RU2797408C2 - Regulators-derivatives of steroids, methods of their obtaining and their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof, and its use for the preparation of a medicinal product that activates the GABA_A receptor, as well as for the treatment of a disease associated with the central nervous system (CNS) selected from the following group: sleep disorder, mood disorder, schizophrenia spectrum disorder, spasmodic disorder, memory disorder and/or cognitive disorder, dyskinesia, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder, and/or withdrawal syndrome and tinnitus. In the general formula (IV), Z is selected from the group consisting of -CH₂- and -CH₂NH-; ring A is selected from the group consisting of a 3–8 membered heterocyclyl containing one or two heteroatoms selected from N and S, phenyl and a 5–10 membered heteroaryl containing one to four heteroatoms selected from N, where each of 3–8 membered heterocyclyl, phenyl and 5–10 membered heteroaryl optionally further substituted with one or more substituents selected from the group consisting of C_1-3 alkyl, C_1-3 haloalkyl, halogen, oxo, nitro, cyano, methoxy, cyclopropyl, -(CH₂)_n1SR₂₅, -(CH₂)_n1C(O)R₂₅ and -(CH₂)_n1C(O)OR₂₅; each R^a is the same or different and each is selected from the group consisting of hydrogen atom, C_1-3 alkyl, C_1-3 haloalkyl, methoxy, halogen, nitro, cyano, cyclopropyl, -(CH₂)_n1C(O)R₂₃, -(CH₂)_n1C(O)OR₂₃, -(CH₂)_n1S(O)_m1R₂₃ and -(CH₂)_n1 S(O)(NR₂₃)R₂₄, where each of C_1-3 alkyl and cyclopropyl is optionally further substituted with one or more substituents selected from the group consisting of cyano and hydroxy; R_15a is selected from the group consisting of C_1-3 alkyl, C_1-3 haloalkyl, halogen, cyclopropyl, -(CH₂)_n1OR₂₃ and -(CH₂)_n1SR₂₃; R_16a represents a hydrogen atom; or R_15a and R_16a may form cyclopropyl, where cyclopropyl is optionally further substituted with one or more halogens; x is an integer equal to either 0, 1, or 3. The remaining values of the variables are indicated in the claims.

EFFECT: creation of new GABA_A regulators with good activity and excellent metabolism in vivo.

12 cl, 3 tbl, 179 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to the field of drug synthesis and, in particular, relates to a steroid derivative regulator, a method for its preparation and its use.

BACKGROUND OF THE INVENTION

The GABA _A receptor (gamma-aminobutyric acid) is a chemically controlled channel on the cell membrane and belongs to the ion receptor. The GABA _A receptor is widely distributed in the nervous system and can bind to the inhibitory neurotransmitter GABA, leading to the opening of chloride channels and inhibition of neurons. The GABA _A receptor regulator (tetrahydroprogesterone) is a positive regulator of the GABA _A receptor. Binding of tetrahydroprogesterone and the regulator of the intrasynaptic GABA _A receptor can increase the chloride channel opening frequency on the receptor and the influx of chloride ions, thereby increasing phasic current, exerting a rapid inhibitory effect, reducing nerve excitability, and providing anti-anxiety and antidepressant effects. Binding of tetrahydroprogesterone to the extrasynaptic GABA _A receptor provides a continuous current of chloride ions and mediates a long and sustained inhibitory effect. Tetrahydroprogesterone may also increase brain-derived neurotrophic factor (BDNF), promote hippocampal neuronal regeneration, and provide a neuroprotective effect, thereby alleviating symptoms of anxiety and depression; but the specific mechanism of action is not yet clear.

Major depressive disorder (MDD) is a common chronic and relapsing illness. The burden and the adverse effects it causes are becoming more and more serious. Over the past 40 years, research and clinical use of antidepressants has expanded significantly. However, most antidepressants (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, etc.) take 2 to 4 weeks to work. Clinical management of patients with major depressive disorder, especially those with suicidal tendencies, often needs to be immediate and rapid, so there is an urgent need to develop fast-acting antidepressants.

There has been little innovation in the research and development of treatments for depression over the past two decades. The goal of developing a GABA _A receptor regulator is to change patient expectations by changing the treatment regimen for MDD. If successfully developed, the GABA _A receptor regulator could be the first drug to provide a truly new mechanism of action for the treatment of depression in more than two decades. Currently, foreign pharmaceutical companies, including Sage Therapeutics and Marinus et al., are doing their best to develop GABA _A receptor regulators.

Published patent applications relating to GABA _A receptor regulators include: WO 2003077919, WO 2014169833, WO 2016061537, WO 2015180679 and WO 2015027227.

Regulators of GABA _A receptors, which are a popular target in the pharmaceutical industry, currently have good prospects for application.

First, GABA _A receptor regulators can be used in major depressive disorder (MDD). The annual incidence of MDD in China is about 2%, so there is a huge market potential.

Second, current antidepressants take a long time, typically 3 to 4 weeks, to work, have high failure rates of up to 40%, and require long-term medication. GABA _A receptor regulators can provide significant antidepressant effects within 24 hours, and effects can last from a few days to two weeks.

Thirdly, the GABA _A receptor regulator may meet the need for once-daily oral treatment of patients with MDD.

BRIEF DESCRIPTION OF THE INVENTION

The aim of the present invention is to provide a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula (I) is as follows:

Where:

X is selected from the group consisting of -CR ₁₇ - and -N-;

Y is selected from the group consisting of -CR ₂₃ R ₂₄ -, -S(CH ₂ ) _n1 -, -P(CH ₂ ) _n1 -, -O(CH ₂ ) _n1 -, -(CH ₂ ) _n1 NR ₂₂ - ,

R ^x , R ^y , R ^z and R ^f are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , where each of alkyl, haloalkyl, cycloalkyl , heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl , substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -( CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , - (CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

or any two adjacent or non-adjacent groups of R ^x , R ^y , R ^z and R ^f may be linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, where cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from a group consisting of a deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ ;

or any two adjacent groups of R ^x , R ^y , R ^z and R ^f may form a double bond;

R ₂₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , (CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , - (CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O )R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O) NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

when X is -CR ₁₇ -, R ₁₇ is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where each of alkyl , cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy , hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R ₁₇ and any group of R ^x , R ^y , R ^z and R ^f may be linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, where cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group , consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C( O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ ;

R22 is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , (CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -( CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O) R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , - (CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₂₃ , R ₂₄ , R ₂₅ and R ₂₆ are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo , nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

m is an integer equal to 0, 1, 3, 4, 5, 6, 7, 8, 9, or 10;

n is an integer equal to 0, 1, 2 or 3;

o is an integer equal to 0, 1, 2, 3, 4, or 5;

p is an integer equal to 0, 1, 2, 3, 4, 5, or 6;

q is an integer equal to 0, 1, 2, 3, 4, 5, or 6;

m ₁ is an integer equal to 0, 1, or 2, and

n ₁ is an integer equal to 0, 1, 2, 3, 4, or 5.

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (I-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

Y is selected from the group consisting of -S(CH ₂ ) _n1 -,

R _3a and R _3b are the same or different and are each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 S(O)NR ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , where each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and - (CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₅ , R ₆ , R _15a , R _15b , R _16a , R _16b and R ₁₉ are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy , haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 S( O)NR ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino -(CH ₂ ) _n1 R ₂₅ , -( CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S( O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

or any two adjacent or non-adjacent groups of R ₅ , R ₆ , R _15a , R _15b , R _16a , R _16b and R ₁₉ may be linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, where cycloalkyl, heterocyclyl, aryl or heteroaryl is optional further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O) NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₁₇ is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where each of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optional further substituted with one or more substituents selected from the group consisting of deuterium, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

or R ₁₇ and any group of R _16a and R _16b may be bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , - (CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O )R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ ;

R ₂₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , (CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , - (CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O )R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O) NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

n is an integer equal to 0, 1, 2 or 3;

R ₂₂ -R ₂₆ , m ₁ and n ₁ are as defined for the compound of formula (I).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

R _3a is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 S(O)(NR ₂₃ )R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ where each is alkyl, haloalkyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, thiol, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl , heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R _15a , R _15b , R _16a and R _16b are the same or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , (CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C( O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 S(O)(NR ₂₃ )R ₂₄ , - (CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ S( O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano , hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -( CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , - (CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ and R _15a , R _15b , R _16a and R _16b do not simultaneously represent a hydrogen atom;

or any two adjacent or non-adjacent groups of R _15a , R _15b , R _16a and R _16b may be linked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from a group consisting of a deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₁₉ is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, thiol, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 S(O)(NR ₂₃ )R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ ;

R ₂₁ , R ₂₃ -R ₂₆ , m ₁ and n ₁ are as defined for the compound of formula (I).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

R _15a , R _16a and R ₂₁ are as defined for the compound of formula (I).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

Z is selected from the group consisting of -CR ₂₃ R ₂₄ -, -(CH ₂ ) _n1 NR ₂₃ - and -(CH ₂ ) _n1 O(CH ₂ ) _n2 -, and is preferably methylene;

ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl or heteroaryl, where each of cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino , oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -( CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

each R _a is the same or different and each is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , (CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 S(O)(NR ₂₃ )R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , where each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O) NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R _15a is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , - (CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , and -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R _16a is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , - (CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ R ₂₄ ;

or R _15a and R _16a may form cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl , alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and R _15a and R _16a do not simultaneously represent a hydrogen atom;

each of R ₂₃ and R ₂₄ is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl , alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₂₅ -R ₂₆ , m ₁ , n ₁ and x are as defined for the compound of formula (II).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (IV-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

R _15a is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , - (CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , and -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , wherein alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally further substituted one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

ring A, R ^a and x are as defined for the compound of formula (IV).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

R _15a , R _16a , R ^a and x are as defined for the compound of formula (IV).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

R _15a , R _16a , R ^a and x are as defined for the compound of formula (V).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

each R ^d is the same or different and each is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 S(O)(NR ₂₃ )R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C(O)R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , where each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally further substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy , haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -(CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

y is an integer equal to 0, 1, 3, or 4;

ring A, Z, R ^a , R ₂₃ -R ₂₆ , m ₁ , n ₁ and x are as defined for the compound of formula (IV).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (VI-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

ring A, Z, R ^a , R ^d , R ₂₃ -R ₂₆ , m ₁ , n ₁ , x and y are as defined for the compound of formula (VI).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

Y is selected from the group consisting of -S(CH ₂ ) _n1 -,

R ₂₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C( O)R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of the atom deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -( CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O )NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₂₂ -R ₂₆ , m ₁ and n ₁ are as defined for the compound of formula (I).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

R ₂₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C( O)R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of the atom deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -( CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O )NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₂₃ -R ₂₆ , m ₁ and n ₁ are as defined for the compound of formula (I).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

Y is selected from the group consisting of -S(CH ₂ ) _n1 -,

R ₂₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C( O)R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of the atom deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -( CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O )NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ; And

n is an integer equal to 0, 1 or 2;

R ₂₂ -R ₂₆ , m ₁ and n ₁ are as defined for the compound of formula (I).

In a preferred embodiment of the present invention, the compound of formula (I) is a compound of formula (X), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

Where:

M is selected from the group consisting of -CR ₂₃ - and oxygen;

Y is selected from the group consisting of -S(CH ₂ ) _n1 -,

R ₂₁ is selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ , -(CH ₂ ) _n1 NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ , -(CH ₂ ) _n1 NR ₂₃ C( O)R ₂₄ and -(CH ₂ ) _n1 NR ₂₃ S(O) _m1 R ₂₄ , wherein each of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of the atom deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -( CH ₂ ) _n1 R ₂₅ , -(CH ₂ ) _n1 OR ₂₅ , -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ , -(CH ₂ ) _n1 C(O)OR ₂₅ , -(CH ₂ ) _n1 S(O) _m1 R ₂₅ , -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O)NR ₂₅ R ₂₆ , -(CH ₂ ) _n1 C(O )NHR ₂₅ , -(CH ₂ ) _n1 NR ₂₅ C(O)R ₂₆ and -(CH ₂ ) _n1 NR ₂₅ S(O) _m1 R ₂₆ ;

R ₂₂ -R ₂₆ , m ₁ and n ₁ are as defined for the compound of formula (I).

In a preferred embodiment of the present invention, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, ring A is selected from the group consisting of:

In a preferred embodiment, the present invention provides a compound of any formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

Where:

Z is selected from the group consisting of -CH ₂ -, -CH ₂ NH-, -CH ₂ O-, -CH ₂ -, -NH- and -NHSO ₂ -;

Y is selected from the group consisting of -C(O)-, -C(O)CH ₂ -, -C(O)O-, -C(O)CH ₂ NH-, -C(O)CH ₂ O- , -SCH ₂ -, -S(O)CH ₂ -, -S(O) ₂ CH ₂ -, -P(O)R ₂₃ -, -C(O)NH- and -C(O)NHSO ₂ - ; where R ^a is selected from the group consisting of hydrogen, halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 C(O)R ₂₃ , -(CH ₂ ) _n1 C (O)OR ₂₃ , -(CH ₂ ) _n1 C(O)NR ₂₃ R ₂₄ and -(CH ₂ ) _n1 S(O) _m1 R ₂₃ where each is C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _3-6 halocycloalkyl, C _1-6 alkoxy and C _1-6 hydroxyalkyl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C _1-6 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl;

R ^d is selected from the group consisting of hydrogen, halogen, amino, cyano, nitro, C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, C _3-8 halocycloalkyl, C _1-6 alkoxy and C _1-6 hydroxyalkyl;

R ₂₃ and R ₂₄ are the same or different, and are each independently selected from the group consisting of C _1-6 alkyl, C _3-8 cycloalkyl, and 3-8 membered heterocyclyl, where each is C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C _1-3 alkyl, amino, oxo, nitro, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , 3-8 membered heterocyclyl, 6-10 membered aryl and 5-12 membered heteroaryl.

In a preferred embodiment, the present invention provides a compound of any formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

R _15a is selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, halogen, amino, hydroxy, C _3-8 cycloalkyl, C _3-8 halocycloalkyl, 3-8 -membered heterocyclyl, 6-10-membered aryl, 5-12-membered heteroaryl, -(CH ₂ ) _n1 R ₂₃ , -(CH ₂ ) _n1 OR ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , - (CH ₂ ) _n1 SR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ and -(CH ₂ ) _n1 NR ₂₃ R ₂₄ where each is C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy, C _3-8 cycloalkyl, C _3-8 halocycloalkyl, 3-8 membered heterocyclyl, 6-10 membered aryl and 5-12 membered heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, cyano, hydroxy, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, -(CH ₂ ) _n1 NR ₂₅ R ₂₆ and 3-6-membered heterocyclyl;

R _16a is selected from the group consisting of hydrogen, halogen, cyano, C _1-6 alkyl and C _1-6 haloalkyl;

or R _15a and R _16a may form C _3-8 cycloalkyl, where C _3-8 cycloalkyl is optionally further substituted with one or more substituents selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 haloalkyl and halogen , and R _15a and R _16a do not simultaneously represent a hydrogen atom;

R ₂₃ and R ₂₄ are the same or different, and are each independently selected from the group consisting of a hydrogen atom, C _1-6 alkyl, C _3-8 cycloalkyl, and 3-8 membered heterocyclyl, where each of C _1-6 alkyl, C _3-8 cycloalkyl and 3-8 membered heterocyclyl optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C _1-6 alkyl, amino, oxo, nitro, cyano, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, -(CH ₂ ) _n1 NR ₂₅ R ₂₆ , 3-8 membered heterocyclyl, 6-10 -membered aryl and 5-12-membered heteroaryl.

In a preferred embodiment of the present invention, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from the group consisting of:

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of any of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present invention further relates to the use of any of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a GABA _A receptor regulating drug.

The present invention further relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, for the preparation of a medicament for the treatment of a disease associated with the central nervous system (CNS), which is selected from the group, consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, spasmodic disorder, memory and/or cognitive disorder, dyskinesia, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder, and/or withdrawal symptoms or tinnitus.

The present invention further relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the treatment of a disease associated with the CNS.

The present invention further relates to a method for preventing and/or treating a disease associated with the CNS, comprising administering to a patient a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them.

DEFINITIONS

Unless otherwise indicated, terms used in the description and claims have the following meanings:

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably alkyl containing 1 to 8 carbon atoms, more preferably alkyl containing 1 to 6 carbon atoms. carbon, and most preferably alkyl containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2.3 -dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl , 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl , 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and their various branched isomers. The alkyl group may be substituted or unsubstituted. In case it is substituted, the substituent group(s) may be substituted(s) at any available connecting point. The substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl. The alkyl according to the present invention is preferably selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "alkylene" refers to an alkyl whose hydrogen atom is further substituted, for example, "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ - and the like. The term "alkenyl" refers to an alkyl, as defined above, which consists of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl and the like. The alkenyl group may be substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocyclylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl includes cycloalkyl having a spiro ring, a fused ring, or a bridged ring. Cycloalkyl is preferably cyclopropyl.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with individual rings connected via one common carbon atom (called a spiro atom), where the rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron systems. Spirocycloalkyl is preferably 6-14 membered spirocycloalkyl and more preferably 7-10 membered spirocycloalkyl. According to the number of spiroatoms common between the rings, spirocycloalkyl can be subdivided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, and spirocycloalkyl is preferably monospirocycloalkyl or dispirocycloalkyl, and more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/ 6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.

Non-limiting examples of spirocycloalkyl include:

and also include spirocycloalkyl wherein cycloalkyl and heterocyclyl are bonded via a single spiro atom, their non-limiting examples include:

The term "fused cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group where each ring in the system shares an adjacent pair of carbon atoms with another ring, where, where one or more rings may contain one or more double bonds, but none of the rings does not have a fully conjugated π-electron system. The fused cycloalkyl is preferably a 6-14 membered fused cycloalkyl and more preferably a 7-10 membered fused cycloalkyl. According to the number of rings it contains, the fused cycloalkyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and the fused cycloalkyl is preferably bicyclic or tricyclic fused cycloalkyl, and more preferably 5-membered/5-membered or 5-membered/6- membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include:

The term "bridged cycloalkyl" refers to a 5-20 membered all-carbon polycyclic group where every two rings in the system share two unbonded carbon atoms, where the rings may have one or more double bonds, but none of the rings has a fully conjugated π -electronic system. The bridged cycloalkyl is preferably a 6-14 membered bridged cycloalkyl and more preferably a 7-10 membered bridged cycloalkyl. According to the number of rings it contains, bridged cycloalkyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and bridged cycloalkyl is preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl include:

A cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclyl ring, where the ring associated with the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "heterocyclyl" refers to a 3-20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group in which one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer from 0 to 2), but excluding -OO-, -OS- or -SS- in the ring, with the remaining ring atoms being carbon atoms. Preferably, the heterocyclyl has 3 to 12 ring atoms, where 1 to 4 atoms are heteroatoms; more preferably 3 to 10 ring atoms; and most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, 1,4-diazacyclyl and the like, and preferably tetrahydrofuranyl , pyrazolidinyl, morpholinyl, 1,4-diazacyclyl, piperazinyl and pyranyl. Polycyclic heterocyclyl includes heterocyclyl having a spiro ring, a fused ring, or a bridged ring. A heterocyclyl containing a spiro ring, a fused ring, or a bridged ring is optionally bonded to another group via a single bond, or additionally linked to other cycloalkyl, heterocyclyl, aryl, and heteroaryl via any two or more ring atoms.

The term "spiroheterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl group with individual rings connected via one common atom (called a spiro atom), where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S( O) _m (where m is an integer from 0 to 2), with the remaining ring atoms being carbon atoms, where the rings may contain one or more double bonds, but none of the rings has a fully conjugated π electron system. Spiroheterocyclyl is preferably 6-14 membered spiroheterocyclyl and more preferably 7-10 membered spiroheterocyclyl. According to the number of spiroatoms common between the rings, spiroheterocyclyl can be classified into monospiroheterocyclyl, dispyroheterocyclyl or polyspiroheterocyclyl, and spiroheterocyclyl is preferably monospiroheterocyclyl or dispyroheterocyclyl, and more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6 -membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl group where each ring in the system shares an adjacent pair of atoms with another ring, where one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π-electron system, and where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms. The fused heterocyclyl is preferably a 6-14 membered fused heterocyclyl and more preferably a 7-10 membered fused heterocyclyl. According to the number of rings it contains, fused heterocyclyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and preferably bicyclic or tricyclic fused heterocyclyl, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl . Non-limiting examples of fused heterocyclyl include:

The term "bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclyl group where every two rings in the system share two unbonded atoms, where the rings may have one or more double bonds, but none of the rings has a fully conjugated π-electron system, and where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms. The bridged heterocyclyl is preferably a 6-14 membered bridged heterocyclyl and more preferably a 7-10 membered bridged heterocyclyl. According to the number of rings it contains, bridged heterocyclyl can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and bridged heterocyclyl is preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyl include:

The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring linked to the parent structure is heterocyclyl. Non-limiting examples include:

и т.п.

and so on.

The heterocyclyl may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

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

Aryl may be substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "heteroaryl" refers to a 5-12 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of O, S and N. Heteroaryl is preferably a 5-10 membered heteroaryl and more preferably 5- or 6 -membered heteroaryl, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, preferably triazolyl, tetrazolyl, thienyl, imidazolyl, pyrazolyl, pyridazinyl , pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl or pyrimidinyl, and more preferably triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, thiazolyl, oxazolyl, isoxazolyl or imidazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring linked to the parent structure is a heteroaryl ring. Non-limiting examples include:

Heteroaryl may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "alkoxy" refers to the group -O-(alkyl) or -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted. When it is substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

"Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, where alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, where alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxy group(s), where alkyl is as defined above.

"Alkenyl" refers to a chain alkenyl, also known as an alkene group, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably an alkenyl having 2 to 8 carbon atoms, more preferably an alkenyl having 2 up to 6 carbon atoms and most preferably alkenyl having 2 to 3 carbon atoms. Alkenyl may be further substituted with another related group, e.g., alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio, carboxy or alkoxycarbonyl.

"Alkynyl" refers to (CH≡C-) which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably alkynyl having 2 to 8 carbon atoms, more preferably alkynyl having 2 to 6 carbon atoms, and most preferably alkynyl having 2 to 3 carbon atoms. Alkynyl may be further substituted with another related group, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, carboxy, and alkoxycarbonyl.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to the -NH ₂ group.

"Cyano" refers to the -CN group.

"Nitro" refers to the -NO ₂ group.

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

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

"E12O" refers to diethyl ether.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone) dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bis(trimethylsilyl)amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

Various expressions such as "X is selected from the group consisting of A, B or C", "X is selected from the group consisting of A, B and C", "X is A, B or C", "X is A, B and C, etc. have the same meaning, i.e. X can be one or more of A, B, and C.

