSO) and Low control (10uM positive compound) experimental groups, the % inhibition was calculated using the following formula: % Inhibition=100x(CPM High control -CPM Sample ) / (CPM High control -CPM Low control ) The IC of a compound is calculated using the following four-parameter nonlinear logistic equation. 50 The following was calculated: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)) During the ceremony: X is the log of compound concentration; Y is % Inhibition.

[0276] In the present invention, the inhibition of the TBPS binding activity of the compound was measured in the above experiment, but the measured IC 50 The values ​​are shown in Table 1. [Table 2]

[0277] Conclusion: The compound according to the present invention has a clear inhibitory effect on TBPS binding activity.

[0278] 2. Pharmacokinetic measurements of Balb / C mice 1. Research purpose: Using Balb / C mice as test animals, we will study the pharmacokinetic behavior of the compounds from Examples 2, 5, 7, 12, 18, 23, 26, 38, 41, 50, 51, and 66 in mouse bodies (plasma and brain tissue) after oral administration at a dose of 5 mg / kg.

[0279] 2. Experimental plan:

[0280] 2.1 Test chemicals: Examples 2, 5, 7, 12, 18, 23, 26, 38, 41, 50, 51, and 66 of the present invention were prepared in the laboratory.

[0281] 2.2 Test animals: Male Balb / c mice purchased from Shanghai Jiesijie Laboratory Animals Co., Ltd., with animal production license number (SCXK(Hu)2013-0006 N0.311620400001794).

[0282] 2.3 Administration: Each group consisted of 24 male Balb / C mice. After a one-night fast, each group received a dose of 50 mg / kg in a volume of 10 mL / kg.

[0283] 2.4 Sample Collection: Mice were lethal with CO2 before administration and at 0,0.5, 1, 2, 4, 6, 8, and 24 hours after administration. 0.2 mL of blood was collected from the heart, placed in an EDTA-K2 test tube, centrifuged at 6000 rpm for 6 minutes at 4°C, and stored at -80°C. Whole brain tissue was removed, weighed, and placed in a 2 mL centrifuge tube, and stored at -80°C.

[0284] 2.5 Sample preparation: 1) 40 μL of plasma sample was mixed with 160 μL of acetonitrile to allow precipitation, and then centrifuged at 3500 g for 5-20 minutes. 2) 30 μL of plasma and brain homogenate samples were mixed with 90 μL of acetonitrile containing an internal standard (100 ng / mL) to allow precipitation, and then the mixture was centrifuged at 13,000 rpm for 8 minutes. 3) Add 70 μL of water to 70 μL of the supernatant after treatment, vortex for 10 minutes to mix, then take 20 μL and perform LC / MS / MS analysis to determine the concentration of the test compound. The LC / MS / MS analyzer used was an AB Sciex API 4000 Qtrap.

[0285] 2.6 Liquid phase analysis ● Liquid chromatography conditions: Shimadzu LC-20 AD pump ● Chromatography column: Agilent ZORBAX XDB-C18 (50 × 2.1 mm, 3.5 μm) Mobile phase: Solution A is 0.1% formic acid aqueous solution, and solution B is acetonitrile. ● Flow rate: 0.4mL / min ● Elution time: 0-4.0 minutes, the eluate is as follows: [Table 3]

[0286] 3. Experimental Results and Analysis The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of mouse pharmacokinetic experiments are shown in Table 2 below: [Table 4-1] [Table 4-2]

[0287] As can be seen from the mouse pharmacokinetic experiment results in the table, the compounds of the present invention examples exhibit good metabolic properties, with high exposure AUC and maximum blood concentration C. max All of them are good.

[0288] 3. Drug efficacy experiments in a mouse forced swimming model 3.1 Experimental Objectives The antidepressant effects of the compound will be evaluated using a mouse forced swimming model.