The hydrogen atom of the present invention may be replaced by its deuterium isotope. Any of the hydrogen atoms in the compounds of the examples of the present invention may also be replaced by a deuterium atom.

"Optional" or "optional" means that the following phenomenon or circumstance may, but need not, occur, and such description includes the situation in which the phenomenon or circumstance occurs or does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that an alkyl group may, but need not, be present, and such description includes the situation where the heterocyclyl is substituted with alkyl and when the heterocyclyl is not substituted with alkyl.

"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms, independently substituted with the appropriate number of substituents. Of course, substituents exist only in their possible chemical positions. One skilled in the art is able to determine whether or not substitution can be made through experimentation or theoretical knowledge without undue effort. For example, the combination of amino or hydroxy groups having free hydrogen atoms and carbon atoms having unsaturated bonds (such as olefins) may be unstable.

"Pharmaceutical composition" refers to a mixture of one or more of the described compounds according to the present invention 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 the pharmaceutical composition is to facilitate the introduction of the compound into the body, which facilitates the absorption of the active ingredient necessary for the manifestation of biological activity.

A "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective for use in mammals and has the desired biological activity.

DETAILED DESCRIPTION OF THE INVENTION

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

EXAMPLES

The structures of the compounds according to the present invention were identified using nuclear magnetic resonance (NMR) and/or liquid chromatography with mass spectrometry (LC-MS). NMR shifts (δ) are given in parts per million (ppm). NMR spectra were determined on a Bruker AVANCE-400 instrument. The determination solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CDCl ₃ ) and deuterated chloroform (CD ₃ OD) and the internal standard was tetramethylsilane (TMS).

Liquid chromatography with mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. High performance liquid chromatography (HPLC) was performed on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 chromatographic column 150×4.6 mm) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 chromatographic column 150×4.6 mm).

Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used as a thin layer silica gel chromatography (TLC) plate. The size of the silica gel plate used in TLC was 0.15 to 0.2 mm, and the size of the silica gel plate used in product purification was 0.4 mm to 0.5 mm. Yantai Huanghai silica gel of 200 to 300 mesh was commonly used as a support for column chromatography.

The starting materials used in the examples of the present invention are known and commercially available, or can be synthesized by adopting or in accordance with methods known in the art.

Unless otherwise indicated, all reactions according to the present invention were carried out with continuous stirring with a magnetic stirrer in an atmosphere of dry nitrogen or argon, the solvent was dry, and the reaction temperature was in degrees Celsius.

Example 1

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

Stage 1: receiving

(3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one

Potassium tert-butoxide (2.3 g, 20.7 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml) and the reaction system was purged with nitrogen. To the above solution was added (3R, 5R, 8R,9R, 10S,13S,14S)-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (3 g, 10.3 mmol) to give an orange solution which was then stirred at 25° C. for 10 minutes. Methyl benzene sulfinate (3.2 g, 20.7 mmol) was added, after which the reaction solution was stirred at 30° C. for half an hour. Water (100 ml) was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate (100 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (3R, 5R, 8R,9R, 10S,13S,14S)-3-hydroxy-3,13-dimethyl- 16-(phenylsulfinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one (3.5 g, yield: 82%).

Stage 2: receiving

(3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12, 13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one

(3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-16-(phenylsulfinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one was dissolved in xylene (50 ml ) and purged the reaction system with nitrogen. Sodium carbonate (24.7 g, 0.17 mol) was added, after which the reaction solution was stirred at 140° C. overnight. The reaction solution was filtered and the organic phase was concentrated. The obtained crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl- 1,2,3,4,5,6,7,8,9,10,11,12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (1.5 g, yield: 62 %).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (dd, J=5.9, 1.2 Hz, 1H), 6.03 (dd, J=6.0, 3.2 Hz, 1H) , 2.42-2.33(m, 1H), 1.90-1.79(m, 4H), 1.76-1.66(m, 2H), 1.58-1.48(m, 5H), 1.47-1.37 (m, 4H), 1.36-1.23 (m, 7H), 1.08 (s, 3H).

Stage 3: receiving

(2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one

Trimethyl sulfoxide (0.92 g, 4.2 mmol) was dissolved in anhydrous dimethyl sulfoxide (10 ml) and the reaction system was purged with nitrogen. Sodium hydride (168 mg, 4.2 mmol) was added, after which the reaction solution was stirred for 1 hour. A solution of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11 was added, 12,13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (1.0 g, 3.5 mmol) in dimethyl sulfoxide (5 ml), after which the reaction solution was stirred at room temperature overnight. Water (50 ml) was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-hydroxy-2, 6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one (0.75 g, yield: 71%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.06-2.00 (m, 1H), 1.97-1.91 (m, 1H), 1.88-1.79 (m, 3H), 1.78-1.67 (m, 6H), 1.63-1.54 (m, 2H), 1.48-1.39 (m, 3H), 1.37-1.25 (m, 9H ), 1.15-1.05 (m, 2H), 0.96 (s, 3H).

Step 4. Obtaining (2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-ethylidene-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2- ola

PPh ₃ EtBr (14.8 g, 40 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 ml) and the reaction system was purged with nitrogen. Sodium hydride (1.6 g, 40 mmol) was added, after which the reaction solution was stirred at room temperature for 1 hour. (2R,4aS,4bR,6aS,7aS,8aS,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylhexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7(1H)- he (0.6 g, 2.0 mmol), after which the reaction solution was stirred at 100° C. overnight. The reaction solution was cooled to room temperature. Water (200 ml) was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate (200 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-ethylidene-2, 6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (0.5 g, yield: 81%).

Stage 5. Receiving

(2R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2- ola

(R,4aS,4bR,6aS,7aS,8aR,8bR,8cR,10aR)-7-ethyliden-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-ol (0, 4 g, 1.3 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml). The solution was cooled to 0°C, after which BH ₃ /THF (12.7 ml, 12.7 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC (thin layer chromatography) showed the completion of the reaction. The reaction solution was cooled to 0°C, after which 3 M NaOH aqueous solution (4 ml) was added slowly, followed by H ₂ O ₂ (3 ml). The reaction solution was stirred at room temperature for 2 hours, and TLC showed completion of the reaction. Ethyl acetate (50 ml) was added, after which the reaction solution was washed successively with saturated aqueous Na ₂ S ₂ O ₃ (30 ml) and water (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product (0.4 g, yield: 100%, crude) which was immediately used in the next step.

Stage 6: receiving

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl) ethane-1-one

(2R,4aS,4bR,6aS,7aR,8aR,8bR,8cR,10aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2- ol (0.4 g, 1.2 mmol) was dissolved in dichloromethane (20 ml). PCC (pyridinium chlorochromate) (0.52 g, 40 mmol) was added, after which the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered and the organic phase was concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to give 1-((2R,4aS,4bR,6a8.7S,7aS,8aR,8bR,8cR,10aR)-2 -hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (0.35 g, yield: 83%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.74 (d, J=4.1 Hz, 1H), 2.21 (s, 3H), 1.97-1.91 (m, 1H), 1 .87-1.62(m, 7H), 1.56-1.50(m, 1H), 1.44-1.21(m, 15H), 1.12-1.00(m, 1H) , 0.90-0.83 (m, 1H), 0.72 (s, 3H), 0.44-0.36 (m, 1H).

Example 2 Getting

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

Stage 1: receiving

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylaloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a ]phenanthren-7-yl)ethane-1-one

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

Stage 2: receiving

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

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a ]phenanthren-7-yl)ethan-1-one (87 mg, 0.21 mmol), 1H-pyrazole-4-carbonitrile (59 mg, 0.64 mmol) and potassium carbonate (145 mg, 1.05 mmol) was dissolved in tetrahydrofuran (2 ml), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (33 mg, yield: 37%).

MS m/z (mass/charge) (ESI (Electric Field Sputter Ionization)): 404.2 [M-H ₂ O+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.82 (s, 1H), 5.24-5.13 (m, 2H), 2.84 (d, J= 2.7 Hz, 1H), 1.98-1.92 (m, 1H), 1.87-1.77 (m, 4H), 1.76-1.66 (m, 3H), 1.57 -1.51 (m, 1H), 1.46-1.24 (m, 15H), 1.12-1.02 (m, 1H), 1.00-0.96 (m, 1H), 0 .78 (s, 3H), 0.54-0.46 (m, 1H).

Example 3 and Example 4 Getting

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

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

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a ]phenanthren-7-yl)ethan-1-one (80 mg, 0.19 mmol), 1H-pyrazole-4-carbonitrile (55 mg, 0.58 mmol) and potassium carbonate (131 mg, 0.95 mmol) was dissolved in tetrahydrofuran (3 ml), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (34.7 mg, yield: 42%) and 1-(2-((2R ,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2 -oxoethyl)-1H-pyrazole-3-carbonitrile (3.7 mg, yield: 4.5%).

Example 3:

MS m/z (ESI): 404.2 [MH ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (d, J=2.4 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 5.29-5.13 (m, 2H), 2.83 (d, J=2.9 Hz, 1H), 1.97-1.92 (m, 1H), 1.86-1.79 (m, 4H), 1, 73-1.64 (m, 3H), 1.58-1.52 (m, 1H), 1.43-1.27 (m, 15H), 1.12-0.96 (m, 2H), 0.79 (s, 3H), 0.53-0.44 (m, 1H).

Example 4:

MS m/z (ESI): 404.2 [M-H ₂ O+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52 (d, J=2.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 5.11-4.96 (m, 2H), 2.92 (s, 1H), 1.93-1.87 (m, 1H), 1.82-1.74 (m, 2H), 1.72-1.62 (m , 4H), 1.51 (s, 1H), 1.46-1.24 (m, 15H), 1.18-1.09 (m, 2H), 1.04 (s, 3H), 0, 89-0.84 (m, 1H), 0.46-0.40 (m, 1H).

Example 5

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

Stage 1: receiving

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

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a ]phenanthren-7-yl)ethan-1-one (60 mg, 0.15 mmol), 4-(trifluoromethyl)-1H-pyrazole (60 mg, 0.44 mmol) and potassium carbonate (104 mg, 0.75 mmol) was dissolved in tetrahydrofuran (3 ml), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (22.2 mg, yield: 33%).

MS m/z (ESI): 465.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.73 (s, 1H), 5.25-5.09 (m, 2H), 2.83 (d, J= 3.6 Hz, 1H), 2.00-1.91 (m, 1H), 1.89-1.79 (m, 4H), 1.78-1.65 (m, 3H), 1.58 -1.52 (m, 1H), 1.47-1.22 (m, 15H), 1.15-0.95 (m, 2H), 0.79 (s, 3H), 0.52-0 .44 (m, 1H).

Example 6

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

Stage 1: receiving

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

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a ]phenanthren-7-yl)ethan-1-one (80 mg, 0.2 mmol), 3-(trifluoromethyl)-1H-pyrazole (80 mg, 0.6 mmol) and potassium carbonate (138 mg, 1.0 mmol) was dissolved in tetrahydrofuran (5 ml), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1 -yl)ethan-1-one (17 mg, yield: 18%).

MS m/z (ESI): 447.3 [MH ₂ O+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=1.9 Hz, 1H), 6.60 (d, J=1.9 Hz, 1H), 5.27 -5.13 (m, 2H), 2.83 (d, J=3.7 Hz, 1H), 1.99-1.90 (m, 1H), 1.89-1.76 (m, 4H), 1, 75-1.61 (m, 3H), 1.58-1.50 (m, 1H), 1.50-1.21 (m, 15H), 1.13-0.96 (m, 2H), 0.79 (s, 3H), 0.52-0.45 (m, 1H).

Example 7 and Example 8

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

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

Stage 1: receiving

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

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2- a]phenanthren-7-yl)ethan-1-one (80 mg, 0.19 mmol), 1H-1,2,3-triazole (40 mg, 0.58 mmol) and potassium carbonate (131 mg, 0.19 mmol) 95 mmol) was dissolved in tetrahydrofuran (3 ml), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (7) (9.2 mg, yield: 12%) and

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (8) (17.8 mg, yield: 23%). Example 7:

MS m/z (ESI): 380.3 [MH ₂ O+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (s, 2H), 5.55-5.36 (m, 2H), 2.82 (d, J=4.1 Hz, 1H), 1 .99-1.92 (m, 1H), 1.87-1.74 (m, 4H), 1.73-1.52 (m, 5H), 1.47-1.26 (m, 14H) , 1.14-0.98 (m, 2H), 0.84 (s, 3H), 0.52-0.43 (m, 1H).

Example 8:

MS m/z (ESI): 398.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 7.66 (s, 1H), 5.52-5.35 (m, 2H), 2.87 (d, J= 3.9 Hz, 1H), 2.02-1.92 (m, 1H), 1.89-1.78 (m, 4H), 1.76-1.65 (m, 3H), 1.59 -1.52 (m, 1H), 1.48-1.23 (m, 15H), 1.15-0.98 (m, 2H), 0.80 (s, 3H), 0.56-0 .45 (m, 1H).

Example 9 and Example 10

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(2H-tetrazol-2-yl)ethan-1-one (9)

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

Stage 1: receiving

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(2H-tetrazol-2-yl)ethan-1-one (9) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2 -hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-tetrazol-1-yl)ethan-1-one (10)

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2- a]phenanthren-7-yl)ethan-1-one (50 mg, 0.12 mmol), 1H-tetrazole (26 mg, 0.37 mmol) and potassium carbonate (83 mg, 0.6 mmol) were dissolved in tetrahydrofuran (3 ml) and stirred the resulting reaction solution at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4,5] cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (9) (11.6 mg, yield: 24%) and 1-(( 2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)- 2-(1H-tetrazol-1-yl)ethan-1-one (10) (4.4 mg, yield: 9%).

Example 9:

MS m/z (ESI): 381.2 [MH ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ8.58 (s, 1H), 5.74-5.62 (m, 2H), 2.88 (d, J=3.8 Hz, 1H), 1, 97-1.91 (m, 1H), 1.87-1.79 (m, 4H), 1.75-1.64 (m, 3H), 1.58-1.55 (m, 1H), 1.45-1.35 (m, 7H), 1.34-1.24 (m, 8H), 1.14-1.01 (m, 2H), 0.85 (s, 3H), 0. 56-0.48 (m, 1H).

Example 10:

MS m/z (ESI): 399.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ8.77 (s, 1H), 5.57-5.39 (m, 2H), 2.90 (s, 1H), 2.00-1.91 (m , 1H), 1.88-1.79 (m, 4H), 1.76-1.65 (m, 3H), 1.59-1.56 (m, 1H), 1.46-1.37 (m, 7H), 1.35-1.24 (m, 8H), 1.13-0.99 (m, 2H), 0.79 (s, 3H), 0.58-0.49 (m , 1H).

Example 11

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(4-(methylsulfonyl)piperazin-1-yl)ethan-1-one

2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethylocta decahydrocyclopropa[4,5]cyclopenta[1,2- a]phenanthren-7-yl)ethan-1-one (50mg, 0.12mmol), 1-(methylsulfonyl)piperazine (60mg, 0.36mmol) and potassium carbonate (83mg, 0.6mmol) was dissolved in tetrahydrofuran (3 ml), and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by HPLC to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4,5] cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)piperazin-1-yl)ethan-1-one (13.7 mg, yield: 23%).

MS m/z (ESI): 493.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.63 (br, 2H), 3.47 (br, 4H), 2.93 (br, 4H), 2.82 (s, 3H), 2.73 (s, 1H), 1.90-1.88 (m, 1H), 1.86-1.81 (m, 2H), 1.81-1.70 (m, 3H), 1.70-1 .64 (m, 2H), 1.57-1.50 (m, 1H), 1.41 (s, 5H), 1.34-1.22 (m, 10H), 1.12-0.99 (m, 1H), 0.92-0.85 (m, 1H), 0.73 (s, 3H), 0.49-0.39 (m, 1H).

Example 12

1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1 -He

Stage 1: preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

Trimethylsilyl triflate (5.6 mL, 31.0 mmol) was added dropwise to a solution of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene -17-one (3 g, 10.3 mmol) and triethylamine (36.0 ml, 258.2 mmol) in toluene (45 ml), and the resulting reaction solution was heated under reflux for 2 hours. The reaction solution was cooled, washed with saturated sodium bicarbonate, and extracted with n-hexane. The organic phase was concentrated to dryness to give the crude product (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane). A selective fluorine-containing reagent (4.0 g, 11.4 mmol) was added to a solution of (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6 ,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane) in N,N-dimethylformamide (25 ml), and the resulting reaction solution was stirred at room temperature for 2 hours to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3,13-dimethyl-3-( (trimethylsilyl)oxy)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one. A solution of tetrabutylammonium fluoride in tetrahydrofuran (11.4 ml, 1 M) was added and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate and washed three times with saturated brine. The organic phase was concentrated to dryness and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=6:4) to give (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy -3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (2.0 g, yield: 50.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.09 (dd, J=50.6, 7.5 Hz, 1H), 2.18-1.58 (m, 10H), 1.54-1, 01 (m, 14H), 0.92 (s, 3H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ minus 192.59.

Stage 2: preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

Sodium hydride (123 mg, 3.08 mmol, 60 wt.%) was added to a solution of ethyltriphenylphosphonium bromide (1.2 g, 3.24 mmol) in dimethyl sulfoxide (20 ml) in portions under a nitrogen atmosphere, and the resulting reaction solution was stirred at room temperature within 1 hour. (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (200 mg, 0. 65 mmol) and heated the reaction solution to 70° C. under nitrogen overnight. The reaction solution was cooled and brine was added. 1 N hydrochloric acid was added to adjust the pH to 6, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with brine and concentrated to dryness to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=7:3) to give (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-3-ol (80 mg, yield: 38.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.71-5.59 (m, 1H), 5.12 (dt, J=57.2, 7.0 Hz, 1H), 2.27-2, 11 (m, 2H), 1.92-1.24 (m, 21H), 1.22-1.09 (m, 4H), 1.06 (s, 3H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) 5 minus 153.69.

Stage 3: preparation of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3- ola

(3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml). A solution of borane in tetrahydrofuran (1 M, 2.5 ml) was added dropwise, and the resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled with ice water, and a sodium hydroxide solution (3 M, 1 ml) was slowly added dropwise while a large amount of gas was released. Hydrogen peroxide (25%, 0.58 ml) was slowly added dropwise, after which the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with sodium thiosulfate solution and brine, and dried to obtain (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3.13 -dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg), which was immediately used in the next step.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.47-5.16 (m, 1H), 4.22-4.05 (m, 1H), 2.42-2.17 (m, 1H), 1.94-0.93 (m, 27H), 0.87 (s, 3H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ minus 178.27.

Stage 4: receiving

1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1 -she

Pyridinium chlorochromate (102 mg, 0.47 mmol) was added to a solution of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (80 mg) in acetone (2 ml), and the resulting reaction solution was reacted at 60°C for 6 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=5:2) to obtain 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3 -hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (22 mg, yield: 25%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.64-5.35 (m, 1H), 2.44-2.09 (m, 6H), 1.97-1.75 (m, 4H), 1.74-1.00 (m, 20H), 0.98-0.68 (m, 2H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ minus 168.20.

Example 13

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

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

3.0 M methylmagnesium bromide (8.5 ml, 25.5 mmol) and 20 ml anhydrous tetrahydrofuran were added to a dry 100 ml round bottom flask. The reaction system was purged with nitrogen and cooled to 0°C. Copper iodide (3.94 g, 20.7 mmol) was added, after which the reaction solution was stirred at 0° C. for 1 hour. (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12, 13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (2 g, 6.9 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran, and the resulting solution was slowly added dropwise to the reaction system. The reaction solution was stirred for 3 hours, and TLC showed completion of the reaction. A saturated ammonium chloride solution was added to terminate the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=2:1) to give (3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro- 17H-cyclopenta[a]phenanthren-17-one (1.56 g, yield: 75%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.51-2.42 (m, 2H), 2.24 (d, J=17.6 Hz, 1H), 1.89-1.63 (m, 7H), 1.54-1.18 (m, 16H), 1.10 (d, J=7.6 Hz, 3H), 1.03 (s, 3H).

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

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

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

(3R,5R,8R,9R,10S,13S,14S,15R,E)-17-ethylidene-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (1.37 mg, 4 .33 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml). The solution was cooled to 0°C, after which BH ₃ /THF (43 ml, 43 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed completion of the reaction. The reaction solution was cooled to 0°C, after which 3 M NaOH aqueous solution (40 ml) was added slowly, followed by H ₂ O ₂ (30 ml). The reaction solution was stirred at room temperature for 2 hours, and TLC showed completion of the reaction. Ethyl acetate (50 ml) was added, after which the reaction solution was washed successively with saturated aqueous Na ₂ S ₂ O ₃ (30 ml) and water (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product (1.37 g) which was used immediately in the next step.

Step 4: 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) ethane-1-he

(3R,5R,8R,9R,10S,13S,14S,15R,17S)-17-((R)-1-hydroxyethyl)-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3- ol (1.37 g, crude) was dissolved in dichloromethane (30 ml). PCC (1.8 g, 8.66 mmol) was added, after which the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered and the organic phase was concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 1/1) to give 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3.13 ,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (780 mg, yield for two steps: 54.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.49 (dd, J=8.8, 10.4 Hz, 1H), 2.14-2.03 (m, 5H), 1.95-1, 79 (m, 5H), 1.69-1.06 (m, 18H), 0.96 (d, J=7.2 Hz, 3H), 0.78 (s, 3H).

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

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

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

2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )ethan-1-one (82 mg, 0.2 mmol), 1H-pyrazole-4-carbonitrile (28 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml) and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopent [a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (41 mg, yield: 48%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.01 (d, J=17.9 Hz, 1H), 4.90 (d , J=17.9 Hz, 1H), 2.62-2.48 (m, 1H), 2.30-2.06 (m, 3H), 2.04-1.75 (m, 7H), 1.75-1.04 (m, 15H), 0.99 (d, J=7.1 Hz, 3H), 0.84 (s, 3H).

MS m/z (ESI): 424.6 [M+H] ⁺ .

Example 14 and Example 15

1-(2-((3R,5R,10S,13S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)- 1Н-pyrazole-4-carbonitrile (14)

1-(2-((3R,5R,10S,13S,16S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)- 1Н-pyrazole-4-carbonitrile (15)

Example 14 and Example 15 were synthesized according to the following specific scheme:

Example 14: MS m/z (ESI): 428.3 [M+1] ⁺ .

Example 15: MS m/z (ESI): 428.3 [M+1] ⁺ .

Example 16 and Example 17

1-(2-((3R,5R,10S,13S,16R)-3-hydroxy-3,13-dimethyl-16-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- oxoethyl)-1H-pyrazole-4-carbonitrile (16)

1-(2-((3R,5R,10S,13S,16S)-3-hydroxy-3,13-dimethyl-16-(trifluoromethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- oxoethyl)-1H-pyrazole-4-carbonitrile (17)

Example 16 and Example 17 were synthesized according to the following specific scheme:

Example 16: MS m/z (ESI): 478.3 [M+1] ⁺ .