[0289] 3.2 Main experimental equipment and reagents 3.2.1 Equipment Forced swimming device (JLBehv-FSC-4, Shanghai Jilu Software Science and Technology Co., Ltd.) 3.2.2 Reagents Sodium carboxymethylcellulose (CMC-Na, SLBV9664, Sigma) Tween 80 (BCBV8843, Sigma) 3.2.3 Examination Compounds Compounds of Example 2, Example 5, Example 7, Example 18, Example 23, Example 26, and Example 50 of the present invention, prepared in the laboratory.

[0290] 3.3 Experimental Steps 3.3.1 Adaptation: Prior to the forced swimming test, male ICR mice (25-35g) were adapted to the experimental environment for 3 days. 3.3.2 Group Dosing: According to the experimental design, mice were randomly divided into groups based on their body weight the day before the experiment, with each group consisting of 12 mice. Before the experiment, each compound was administered intragastricly based on the brain Tmax time in mouse pharmacokinetic experiments. The details are as follows: 1) Model group (0.5% CMC-Na + 1% Tween 80 solution, po, 10 mL / kg); 2) Compounds from Examples 2, 5, 7, 18, 23, 26, and 50 (10 mg / kg, 10 mL / kg); At the time of administration, the compounds from each example were suspended in 0.5% CMC-Na-1% Tween 80 solution to the desired concentration. 3.3.2 Mandatory swimming test: After administration for 0.5 to 1 hour, ICR mice were placed in a transparent glass drum (water depth 18 cm, water temperature 25-26°C, one mouse per drum) in a forced swimming apparatus and forced to swim for 6 minutes. The floating time of the ICR mice was recorded in the forced swimming apparatus for 6 minutes, and the data from the following 4 minutes was used for data analysis. Immediately after the swimming test, the mice were removed, the water adhering to them was wiped off, and they were returned to their original cages.

[0291] Note: The criteria for determining immobility are that the mouse is not struggling in the water, is floating, and only its small limbs are moving to keep its head above the water.

[0292] 3.4 Data Analysis Percentage of floating time = 100 * floating time / 240 s.

[0293] 3.5 Experimental Data: [Table 5]

[0294] 3.6 Experimental Results As is clear from the results above, each example of the experiment in this patent can significantly reduce the cumulative immobility time during forced swimming in mice and has a clear antidepressant effect.

[0295] Example 2 showed a clear difference in the 4-minute downtime compared to the model group, and Examples 5, 23, and 50 also showed a very clear difference in the 4-minute downtime compared to the model group.

[0296] IV. Drug efficacy experiments in a PTZ-induced mouse epilepsy model 4.1 Experimental Objectives A PTZ-induced CD-1 mouse epilepsy model will be constructed, and the antiepileptic effects of the compounds in Example 5 and Example 23 will be evaluated using this model.

[0297] 4.2 Experimental Method 4.21 Test animals Thirty male CD-1 mice were purchased from Beijing Weitong Lihua Laboratory Animals Co., Ltd. The test animals were delivered to the animal room in Building 3 of Shanghai Ruizhi Chemical Co., Ltd., and formal experiments were conducted after a 7-day adaptation period. The average weight of the animals on the day of the experiment was 32.2 ± 0.2 g. Rearing environment: 5 mice per cage, room temperature 23 ± 2°C, 12 / 12 hour light / dark cycle, and free access to food and water.

[0298] Participants were randomly assigned to groups on the day of the experiment and used for the test.

[0299] 4.22 Test Compounds The test compounds of Example 5 and Example 23 (prepared in the laboratory), and the test drugs stored in a refrigerator at 4°C.

[0300] [Table 6] 4.2.1 Laboratory Equipment ● Sterile disposable syringe with 1ml needle (purchased from Zhejiang Kandelai Medical Instruments Co., Ltd.) ● Pipette: Eppendorf Research Plus (100-1000 μL) ● Vortex Mixer: Kylin-Bell Vortex 5 ● Ultrasonic device: JL-360 type ultrasonic cleaner ● Balance: METTLER TOLEDO XS204 precision balance ● Balance: METTLER TOLEDO XS6002S electronic balance ● Organic glass box: 25cm long * 15cm wide * 15cm high, designed with one side wall being opaque, specially customized by Suzhou Fengshi Laboratory Animal Equipment Co., Ltd. ● 3-channel timer: Oregon / Model NO. WB-388. 4.2.2 Grouping of test animals 1) Vehicle / PTZ: 0.5% CMC-Na + 1% Tween-80 (10 ml / kg, po), administered 0.5 hr before PTZ administration; PTZ (120 ml / kg, sc), administered before experiment; 2) Compounds in the examples at 3 mg / kg / PTZ: Examples 5 and 23 (3 mg / kg, 10 ml / kg, po), 0.5 hr before PTZ administration, PTZ (120 ml / kg, sc), administered before experiment.

[0301] 4.3 Experimental Steps 4.3.1 Preparation of Solvents 1) 0.5% CMC-NA + 1% Tween-80 (dosage volume: 10 mL / kg): 1 g of sodium carboxymethylcellulose was accurately weighed and placed in a 250 mL solvent bottle, and 150 mL of redistilled water was added. The mixture was stirred with a magnetic stirrer at room temperature for 4 hours to obtain a homogeneous clarified solution. 2 mL of Tween-80 was then gradually added and the mixture was stirred continuously at room temperature for 3 hours to obtain a homogeneous clarified solution. This solution was gradually transferred to a 200 mL volume bottle, redistilled water was added to bring the volume to 200 mL, and the mixture was transferred to a 250 mL solvent bottle. The mixture was stirred continuously with a magnetic stirrer for 1 hour to obtain a homogeneous clarified solution.

[0302] 2) 30% hydroxypropyl-β-cyclodextrin: 30.6122 g of hydroxypropyl-β-cyclodextrin (purity: 98%) was accurately weighed and placed in a 100 mL solvent bottle. 60 mL of redistilled water was added, and the mixture was vortexed in a vortex mixer for 3 minutes. The mixture was then sonicated at room temperature for 15 minutes to obtain a homogeneous clarified solution. Afterward, redistilled water was added to bring the volume to 100 mL. The mixture was vortexed in a vortex mixer for 1 minute, followed by sonication at room temperature for 5 minutes to obtain a homogeneous clarified solution.

[0303] 4.3.2 Preparation of the test compound 1) 12 mg / mL PTZ (Dosage: 120 mg / kg, Volume: 10 mL / kg): 248 mg of PTZ was accurately weighed and placed in a 40 mL brown reagent bottle. 20.667 mL of physiological saline was added, and the mixture was vortexed in a vortex mixer for 2 minutes. After sonication at room temperature for 2 minutes, a homogeneous clarified solution (concentration: 12 mg / mL) was obtained.

[0304] 2) Examples 5 and 23 with 0.3 mg / mL (dosage: 3 mg / kg, volume: 10 mL / kg): A fixed amount of 0.5% CMC-Na + 1% Tween 80 was weighed and placed in a reagent bottle containing fixed amounts of Example 5 and Example 23. The mixture was vortexed in a vortex mixer for 3 minutes, followed by sonication at room temperature for 15 minutes to obtain a homogeneous suspension solution (concentration: 0.3 mg / mL).

[0305] 4.3.3 Experimental Method 1) The experimental animals were placed in the control room one hour before the experiment to allow them to adapt to the environment; 2) The subjects were randomly divided into groups, labeled, and their weight was measured; 3) Example 5 and Example 23 were administered one hour before PTZ administration, or 0.5% CMC-NA + 1% Tween-80, Example 5, and Example 23 were administered 0.5 hours before PTZ administration; 4) PTZ (120 mg / kg) was administered subcutaneously before the experimental observation, and this point was recorded as the start of the observation; 5) Immediately after administering PTZ, the animals were placed in an observation box and observed for 30 minutes, and the following were recorded: a) the incubation period until the first clonic seizure, b) the incubation 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 of death of the animals; 6) If the animals did not have epileptic seizures during the 30-minute observation period, the incubation period was recorded as 1800 seconds and the number of seizures was recorded as 0. ● Clonic seizure: The entire skin of the animal experiences seizures for 3 seconds or more, accompanied by falls; ● Tonic seizure: The limbs extend at a 90° angle to the body; 6) Observe and record any side effects that may be induced by the drug after administration, and categorize them into four levels: ● None: Normal ● Mild sedation ● Moderate sedation ● Severe sedation 7) Exam time: 12:00 am - 4:30 pm.