Example 17: MS m/z (ESI): 478.3 [M+1] ⁺ .

Example 18

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-chloro-1H-pyrazole, respectively, 2-(4-chloro-1H-pyrazol-1-yl) was obtained -1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene- 7-yl)ethan-1-one (21.9 mg, yield: 26%).

MS m/z (ESI): 431.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ7.45 (d, J=11.8 Hz, 2H), 5.17-5.01 (m, 2H), 2.81 (d, J=3.5 Hz, 1H), 1.99-1.91 (m, 1H), 1.86-1.79 (m, 3H), 1.77-1.62 (m, 3H), 1.57-1, 49 (m, 3H), 1.44-1.20 (m, 14H), 1.12-0.96 (m, 2H), 0.78 (s, 3H), 0.51-0.44 ( m, 1H).

Example 19

(2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyl-N-phenyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7-carboxamide

Example 19 was synthesized according to the following custom scheme:

Example 20

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

Example 20 was synthesized according to the following custom scheme:

MS m/z (ESI): 467.3 [M+1] ⁺ .

Example 21

1-(2-((3,5R,8R,9R,10S8,13R,14S,17S)-3-hydroxy-15-(isopropylsulfonyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

Example 21 was synthesized according to the following custom scheme:

MS m/z(ESI): 516.3 [M+1] ⁺ .

Example 23

1-(2-((2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-hydroxy-2-(methoxymethyl)-6a-methyloctadecahydrocyclopropa[4.5]cyclopenta[1,2-a] phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

Example 23 was synthesized according to the following custom scheme:

MS m/z (ESI): 452.3 [M+1] ⁺ .

Example 24

1-((2R,4aS,4bR,6aS,7S,8bR,8cR,10aR)-2-hydroxy-2-(methoxymethyl)-6a-methyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(4-methyl-1H-pyrazol-1-yl)ethan-1-one

Example 25

1-(2-((2R,4aR,4bS,6aS,8bS,8cR,10aR)-2-hydroxymethyl-4a-(methoxymethyl)-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a] phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

Example 25 was synthesized according to the following custom scheme:

MS m/z (ESI): 466.3 [M+1] ⁺ .

Example 26

1-(2-((2R,4aR,4bS,6aS,8bS,8cR,10aR)-2-hydroxymethyl-4a-(methoxymethyl)-2,6a-dimethyloctadecahydrocyclopropa[4.5]cyclopenta[1,2-a] phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile

MS m/z (ESI): 466.3 [M+1] ⁺ .

Example 33 and Example 34

3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1, 2-а]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (33)

5-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1, 2-а]phenanthren-7-yl)-2-oxoethyl)-1Н-pyrazole-4-carbonitrile (34)

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 5-cyclopropyl-1H-pyrazole-4-carbonitrile, respectively, 3-cyclopropyl-1-(2-(( 2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)- 2-oxoethyl)-1H-pyrazole-4-carbonitrile (33) (19.2 mg, yield: 21%) and 5-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS, 8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (34) (3.0 mg, yield: 3.3%).

Example 33:

MS m/z (ESI): 462.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ7.73 (s, 1H), 5.14-4.98 (m, 2H), 2.80 (d, J=2.2 Hz, 1H), 2, 05-1.89 (m, 2H), 1.86-1.78 (m, 4H), 1.75-1.64 (m, 3H), 1.58-1.52 (m, 2H), 1.46-1.33 (m, 7H), 1.33-1.20 (m, 7H), 1.14-0.92 (m, 6H), 0.76 (s, 3H), 0. 53-0.43 (m, 1H).

Example 34:

MS m/z (ESI): 462.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ7.69 (s, 1H), 5.33-5.13 (m, 2H), 2.85 (d, J=3.8 Hz, 1H), 2, 00-1.92 (m, 1H), 1.86-1.79 (m, 3H), 1.76-1.62 (m, 4H), 1.60-1.51 (m, 2H), 1.45-1.34 (m, 7H), 1.34-1.22 (m, 7H), 1.17-0.94 (m, 7H), 0.81 (s, 3H), 0. 54-0.45 (m, 1H).

Example 37A and Example 37B

1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a] phenanthren-7-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (37A)

1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a] phenanthren-7-yl)-2-oxoethyl)-5-methyl-1H-pyrazole-4-carbonitrile (37B)

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 3-methyl-1H-pyrazole-4-carbonitrile, respectively, gave a mixture of Example 37A and Example 37B (approximately 3:1 ) (25.9 mg, white solid, yield: 39.3%). The mixture was then further separated by preparative chromatography to give 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4, 5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-3-methyl-1H-pyrazole-4-carbonitrile (37A) and 1-(2-((2R,4aS,4bR, 6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-а]phenanthren-7-yl)-2-oxoethyl)-5 -methyl-1H-pyrazole-4-carbonitrile (37B).

Example 37A: MS m/z (ESI): 436.3 [M+H] ⁺

Example 37B: MS m/z (ESI): 436.3 [M+H] ⁺

Example 40

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 2,4-difluoroaniline, respectively, 2-((2,4-difluorophenyl)amino)-1-(( 2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethane -1-one (3.9 mg, white solid, yield: 3.9%).

MS m/z (ESI): 458.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.84-6.75 (m, 2H), 6.65-6.59 (m, 1H), 4.12 (dd, J ₁ =5.2 Hz , J ₂ =24.8 Hz, 2H), 3.61-3.27 (br, 1H), 2.80 (d, J=3.6 Hz, 1H), 2.01-1.77 (m , 10H), 1.76-1.56 (m, 3H), 1.53-1.46 (m, 1H), 1.28-1.19 (m, 10H), 1.00-0.93 (m, 2H), 0.73 (m, 3H), 0.50-0.44 (m, 1H).

Example 41 and Example 42

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

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 1H-pyrazolo[3,4-c]pyridine, respectively, were obtained 1-((2R,4aS,4bR,6aS ,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(2H-pyrazolo[ 3,4-c]pyridin-2-yl)ethan-1-one (41) (5.4 mg, yield: 6.2%) and 1-((2R,4aS,4bR,6aS,7S,7aS, 8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-pyrazolo[3,4-c ]pyridin-1-yl)ethan-1-one (42) (7.0 mg, yield: 8%).

Example 41:

MS m/z (ESI): 448.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.43 (s, 1H), 8.39 (s, 1H), 8.19 (d, J=6.4 Hz, 1H), 8.08 (d , J=6.4 Hz, 1H), 5.77-5.61 (m, 2H), 2.96 (s, 1H), 2.01-1.92 (m, 1H), 1.88- 1.81 (m, 4H), 1.74-1.69 (m, 3H), 1.59-1.55 (m, 2H), 1.48-1.43 (m, 5H), 1. 33-1.27 (m, 9H), 1.10-1.05 (m, 2H), 0.85 (s, 3H), 0.60-0.54 (m, 1H).

Example 42:

MS m/z (ESI): 448.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.16 (s, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.25 (s, 1H), 7.87 (d , J=5.2 Hz, 1H), 5.72-5.60 (m, 2H), 2.96 (d, J=3.9 Hz, 1H), 2.01-1.94 (m, 1H), 1.87-1.81 (m, 4H), 1.75-1.67 (m, 3H), 1.58-1.52 (m, 2H), 1.44-1.39 ( m, 5H), 1.33-1.25(m, 9H), 1.12-1.02(m, 2H), 0.86(s, 3H), 0.56-0.50(m, 1H).

Example 46

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-fluoropyrazole, respectively, 2-(4-fluoro-1H-pyrazol-1-yl)-1-( (2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl) ethan-1-one (6.2 mg, white solid, yield: 7.7%).

MS m/z (ESI): 415.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (d, J=4.0 Hz, 1H), 7.32 (d, J=4.0 Hz, 1H), 5.03 (d, J =3.6Hz, 2H), 2.80(d, J=3.6Hz, 1H), 2.01-1.93(m, 2H), 1.85-1.80(m, 3H) , 1.73-1.61 (m, 6H), 1.41-1.32 (m, 9H), 1.27 (s, 3H), 1.12-1.02 (m, 2H), 0 .99-0.96 (m, 1H), 0.78 (s, 3H), 0.50-0.44 (m, 1H).

Example 51

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and ethyl 1H-pyrazole-4-carboxylate, respectively, ethyl 1-(2-((2R,4aS, 4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl) -1H-pyrazole-4-carboxylate (29.6 mg, white solid, yield: 43%).

MS m/z (ESI): 469.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (s, 2H), 5.32-4.99 (m, 2H), 4.36-4.24 (m, 2H), 2.83 ( s, 1H), 1.99-1.92 (m, 1H), 1.87-1.79 (m, 3H), 1.72-1.52 (m, 6H), 1.49-1, 16 (m, 17H), 1.14-0.96 (m, 2H), 0.83 (s, 3H), 0.53-0.44 (m, 1H).

Example 53, Example 54A and Example 54B

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(5-methoxy-2H-benzo[d][1,2,3]triazol-2-yl)ethan-1-one (53)

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54А)

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54B)

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 6-methoxy-1H-benzo[d][1,2,3]triazole, respectively, 1-(( 2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)- 2-(5-Methoxy-2H-benzo[d][1,2,3]triazol-2-yl)ethan-1-one (11.8 mg, yield: 13.6%) and a mixture of Example 54A and Example 54B (approx 1:1) (34 mg, yield: 39%). The mixture was then further separated by preparative chromatography to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4,5]cyclopent [1,2-a]phenanthren-7-yl)-2-(6-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54A) and 1 -((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7- yl)-2-(5-methoxy-1H-benzo[d][1,2,3]triazol-1-yl)ethan-1-one (54B).

Example 53:

MS m/z (ESI): 478.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ7.74 (d, J=10.1 Hz, 1H), 7.14-7.03 (m, 2H), 5.73-5.59 (m, 2H ), 3.88 (s, 3H), 2.88 (d, J=4.1 Hz, 1H), 2.01-1.93 (m, 1H), 1.86-1.78 (m, 4H), 1.74-1.63 (m, 3H), 1.55-1.51 (m, 1H), 1.46-1.25 (m, 15H), 1.15-1.00 ( m, 2H), 0.88 (s, 3H), 0.53-0.45 (m, 1H).

Example 54A:

MS m/z (ESI): 478.3 [M+H] ⁺

Example 54B:

MS m/z (ESI): 478.3 [M+H] ⁺

Example 59

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

2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )ethan-1-one (82 mg, 0.2 mmol), 4-(trifluoromethyl)-1H-pyrazole (41 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml) and stirred the resulting reaction solution at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[ a]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (24.6 mg, yield: 26%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 2H), 5.00 (d, J=16 Hz, 1H), 4.90 (d, J=16 Hz, 1H), 2, 58-2.54 (m, 1H), 1.88-1.83 (m, 2H), 1.69-1.58 (m, 5H), 1.50-1.25 (m, 19H), 0.98 (d, J=8.0 Hz, 3H), 0.85 (s, 3H).

MS m/z (ESI): 467.3 [M+H] ⁺

Example 60

1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) -2-oxoethyl)-1H-pyrazole-3-carbonitrile (60)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy -3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (12.5 mg, yield: 20.2%).

MS m/z (ESI): 424.1 [M+H] ⁺ .

*H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 5.07-4.84 (m, 2H), 2.55 (t, J=8.1 Hz, 1H), 2.33-1.06 (m, 25H), 0.98 (d, J=7.0 Hz, 3H) , 0.84 (s, 3H).

Example 61 and Example 132

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- (2H-1,2,3-triazol-2-yl)ethan-1-one (61)

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- (1H-1,2,3-triazol-1-yl)ethan-1-one (132)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3, 13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (9.5 mg, yield: 16 ,3%) and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (13 mg, yield: 22.3%).

Example 61:

MS m/z (ESI): 400.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.68 (s, 2H), 5.29-5.15 (m, 2H), 2.52 (t, J=8.0 Hz, 1H), 2, 17-1.29 (m, 24H), 1.15-1.05 (m, 1H), 0.97 (d, J=7.0 Hz, 3H), 0.87 (s, 3H).

Example 132:

MS m/z (ESI): 400.2 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ7.77 (s, 1H), 7.65 (s, 1H), 5.32-5.02 (m, 2H), 2.60 (t, J=9, 1 Hz, 1H), 2.30-2.12 (m, 2H), 1.99-1.27 (m, 22H), 1.17-1.06 (m, 1H), 0.99 (d , J=6.9 Hz, 3H), 0.84 (s, 3H).

Example 62

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- (5-methyl-2H-tetrazol-2-yl)ethan-1-one (62)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3, 13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (4.7 mg, yield: 7%) .

MS m/z (ESI): 415.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.36 (s, 2H), 2.57 (s, 3H), 2.27-2.11 (m, 2H), 2.00-198 (m, 1H), 1.87-1.83 (m, 5H), 1.77-1.57 (m, 6H), 1.52-1.30 (m, 12H), 1.11 (s, 2H) , 0.98 (d, J=7.0 Hz, 3H), 0.88 (s, 3H).

Example 63

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

2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )ethan-1-one (82 mg, 0.2 mmol), 2H-tetrazole (21 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml) and stirred the resulting reaction solution at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by high performance liquid chromatography to give 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[ a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (15.7 mg, yield: 20%).

MS m/z (ESI): 401.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.58 (s, 1H), 4.46 (s, 2H), 2.62-2.58 (m, 1H), 1.89-1.84 ( m, 2H), 1.70-1.26 (m, 23H), 0.99 (d, J=8.0 Hz, 3H), 0.88 (s, 3H).

Example 64

2-(2,4-difluorophenoxy)-1-((3R,5R,8R,9R,10S,13S,14S8,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a ]phenanthren-17-yl)ethan-1-one (64)

Stage 1: preparation of 2-(2,4-difluorophenoxy)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one (64)

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 2-(2,4-difluorophenoxy)-1-((3R,5R,8R,9R,10S,13S,14S,15R ,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (34 mg, yield: 45%).

MS m/z (ESI): 461.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.91-6.82 (m, 2H), 6.77 (ddd, J=9.1, 5.3, 1.6 Hz, 1H), 4, 56 (q, J=16.7 Hz, 2H), 2.74-2.68 (m, 1H), 2.27-2.14 (m, 1H), 2.13-1.99 (m, 1H), 1.95-1.74 (m, 4H), 1.74-1.61 (m, 3H), 1.57 (s, 3H), 1.52-1.35 (m, 4H) , 1.36-1.18 (m, 6H), 1.21-1.00 (m, 3H), 0.98 (d, J=7.2 Hz, 3H), 0.82 (s, 3H ).

Example 69

3-cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (69)

Step 1: Preparation of 3-cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[ a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (69)

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, was obtained 3-cyclopropyl-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S) -3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (30 mg, yield: 41%).

MS m/z (ESI): 464.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (s, 1H), 4.82 (q, J=17.9 Hz, 2H), 2.51-2.46 (m, 1H), 2 .27-2.18 (m, 1H), 2.19-2.08 (m, 1H), 2.04-1.91 (m, 2H), 1.90-1.80 (m, 4H) , 1.68-1.60 (m, 4H), 1.57 (s, 3H), 1.51-1.29 (m, 8H), 1.18-1.03 (m, 3H), 1 .02-0.95 (m, 7H), 0.82 (s, 3H).

Example 71

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

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

1.0 M cyclopropylmagnesium bromide (12.7 ml, 12.7 mmol) and 20 ml of anhydrous tetrahydrofuran were added to a dry 100 ml round bottom flask. The reaction system was purged with nitrogen and cooled to 0°C. Copper iodide (1.97 g, 10.4 mmol) was added, after which the reaction solution was stirred at 0° C. for 1 hour. (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12, 13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (1 g, 3.5 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran, and the resulting solution was slowly added dropwise to the reaction system. The reaction solution was stirred for 3 hours, and TLC showed completion of the reaction. A saturated ammonium chloride solution was added to terminate the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain (3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3, 13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.11 g, yield: 96%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.45-2.30 (m, 2H), 1.85-1.76 (m, 9H), 1.59-1.52 (m, 5H), 1.59-1.27(m, 12H), 1.11-0.98(m, 1H), 0.67-0.64(m, 1H), 0.47-0.43(m, 1H ), 0.22-0.18 (m, 1H), 0.09-0.07 (m, 1H).

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

Ethyltriphenylphosphonium bromide (12.5 g, 33 mmol) was dissolved in anhydrous dimethyl sulfoxide (50 ml) and the reaction system was purged with nitrogen. Sodium hydride (1.32 g, 33 mmol) was added, after which the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.1 g, 3.3 mmol), after which the reaction solution was stirred at 60° C. overnight. The reaction solution was cooled to room temperature. Water (200 ml) was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate (200 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to obtain (3R,5R,8R,9R,10S,13S,14S,15S,E)-15-cyclopropyl-17- ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.67 g, yield: 59%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.15-5.09 (m, 1H), 2.45-2.38 (m, 1H), 2.38-2.18 (m, 2H), 1.90-1.07 (m, 28H), 0.86-0.78 (m, 1H), 0.56-0.50 (m, 1H), 0.38-0.32 (m, 1H ), 0.12-0.02 (m, 2H).

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

(3R,5R,8R,9R,10S,13S,14S,15S,E)-15-cyclopropyl-17-ethylidene-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.67 mg , 1.96 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml). The solution was cooled to 0°C, after which BH ₃ /THF (9.8 ml, 9.8 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and TLC showed completion of the reaction. The reaction solution was cooled to 0°C, after which a 3 M NaOH aqueous solution (10 ml) was slowly added, followed by the addition of hydrogen peroxide (8 ml). The reaction solution was stirred at room temperature for 2 hours, and TLC showed completion of the reaction. Ethyl acetate (50 ml) was added, after which the reaction solution was washed successively with saturated aqueous Na ₂ S ₂ O ₃ (30 ml) and water (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product (0.71 g) which was used immediately in the next step.

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

(3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-17-((R)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenathren- 3-ol (0.71 g, crude) was dissolved in dichloromethane (20 ml). Pyridinium chlorochromate (1.27 g, 5.88 mmol) was added, after which the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered and the organic phase was concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 1/1) to give 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy -3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (480 mg, yield for two steps: 68.3%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.45-2.40 (m, 1H), 2.18-2.10 (m, 4H), 1.99-1.03 (m, 24H), 0.84-0.79 (m, 4H), 0.60-0.53 (m, 1H), 0.43-0.38 (m, 1H), 0.14-0.02 (m, 2H ).

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

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

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

1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane -1-one (60 mg, 0.14 mmol), 1H-pyrazole-4-carbonitrile (28 mg, 0.3 mmol) and potassium carbonate (54 mg, 0.3 mmol) were dissolved in anhydrous tetrahydrofuran (5 ml) and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated. The resulting crude product was purified by HPLC to give 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (31 mg, yield: 49%).

MS m/z (ESI): 450.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.02 (d, J=16.0 Hz, 1H), 4.92 (d , J=16.0 Hz, 1H), 2.51-2.47 (m, 1H), 2.09-1.71 (m, 9H), 1.48-1.10 (m, 16H), 0.90 (s, 3H), 0.83-0.79 (m, 1H), 0.62-0.58 (m, 1H), 0.45-0.40 (m, 1H), 0. 14-0.11 (m, 1H), 0.05-0.02 (m, 1H).

Example 72

1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (72)

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

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, was obtained 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3 -hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (20 mg, yield: 20%).

MS m/z (ESI): 432.2 [M-H ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=2.4 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 4.98 (dd, J =40.0, 17.8 Hz, 2H), 2.52-2.45(m, 1H), 2.24-2.13(m, 1H), 2.11-2.03(m, 1H ), 2.04-1.95 (m, 2H), 1.90-1.82 (m, 2H), 1.75-1.66 (m, 2H), 1.54-1.23 (m , 16H), 1.18-1.05 (m, 2H), 0.93-0.79 (m, 4H), 0.63-0.55 (m, 1H), 0.45-0.37 (m, 1H), 0.18-0.09 (m, 1H), 0.08-0.01 (m, 1H).

Example 73 and Example 145

1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(2H-1,2,3-triazol-2-yl)ethan-1-one (73)

1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(1H-1,2,3-triazol-1-yl)ethan-1-one (145)

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

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, were obtained 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy- 3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (7.6 mg, yield: 7 .8%) and 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (11.6 mg, yield: 11.9%).

Example 73:

MS m/z (ESI): 408.3 [M-H ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (s, 2H), 5.24 (s, 2H), 2.49-2.42 (m, 1H), 2.23-2.14 ( m, 1H), 2.10-1.94 (m, 3H), 1.91-1.81 (m, 3H), 1.75-1.66 (m, 2H), 1.48-1, 24 (m, 15H), 1.17-1.04 (m, 2H), 0.94 (s, 3H), 0.86-0.76 (m, 1H), 0.63-0.54 ( m, 1H), 0.45-0.38 (m, 1H), 0.14-0.01 (m, 2H).

Example 145:

MS m/z (ESI): 426.3[M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (s, 1H), 7.67 (s, 1H), 5.22 (dd, J=47.1, 17.8 Hz, 2H), 2 .59-2.50 (m, 1H), 2.25-2.15 (m, 1H), 2.14-1.98 (m, 2H), 1.96-1.79 (m, 3H) , 1.76-1.58 (m, 6H), 1.56-1.25 (m, 12H), 1.22-1.04 (m, 2H), 0.91 (s, 3H), 0 .87-0.77 (m, 1H), 0.62-0.55 (m, 1H), 0.47-0.36 (m, 1H), 0.18-0.02 (m, 2H) .

Example 74

1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (74)

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

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy- 3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (8.5 mg, yield: 9%) .

MS m/z (ESI): 441.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.36 (s, 2H), 2.57 (s, 3H), 2.54-2.47 (m, 1H), 2.25-2.15 ( m, 1H), 2.13-1.95 (m, 3H), 1.92-1.79 (m, 3H), 1.77-1.66 (m, 2H), 1.50-1, 24 (m, 15H), 1.18-1.05 (m, 2H), 0.94 (s, 3H), 0.87-0.78 (m, 1H), 0.63-0.55 ( m, 1H), 0.45-0.37 (m, 1H), 0.17-0.02 (m, 2H).

Example 81

1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (81)

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

Tetrahydrofuran (15 ml) was added to a 100 ml three-necked flask, followed by the addition of ethylmagnesium bromide (10 ml, 1M, 10 mmol) at 0°C under nitrogen, followed by the addition of copper iodide (1.6 g, 8.4 mmol) . The reaction solution was stirred at 0°C for 1 hour. (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-1,2,3,4,5,6,7,8,9,10,11,12, 13,14-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one (800 mg, 2.8 mmol) was dissolved in tetrahydrofuran (5 ml), and the resulting solution was slowly added dropwise to the reaction solution, which was then stirred at 0° C within 4 hours. A saturated ammonium chloride aqueous solution was added to terminate the reaction, and the reaction solution was extracted with ethyl acetate (20 ml). The organic phase was washed with brine (10 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness using rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to give (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-3-hydroxy-3,13- dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (750 mg, yield: 84.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.37-2.30 (m, 1H), 2.15-2.02 (m, 2H), 1.91-1.31 (m, 17H), 1.27 (s, 3H), 1.24-1.03 (m, 4H), 0.98 (s, 3H), 0.90 (t, J=7.3 Hz, 3H).

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

Dimethyl sulfoxide (20 ml) was added to a 100 ml three-necked flask, after which ethyltriphenylphosphonium bromide (8.7 g, 23.5 mmol) was added under nitrogen. Sodium hydride (60%) (940 mg, 23.5 mmol) was added portionwise, after which the reaction solution was stirred at room temperature for 1 hour. (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (750 mg, 2.35 mmol) was dissolved in dimethyl sulfoxide (5 ml), and the resulting solution was slowly added dropwise to the reaction solution, which was then stirred under nitrogen at 80° C. for 5 hours. The reaction solution was cooled to room temperature. A saturated ammonium chloride aqueous solution was added to terminate the reaction, and the reaction solution was extracted with ethyl acetate (50 ml). The organic phase was washed with brine (20 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness using rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 3/1) to give (3R,5R,8R,9R,10S,13S,14S,15R)-15-ethyl-17-ethylidene-3,13- dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (580 mg, yield: 71.7%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.22-5.06 (m, 1H), 2.54-2.39 (m, 1H), 2.28-2.09 (m, 2H), 1.96-1.80 (m, 4H), 1.78-1.59 (m, 6H), 1.55-1.33 (m, 11H), 1.26 (s, 3H), 1, 20-1.08 (m, 3H), 1.05 (s, 3H), 0.82 (t, J=7.3 Hz, 3H).

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

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

Stage 4:

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane -1-he

In accordance with step 4 of Example 71, (3R,5R,8R,9R,10S,13S,14S,15R,17R)-15-ethyl-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol, respectively, 1-((3R, 5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13 -dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, yield: 83.8%).

1H NMR (400 MHz, CDCl ₃ ) δ 2.51 (t, J=8.0 Hz, 1H), 2.12 (s, 3H), 2.00-1.30 (m, 20H), 1, 28 (s, 3H), 1.25-1.00 (m, 4H), 0.84 (t, J=7.2 Hz, 3H), 0.73 (s, 3H).

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

In accordance with stage 5 of example 71, the starting material was

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane -1-one, respectively, was obtained -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (500 mg, yield: 81.4%).

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

In accordance with stage 6 of example 71, the starting material was

2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17 -yl)ethan-1-one, respectively, 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13 -dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (24 mg, yield: 38.8%).

MS m/z (ESI): 438.2 [M+H]+.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.81 (s, 1H), 5.08-4.78 (m, 2H), 2.58 (t, J= 8.0 Hz, 1H), 2.07-1.29 (m, 20H), 1.28 (s, 3H), 1.27-1.06 (m, 4H), 0.85 (t, J = 7.3 Hz, 3H), 0.79 (s, 3H).

Example 91

2-(4-chloro-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (91)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 2-(4-chloro-1H-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S ,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (10 mg, yield: 14%).

MS m/z (ESI): 433.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (s, 1H), 7.41 (s, 1H), 4.86 (q, J=17.9 Hz, 2H), 2.61-2 .44 (m, 1H), 2.30-2.07 (m, 2H), 2.02-1.91 (m, 1H), 1.86-1.80 (m, 4H), 1.76 -1.57 (m, 4H), 1.51-1.38 (m, 6H), 1.37-1.20 (m, 6H), 1.20-1.03 (m, 2H), 0 .98 (d, J=7.1 Hz, 3H), 0.83 (s, 3H).

Example 92 and Example 93

2-(5-fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR )-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[l,2-a]phenanthren-7-yl)ethan-1-one (92)

2-(5-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR )-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[l,2-a]phenanthren-7-yl)ethan-1-one (93A) and

2-(6-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR )-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (93B)

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 5-fluoro-2H-benzo[d][1,2,3]triazole, respectively, were obtained 2-(5 -fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2- hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (11.5 mg, white solid, yield: 12.7%) and mixture Example 93A and Example 93B (approximately 3:2) (21.6 mg, white solid, yield: 23.9%). The mixture was then further separated by preparative chromatography to give 2-(5-fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-((2R,4aS,4bR,6aS,7S ,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 2-(6 -fluoro-1H-benzo[d][1,2,3]triazol-1-yl)-1-(2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy -2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one.

Example 92:

MS m/z (ESI): 466.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (dd, J ₁ =9.2 Hz, J ₂ =4.8 Hz, 1H), 7.47 (dd, J ₁ =9.2 Hz, J ₂ =2.0 Hz, 1H), 7.23-7.18 (m, 1H), 5.73 (dd, J ₁ =17.6 Hz, J ₂ =4.4 Hz, 2H), 2 .90 (d, J=4.0 Hz, 1H), 1.99-1.96 (m, 1H), 1.85-1.81 (m, 4H), 1.74-1.63 (m , 3H), 1.57-1.38 (m, 10H), 1.30-1.11 (m, 6H), 1.14-1.01 (m, 2H), 0.88 (s, 3H ), 0.53-0.48 (m, 1H).

Example 93A:

MS m/z (ESI): 466.2 [M+H] ⁺

Example 93B:

MS m/z (ESI): 466.2 [M+H] ⁺

Example 94

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-а]phenanthren-7-yl)ethan-1-one and 2,4-difluorophenol, respectively, 2-(2,4-difluorophenoxy)-1-((2R,4aS ,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1- he (27.4 mg, white solid, yield: 38.6%).

MS m/z (ESI): 441.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.93-6.80 (m, 2H), 6.79-6.74 (m, 1H), 4.77 (dd, J ₁ =16.8 Hz , J ₂ =3.6 Hz, 2H), 2.93 (d, J=3.2 Hz, 1H), 1.89-1.76 (m, 5H), 1.75-1.60 (m , 3H), 1.55-1.50 (m, 1H), 1.46-1.41 (m, 6H), 1.27-1.11 (m, 9H), 0.98-0.95 (m, 1H), 0.94-0.89 (m, 1H), 0.76 (s, 3H), 0.46-0.39 (m, 1H).

Example 95

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-methyl, respectively, was obtained 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR ,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-methyl-1H-pyrazol-1-yl) ethan-1-one (12.6 mg, white solid, yield: 15.7%).

MS m/z (ESI): 411.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 (s, 1H), 7.26 (s, 1H), 5.23 (m, 2H), 2.83 (d, J=4.4 Hz , 1H), 2.13 (s, 3H), 1.98-1.85 (m, 2H), 1.83-1.69 (m, 9H), 1.60-1.56 (m, 1H ), 1.40-1.27 (m, 12H), 1.09-1.01 (m, 2H), 0.80 (s, 3H), 0.48-0.45 (m, 1H).

Example 96

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

Stage 1: preparation of 2-((4-fluorophenyl)amino)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro- 1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

2-bromo-1-((3R,5R,8R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethane -1-one (50 mg, 0.12 mmol) was dissolved in tetrahydrofuran (3 ml). 4-fluoroaniline (42 mg, 0.2 mmol) and triethylamine (60 mg, 0.6 mmol) were added, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the resulting residue was purified by high performance liquid chromatography to give 2-((4-fluorophenyl)amino)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3- hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (7 mg, white solid, yield: 13%).

MS m/z (ESI): 442.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.95-6.86 (m, 2H), 6.59-6.53(m, 2H), 3.95-3.85(m, 2H), 2.55-2.47 (m, 1H), 2.25-2.15 (m, 2H), 1.90-1.80 (m, 5H), 1.75-1.25 (m, 18H ), 1.00 (d, J=8.0 Hz, 3H), 0.81 (s, 3H).

Example 97

2-((4-fluorophenyl)amino)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5] cyclopenta[1,2-а]phenanthren-7-yl)ethan-1-one

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and p-fluoroaniline, respectively, 2-((4-fluorophenyl)amino)-1-((2R,4aS, 4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (14.9 mg, yellow oil, yield: 26.7%).

MS m/z (ESI): 440.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.00-6.95 (m, 2H), 6.91-6.83 (m, 2H), 4.19 (dd, J ₁ =20.0 Hz , J ₂ =2.8 Hz, 2H), 2.80 (d, J=4.0 Hz, 1H), 1.92-1.58 (m, 14H), 1.45-1.40 (m , 8H), 1.27 (s, 3H), 1.09-0.91 (m, 2H), 0.69 (s, 3H), 0.48-0.43 (m, 1H).

Example 98

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

In accordance with example 63, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and imidazole, respectively, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR ,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(1H-imidazol-1-yl)ethan-1-one ( 23.3 mg, white solid, yield: 34.4%).

MS m/z (ESI): 397.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (s, 1H), 7.12 (s, 1H), 6.88 (s, 1H), 4.98-4.87 (m, 2H) , 2.82 (d, J=2.8 Hz, 1H), 1.94-1.91 (m, 1H), 1.85-1.81 (m, 4H), 1.70-1.53 (m, 10H), 1.41-1.28 (br, 9H), 1.13-0.95 (m, 2H), 0.78 (s, 3H), 0.52-0.46 (m , 1H).

Example 99 and Example 100

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

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4,5,6,7-tetrahydro-2H-indazole, respectively, were obtained 1-((2R,4aS,4bR ,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4, 5,6,7-tetrahydro-1H-indazol-1-yl)ethan-1-one (99) (5.5 mg, white solid, yield: 6.8%) and 1-((2R,4aS, 4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4 ,5,6,7-tetrahydro-2H-indazol-2-yl)ethan-1-one (100) (3.1 mg, white solid, yield: 3.8%).

Example 99:

MS m/z (ESI): 415.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.12 (s, 1H), 5.14-5.05 (m, 2H), 2.80 (d, J=4.0 Hz, 1H), 2 .69 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H), 1.97-1.93 (m, 1H), 1.85-1, 61 (m, 12H), 1.55-1.52 (m, 2H), 1.43-1.21 (m, 13H), 1.11-0.94 (m, 2H), 0.79 ( s, 3H), 0.48-0.42 (m, 1H).

Example 100:

MS m/z (ESI): 415.3[M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50 (s, 1H), 5.74-5.35 (m, 2H), 2.89 (d, J=4.0 Hz, 1H), 2 .58 (t, J=6.0 Hz, 2H), 2.48 (t, J=6.0 Hz, 2H), 1.96-1.91 (m, 1H), 1.80-1, 72 (m, 8H), 1.40-1.22 (m, 19H), 1.12-0.99 (m, 2H), 0.82 (s, 3H), 0.51-0.45 ( m, 1H).

Example 101

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 5-methyl-1H-4-tetrazole, respectively, 1-((2R,4aS,4bR,6aS,7S ,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(5-methyl-1H- tetrazol-1-yl)ethan-1-one (19 mg, white solid, yield: 23.5%).

MS m/z (ESI): 413.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.58 (dd, J ₁ =17.6 Hz, J ₂ =7.6 Hz, 2H), 2.86 (d, J=4.0 Hz, 1H ), 2.57 (s, 3H), 1.96-1.93 (m, 1H), 1.89-1.61 (m, 8H), 1.55-1.22 (m, 14H), 1.14-0.97 (m, 3H), 0.84 (s, 3H), 0.47-0.53 (m, 1H).

Example 102

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and azetidin-1-yl(1H-pyrazol-4-yl)methanone, respectively, 2-(4-(azetidine -1-carbonyl)-1H-pyrazol-1-yl)-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[ 4,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one (10.0 mg, yield: 14.3%).

MS m/z (ESI): 480.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.80 (m, 1H), 7.80-7.74 (m, 1H), 5.20-5.05 (m, 2H), 4.53-4.10 (m, 4H), 2.82 (d, J=3.3 Hz, 1H), 2.44-2.31 (m, 2H), 1.98-1.90 ( m, 1H), 1.86-1.79 (m, 3H), 1.74-1.64 (m, 3H), 1.57-1.53 (m, 2H), 1.44-1, 24 (m, 15H), 1.13-0.97 (m, 2H), 0.79 (s, 3H), 0.51-0.44 (m, 1H).

Example 103

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one and 4-nitro-1H-pyrazole, respectively, 1-((2R,4aS,4bR,6aS,7S,7aS ,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-nitro-1H-pyrazole- 1-yl)ethan-1-one (32.5 mg, yield: 60%).

MS m/z (ESI): 424.2 [M+HH ₂ O] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ8.20 (s, 1H), 8.09 (s, 1H), 5.26-5.09 (m, 2H), 2.85 (s, 1H), 1.98-1.91 (m, 1H), 1.87-1.79 (m, 4H), 1.74-1.65 (m, 3H), 1.56-1.52 (m, 2H ), 1.47-1.35 (m, 7H), 1.34-1.24 (m, 7H), 1.13-0.97 (m, 2H), 0.79 (s, 3H), 0.55-0.47 (m, 1H).

Example 104

(3R,5R,8R,9R,10S,13S,14S,16R,178)-17-acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (104)

Stage 1: receiving

(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile

1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12 ,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (270 mg, 0.853 mmol), ammonium chloride (250 mg, 4.69 mmol) and 18-crown- 6 (23 mg, 0.853 mmol) was added to a mixed solution of dimethyl sulfoxide (7 ml) and water (2 ml) at 85°C, followed by the addition of a mixed solution of sodium cyanide (230 mg, 4.69 mmol), dimethyl sulfoxide (4 ml) and water (1 ml). The reaction solution was stirred at 85°C for 16 hours. Water (30 ml) was added, after which the reaction solution was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to dryness, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give (3R,5R,8R,9R,10S,13S,14S,16R,17S)-17- acetyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile as a white solid (250 mg, yield: 85%).

Example 105

1-(2-((3R,5R,8R,9R,10S,13S,14R,17S)-3-hydroxy-3,13-dimethyl-15-(nitromethyl)hex adecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

Example 105 was synthesized according to the following custom scheme:

MS m/z (ESI): 469.3 [M+1] ⁺ .

Example 121

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

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 3-cyclopropyl-1-(2-((2R,4aS,4bR,6aS,7S,7aS, 8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (19.2 mg, yield: 21%).

MS m/z (ESI): 462.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 5.13-4.95 (m, 2H), 2.80 (d, J=2.2 Hz, 1H), 2 .04-1.89 (m, 2H), 1.86-1.79 (m, 3H), 1.76-1.63 (m, 3H), 1.58-1.49 (m, 3H) , 1.46-1.21 (m, 14H), 1.12-0.93 (m, 6H), 0.76 (s, 3H), 0.51-0.43 (m, 1H).

Example 122

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(4-(methylthio)-1Н-pyrazol-1-yl)ethan-1-one(122)

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR )-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan- 1-one (8.7 mg, yield: 16%).

MS m/z (ESI): 443.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (s, 1H), 7.45 (s, 1H), 5.17-5.00 (m, 2H), 2.81 (d, J= 3.8 Hz, 1H), 2.35 (s, 3H), 1.99-1.91 (m, 1H), 1.88-1.76 (m, 4H), 1.73-1.63 (m, 3H), 1.55-1.50 (m, 1H), 1.43-1.18 (m, 15H), 1.12-0.97 (m, 2H), 0.79 (s , 3H), 0.50-0.41 (m, 1H).

Example 123 and Example 124

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one (123) and 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR, 8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl )ethane-1-he(124)

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

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(4-(methylthio)-1H-pyrazol-1-yl)ethan-1-one (80 mg, 0.18 mmol) was dissolved in dichloromethane (10 ml) and the solution was cooled to minus 78°C . Was added m-chloroperoxybenzoic acid (55 mg, 0.27 mmol) and stirred the reaction solution for 1 hour. Water (10 ml) was added, after which the reaction solution was washed with a saturated aqueous sodium bicarbonate solution (10 ml). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by HPLC to give 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4,5] cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(methylsulfinyl)-1H-pyrazol-1-yl)ethan-1-one (17.2 mg, yield: 20%) and 1 -((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7- yl)-2-(4-(methylsulfonyl)-1H-pyrazol-1-yl)ethan-1-one (20.4 mg, yield: 25%).

Example 123:

MS m/z (ESI): 441.3 [MH ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.83 (s, 1H), 5.30-5.09 (m, 2H), 2.91 (s, 3H) : 2.85-2.82 (m, 1H), 1.98-1.90 (m, 1H), 1.87-1.78 (m, 3H), 1.75-1.50 (m, 8H), 1.47-1.21 (m, 12H), 1.13-0.96 (m, 2H), 0.79 (s, 3H), 0.54-0.45 (m, 1H) .

Example 124:

MS m/z (ESI): 457.2 [MH ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.87 (s, 1H), 5.26-5.10 (m, 2H), 3.14 (s, 3H) : 2.85 (d, J=2.7 Hz, 1H), 1.98-1.91 (m, 1H), 1.87-1.79 (m, 3H), 1.76-1.64 (m, 3H), 1.59-1.52 (m, 1H), 1.50-1.18 (m, 16H), 1.15-0.96 (m, 2H), 0.79 (s , 3H), 0.55-0.46 (m, 1H).

Example 125

3-fluoro-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1, 2-а]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (125)

Step 1: Preparation of 3-fluoro-4-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4,5] cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 3-fluoro-4-(2-((2R,4aS,4bR,6aS,7S,7aS, 8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (12.5 mg, yield : 18%).

MS m/z (ESI): 44S.2 [MH ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.33 (m, 2H), 6.91-6.84 (m, 1H), 4.91 (s, 2H), 2.96- 2.88 (m, 1H), 1.90-1.76 (m, 4H), 1.75-1.62 (m, 3H), 1.55-1.26 (m, 17H), 1, 12-1.04 (m, 1H), 0.98-0.92 (m, 1H), 0.78 (s, 3H), 0.50-0.41 (m, 1H).

Example 126

5-fluoro-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1, 2-а]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (126)

Step 1: Preparation of 5-fluoro-2-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4,5] cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 5-fluoro-2-(2-((2R,4aS,4bR,6aS,7S,7aS, 8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethoxy)benzonitrile (11.4 mg, yield : 10%).

MS m/z (ESI): 44S.2 [MH ₂ OH] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.28 (m, 1H), 7.25-7.18 (m, 1H), 6.78-6.72 (m, 1H), 4.91-4.78 (m, 2H), 2.99 (d, J=3.3 Hz, 1H), 1.91-1.78 (m, 4H), 1.76-1.64 ( m, 3H), 1.57-1.25 (m, 17H), 1.08-0.92 (m, 2H), 0.78 (s, 3H), 0.50-0.40 (m, 1H).

Example 127

1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a] phenanthren-7-yl)-2-oxoethyl)-1Н-pyrazole-3,5-dicarbonitrile(127)

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 1-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR, 8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)-1H-pyrazol-3,5-dicarbonitryl ( 1S, 0 mg, yield: 31.8%).

MS m/z (ESI): 429.2 [MH ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (s, 1H), 5.38 (q, J=18.0 Hz, 2H), 2.87 (d, J=3.0 Hz, 1H ), 1.97-1.91 (m, 1H), 1.88-1.75 (m, 4H), 1.76-1.64 (m, 3H), 1.58-1.51 (m , 1H), 1.48-1.26 (m, 15H), 1.15-0.99 (m, 2H), 0.83 (s, 3H), 0.58-0.48 (m, 1H ).

Example 128

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)ethan-1-one (128)

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

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR )-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(4-(oxazol-2-yl)-1H-pyrazol-1- yl)ethan-1-one (16.0 mg, yield: 14%).

MS m/z (ESI): 464.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 7.13 (s, 1H), 5.27 -5.13 (m, 2H), 2.85 (d, J=4.0 Hz, 1H), 2.01-1.93 (m, 1H), 1.87-1.65 (m, PN ), 1.58-1.50 (m, 1H), 1.44-1.22 (m, 11H), 1.14-0.98 (m, 2H), 0.81 (s, 3H), 0.53-0.44 (m, 1H).

Example 129

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-(pyridazin-4-yloxy)ethan-1-one (129)

Stage 1: preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a ]phenanthren-7-yl)-2-(pyridazin-4-yloxy)ethan-1-one

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR )-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-(pyridazin-4-yloxy)ethan-1-one (16.0 mg , yield: 26%).

MS m/z (ESI): 425.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.61 (d, J=6.8 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H ), 5.17-4.85 (m, 2H), 2.83 (s, 1H), 1.99-1.90 (m, 1H), 1.88-1.78 (m, 3H), 1.76-1.54 (m, 10H), 1.46-1.25 (m, 10H), 1.14-0.95 (m, 2H), 0.79 (s, 3H), 0. 55-0.46 (m, 1H).

Example 130

1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-7 -yl)-2-((2-(trifluoromethyl)pyrimidin-5-and l)oxy)ethan-1-one

Stage 1: preparation of 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocycloprop[4,5]cyclopenta[1,2-a ]phenanthren-7-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy) ethan-1-one

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR )-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan- 1-one (23.0 mg, yield: 38.3%).

MS m/z (ESI): 493.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ S.45 (s, 2H), 5.01 (s, 2H), 2.86 (s, 1H), 1.89 (m, 1H), 1.83 (m, 4H), 1.75 (dm, 1H), 1.68 (m, 2H), 1.57 (m, 1H), 1.38 (m, 8H), 1.31 (m, 2H) , 1.28 (s, 3H), 1.26-1.20 (m, 1H), 1.13-1.03 (m, 1H), 0.96 (m, 1H), 0.80 (s , 3H), 0.48 (m, 1H).

Example 131

1-((3R,5R,8R,9R,10S,13S,14S,15R,178)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- (3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (131)

Step 1: 1-((3R,5R8,R9,R10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2 -(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3, 13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (20.5 mg, yield: 30 ,1%).

MS m/z (ESI): 467.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.43 (m, 1H), 6.59 (d, J=2.4 Hz, 1H), 5.14-4.85 (m, 2H), 2.54 (t, J=S.1 Hz, 1H), 2.26-2.08 (m, 2H), 2.02-1.93 (m, 1H), 1.90-1 .79 (m, 4H), 1.74-1.59 (m, 3H), 1.57-1.19 (m, 14H), 1.21-1.04 (m, 1H), 0.98 (d, J=7.0 Hz, 3H), 0.84 (s, 3H).

Example 133

2-(4-(azetidine-1-carbonyl)-1Н-pyrazol-1-yl)-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3 ,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one(133)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,178)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-1-((3R,5R ,8R,9R,10S,13S,14S,15R,178)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (12.0 mg , yield: 21%).