[0306] 4.4 Adaptation to the Environment The experimental animals were placed in the control room one hour before the experiment to allow them to adapt to the environment. 4.5 Group-based administration Mice were randomly divided into groups, labeled, and their body weight was measured, with each group consisting of 10 mice. The test compound was orally administered to each group 30-60 minutes before PTZ administration, at a dose volume of 10 mL / kg.

[0307] 4.6 PTZ Model Fabrication and Testing Before the experimental observation, PTZ (120 mg / kg) was administered subcutaneously, and this point was recorded as the start of observation. Immediately after PTZ administration, the animals were placed in an observation box and observed for 30 minutes, and the following were recorded: a) the incubation period until the first clonic seizure, b) the incubation 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 of death of the animal. If an animal did not have an epileptic seizure during the 30-minute observation period, the incubation period was recorded as 1800 sec and the number of seizures was recorded as 0.

[0308] 4.7 Data Analysis All quantitative data are presented as mean ± standard error (Mean ± SEM), and the data are validated and analyzed using Prism 6.0 statistical software.

[0309] 4.8 Experimental Data: [Table 7]

[0310] 4.9 Experimental Results Compared to the control group, each experimental application clearly extended the latency period and frequency of clonic seizures and generalized tonic-clonic seizures, protected 60% of the animals from death, significantly extended the latency period to death, and demonstrated excellent antiepileptic activity.

Claims

1. A compound represented by general formula (VIII), its stereoisomer, or a pharmacoposifiable salt thereof. 【Chemistry 1】 (In the formula, Z is methylene, Ring A is C ３－１２ A 3-12 membered heterocyclyl group having 1-4 heteroatoms selected from the group consisting of cycloalkyl groups, N, O, and S, C ６－１４ Selected from the group consisting of an aryl group and a 5-14 membered heteroaryl group having 1-4 heteroatoms selected from the group consisting of O, S, and N, R ａ are the same or different, each R ａ being a hydrogen atom, a cyano group, a halogen, a nitro group, C １－６ alkyl group 、 C ２－６ alkynyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C ３－６ cycloalkyl group, C １－６ hydroxyalkyl group, a 5- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, -(CH ２ ) ｎ１ OR ２３ -(CH ２ ) ｎ１ SR ２３ -(CH ２ ) ｎ１ C(O)R ２３ -(CH ２ ) ｎ１ C(O)NR ２３ R ２４ -(CH ２ ) ｎ１ C(O)OR ２３ and -(CH ２ ) ｎ１ S(O) ｍ１ R ２３ selected from the group consisting of, wherein said C １－６ alkyl group 、 C １－６ alkoxy group, C １－６ haloalkyl group, C ３－６ cycloalkyl group, C １－６ hydroxyalkyl group, a 5- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group may each be further substituted by one or more substituents selected from the group consisting of a hydrogen atom, C １－６ alkyl group, a halogen, a cyano group, a hydroxy group, C ３－６ cycloalkyl group, C １－６ hydroxyalkyl group, a 5- to 10-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group, R ２３ , R ２４ They are either the same or different, and each is independently a hydrogen atom, a deuterium atom, and C １－６ alkyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated group, hydroxyl group, amino group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ A 3-12 membered heterocyclyl group having 1-4 heteroatoms selected from the group consisting of cycloalkyl groups, N, O, and S, C ６－１４ Selected from the group consisting of an aryl group and a 5-14 membered heteroaryl group having 1-4 heteroatoms selected from the group consisting of O, S, and N, among which the C １－６ alkyl group, C １－６ Deuterated alkyl groups, C １－６ Alkyl halogenated compounds, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－１２ A 3-12 membered heterocyclyl group having 1-4 heteroatoms selected from the group consisting of cycloalkyl groups, N, O, and S, C ６－１４ Each of the aryl groups and the 5-14 membered heteroaryl groups having 1-4 heteroatoms selected from the group consisting of O, S, and N contains a deuterium atom, C １－６ Alkyl group, halogen, hydroxyl group, amino group, oxo group, nitro group, cyano group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, C １－６ Hydroxyalkyl group, C ３－１２ A 3-12 membered heterocyclyl group having 1-4 heteroatoms selected from the group consisting of cycloalkyl groups, N, O, and S, C ６－１４ The aryl group may be further substituted with one or more substituents selected from the group consisting of an aryl group and a 5-14 membered heteroaryl group having 1 to 4 heteroatoms selected from the group consisting of O, S, and N. x is an integer of 0, 1, 3, 4, or 5.