MS m/z (ESI): 482.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (s, 2H), 5.00-4.77 (m, 2H), 4.38-4.25 (m, 4H), 2.54 ( t, J=7.6 Hz, 1H), 2.43-2.32 (m, 2H), 2.26-2.08 (m, 2H), 1.98-1.96 (m, 1H) , 1.88-1.83(m, 3H), 1.69-1.62(m, 5H), 1.48-1.42(m, 4H), 1.38-1.26(m, 9H), 1.16-1.07 (m, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.84 (s, 3H).

Example 134

3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,178)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene- 17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (134)

Step 1: Preparation of 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,178)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[ a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the product 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S )-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (37 mg, yield: 55.3%) .

MS m/z (ESI): 456.2 [M-H]-.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (s, 1H), 5.03-4.75 (m, 2H), 2.54 (t, J=S.0 Hz, 1H), 2 .31-2.13 (m, 2H), 1.93-1.06 (m, 23H), 0.99 (d, J=7.1 Hz, 3H), 0.83 (s, 3H).

Example 135

1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) -2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (135)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the product 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3- hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (18 mg, yield: 27.5%).

MS m/z (ESI): 447.2 [M-H] ^- .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (s, 1H), 5.23-5.07 (m, 2H), 2.68-2.52 (m, 1H), 2.28- 1.36 (m, 21H), 1.28 (s, 3H), 1.18-1.08 (m, 1H), 1.00 (d, J=6.9 Hz, 3H), 0.88 (s, 3H).

Example 136

3-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl) -2-oxoethyl)thiazolidine-2,4-dione (136)

Step 1: 3-(2-((3R,5R,8R,9R,10S,13S,14S,15R,178)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17 -yl)-2-oxoethyl)thiazolidine-2,4-dione

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,178)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 3-(2-((3R,5R,8R,9R,10S,13S,14S,15R,178)-3-hydroxy -3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione (24.0 mg, yield: 31.5%).

MS m/z (ESI): 430.2 [MH ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.37 (s, 2H), 4.04-3.98 (m, 2H), 2.56-2.49 (m, 1H), 2.22- 2.03 (m, 2H), 1.91-1.81 (m, 4H), 1.73-1.61 (m, 3H), 1.47-1.26 (m, 15H), 1, 17-1.05 (m, 2H), 0.97 (d, J=7.1 Hz, 3H), 0.81 (s, 3H).

Example 137

1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,178)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (137)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the product 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)- 15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitryl (16 mg, yield: 25.9% ).

MS m/z (ESI): 43S.2[M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J=2.5 Hz, 1H), 6.73 (d, J=2.4 Hz, 1H), 5.22-4.78 (m, 2H), 2.57 (t, J=8.0 Hz, 1H), 2.15-1.30 (m, 20H), 1.28 (s, 3H), 1.16-1, 03 (m, 4H), 0.84 (t, J=7.3 Hz, 3H), 0.79 (s, 3H).

Example 138

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13,15-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one(138)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the product 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl -3-hydroxy-3,13,15-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (23 mg, yield: 33.9%).

MS m/z (ESI): 481.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J=4.0 Hz, 1H), 6.59 (d, J=4.0 Hz 1H), 5.07-4.89 ( m, 2H), 2.56 (t, J=9.3 Hz, 1H), 2.20-1.29 (m, 20H), 1.28 (s, 3H), 1.27-1.03 (m, 4H), 0.84 (t, J=7.3 Hz, 3H), 0.80 (s, 3H).

Example 139

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (139)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,178)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the product 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl -3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (13.5 mg, yield: 22.3%).

MS m/z (ESI): 429.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.39-5.29 (m, 2H), 2.63-2.57 (m, 1H), 2.56 (s, 3H), 2.10- 1.30 (m, 20H), 1.28 (s, 3H), 1.27-1.05 (m, 4H), 0.87-0.81 (m, 6H).

Example 140 and Example 141

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(1H-1,2,3-triazol-1-yl)ethan-1-one (140)

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(2Н-1,2,3-triazol-2-yl)ethan-1-one(141)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the products 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl -3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (17 mg, yield: 29.1%) and 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a ]phenanthren-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethan-1-one (9.2 mg, yield: 15.7%).

Example 140:

MS m/z (ESI): 414.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.67 (s, 1H), 5.37-5.09 (m, 2H), 2.62 (t, J= 9.2 Hz, 1H), 2.28-1.20 (m, 25H), 1.16-1.05 (m, 2H), 0.85 (t, J=7.3 Hz, 3H), 0.80 (s, 3H). Example 141:

MS m/z (ESI): 414.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (s, 2H), 5.28-5.20 (m, 2H), 2.54 (t, J=8.0 Hz, 1H), 1 .99-1.23 (m, 25H), 1.13-1.06 (m, 2H), 0.88-0.78 (m, 6H).

Example 142

1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,178)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (142)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the product 1-(2-((3R,5R,8R,9R,10S,13S,14S,15R,17S)- 15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (5 mg, yield: 9.2 %).

MS m/z (ESI): 463.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (s, 1H), 5.29-5.02 (m, 2H), 2.61 (t, J=9.3 Hz, 1H), 2 .24-1.34 (m, 19H), 1.28 (s, 3H), 1.26-1.02 (m, 5H), 0.92-0.76 (m, 6H).

Example 143

1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (143)

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

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, was obtained 1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3 -hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarbonitrile (19.6 mg, yield: 18%).

MS m/z (ESI): 473.2 [M-H] ^-

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (s, 1H), 5.24-5.09 (m, 2H), 2.58-2.50 (m, 1H), 2.26- 2.07 (m, 2H), 2.06-1.95 (m, 2H), 1.90-1.80 (m, 2H), 1.78-1.66 (m, 2H), 1, 58-1.22 (m, 16H), 1.19-1.06 (m, 2H), 0.94 (s, 3H), 0.87-0.78 (m, 1H), 0.64- 0.56 (m, 1H), 0.45-0.39 (m, 1H), 0.18-0.02 (m, 2H).

Example 144

1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13,15-dimethyl hexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (144)

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

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy- 3,13,15-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (1S, 0 mg, yield : 23%).

MS m/z (ESI): 491.3 [M-H] ^-

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J=2.0 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 5.08-4.90 (m, 2H), 2.53-2.42 (m, 1H), 2.24-1.94 (m, 4H), 1.91-1.79 (m, 3H), 1.78-1 .66 (m, 2H), 1.52-1.22 (m, 15H), 1.18-1.02 (m, 2H), 0.91 (s, 3H), 0.88-0.76 (m, 1H), 0.65-0.54 (m, 1H): 0.48-0.36 (m, 1H), 0.18-0.00 (m, 2H).

Example 146

1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(2H-tetrazol-2-yl)ethan-1-one (146)

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

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy- 3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (12.9 mg, yield: 13.2%).

MS m/z (ESI): 409.3 [M-H ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ S.57 (s, 1H), 5.46 (s, 2H), 2.58-2.47 (m, 1H), 2.24-1.94 ( m, 4H), 1.93-1.80 (m, 3H), 1.77-1.66 (m, 2H), 1.50-1.21 (m, 15H), 1.18-1, 06 (m, 2H), 0.95 (s, 3H), 0.87-0.78 (m, 1H), 0.64-0.55 (m, 1H), 0.46-0.38 ( m, 1H), 0.17-0.01 (m, 2H).

Example 147

3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthren-17-yl)-2-oxoethyl)-1Н-pyrazole-4-carbonitrile (147)

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

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadeca hydro-1H- cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 3-chloro-1-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)- 15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazol-4-carbonitryl (13.5 mg, yield: 17, 4%).

MS m/z (ESI): 482.2 [M-H] ^-

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (s, 1H), 5.01-4.76 (m, 2H), 2.55-2.41 (m, 1H): 2.22- 1.94 (m, 4H), 1.91-1.77 (m, 3H), 1.76-1.66 (m, 2H), 1.56-1.24 (m, 15H), 1, 18-1.04 (m, 2H), 0.90 (s, 3H), 0.87-0.75 (m, 1H), 0.64-0.53 (m, 1H), 0.46- 0.38 (m, 1H), 0.17-0.02 (m, 2H).

Example 148

3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)-2-oxoethyl)thiazolidine-2,4-dione(148)

Stage 1: preparation of 3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, was obtained 3-(2-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3 -hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)thiazolidine-2,4-dione (10.0 mg, yield: 13%).

MS m/z (ESI): 456.2 [M-H ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.38 (s, 2H), 4.04 (s, 2H), 2.51-2.43 (m, 1H), 2.24-2.00 ( m, 4H), 1.91-1.80 (m, 3H), 1.75-1.67 (m, 2H), 1.49-1.27 (m, 15H), 1.17-1, 05 (m, 2H), 0.88 (s, 3H), 0.84-0.78 (m, 1H), 0.62-0.53 (m, 1H), 0.46-0.36 ( m, 1H), 0.15-0.01 (m, 2H).

Example 149

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-(2H-tetrazol-2-yl)ethan-1-one (149)

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

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl-3-hydroxy-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, the product 1-(3R,5R,8R,9R,10S,13S,14S,15R,17S)-15-ethyl- 3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(2H-tetrazol-2-yl)ethan-1-one (11 mg, white solid, yield: 18 ,8%).

MS m/z (ESI): 397.2 [M-H ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 5.50-5.41 (m, 2H), 2.62 (t, J=8.5 Hz, 1H), 2 .29-1.30 (m, 20H), 1.28 (s, 3H), 1.27-1.05 (m, 4H), 0.85-0.82 (m, 6H).

Example 150

1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- ((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (150)

Stage 1: preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one

In accordance with example 5, 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3,13,15-trimethylhexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15R,17S)-3-hydroxy-3, 13,15-trimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (16.1 mg, yield: 19 %).

MS m/z (ESI): 477.3 [M-H ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 2H), 4.85-4.71 (m, 2H), 2.67-2.57 (m, 1H), 2.30- 2.10 (m, 2H), 1.93-1.81 (m, 4H), 1.74-1.61 (m, 3H), 1.48-1.23 (m, 15H), 1, 18-1.06 (m, 2H), 1.00 (d, J=7.1 Hz, 3H), 0.87 (s, 3H).

Example 151

1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)- 2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (151)

Stage 1: preparation of 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17 -yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one

In accordance with example 5, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one, respectively, 1-((3R,5R,8R,9R,10S,13S,14S,15S,17S)-15-cyclopropyl-3-hydroxy- 3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)ethan-1-one (22.9 mg, yield: 27 .6%).

MS m/z (ESI): 503.3 [M-H ₂ O+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 2H), 4.87-4.69 (m, 2H), 2.62-2.50 (m, 1H), 2.25- 1.96 (m, 3H), 1.92-1.84 (m, 3H), 1.77-1.66 (m, 2H), 1.54-1.23 (m, 15H), 1, 18-1.04 (m, 2H), 0.93 (s, 3H), 0.87-0.78 (m, 1H), 0.65-0.56 (m, 1H), 0.49- 0.38 (m, 1H), 0.20-0.02 (m, 2H).

Example 152

3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a] phenanthren-7-yl)-2-oxoethyl)thiazolidine-2,4-dione (152)

Stage 1: preparation of 3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1, 2-а]phenanthren-7-yl)-2-oxoethyl)thiazolidine-2,4-dione

In accordance with example 5, 2-bromo-1-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4 ,5]cyclopenta[1,2-a]phenanthren-7-yl)ethan-1-one, respectively, 3-(2-((2R,4aS,4bR,6aS,7S,7aS,8aR,8bR, 8cR,10aR)-2-hydroxy-2,6a-dimethyloctadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7-yl)-2-oxoethyl)thiazolidine-2,4-dione (7.1 mg , yield: 9.3%).

MS m/z (ESI): 446.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.66-4.50 (m, 2H), 4.04 (s, 2H), 2.78 (d, J=4.0 Hz, 1H), 1 .98-1.92 (m, 1H), 1.85-1.52 (m, 11H), 1.44-1.24 (m, 12H), 1.13-0.97 (m, 2H) , 0.77 (s, 3H), 0.49-0.41 (m, 1H).

Example 157

1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a ]phenanthren-17-yl)ethan-1-one (157)

Stage 1: preparation of (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[ a] phenanthrene-17-one

(8R,9S,13S,14S)-3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthrene-17- it (4.1 g, 15 mmol) and dichloromethane/methanol solution (1/1, 50 ml) were added to a 100 ml three-necked flask followed by potassium carbonate (6.2 g, 45 mmol) and benzyl bromide (7.6 d, 45 mmol). The reaction solution was heated under reflux at 65° C. for 5 hours. The reaction solution was cooled, filtered and washed with methanol. The reaction solution was concentrated, and the resulting residue was purified by petroleum ether/ethyl acetate (1/3) column chromatography to obtain (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9 ,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one (5 g, yield: 93%).

1H NMR (400 MHz, CDCl ₃ ) δ 7.45-7.29 (m, 5H), 7.20 (d, J=8.5 Hz, 1H), 6.79 (dd, J=8.6 , 2.7 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 5.04 (s, 2H), 2.95-2.85 (m, 2H), 2.50 (dd, J=18.8, 8.5 Hz, 1H), 2.43-2.36 (m, 1H), 2.30-2.23 (m, 1H), 2.20-1.94 (m, 4H), 1.63-1.40 (m, 6H), 0.91 (s, 3H).

Stage 2: preparation of (8S,9S,13S,14S)-3-(benzyloxy)-17-ethylidene-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro- 6H-cyclopenta[a]phenanthrene

Potassium tert-butoxide (7.8 g, 70 mmol) was suspended in tetrahydrofuran (100 ml). Ethyltriphenylphosphonium bromide (26.3 g, 70 mmol) was added slowly at 0°C, and the reaction solution was stirred at 60°C for 2 hours. (8R,9S,13S,14S)-3-(benzyloxy)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta was added to the above reaction solution. [a]phenanthrene-17-he. After reacting at 60° C. for 2 hours, the reaction solution was cooled to room temperature. A saturated ammonium chloride aqueous solution was added to terminate the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and concentrated. The resulting residue was purified by petroleum ether column chromatography to give (8S,9S,13S,14S)-3-(benzyloxy)-17-ethylidene-13-methyl-7,8,9,11,12,13,14, 15,16,17-decahydro-6H-cyclopenta[a]phenanthrene (5 g, yield: 96%).

Stage 3: preparation of 1-((8S,9S,13S,14S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H -cyclopenta[a]phenanthren-17-yl)ethan-1-ol

(8S,9S,13S,14S)-3-(benzyloxy)-17-ethylidene-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[ a]phenanthrene (2.5 g, 6.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml). A solution of borane in tetrahydrofuran (1 M, 20 ml) was added dropwise, and the resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled with ice water, and a sodium hydroxide solution (10%, 15 ml) was slowly added dropwise while a large amount of gas was evolved. Hydrogen peroxide (30%, 20 ml) was slowly added dropwise, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with sodium thiosulfate solution and brine, and dried to give a product (2.5 g) which was immediately used in the next step.

Step 4: Preparation of 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro -6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

1-((8S,9S,13S,14S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a ]phenanthren-17-yl)ethan-1-ol (2.5 g, 6.5 mmol) was dissolved in dichloromethane (30 ml). Pyridinium chlorochromate (2.06 g, 9.6 mmol) was added and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was filtered and concentrated to dryness by rotary evaporation. The resulting residue was purified by petroleum ether/ethyl acetate (1/5) column chromatography to give 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-13-methyl-7,8,9, 11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (1.6 g, yield: 65%).

1H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.28 (m, 5H), 7.20 (d, J=8.6 Hz, 1H), 6.78 (dd, J=8.5 , 2.6 Hz, 1H), 6.72 (d, J=2.6 Hz, 1H), 5.03 (s, 2H), 2.90-2.80 (m, 2H), 2.61 (t, J=9.1 Hz, 1H), 2.40-2.17 (m, 4H), 2.15 (s, 3H), 1.96-1.27 (m, 9H), 0, 65 (s, 3H).

Step 5: Preparation of 1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H -cyclopenta[a]phenanthren-17-yl)ethan-1-one

1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta [a]phenanthren-17-yl)ethan-1-one (200 mg, 0.52 mmol) was dissolved in methanol/tetrahydrofuran (5 ml/5 ml). Palladium hydroxide on activated charcoal (30 mg, 20%) was added and the reaction solution was reacted under a hydrogen atmosphere at 45° C. for 12 hours to give the final product 1-((8S,9S,13S,14S,17S)-3- hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (50 mg, yield : 32%).

MS m/z(ESI): 298.1 [M]+.

1H NMR (400 MHz, CDCl ₃ ) δ 7.15 (d, J=8.4 Hz, 1H), 6.63 (dd, J=8.4, 2.6 Hz, 1H), 6.56 ( d, J=2.6 Hz, 1H), 4.62 (s, 1H), 2.92-2.74 (m, 2H), 2.62 (t, J=9.1 Hz, 1H), 2.40-2.17 (m, 4H), 2.16 (s, 3H), 1.95-1.30 (m, 9H), 0.65 (s, 3H).

Example 158

1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a ]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (158)

Stage 1: preparation of 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16 ,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-bromoethan-1-one

1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta [a]phenanthren-17-yl)ethan-1-one (300 mg, 0.78 mmol) was dissolved in methanol (15 ml). Five drops of hydrogen bromide solution were added, followed by the dropwise addition of liquid bromine (255 mg, 1.6 mmol). After stirring at room temperature for 2 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness by rotary evaporation to give 300 mg of product 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13 -methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-bromoethan-1-one, which was immediately used at the next stage.

Stage 2: preparation of 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16 ,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro -6H-cyclopenta[a]phenanthren-17-yl)-2-bromoethan-1-one (300 mg, 0.55 mmol) was dissolved in tetrahydrofuran (10 ml). Cesium carbonate (536 mg, 1.65 mmol) and 1,2,3-triazole (190 mg, 2.7 mmol) were added and the reaction solution was reacted at 35° C. for 5 hours. The reaction solution was filtered and concentrated. The resulting residue was purified by petroleum ether/ethyl acetate (1/1) column chromatography to give 1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7, 8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl) ethan-1-one (70 mg, yellow solid, yield: 20%).

MS m/z (ESI): 534.1/536.1(50/50) [M+H] ⁺ .

Stage 2: preparation of 1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H -cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one

1-((8S,9S,13S,14S,17S)-3-(benzyloxy)-2-bromo-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro -6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (70 mg, 0.13 mmol) was dissolved in methanol/ tetrahydrofuran (5 ml/5 ml). Was added palladium hydroxide on activated carbon (30 mg, 20%) and the reaction solution was subjected to interaction in a hydrogen atmosphere at 45°C for 12 hours. The reaction solution was filtered and concentrated to give 1-((8S,9S,13S,14S,17S)-3-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethan-1-one (30 mg, white solid, yield: 62.6 %).

MS m/z (ESI): 366.1 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 7.78 (s, 1H), 7.67 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.65 (dd, J=6.4, 2.4 Hz, 1H), 6.60-6.56 (m, 1H), 5.40-5.15 (m, 2H), 5.04 (s, 1H), 2 .89-2.70 (m, 3H), 2.40-2.21 (m, 3H), 1.96-1.27 (m, 10H), 0.71 (s, 3H).

Example 159

((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (159)

Stage 1: preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

(3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (5 g, 17 mmol) (Shanghai Yinling Pharmaceutical Technology Co ., Ltd.), 2,6-lutidine (4.5 g, 42.5 mmol) and anhydrous dichloromethane (80 ml) were added sequentially to a 100 ml round bottom flask. The reaction system was cooled to 0° C. in an ice water bath and tert-butyldimethylsilyl trifluoromethanesulfonate (9 g, 34 mmol) was added dropwise. The reaction system was warmed to room temperature and stirred overnight. TLC showed completion of the reaction. The reaction solution was diluted with dichloromethane. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (petroleum ether : ethyl acetate = 20:1) to obtain (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3.13 -dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (6.2 g, yield: 90.1%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.37 (dd, J=18.8, 8.0 Hz, 1H), 2.06-1.97 (m, 1H), 1.90-1, 84 (m, 1H), 1.75-1.68 (m, 5H), 1.59-1.55 (m, 1H), 1.47-0.89 (m, 17H), 0.80 ( s, 3H), 0.79 (s, 9H), 0.00 (m, 6H).

Stage 2: preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8 ,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yltrifluoromethanesulfonate

(3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (1.2 g, 3 mmol) and 50 ml of anhydrous tetrahydrofuran were successively added to a 100 ml round bottom flask. The reaction system was cooled to minus 78°C and a solution of potassium hexamethyldisilazide in tetrahydrofuran (3 ml, 3 mmol) was added dropwise to the reaction system. The reaction solution was stirred at minus 78° C. for 1 hour, after which N-phenylbis(trifluoromethanesulfonimide) (1.29 g, 3.6 mmol) dissolved in 5 ml of anhydrous tetrahydrofuran was added dropwise to the reaction system. After completion of the addition, the reaction solution was naturally warmed to room temperature and stirred overnight. After completion of the reaction, a saturated ammonium chloride solution was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluent: petroleum ether) to give (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2 ,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-yltrifluoromethanesulfonate (1.4 g, yield: 87% ).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.56 (s, 1H), 2.27-2.18 (m, 1H), 2.00-1.93 (m, 1H), 1.80- 1.61 (m, 7H), 1.49-1.23 (m, 15H), 0.97 (s, 3H), 0.86 (s, 9H), 0.08 (s, 6H).

Stage 3: preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7, 8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide

(3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yltrifluoromethane sulfonate (840 mg, 1.57 mmol), dimethylphosphine oxide (146 mg, 1.89 mmol), palladium diacetate (35 mg, 0.16) mmol), 1,4-bis(diphenylphosphino)butane (69 mg, 0.16 mmol), N,N-diisopropylethylamine (1.6 g, 12.6 mmol) and 10 ml of anhydrous dimethyl sulfoxide in succession added to a 100 ml round bottom flask. The reaction system was purged with nitrogen, heated slowly to 120° C. and stirred overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3 ,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (642 mg, yield: 88%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.54 (dd, J=10.8, 1.6 Hz, 1H), 2.33-2.27 (m, 1H), 2.11-2, 01 (m, 2H), 1.66-1.58 (m, 12H), 1.48-1.1.13 (m, 15H), 1.00 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H).

Step 4: Preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11 ,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide

((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9, 10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (642 mg, 1.38 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran in a 100 ml round bottom flask and added to the reaction system 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 ml). The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2, 3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (170 mg, yield: 35%) .

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.57-6.54 (m, 1H), 2.45 (br, 1H), 2.35-2.28 (m, 1H), 2.12- 2.00 (m, 2H), 1.87-1.70 (m, 4H), 1.67-1.14 (m, 23H), 1.00 (s, 3H).

Step 5: Preparation of ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide

((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-Tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)dimethylphosphine oxide (100 mg, 0.29 mmol), palladium on charcoal (100 mg, 10%) and 10 ml of ethyl acetate were added to a 100 ml round bottom flask. ml. The reaction system was purged with hydrogen three times and reacted at 1 atmosphere overnight. After completion of the reaction, the reaction solution was filtered through Celite to remove excess palladium-carbon, and the filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to give ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)dimethylphosphine oxide (39.5 mg, yield: 39%).

MS m/z (ESI): 353.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.13-1.62 (m, 22H), 1.35-1.27 (m, 8H), 1.16-1.06 (m, 4H), 0.99 (s, 3H).

Example 160

((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (160)

Stage 1: preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7, 8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide

(3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yltrifluoromethanesulfonate (350 mg, 0.65 mmol), diphenylphosphine oxide (158 mg, 0.78 mmol), palladium diacetate (35 mg , 0.16) mmol), 1,4-bis(diphenylphosphino)butane (69 mg, 0.16 mmol), N,N-diisopropylethylamine (660 mg, 5.2 mmol) and 10 ml of anhydrous dimethyl sulfoxide were added successively to a round bottom 100 ml flask. The reaction system was purged with nitrogen, heated slowly to 120° C. and stirred overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3 ,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (290 mg, yield: 76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.80 (m, 2H), 7.67-7.62 (m, 2H), 7.59-7.40 (m, 6H), 6.01-5.98 (m, 1H), 2.31-2.25 (m, 1H), 2.09-2.02 (m, 2H), 1.89-1.10 (m, 21H ), 1.07 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H).

Stage 2: preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11 ,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide

((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9, 10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (270 mg, 0.46 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran in a 100 ml round bottom flask and added to the reaction system 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 ml). The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2, 3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (120 mg, yield: 55%) .

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.57-6.54 (m, 1H), 2.45 (br, 1H), 2.35-2.28 (m, 1H), 2.12- 2.00 (m, 2H), 1.87-1.70 (m, 4H), 1.67-1.14 (m, 26H), 1.00 (s, 3H).

Step 3: Preparation of ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide

((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-Tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (120 mg, 0.25 mmol), palladium on charcoal (120 mg, 10%) and 10 mL of ethyl acetate were added to a 100 ml round bottom flask. ml. The reaction system was purged with hydrogen three times and reacted at 1 atmosphere overnight. After completion of the reaction, the reaction solution was filtered through Celite to remove excess palladium-carbon, and the filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to give ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)diphenylphosphine oxide (40 mg, yield: 33%).

MS m/z (ESI): 477.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.91-7.83 (m, 4H), 7.54-7.44 (m, 6H), 2.37-2.15 (m, 2H), 2.11-2.09 (m, 1H), 2.07-1.95 (m, 6H), 1.84-1.04 (m, 22H).

³¹ P NMR (162 MHz, CDCl ₃ ) δ 30.00.

Example 161

1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1- he (161)

Stage 1: preparation of (8R,10R,13S,14S)-10,13-dimethyl-17-oxo-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro- 1H-cyclopenta[a]phenanthren-3-yl acetate

(8R,10R,13S,14S)-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene- 3,17(2H)-dione (19.0 g, 66.43 mmol) was dissolved in ethyl acetate (500 ml) and acetic anhydride (100 ml) and perchloric acid (0.5 ml) were added. The reaction solution was stirred at room temperature for 1 hour, and TLC showed; completion of the reaction. A saturated carbonate solution was added to the reaction solution; sodium (300 ml). The organic phase was washed with saturated sodium carbonate solution: (300 ml*2) and brine (300 ml), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether=0-40%) to obtain "(8R,10R,13S,14S)-10,13-dimethyl-17-oxo-2,7,8,9 ,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (13.0 g, yield: 59.7%).

1 H NMR (400 MHz, CDCl ₃ ) δ: 5.71 (s, 1H), 5.42 (t, J=2.4 Hz, 1H), 2.51-2.43 (m, 2H) 2, 34-2.27 (m, 1H), 2.18-2.04 (m, 5H), 2.00-1.69 (m, 6H), 1.62-1.27 (m, 5H), 1.13-1.06 (m, 1H) 1.03 (s, 3H), 0.92 (s, 3H).

Stage 2: preparation of (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro- 3H-cyclopenta[a]phenanthrene-3,17(2H)-dione

(8R,10R,13S,14S)-10,13-dimethyl-17-oxo-2,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[ a]phenanthren-3-yl acetate (5.0 g, 15.24 mmol) was dissolved in ethanol (18 (mL) and m-chloroperoxybenzoic acid (5.0 g, 24.71 mmol) was added. The reaction solution was stirred at room temperature for 3 hours and LC/MS showed completion of the reaction Saturated sodium carbonate solution (200 ml) was added followed by extraction of the reaction solution with ethyl acetate (300 ml) The organic phase was washed with saturated sodium carbonate solution (200 ml*2) and saturated brine (200 ml), dried over anhydrous sodium sulfate and concentrated to give (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyl-1,6,7,8,9,10,11, 12,13,14,15,16-dodecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (3.5 g, yield): 76.0%).

MS m/z (ESI): 303.0 [M+H] ⁺ .

Stage 3: preparation of (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione

(8R,10R,13S,14S)-6-hydroxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-3H-cyclopenta[ a]phenanthrene-3,17(2H)-dione (8.0 g, 26.5 mmol) was dissolved in pyridine (50 ml) and 10% Lindlar Pd catalyst (2.0 g) was added to the above solution. The reaction system was supplied with a hydrogen balloon, purged with hydrogen three times and stirred at room temperature for 16 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (30 ml). The filtrate was diluted with ethyl acetate (200 ml) and washed with 1 N hydrochloric acid (100 ml*2). The organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to give (8R,10R,13S,14S)-6-hydroxy-10,13-dimethyltetradecahydro-3H-cyclopenta[a]phenanthrene-3 ,17(2H)-dione (2.0 g, yield: 25.0%).

1H NMR (400 MHz, DMSO-d6) δ: 4.60 (s, 1H), 3.51 (m, 1H), 2.45-2.31 (m, 3H), 2.06-1.82 (m, 7H), 1.69-1.51 (m, 5H), 1.48-1.23 (m, 5H), 1.14 (s, 3H), 0.82 (s, 3H).

Stage 4: preparation of (6R,8R,10S,13S,14S)-13-methyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene-3,17-dione

(8R,10R,13S,14S)-6-hydroxy-10,13-dimethyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (1.0 g, 3.29 mmol) was dissolved in the mixture benzene (50 ml)/pyridine (0.8 ml) and lead tetraacetate (7.3 g, 16.5 mmol) was added to the above solution. The reaction solution was stirred under an incandescent lamp (500 W) for 2 hours, after which the reaction was stopped. Ethyl acetate (100 ml) was added to the reaction solution to precipitate a large amount of a solid, after which the reaction solution was filtered. The filtrate was washed with 1 N hydrochloric acid (50 ml*2). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to give (6R,8R,10S,13S,14S)-13-methyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene- 3,17-dione (600 mg, yield: 60.0%).

1H NMR (400 MHz, CDCl ₃ ) δ: 4.25-4.22 (m, 1H), 4.06 (d, J=8.4 Hz, 1H), 3.39 (d, J=8 .4 Hz, 1H), 2.63-2.44 (m, 3H), 2.35-2.06 (m, 5H), 1.98-1.80 (m, 4H), 1.72- 1.24 (m, 8H), 0.96 (s, 3H).

Stage 5: preparation of (3R,6R,8R,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17(1H)-one

2,6-di-tert-butyl-p-methylphenol (3.5 g, 15.9 mmol) and toluene (35 ml) were added to a three-necked flask. 2M trimethylaluminum (4 ml, 8 mmol) was added dropwise at 0-10° C. under nitrogen. After completion of the addition, the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled to minus 78°C in a dry ice/acetone bath, and (6R,8R,10S,13S,14S)-13-methyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene-3, 17-dione (0.8 g, 2.65 mmol) dissolved in toluene (30 ml), after which the reaction solution was subjected to interaction at minus 78°C for 1 hour. 3M methylmagnesium bromide (2.3 ml, 6.9 mmol) was added, after which the reaction solution was reacted at minus 78° C. for 1 hour. A saturated ammonium chloride solution (50 ml) was added, after which the reaction solution was extracted with ethyl acetate (120 ml). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain (3R,6R,8R,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-6,10-( epoxymethano)cyclopenta[a]phenanthren-17(1H)-one (400 mg, yield: 47.5%).

1H NMR (400 MHz, CDCl ₃ ) δ: 4.15-4.12 (m, 1H), 3.96 (d, J=8.0 Hz, 1H), 3.32 (d, J=8, 0 Hz, 1H), 2.48-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.92-1.79 (m, 5H), 1.75-1 .63 (m, 3H), 1.60-1.43 (m, 6H), 1.38-1.10 (m, 7H), 0.92 (s, 3H).

Stage 6: preparation of (3R,6R,8S,10S,13S,14S)-17-ethyliden-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol

Ethyltriphenylphosphonium bromide (11.65 g, 31.4 mmol) was dissolved in dimethyl sulfoxide (25 ml). 60% sodium hydride (1.26 g, 31.4 mmol) was added, after which the reaction solution was stirred at room temperature under nitrogen atmosphere for 1 hour. (3R,6R,8R,10S,13S,14S)-3-hydroxy-3,13-dimethyltetradecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17(1H)-one (0.5 g, 1 .57 mmol) was dissolved in dimethyl sulfoxide (5 ml), after which the reaction solution was heated to 60° C. and reacted for 16 hours. A saturated ammonium chloride solution (50 ml) was added, after which the reaction solution was extracted with ethyl acetate (60 ml). The organic phase was washed successively with saturated sodium carbonate solution (50 ml*2) and brine (300 ml), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain (3R,6R,8S,10S,13S,14S)-17-ethylidene-3,13-dimethylhexadecahydro-6,10-( epoxymethano)cyclopenta[a]phenanthren-3-ol (350 mg, yield: 67.6%).

1H NMR (400 MHz, CDCl ₃ ) δ: 5.12-5.09 (m, 1H), 4.15-4.12 (m, 1H), 3.96 (d, J=8.0 Hz, 1H), 3.26 (d, J=8.0 Hz, 1H), 2.39-2.13 (m, 3H), 1.91-1.85 (m, 3H), 1.70-1 .50 (m, 12H), 1.30-1.07 (m, 8H), 0.91 (s, 3H).

Stage 7: preparation of (3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene -3-ola

(3R,6R,8S,10S,13S,14S)-17-ethylidene-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol (250 mg, 0.76 mmol) was dissolved in tetrahydrofuran (8 ml) and cooled the solution to 0°C. A solution of borane in tetrahydrofuran (1 M, 15 ml, 15 mmol) was added and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was cooled to 0° C. and sodium hydroxide (3 M, 10 ml) was added dropwise. After completion of the addition, hydrogen peroxide (30%, 8 ml) was added dropwise, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate (60 ml) and washed with saturated sodium thiosulfate solution (30 ml). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give (3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-hydroxyethyl)-3, 13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol (260 mg, yield: 100%), which was used immediately in the next step without further purification.

Step 8: Preparation of 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl) ethane-1-she

(3R,6R,8S,10S,13S,14S,17S)-17-((S)-1-hydroxyethyl)-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-3-ol (260 mg, 0.75 mmol) was dissolved in dichloromethane (10 ml) and the solution was cooled to 0°C. PCC (322 mg, 1.5 mmol) was added, after which the reaction solution was stirred at room temperature for 3 hours. TLC showed completion of the reaction. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (20 ml). The filtrate was diluted with ethyl acetate (30 ml) and washed with saturated sodium thiosulfate solution (30 ml). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:2) to give 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro- 6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (150 mg, yield: 57.8%).

1H NMR (400 MHz, CDCl ₃ ) δ: 4.14-4.12 (m, 1H), 3.94 (d, J=7.6 Hz, 1H), 3.27 (d, J=7, 6 Hz, 1H), 2.53 (t, J=8.8 Hz, 1H), 2.18-2.04 (m, 5H), 1.91-1.86 (m, 3H), 1, 70-1.49 (m, 10H), 1.34-1.49 (m, 8H), 0.66 (s, 3H).

Example 162

1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)- 2-oxoethyl)-1H-pyrazole-4-carbonitrile (162)

Step 1: Preparation of 2-bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene- 17-yl) ethane-1-one

1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1- it (135 mg, 0.39 mmol) was dissolved in methanol (6 ml). A drop of hydrogen bromide was added, followed by the addition of 5 drops of liquid bromine with stirring at room temperature, after which the reaction solution was stirred at room temperature for 1 hour. TLC showed completion of the reaction. A saturated sodium bicarbonate solution (30 ml) was added, after which the reaction solution was extracted with ethyl acetate (50 ml). The organic phase was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to give 2-bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3.13 -dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)ethan-1-one (160 mg, yield: 96.5%), which was used immediately in the next step without further purification.

Step 2: Preparation of 1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthrene-17 -yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

2-bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl) ethan-1-one (85 mg, 0.2 mmol) and 4-cyanopyrazole (92 mg, 1.0 mmol) were dissolved in tetrahydrofuran (5 ml) and potassium carbonate (138 mg, 1.0 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, and TLC and LC/MS showed completion of the reaction. The reaction solution was filtered and concentrated. The resulting residue was purified by preparative flash chromatography to give 1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano) cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (29.7 mg, yield: 34.0%).

MS m/z (ESI): 438.3 [M+H] ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ: 7.87 (s, 1H), 7.81 (s, 1H), 5.01-4.87 (m, 2H), 4.15-4.12 ( m, 1H), 3.93 (d, J=8.4 Hz, 1H), 3.28 (d, J=8.4 Hz, 1H), 2.60 (t, J=6.8 Hz, 1H), 2.22-2.08 (m, 2H), 1.91-1.49 (m, 13H), 1.39-1.24 (m, 6H), 1.19-1.13 ( m, 2H), 0.72 (s, 3H).

Example 163

1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)- 2-oxoethyl)-1H-pyrazole-3-carbonitrile (163)

Preparation of 1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl) -2-oxoethyl)-1H-pyrazole-3-carbonitrile

2-bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl) ethane-1-one (80 mg, 0.19 mmol) and 4-cyanopyrazole (88 mg, 0.95 mmol) were dissolved in tetrahydrofuran (5 ml) and potassium carbonate (130 mg, 0.95 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, and TLC and LC/MS showed completion of the reaction. The reaction solution was filtered and concentrated. The resulting residue was purified by preparative flash chromatography to give 1-(2-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano) cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile (36.5 mg, yield: 44.4%).

MS m/z (ESI): 438.3 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ: 7.49 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 5.10-4.90 (m, 2H), 4.15-4.12 (m, 1H), 3.94 (d, J=8.0 Hz, 1H), 3.28 (d, J=8.0 Hz, 1H) , 2.60 (t, J=8.8 Hz, 1H), 2.21-2.09 (m, 2H), 1.91-1.50 (m, 13H), 1.39-1.24 (m, 6H), 1.19-1.13 (m, 2H), 0.72 (s, 3H).

Example 164

1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)-2-( 4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (164)

Preparation of 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl)-2- (4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

2-bromo-1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a]phenanthren-17-yl) ethane-1-one (80 mg, 0.19 mmol) and 4-trifluoromethylpyrazole (128 mg, 0.95 mmol) were dissolved in tetrahydrofuran (5 ml) and potassium carbonate (130 mg, 0.95 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, and TLC and LC/MS showed completion of the reaction. The reaction solution was filtered and concentrated. The resulting residue was purified by preparative flash chromatography to give 1-((3R,6R,8S,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-6,10-(epoxymethano)cyclopenta[a ]phenanthren-17-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (29.5 mg, yield: 32.7%).

MS m/z (ESI): 481.2 [M+H]+.

1H NMR (400 MHz, CDCl ₃ ) δ: 7.72 (s, 2H), 5.01-4.87 (m, 2H), 4.15-4.12 (m, 1H), 3.94 ( d, J=8.0 Hz, 1H), 3.28 (d, J=8.0 Hz, 1H), 2.60 (t, J=8.8 Hz, 1H), 2.22-2, 09 (m, 2H), 1.91-1.45 (m, 13H), 1.39-1.24 (m, 6H), 1.19-1.13 (m, 2H), 0.73 ( s, 3H).

Example 165

1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochryzen-1-yl)-2-oxoethyl)-1H-pyrazole-4- carbonitrile (165)

Stage 1: preparation of (3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate

(3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (580 mg, 2.0 mmol) was dissolved in acetic anhydride (15 ml). Pyridine (158 mg, 2.0 mmol) was added and the reaction solution was reacted under N ₂ at 80° C. overnight. The reaction solution was concentrated under reduced pressure to remove acetic anhydride. H ₂ O (20 ml) was added to the resulting residue, after which the mixture was extracted with EA (ethyl acetate) (15 ml×3). The EA phases were combined, washed successively with H ₂ O (20 ml) and brine (20 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give (3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (560 mg , yield: 84%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.44 (dd, J=19.2, S. 1 Hz, 1H), 2.24-2.06 (m, 1H), 1.97 (s, 3H), 1.96-1.76 (m, 8H), 1.71-1.57 (m, 3H), 1.55 (s, 3H), 1.55-0.99 (m, 10H) , 0.87 (s, 3H).

Stage 1: preparation of ethyl 2-((3R,5R,8R,9R,10S,13S,14S)-3-acetoxy-17-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )-2-diazoacetate

(3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-17-oxohexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate (400 mg, 1.2 mmol) and ethyl diazoacetate ( 206 mg (1.8 mmol) was dissolved in THF (15 ml) The reaction solution was cooled to minus 70°C and LDA (2 ml) was added dropwise After completion of the dropwise addition, the reaction solution was subjected to interaction at the same temperature for 1 hours A solution of AcOH (400 mg) in ether (20 ml) was added, the reaction solution was warmed to room temperature and H ₂ O (50 ml) was added The reaction solution was extracted with ether (25 ml×2) The ether phases were combined, washed successively with H ₂ O (50 ml), saturated NaHCO ₃ solution (30 ml) and brine (30 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to dryness The resulting residue was purified using column chromatography to obtain ethyl 2-((3R,5R,8R,9R,10S,13S,14S)-3-acetoxy-17-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- diazoacetate (500 mg, yield: 93%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 4.70 (bs, 1H), 4.36-4.17 (m, 2H), 2.24-2.11 (m, 1H), 2.00 ( s, 3H), 1.96-1.87(m, 2H), 1.85-1.83(m, 4H), 1.74-1.58(m, 4H), 1.55(s, 3H), 1.52-1.35 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 1.29-1.17 (m, 4H), 1.17-0 .94 (m, 5H), 0.92 (s, 3H), 0.91-0.81 (m, 1H).

Stage 3: preparation of ethyl-(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-acetoxy-8,12a-dimethyl-1-oxooctadecahydrochrysene-2-carboxylate

Ethyl-2-((3R,5R,8R,9R,10S,13S,14S)-3-acetoxy-17-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- diazoacetate (500 mg, 1.1 mmol) was dissolved in ethylene glycol dimethyl ether (10 ml). Rhodium acetate dimer (5.0 mg) was added and the reaction solution was reacted under N ₂ atmosphere at room temperature for 0.5 hour. The reaction solution was filtered to remove an insoluble matter, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to give ethyl-(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-acetoxy-8,12a-dimethyl-1-oxooctadecahydrochrysene-2-carboxylate (436 mg, yield: 93%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 12.35 (s, 0.82H), 4.13 (q, J=7.1 Hz, 2H), 3.63 (dd, J=13.5, 6.0 Hz, 0.15H), 2.27 (dd, J=16.2, 6.1 Hz, 1H), 2.14-1.96 (m, 2H), 1.89 (s, 3H ), 1.88-1.65 (m, 7H), 1.58 (dd, J=20.4, 10.4 Hz, 3H), 1.48 (s, 3H), 1.36-1, 13 (m, 8H), 1.11-1.04 (m, 2H), 1.03 (s, 3H), 0.99-0.88 (m, 3H).

Stage 4: receiving

(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydrochrysen-1(2H)-o

on

KOH (4.0 g) was dissolved in methanol (60 ml). Ethyl-(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-acetoxy-8,12a-dimethyl-1-oxooctadecahydrochrysene-2-carboxylate (400 mg) was added, after which the reaction solution was heated under reflux to N ₂ atmosphere for 1 hour. The reaction solution was cooled to room temperature and poured into ice water (150 ml). After stirring for 20 minutes, the reaction solution was filtered. The filter cake was washed with a small amount of water and acetone and dried to give (4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydrochryzene-1(2H)-o (320 mg) .

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.61 (td, J=14.0, 6.8 Hz, 1H), 2.25-2.15 (m, 1H), 2.11-2, 00 (m, 1H), 1.87 (dd, J=9.8, 7.7 Hz, 2H), 1.84-1.70 (m, 5H), 1.67-1.57 (m, 3H), 1.56-1.47(m, 2H), 1.45-1.27(m, 7H), 1.26(s, 3H), 1.20-1.10(m, 1H) , 1.08 (s, 3H), 1.07-0.91 (m, 2H).

Step 5: Preparation of (2R,4a8,4bR,6a8,10a8,10bR,12aR)-7-ethyliden-2,6a-dimethyloctadecahydrochrysen-2-ol

In accordance with stage 4 of example 1, the starting material was

(4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethylhexadecahydrochrysen-1(2H)-one, respectively, (2R,4aS,4bR,6aS,10aS,10bR, 12aR)-7-ethyliden-2,6a-dimethyloctadecahydrochrysen-2-ol (288 mg).

Step 6: Preparation of (2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydrochrysen-2-ol

In accordance with stage 5 of example 1, the starting material was

(2R,4aS,4bR,6aS,10aS,10bR,12aR)-7-ethylidene-2,6a-dimethyloctadecahydrochrysen-2-ol, respectively, (2R,4aS,4bR,6aS,7S,10aS,10bR,12aR )-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydrochrysen-2-ol (150 mg containing a small amount of impurities), which was immediately used in the next step without purification.

Step 7: Preparation of 1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochryzen-1-yl)ethan-1-one

In accordance with stage 6 of example 1, the starting material was

(2R,4aS,4bR,6aS,7S,10aS,10bR,12aR)-7-(1-hydroxyethyl)-2,6a-dimethyloctadecahydrochrysen-2-ol, respectively, was obtained

1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochryzen-1-yl)ethan-1-one (80mg, containing a small amount of impurities), which was immediately used in the next step without purification.

Stage 8: receiving

2-bromo-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochryzen-1-yl)ethan-1-one

In accordance with step 1 of example 2, 1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochryzen-1-yl)ethan-1 -one, respectively, was obtained by he (50 mg, containing a small amount of impurities), which was immediately used in the next stage without purification.