2. The aforementioned ring A is C ３－６ A 3- to 8-membered heterocyclyl group having 1 to 4 heteroatoms selected from the group consisting of cycloalkyl groups, N, O, and S, C ６－１０ Selected from the group consisting of an aryl group and a 5-10 membered heteroaryl group having 1-4 heteroatoms selected from the group consisting of O, S, and N, A compound represented by the general formula (VIII) as described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. The aforementioned ring A is 【Chemistry 2】 A compound represented by the general formula (VIII) described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

4. Ra is a hydrogen atom, a cyano group, a halogen, a nitro group, C １－６ alkyl group, C ２－６ alkynyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C ３－６ cycloalkyl group, C １－６ hydroxyalkyl group, 5- to 10-membered heterocyclyl group, 5- to 10-membered heteroaryl group, -(CH ２ ) ｎ１ OR ２３ , -(CH ２ ) ｎ１ SR ２３ , -(CH ２ ) ｎ１ C(O)R ２３ , -(CH ２ ) ｎ１ C(O)NR ２３ R ２４ , -(CH ２ ) ｎ１ C(O)OR ２３ and -(CH ２ ) ｎ１ S(O) ｍ１ R ２３ selected from the group consisting of, wherein said C １－６ alkyl group, C １－６ [[ID=5�]]alkoxy group, C １－６ haloalkyl group, C ３－６ cycloalkyl group, C １－６ hydroxyalkyl group, 5- to 10-membered heterocyclyl group and 5- to 10-membered heteroaryl group may each be further substituted with one or more substituents selected from the group consisting of a hydrogen atom, C １－６ alkynyl group, a halogen, a cyano group, a hydroxy group, C ３－６ cycloalkyl group, C １－６ hydroxyalkyl group, 5- to 10-membered heterocyclyl group and 5- to 10-membered heteroaryl group, R ２３ and R ２４ These are, independently, hydrogen atoms and C １－６ Selected from the group consisting of alkyl groups and 3-8 membered heterocyclyl groups, A compound represented by the general formula (VIII) as described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. The ring A is 【Transformation 3】 Selected from the group consisting of, Ra is either the same or different, and each Ra is selected from the group consisting of a hydrogen atom, a cyano group, a halogen, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, and a C3-6 cycloalkyl group. A compound represented by the general formula (VIII) as described in claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 6】 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 A compound selected from the group consisting of the following, its stereoisomer, or a pharmaceutically acceptable salt thereof. 【Request Item 7】 【Chemistry 5-1】 【Chemistry 5-2】 A compound selected from the group consisting of the following, its stereoisomer, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (VIII) as described in any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. A compound represented by general formula (VIII) as described in any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 8, GABA Ａ Use in the manufacture of receptor modulator drugs.

10. Use of a compound represented by general formula (VIII) according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the manufacture of a drug for treating a CNS-related disorder selected from the group consisting of sleep disorders, mood disorders, schizophrenia spectrum disorder, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorder, pain, traumatic brain injury, vascular disorders, substance abuse disorders and / or withdrawal syndromes, or tinnitus.

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