Step 9: Preparation of 1-(2-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochryzen-1-yl)-2-oxoethyl)-1H- pyrazole-4-carbonitrile

In accordance with example 5, 2-bromo-1-((1S,4aS,4bR,6aR,8R,10aS,10bR,12aS)-8-hydroxy-8,12a-dimethyloctadecahydrochryzen-1-yl)ethane was used as the starting material -1-one, respectively, was obtained oxoethyl)-1H-pyrazole-4-carbonitrile (5.5 mg).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (s, 1H), 7.83 (s, 1H), 5.06-4.88 (m, 2H), 2.47 (d, J= 4.9 Hz, 1H), 1.90-1.81 (m, 2H), 1.78-1.67 (m, 5H), 1.58-1.50 (m, 6H), 1.41 -1.34 (m, 4H), 1.29-1.24 (m, 9H), 0.99 (s, 3H), 0.96-0.83 (m, 3H).

Example 166

1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2- oxoethoxy)methyl)cyclopropane-1-carbonitrile (166)

Stage 1: preparation of 1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )-2-oxoethoxy)methyl)cyclopropane-1-carbonitrile

2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1 -one (80 mg, 0.2 mmol), 1-(hydroxymethyl)cyclopropane-1-carbonitrile (29 mg, 0.3 mmol) and potassium carbonate (138 mg, 1.0 mmol) were dissolved in N,N-dimethylacetamide (3 ml) and stirred the resulting reaction solution at 70°C overnight. Water (20 ml) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (20 ml×2). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate: 50/1-3/1) to give 1-((2-((3R,5R,8R,9R,10S,13S,14S,17S)-3 -hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)methyl)cyclopropane-1-carbonitrile (10 mg, yield: 12%).

1H NMR (400 MHz, CDCl ₃ ) δ 4.21-4.09 (m, 2H), 3.53 (s, 2H), 2.61-2.54 (m, 1H), 2.21-2 .12 (m, 1H), 1.90-1.78 (m, 4H), 1.75-1.61 (m, 4H), 1.49-1.40 (m, 5H), 1.34 -1.26 (m, 13H), 1.10-1.04 (m, 4H), 0.63 (s, 3H).

Example 167

1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)- 1Н-pyrazole-4-carbonitrile

Stage 1: preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thione

(3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thione (1.2 g, 3 mmol), 2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-sulfide (971 mg, 2.4 mmol) and 20 ml of anhydrous toluene were added successively to a dry 100 ml round bottom flask. The reaction system was purged with argon, heated to reflux and stirred overnight. After completion of the reaction, the reaction solution was filtered through neutral alumina, and the filtrate was concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 50/1) to obtain (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3 o-17H-Cyclopenta[a]phenanthrene-17-thione ,13-dimethylhexadecahydro (860 mg, yield: 68%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.90 (dd, J=8.4, 21.6 Hz, 1H), 2.63-2.55 (m, 1H), 1.97-1, 93 (m, 2H), 1.73-1.17 (m, 22H), 0.84 (s, 3H), 0.79 (s, 9H), 0.07 (s, 6H).

Stage 2: preparation of (3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thiol

(3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene-17-thione (860 mg, 2 mmol ) and 30 ml of anhydrous tetrahydrofuran were added to a dry 100 ml round bottom flask. The reaction system was cooled to 0° C. and 1.0 M tri-tert-butoxylithium aluminum hydride (6 ml, 6 mmol) was added dropwise. The reaction solution was stirred at 0°C for 2 hours and stirred at room temperature for 1 hour. TLC showed completion of the reaction. A saturated sodium bicarbonate solution was added to gently terminate the reaction, and the reaction solution was extracted with dichloromethane. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation to give a crude product which was immediately used in the next step without purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.60-2.58 (m, 1H), 2.10-2.07 (m, 1H), 1.72-0.98 (m, 25H), 0.79(s, 9H), 0.64(s, 3H), 0.04(s, 6H).

Stage 3: preparation of 1-(hydroxymethyl)-1H-pyrazole-4-carbonitrile

1H-pyrazole-4-carbonitrile (930 mg, 10 mmol), 30% formaldehyde aqueous solution (8 g, 100 mmol) and 10 ml methanol were added to a 100 ml round bottom flask. The reaction system was stirred at room temperature overnight. The reaction solution was concentrated to dryness by rotary evaporation to give 1-(hydroxymethyl)-1H-pyrazole-4-carbonitrile (900 mg, 73%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.87 (s, 1H), 4.96-4.80 (m, 2H). Stage 4: preparation of 1-(chloromethyl)-1H-pyrazole-4-carbonitrile

1-(hydroxymethyl)-1H-pyrazole-4-carbonitrile (900 mg, 7.3 mmol), triethylamine (1.5 g, 14.6 mmol) and 20 ml dichloromethane were added to a 100 ml round bottom flask. P-toluenesulfonyl chloride (2.1 g, 11 mmol) was added portionwise with stirring and the reaction system was stirred at room temperature overnight. Water was added to stop the reaction, and the reaction solution was extracted with dichloromethane. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to give 1-(chloromethyl)-1H-pyrazole-4-carbonitrile (790 mg, 76.7%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.89 (s, 1H), 5.87 (s, 2H).

Stage 5: preparation of 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a] phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile

(3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexade cahydro-17H-cyclopenta[a]phenanthrene-17-thiol (210 mg, 0 .5 mmol), 1-(chloromethyl)-1H-pyrazole-4-carbonitrile (72 mg, 0.6 mmol), potassium carbonate (136 mg, 1 mmol), sodium iodide (10 mg, catalytic amount) and 5 ml anhydrous N,N-dimethylformamide was added to a dry 100 ml round bottom flask. The reaction system was heated to 60° C. and stirred overnight. The reaction solution was cooled to room temperature. Water was added to terminate the reaction, and the reaction solution was extracted with dichloromethane. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to give 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl )hydroxy)-3,13-dimethylhexa decahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile (170 mg, yield: 64.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.79 (s, 1H), 5.18 (dd, J=14.4, 19.2 Hz, 2H), 2 .62 (t, J=7.2 Hz, 1H), 2.05-1.98 (m, 2H), 1.90-0.90 (m, 24H), 0.86 (s, 9H), 0.72 (s, 3H), 0.07 (s, 6H).

Stage 6:

1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)- 1H-pyrazole-4-carbonitrile

1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)thio)methyl)-1H-pyrazole-4-carbonitrile (170 mg, 0.32 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran in a 100 ml round bottom flask and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran ( 5 ml). The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to give 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3 ,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)-1H-pyrazole-4-carbonitrile (100 mg, yield: 75%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.79 (s, 1H), 5.28-5.02 (m, 2H), 2.58 (t, J= 9.4 Hz, 1H), 2.12-1.93 (m, 1H), 1.89-0.94 (m, 26H), 0.72 (s, 3H).

Example 168 and Example 169 17-yl)sulfinyl)methyl)-1H-pyrazole-4-carbonitrile (168)

1-(((R)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfinyl )methyl)-1Н-pyrazole-4-carbonitrile (169)

1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)- 1H-pyrazole-4-carbonitrile (25 mg, 0.06 mmol) was dissolved in 5 ml of anhydrous dichloromethane in a 100 ml round bottom flask. At minus 20° C., m-chloroperoxybenzoic acid (15 mg, 0.073 mmol) was added, and the reaction solution was stirred at this temperature for 1 hour. After completion of the reaction, a saturated sodium bicarbonate solution was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to give 1-(((S)-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H- cyclopenta[a]phenanthren-17-yl)sulfinyl)methyl)-1H-pyrazole-4-carbonitrile (7.5 mg, 29%) and 1-(((R)-((3R,5R,8R,9R, 10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfinyl)methyl)-1H-pyrazole-4-carbonitrile (6.5 mg, yield : 25%).

Example 168

MS m/z (ESI): 430.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.90 (s, 1H), 5.21 (d, J=12.0 Hz, 1H), 5.03 (d , J=12.0 Hz, 1H), 2.54 (t, J=9.2 Hz, 1H), 2.12-1.93 (m, 2H), 1.85-1.02 (m, 25H), 0.89 (s, 3H).

Example 169:

MS m/z (ESI): 430.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.91 (s, 1H), 5.18 (d, J=13.6 Hz, 1H), 5.03 (d , J=13.6 Hz, 1H), 2.32 (t, J=8.8 Hz, 1H), 2.05-1.94 (m, 2H), 1.85-1.12 (m, 25H), 1.05 (s, 3H).

Example 170

1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfonyl)methyl)- 1Н-pyrazole-4-carbonitrile (170)

Stage 1: preparation of 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)sulfonyl )methyl)-1H-pyrazole-4-carbonitrile

1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)thio)methyl)- 1H-pyrazole-4-carbonitrile (25 mg, 0.06 mmol) was dissolved in 5 ml of anhydrous dichloromethane in a 100 ml round bottom flask. At 0° C., m-chloroperoxybenzoic acid (30 mg, 0.15 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, a saturated sodium bicarbonate solution was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by preparative HPLC to give 1-((((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[ a]phenanthren-17-yl)sulfonyl)methyl)-1H-pyrazole-4-carbonitrile (9.1 mg, 34%).

MS m/z (ESI): 446.3 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.89 (s, 1H), 5.24 (d, J=14.8 Hz, 1H), 5.02 (d , J=14.8 Hz, 1H), 2.88 (t, J=9.2 Hz, 1H), 2.24-2.18 (m, 1H), 2.11-1.92 (m, 3H), 1.84-1.00 (s, 26H).

Example 171

((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (171)

Stage 1: preparation of ((3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6, 7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide

(3R,5R,8R,9R,10S,13S,14S,17S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9 ,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yltrifluoromethanesulfonate (230 mg, 0.43 mmol), methylphenylphosphine oxide (92 mg, 0.64 mmol), palladium diacetate ( 10 mg, 0.04 mmol), 1,4-bis(diphenylphosphino)butane (18 mg, 0.04 mmol), N,N-diisopropylethylamine (443 mg, 3.4 mmol) and 10 ml of anhydrous dimethyl sulfoxide were added in succession into a 100 ml round bottom flask. The reaction system was purged with nitrogen, heated slowly to 120° C. and stirred overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The resulting crude product was purified by column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S,)-3-((t-butyldimethylsilyl)oxy)- 3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide ( 170 mg, yield: 75%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77-7.72 (m, 2H), 7.55-7.48 (m, 3H), 6.53-6.50 (m, 1H), 2.44-1.16(m, 27H), l.00(s, 3H), 0.86(s, 9H), 0.05(s, 6H).

Stage 2: preparation of ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11 ,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide

((3R,5R,8R,9R,10S,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-3,13-dimethyl-2,3,4,5,6,7,8,9, 10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (170 mg, 0.32 mmol) was dissolved in 5 ml of anhydrous tetrahydrofuran in a 100 ml round bottom flask and added to the reaction system 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5 ml). The reaction solution was stirred at 60° C. overnight. After completion of the reaction, the reaction system was cooled to room temperature. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation. The obtained crude product was purified by column chromatography (eluent: dichloromethane/methanol = 10/1) to obtain ((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2, 3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)diphenylphosphine oxide (50 mg, yield: 38%) .

Stage 3: receiving

((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide

((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13 ,14,15-Tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)methylphenylphosphine oxide (50 mg, 0.12 mmol), palladium-carbon (50 mg, 10%) and 10 mL of ethyl acetate were added to a 100 ml round bottom flask. ml. The reaction system was purged with hydrogen three times and reacted at 1 atmosphere overnight. After completion of the reaction, the reaction solution was filtered through Celite to remove excess palladium-carbon, and the filtrate was concentrated to dryness by rotary evaporation. The resulting crude product was purified by high performance liquid chromatography to give ((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17- yl)methylphenylphosphine oxide (10 mg, yield: 20%).

MS m/z (ESI): 415.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79-7.74 (m, 2H), 7.55-7.50 (m, 3H), 2.41-2.34 (m, 1H), 2.03-1.60(m, 12H), 1.55-0.73(m, 21H).

Example 172

1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one hydrochloride

Stage 1: preparation of (3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

(5R,8R,9R,10S,13S,14S)-13-methyltetradecahydro-3H-cyclopenta[a]phenanthrene-3,17(2H)-dione (5.90 g, 21.50 mmol) was dissolved in anhydrous tetrahydrofuran ( 150 ml) at minus 78°C. The reaction system was purged with nitrogen, and potassium triisobutylborohydride (1.0 M in THF, 32.25 mL, 32.25 mmol) was added dropwise to the reaction system. The reaction solution was subjected to interaction at minus 78°C for 3 hours. An aqueous sodium hydroxide solution (10 mass %, 56.6 ml) and hydrogen peroxide (82.6 ml) were added dropwise successively, after which the reaction solution was stirred at room temperature for half an hour. Saturated sodium thiosulfate (100 ml) was added, after which the reaction solution was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate (100 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness by rotary evaporation. The resulting crude product was purified by flash column chromatography (petroleum ether: ethyl acetate: 4:1) to give (3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-13-methylhexadecahydro-17H-cyclopenta[ a]phenanthren-17-one (5.0 g, white solid, yield: 84%).

Stage 2: preparation of (3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

Sodium hydride (1.45 g, 36.18 mmol, 60% in mineral oil) was added portionwise to a solution of ethyltriphenylphosphonium bromide (13.44 g, 36.18 mmol) in dimethyl sulfoxide (100 ml) under nitrogen atmosphere. The reaction solution was stirred at room temperature for 1 hour, and a solution of (3S,5R,8R,9R,10S,13S,14S)-3-hydroxy-13-methylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one was added dropwise in dimethyl sulfoxide (40 ml). The reaction solution was heated to 60° C. overnight under a nitrogen atmosphere. The reaction solution was cooled to room temperature. Saturated brine (200 ml) was added, after which the reaction solution was extracted with dichloromethane (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to dryness by rotary evaporation. The resulting crude product was purified by flash column chromatography (petroleum ether: ethyl acetate: 10:1) to give (3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[ a]phenanthren-3-ol (1.60 g, white solid, yield: 76.7%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.14-5.08 (m, 1H), 4.13-4.11 (m, 1H), 2.40-2.33 (m, 1H), 2.28-2.11(m, 3H), 1.91-1.83(m, 1H), 1.74-1.58(m, 8H), 1.47-1.38(m, 5H ), 1.38-1.34 (m, 2H), 1.29-1.07 (m, 7H), 0.88 (s, 3H).

Stage 3: preparation of (3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-methanesulfonate

(3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (0.40 g, 1.39 mmol) was dissolved in dichloromethane ( 20 ml) at room temperature. Pyridine (0.33 g, 4.16 mmol) and methanesulfonyl chloride (0.32 g, 2.77 mmol) were added dropwise successively, after which the reaction solution was reacted at room temperature overnight. After completion of the reaction, the reaction solution was diluted with dichloromethane (40 ml) and washed with saturated brine (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to dryness. The resulting crude product was purified by flash column chromatography (petroleum ether: ethyl acetate: 10:1) to give (3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[ a]phenanthren-3-ylmethanesulfonate (0.30 g, white solid, yield: 59%).

Stage 4: preparation of (3R,5R,8R,9R,10S,13S,14S)-17-ethylidene-N,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-amine

(3S,5R,8R,9R,10S,13S,14S)-17-ethylidene-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl methanesulfonate (0.20 g, 0.55 mmol) was added to the tube to carry out reactions under the influence of microwave radiation (10 ml) at room temperature, and an alcoholic solution of methylamine (3 ml) was added dropwise to the reaction system. The microwave reaction tube was capped and heated to 80° C. overnight. The reaction solution was cooled to room temperature and concentrated by rotary evaporation to dryness. The resulting residue was dissolved in ethyl acetate (20 ml). The organic phases were washed with brine (20 ml×3), combined, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to dryness. The resulting crude product was purified by flash column chromatography (dichloromethane:methanol:triethylamine: 300:10:3) to give (3R,5R,8R,9R,10S,13S,14S)-17-ethylidene-N,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthrene-3-amine (70 mg, colorless oil, yield: 42.4%).

MS m/z (ESI): 302.5 [M+H] ⁺ .

Step 5: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1- ola

(3R,5R,8R,9R,10S,13S,14S)-17-ethylidene-N,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3-amine (0.07 g, 0.23 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml) in an ice bath, after which a solution of borane in tetrahydrofuran (1.0 M in THF, 2.32 ml, 2.32 mmol) was added dropwise. The reaction solution was subjected to interaction for 3 hours. A sodium hydroxide solution (3 N, 1 ml) and hydrogen peroxide (0.3 ml) were added dropwise successively, after which the reaction solution was stirred at room temperature for half an hour. The reaction solution was diluted with ethyl acetate (20 ml) and washed with saturated brine (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness by rotary evaporation to give the crude product

1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-ol (40 mg , colorless oil, crude product).

MS m/z (ESI): 320.5 [M+H] ⁺ .

Step 6: Preparation of 1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1- she

1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-ol (40 mg 0.125 mmol) was dissolved in dichloromethane (5 ml) at room temperature. Pyridinium chlorochromate (54 mg, 0.25 mmol) was added, after which the reaction solution was subjected to reaction at room temperature for 3 hours. The reaction solution was diluted with dichloromethane (20 ml) and washed with saturated sodium thiosulfate solution (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to dryness. The resulting crude product was purified by column chromatography (dichloromethane:methanol:30:1) to give 1-((3R,5R,8R,9R,10S,13S,14S)-13-methyl-3-(methylamino)hexadecahydro-1H -cyclopenta[a]phenanthren-17-yl)ethan-1-one (15 mg, white solid, yield: 37.7%).

MS m/z (ESI): 318.5 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.61-3.55 (m, 1H), 2.55-2.50 (m, 1H), 2.47 (s, 3H), 2.11 ( s, 3H), 2.01-1.92 (m, 3H), 1.78-1.56 (m, 8H), 1.43-1.01 (m, 13H), 0.61 (s, 3H).

Example 173

1-((3R,5R,8R,9R,10S,13S,14S,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1 -one (173)

Stage 1: preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one

Trimethylsilyl triflate (5.6 mL, 31.0 mmol) was added dropwise to a solution of (3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthrene -17-one (3 g, 10.3 mmol) and triethylamine (36.0 ml, 258.2 mmol) in toluene (45 ml), and the resulting reaction solution was heated under reflux for 2 hours. The reaction solution was cooled, washed with saturated sodium bicarbonate, and extracted with n-hexane. The organic phase was concentrated to dryness to give the crude product (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane). A selective fluorine-containing reagent (4.0 g, 11.4 mmol) was added to a solution of (((3R,5R,8R,9R,10S,13S,14S)-3,13-dimethyl-2,3,4,5,6 ,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,17-diyl)bis(oxy))bis(trimethylsilane) in N,N-dimethylformamide (25 ml), and the resulting reaction solution was stirred at room temperature for 2 hours to obtain (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3,13-dimethyl-3-( (trimethylsilyl)oxy)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one. A solution of tetrabutylammonium fluoride in tetrahydrofuran (11.4 ml, 1 M) was added and the resulting reaction solution was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate and washed three times with saturated brine. The organic phase was concentrated to dryness and the resulting crude product was purified by column chromatography (petroleum ether:ethyl acetate=6:4) to give (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy -3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (2.0 g, yield: 50.9%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.09 (dd, J=50.6, 7.5 Hz, 1H), 2.18-1.58 (m, YuH), 1.54-1, 01 (m, 14H), 0.92 (s, 3H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ minus 192.59.

Stage 2: preparation of (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol

Sodium hydride (123 mg, 3.08 mmol, 60 wt.%) was added to a solution of ethyltriphenylphosphonium bromide (1.2 g, 3.24 mmol) in dimethyl sulfoxide (20 ml) in portions under a nitrogen atmosphere, and the resulting reaction solution was stirred at room temperature within 1 hour. (3R,5R,8R,9R,10S,13S,14S,16R)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-one (200 mg, 0. 65 mmol) and heated the reaction solution to 70° C. under nitrogen overnight. The reaction solution was cooled and brine was added. 1 N hydrochloric acid was added to adjust the pH to 6, and the reaction solution was extracted with ethyl acetate. The organic phase was washed with brine and concentrated to dryness to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=7:3) to give (3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro -1H-cyclopenta[a]phenanthren-3-ol (80 mg, yield: 38.5%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.71-5.59 (m, 1H), 5.12 (dt, J=57.2, 7.0 Hz, 1H), 2.27-2, 11 (m, 2H), 1.92-1.24 (m, 21H), 1.22-1.09 (m, 4H), 1.06 (s, 3H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ minus 153.69.

Stage 3: preparation of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3- ola

(3R,5R,8R,9R,10S,13S,14S,16R)-17-ethylidene-16-fluoro-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (80 mg, 0.25 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml). A solution of borane in tetrahydrofuran (1 M, 2.5 ml) was added dropwise, and the resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled with ice water, and a sodium hydroxide solution (3 M, 1 ml) was slowly added dropwise while a large amount of gas was released. Hydrogen peroxide (25%, 0.58 ml) was slowly added dropwise, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with sodium thiosulfate solution and brine, and dried to obtain (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3.13 -dimethylhexadecahydro o-1H-cyclopenta[a]phenanthren-3-ol (80 mg), which was immediately used in the next step.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.47-5.16 (m, 1H), 4.22-4.05 (m, 1H), 2.42-2.17 (m, 1H), 1.94-0.93(m, 27H), 0.87(s, 3H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ minus 178.27.

Step 4: Preparation of 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )ethane-1-she

Pyridinium chlorochromate (102 mg, 0.47 mmol) was added to a solution of (3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-17-(1-hydroxyethyl)-3,13-dimethylhexadecahydro- 1H-cyclopenta[a]phenanthren-3-ol (80 mg) in acetone (2 ml), and the resulting reaction solution was reacted at 60° C. for 6 hours. The reaction solution was concentrated to dryness, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=5:2) to obtain 1-((3R,8R,9R,10S,13S,14S,16R,17S)-16-fluoro-3 -hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (22 mg, yield: 25%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.64-5.35 (m, 1H), 2.44-2.09 (m, 6H), 1.97-1.75 (m, 4H), 1.74-1.00 (m, 20H), 0.98-0.68 (m, 2H).

¹⁹ F NMR (376 MHz, CDCl ₃ ) δ minus 168.20.

Example 174

1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthrene-8b(2Н )-yl)ethan-1-one (174)

Stage 1: preparation of 1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-bromo-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl )ethane-1-she

1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (600 mg, 1.872 mmol) was dissolved in carbon tetrachloride (10 ml). N-bromosuccinimide (666 mg, 3.744 mmol) and benzoyl peroxide (48 mg, 0.187 mmol) were added, after which the reaction solution was stirred at 80° C. for 2 hours. The reaction solution was cooled to room temperature. Water (30 ml) was added, after which the reaction solution was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=8/1) to give 1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-bromo -3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (light yellow solid, 400 mg, yield: 54%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.09-3.01 (m, 1H), 2.38 (s, 3H), 2.32-2.20 (m, 1H), 2.10- 1.98 (m, 1H), 1.97-1.72 (m, 7H), 1.71-1.58 (m, 1H), 1.57-0.94 (m, 15H), 0, 89-0.81 (m, 1H), 0.76 (s, 3H).

Stage 2: preparation of 1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10 ,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one

1-((3R,5R,8R,9R,10S,13S,14S,17R)-17-bromo-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1 -one (400 mg, 1 mmol) was dissolved in anhydrous toluene (10 ml). 1,8-diazabicycloundec-7-ene (913 mg, 6 mmol) was added, after which the reaction solution was stirred at 110° C. for 16 hours. The reaction solution was cooled to room temperature. Water (20 ml) was added, after which the reaction solution was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give 1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3 ,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1 -one (colorless oil, 160 mg, yield: 51%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.69 (dd, J=3.1, 1.7 Hz, 1H), 2.41-2.28 (m, 2H), 2.25 (s, 3H), 2.07-1.93 (m, 1H), 1.89-1.76 (m, 3H), 1.71-1.69 (m, 4H), 1.53-1.41 ( m, 5H), 1.37-1.29 (m, 4H), 1.27 (s, 3H), 1.24-1.07 (m, 3H), 0.89 (s, 3H).

Stage 3: preparation of 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocycloprop[3,4]cyclopenta[1,2-a]phenanthrene -8b(2Н)-yl)ethan-1-one

Sodium hydride (45 mg, 1.136 mmol, 60%) was suspended in dimethyl sulfoxide (2 ml). Trimethyl sulfoxide (100 mg, 0.451 mmol) was added, after which the reaction solution was stirred at room temperature for 1 hour. A mixed solution of 1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10, 11,12,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (90 mg, 0.284 mmol) and tetrahydrofuran (2 ml), after which the reaction solution was stirred at room temperature for 16 hours. Water (15 ml) was added, after which the reaction solution was extracted with ethyl acetate (10 ml×3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4 -hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (colorless oil, 40 mg, yield: 43%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.26-2.18 (m, 1H), 1.95 (s, 3H), 1.92-1.85 (m, 1H), 1.81 ( m, 2H), 1.72-1.53 (m, 5H), 1.46-1.29 (m, 7H), 1.29-1.17 (m, 7H), 1.16-1, 00 (m, 3H), 0.94 (s, 3H), 0.91-0.78 (m, 2H).

Example 175

1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthrene- 8b(2Н)-yl)-2-oxoethyl)-1Н-pyrazole-4-carbonitrile (175)

Step 1: Preparation of 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2 -a]phenanthrene-8b(2H)-yl)ethan-1-one

1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthrene-8b(2Н )-yl)ethan-1-one (40 mg, 0.121 mmol) was dissolved in methanol (2 ml). A drop of hydrogen bromide and 2 drops of liquid bromine were added, after which the reaction solution was stirred at room temperature for 1.5 hours. Water (15 ml) was added, after which the reaction solution was extracted with ethyl acetate (10 ml×3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocycloprop[3,4]cyclopenta[ 1,2-a]phenanthren-8b(2H)-yl)ethan-1-one (50 mg, crude).

Stage 2: preparation of 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocycloprop[3,4]cyclopenta[1,2- a]phenanthren-8b(2H)-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthrene -8b(2H)-yl)ethan-1-one (40 mg, 0.098 mmol) was dissolved in tetrahydrofuran (5 ml). 4-cyanopyrazole (11 mg, 0.0118 mmol) and potassium carbonate (27 mg, 0.196 mmol) were added, after which the reaction solution was stirred at room temperature for 16 hours. Water (15 ml) was added, after which the reaction solution was extracted with ethyl acetate (10 ml×2). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting crude product was purified by high performance liquid chromatography to give 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a -dimethylhexadecahydrocycloprop[3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (18 mg, yield: 44%).

MS m/z (ESI): 422.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 7.74 (s, 1H), 5.11 (d, J=18.0 Hz, 1H), 4.91 (d , J=18.0 Hz, 1H), 3.61-3.49 (m, 1H), 2.96 (d, J=8.7 Hz, 1H), 2.17-2.05 (m, 2H), 1.90-1.70 (m, 5H), 1.68-1.5 (m, 7H), 1.45-1.35 (m, 5H), 1.34-1.01 ( m, 7H), 0.65 (s, 3H).

Example 176

1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthrene-8b(2Н )-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (176)

Step 1: Preparation of 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocycloprop[3,4]cyclopenta[1,2-a]phenanthrene -8b(2H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one

2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocyclopropa[3,4]cyclopenta[1,2-a]phenanthrene -8b(2H)-yl)ethan-1-one (40 mg, 0.098 mmol) was dissolved in tetrahydrofuran (5 ml). 3-cyanopyrazole (11 mg, 0.0118 mmol) and potassium carbonate (27 mg, 0.196 mmol) were added, after which the reaction solution was stirred at room temperature for 16 hours. Water (15 ml) was added, after which the reaction solution was extracted with ethyl acetate (10 ml x 2). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by high performance liquid chromatography to give 1-((2aR,4R,6aS,6bR,8aS,8bS,9aS,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydrocycloprop[ 3,4]cyclopenta[1,2-a]phenanthren-8b(2H)-yl)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)ethan-1-one (18 mg, yield: 44%).

MS m/z (ESI): 465.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (s, 1H), 7.70 (s, 1H), 4.90 (d, J=17.3 Hz, 1H), 4.71 (d , J=17.3 Hz, 1H), 2.18 (m, 1H), 2.10-2.03 (m, 1H), 1.81 (m, 3H), 1.76-1.58 ( m, 4H), 1.57 - 1.32 (m, YuN), 1.26 (s, 3H), 1.19-1.00 (m, 4H), 0.98 (s, 3H), 0 .92 (m, 2H).

Example 177

1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2',1':4,5] indeno[1,2-b]oxiren-8b-yl)-2-oxoethyl)-1Н-pyrazole-4-carbonitrile (177)

Step 1: Preparation of 1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2',1':4.5 ]indeno[1,2-b]oxiren-8b-yl)ethan-1-one

1-((3R,5R,8R,9R,10S,13S,14S)-3-hydroxy-3,13-dimethyl-2,3,4,5,6,7,8,9,10,11,12 ,13,14,15-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (80 mg, 0.242 mmol) was dissolved in methanol (5 ml) and water (1 ml). Hydrogen peroxide (1.3 ml) and sodium hydroxide (30 mg, 0.75 mmol) were added, after which the reaction solution was stirred at 0° C. for 16 hours. Water (15 ml) was added, after which the reaction solution was extracted with ethyl acetate (15 ml×3). The organic phases were combined, washed with brine (20 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to give 1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4 -hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-b]oxyren-8b-yl)ethan-1-one (60 mg, yield: 75% ).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.66 (s, 1H), 2.03 (s, 3H), 1.94 (m, 1H), 1.87-1.75 (m, 3H) , 1.74-1.61 (m, 3H), 1.47 (m, 2H), 1.43-1.37 (m, 4H), 1.35-1.30 (m, 3H), 1 .25 (s, 6H), 1.17-1.07 (m, 3H), 1.03 (s, 3H).

Stage 2: preparation of 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2',1' :4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one

1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2',1':4,5]indeno[1 ,2-b]oxiren-8b-yl)ethan-1-one (50 mg, 0.15 mmol) was dissolved in methanol (3 ml). A drop of hydrogen bromide and 2 drops of liquid bromine were added, and then the reaction solution was stirred at room temperature for 8 hours. Water (10 ml) was added, after which the reaction solution was extracted with ethyl acetate (10 ml×3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2' ,1':4,5]indeno[1,2-b]oxiren-8b-yl)ethan-1-one (60 mg, crude).

Step 3: Preparation of 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2',1': 4,5]indeno[1,2-b]oxyren-8b-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile

2-bromo-1-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a-dimethylhexadecahydro-8bH-naphtho[2',1':4,5 ]indeno[1,2-b]oxyren-8b-yl)ethan-1-one (60 mg, 0.146 mmol) was dissolved in tetrahydrofuran (3 mL). 4-cyanopyrazole (20 mg, 0.219 mmol) and potassium carbonate (60 mg, 0.438 mmol) were added, after which the reaction solution was stirred at room temperature for 16 hours. Water (15 ml) was added, after which the reaction solution was extracted with ethyl acetate (10 ml×3). The organic phases were combined, washed with brine (15 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting crude product was purified by high performance liquid chromatography to give 1-(2-((2aR,4R,6aS,6bR,8aS,8bS,9aR,10aS,10bR)-4-hydroxy-4,8a -dimethylhexadecahydro-8bH-naphtho[2',1':4,5]indeno[1,2-b]oxyren-8b-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (18 mg, yield: 29%).

MS m/z (ESI): 424.2 [M+H] ⁺

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (s, 1H), 7.82 (s, 1H), 5.07 (d, J=18.3 Hz, 1H), 4.87 (d , J=18.3Hz, 1H), 3.85(s, 1H), 2.03(dd, J=13.1, 5.6Hz, 1H), 1.94-1.91(m, 1H), 1.84-1.78 (m, 3H), 1.76-1.64 (m, 3H), 1.52-1.28 (m, 10H), 1.26 (s, 4H) , 1.19-1.09 (m, 3H), 1.07 (s, 3H).

Example 178

(3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-hydroxy-3,13-dimethyl-17-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl) acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (178)

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

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

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

Mixture

(3R,5R,8R,9R,10S,13S,14S,16R,17S)-17-(2-bromoacetyl)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile ( 100 mg, 0.23 mmol), 4-(trifluoromethyl)-1H-pyrazole (63 mg, 0.46 mmol), potassium carbonate (95 mg, 0.69 mmol) and tetrahydrofuran (5 ml) were stirred at room temperature in within 16 hours. Water (20 ml) was added, after which the reaction solution was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and the resulting crude product was purified by high performance liquid chromatography to give (3R,5R,8R,9R,10S,13S,14S,16R,17S)-3-hydroxy-3,13-dimethyl-17- (2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-16-carbonitrile (25 mg, yield: 23%).

MS m/z (E8I): 478.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76 (s, 1H), 7.74 (s, 1H), 5.01 (dd, J=77.6, 18.0 Hz, 2H), 3 .65-3.36 (m, 1H), 2.96 (d, J=8.7 Hz, 1H), 2.18-2.04 (m, 2H), 1.89-1.71 (m , 5H), 1.69-1.60 (m, 5H), 1.46-1.39 (m, 5H), 1.32-1.25 (m, 5H), 1.24-1.03 (m, 3H), 0.65 (s, 3H).

Example 179

2-(1-hydroxy-4-aminoadamantane)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene -17-yl)ethan-1-one (179)

Stage 1: preparation of 2-(1-hydroxy-4-aminoadamantane)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta [a]phenanthren-17-yl)ethan-1-one

In accordance with example 5, 2-bromo-1-((3R,5R,8R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene was used as the starting material -17-yl)ethan-1-one, respectively, 2-(1-hydroxy-4-aminoadamantane)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3- hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one (7.5 mg, yield: 10.2%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.55 (d, J=2.8 Hz, 2H), 2.72 (s, 1H), 2.50 (t, J=8.9 Hz, 1H ), 2.29-0.93 (m, 40H), 0.64 (s, 3H).

Biological analysis and evaluation

The present invention is further described below in conjunction with the following test cases, which are not intended to limit the scope of the present invention.

I. Study on the ability of a compound of the present invention to bind the GABAd receptor

1.1. Purpose of Experiment: The purpose of this test example is to measure the ability of a compound to allosterically inhibit the binding of an ion channel blocker (tert-butyl bicyclophosphorothionate (TBPS)) to the GABA-A receptor.

Equipment for the experiment:

1.2 Experimental methods

1.2.1 Extraction of the cell membrane of the cerebral cortex:

1. The cerebral cortex of male Sprague-Dawley rats is isolated.

2. A pre-chilled 0.32 M sucrose solution is added to the cerebral cortex (one protease inhibitor tablet per 100 ml is added) (the volume of the sucrose solution is 10 times the volume of the cerebral cortex). The mixture is ground in portions in a glass tissue homogenizer with a volume of 50 ml and mixed well.

3. The mixture is centrifuged at 1500 g, 4° C. for 10 minutes and the supernatant is collected.

4. The mixture is centrifuged at 20,000 g, 4° C. for 30 minutes and the supernatant discarded.

5. The pellet is resuspended in pre-chilled sodium phosphate buffer (PBS) (add one tablet of protease inhibitor per 100 ml). An average of 4 ml of PBS is added per rat and the mixture is well mixed with a glass tissue homogenizer.

6. The mixture is centrifuged at 10,000 g, 4° C. for 10 minutes and the supernatant discarded.

7. Steps 5 and 6 are repeated three times.

8. Finally, the pellet is resuspended in 4 volumes of PBS. The resulting solution is poured, frozen in liquid nitrogen and stored at minus 80°C.

9. Protein concentration is measured by the bicinchoninic acid (BCA) method.

1.2.2 35S-TBPS Binding Assay

1. 230 µl PBS is added to each well of a 1.1 ml well plate.

2. Add 60 μl of cerebral cortex cell membrane solution (5 μg/μl) to each well and mix well.

3. Add test compound (3 µl per well) and incubate plate at 25°C for 5 minutes. The DMSO concentration was 1%. The starting compound concentration was 1 μM and a 3-fold serial dilution was performed to give a total of 8 sequential concentrations and 2 replicate assays. 1% DMSO is used as a negative control and 10 μM P026-2 is used as a positive control.

4. Add GABA to a final concentration of 5 μM and incubate at 25°C for 5 minutes. A 1 mM GABA solution is prepared and 1.5 µl of the solution is added to each well.

5. Add 35S-TBPS to a final concentration of 2 nM. The concentration of the isotope stock solution was 9.7 μM. After a 100-fold dilution with PBS, 6 µl of diluted isotope solution is added to each well.

6. The tablet is incubated at 4°C for 20 hours.

7. FilterMate GF/C plate was pretreated with 0.5% PEI and incubated at 4°C for 1 hour.

8. Wash the FilterMate GF/C plate twice with the universal collector, each time with 50 ml of PBS.

9. The reaction solution is transferred to a GF/C plate and each well is washed 4 times with 900 µl PBS.

10. The washed GF/C plate is placed at 55°C and dried for 10 minutes.

11. Add 40 µl of scintillation solution to each well and read the CPM value using TopCount.

1.2.3 Method of processing experimental data:

In the experiment, the value of CPM (pulses per minute) was read using TopCount. According to the readings of the high control (DMSO) and low control (10 μM positive compound) experimental groups, % inhibition was calculated using the following formula:

The IC ₅₀ of the compound was calculated using the following 4-parameter non-linear logic formula:

Where:

X is the logarithm of the concentration of the compound,

Y is % inhibition.

The effect of the compound of the present invention on TBPS binding activity was determined by the above test, and the measured IC 50 values are shown in Table 1.

Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on TBPS binding activity.

II. Pharmacokinetic analysis in Balb/c mice

1. The purpose of the study:

Balb/c mice were used as experimental animals. The pharmacokinetic profile of the compounds of examples 2, 3, 5, 6, 9, 13, 59, 60, 61, 63, 71-74, 81, 103, 130, 134, 135, 137, 138, 140, 141, 143, 145 was studied. and 146 in mice (plasma and brain tissue) when administered orally at a dose of 5 mg/kg.

2. Study Protocol

2.1 Test compounds:

Compounds of examples 59, 60, 61, 63, 71-74, 81, 103, 130, 134, 135, 137, 138, 140, 141, 143, 145 and 146 of the present invention obtained by the applicant.

2.2 Experimental animals:

Male Balb/c mice were purchased from Shanghai Jiesijie Laboratory Animal Co., LTD, with Certificate No: SCXK (Shanghai) 2013-0006 N0.311620400001794.

2.3 Introduction:

There were 24 male Balb/c mice in each group. After an overnight fast, Balb/c mice are orally administered test compound at a dose of 5 mg/kg and an injection volume of 10 ml/kg.

2.4 Collection of samples:

0.2 ml of blood is taken from the heart before administration and 0, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration. Samples are stored in tubes with EDTA-K ₂ and centrifuged for 6 minutes at 4°C, 6000 rpm to separate the plasma. Plasma samples are stored at minus 80°C. Mice are sacrificed with CO ₂ , all brain tissue is removed, weighed, placed in a 2 ml centrifuge tube and stored at minus 80°C.

2.5 Sample handling:

1) 160 μl of acetonitrile is added to 40 μl of the plasma sample for precipitation, after which the mixture is centrifuged for 5-20 minutes at 3500 xg.

2) 90 µl of acetonitrile containing an internal standard (100 ng/ml) is added to 30 µl of plasma and brain homogenate samples for precipitation, after which the mixture is centrifuged for 8 minutes at 13,000 rpm.

3) Take 70 µl of the treated supernatant, add to 70 µl of water and vortex for 10 minutes. Take 20 μl of the mixture to analyze the concentration of the test compound using LC/MS/MS. Instrument for analysis by LC/MS/MS: AB Sciex API 4000 Qtrap.

2.6 Analysis by liquid chromatography

Liquid chromatography conditions: Shimadzu LC-20AD pump.

Chromatographic column: Agilent ZORBAX XDB-C18 (50x2.1 mm, 3.5 µm);

Mobile phase: eluent A was 0.1% formic acid in water and eluent B was acetonitrile.

Flow rate: 0.4 ml/min

Elution time: 0-4.0 min, eluent was as follows:

3. Research results and analysis

Key pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the pharmacokinetic study in mice are shown in Table 2 below:

From the results of the pharmacokinetic study in mice in the table, it can be seen that the compounds of the examples of the present invention showed good metabolic properties, and both the AUC exposure value and the maximum drug concentration in the blood of Smake showed good results.

III. An in vivo pharmacodynamic study in a mouse forced swim model

3.1 Purpose of the experiment

The antidepressant effect of the compound was evaluated in a forced swimming mouse model.

3.2 Main instruments and reagents used in the experiment

3.2.1 Tools

Forced float device (JLBehv-FSC-4, Shanghai Jiliang Software Technology Co., Ltd.).

3.2.2 Reagents

Sodium carboxymethyl cellulose (CMC-Na, SLBV9664, Sigma)

Tween 80 (BCBV8843, Sigma)

3.2.3 Test compounds

Applicant prepared the compounds of Example 2, Example 3, Example 5, Example 6, Example 9, Example 13, Examples 59-63, Examples 71-74, Example 103, Example 135, Example 137, Example 145 and Example 146 of the present invention.

3.3 Experimental procedures

3.3.1 Adaptation:

Male ICR mice (25-35 g) were adapted to the study environment 3 days before the forced swim test.

According to the study plan, mice were randomly assigned to groups on the day before the test according to body weight, 12 mice in each group. Before the start of the test, the compounds according to each example were administered intragastrically according to their Tmax in the brain in a pharmacokinetic study in mice, as follows:

1) Model group (solution 0.5% CMC-Na - 1% Tween 80, orally, 10 ml/kg);

2) Compounds of Example 2, Example 3, Example 5, Example 6, Example 9, Examples 59-63, Examples 71-73, Example 103, Example 135, Example 137, Example 145 and Example 146 (10 mg/kg, p/ o, 10 ml/kg); example 13 and example 74 (5 mg/kg, p/o, 5 ml/kg).

Upon administration, the compounds of each example were suspended in a solution of 0.5% CMC-Na + 1% Tween 80 to the desired concentration.

3.3.2 Forced Swim Study:

0.5-1 hour after administration, ICR mice were placed in a forced swim device (clear glass drum (water depth 18 cm, water temperature 25-26°C), one mouse per tank) and forced to swim for 6 minutes. The forced swim device recorded free swimming time on the surface of the ICR mice for the full 6 minutes, and data from the last four minutes was used for data analysis. Mice were taken out immediately after the swimming test, wiped dry and placed back in their original cages.

Note: The criterion for determining the immobility time is that the mouse ceases to resist in the water and swims freely on the surface, and only slight movements of the limbs are observed to keep the head on the surface of the water.

3.4 Data analysis

Percentage of free float time on the surface = 100 * free float time on the surface / 240 s.

3.5 Study data

3.6 Test results

From the above results, it can be seen that the compounds of the examples of the present application can significantly reduce the cumulative immobility time of mice forced to swim, and have a significant antidepressant effect.

The immobility time during the last four minutes of the compounds of example 3, example 60, example 61, example 72, example 73, example 137 and example 146 had a very significant difference compared to that in the reference group.

IV. An in vivo pharmacodynamic study in a mouse PTZ (pentylenetetrazole) induced epilepsy model

4.1 Purpose of the study

A model of PTZ-induced epilepsy in CD-1 mice was created and the antiepileptic activity of the compounds of Example 3, Example 60, Example 61 and Example 74 was evaluated using this model.

4.2 Research method

4.2.1 Experimental animals

50 male CD-1 mice were purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd. The experimental animals were acclimated in the animal room in the third building of Shanghai ChemPartner Co., Ltd 7 days before the test. The average body weight of the animals on the day of the test was 32.2±0.2 grams. Feeding medium: 5 animals per cage, room temperature 23±2°C, 12/12 hour light/dark cycle, free access to food and water.

For the study, mice were randomized into groups on the day of the study.

4.2.2 Test compounds

Compounds of example 3, example 60, example 61 and example 74 (obtained by the applicant). The test compounds were stored in a refrigerator at 4°C.

4.2.1 Examination equipment

Sterile 1ml disposable syringe with needle (purchased from Zhejiang Kangdelai Medical Devices Co., Ltd.)

Pipette: Eppendorf Research Plus (100-1000 µl)

Vortex Mixer: Kylin-Bell Vortex 5

Ultrasonic instrument: JL-360 ultrasonic cleaner

Scales: METTLER TOLEDO XS204 precision balances

Scales: electronic scales METTLER TOLEDO XS6002S

Plexiglas box: length 25cm * width 15cm * height 15cm with one opaque side wall, custom made by Suzhou Fengshi Laboratory Animal Equipment Co., Ltd

3-channel timer: Oregon/Model No. WB-388.

4.2.2 Distribution of experimental animals into groups

1) Vehicle/PTZ: 0.5% CMC-Na + 1% Tween-80 (10 ml/kg, po) administered 0.5 hour before PTZ administration; PTZ (120 ml / kg, s / c), administered before the study;

2) 3 mg/kg compounds from examples/PTZ: compounds of example 3, example 60, example 61 and example 74 (3 mg/kg, 10 ml/kg, po) administered 0.5 h before PTZ administration; PTZ (120 ml / kg, s / c), administered before the study.

4.3 Experimental procedures

4.3.1 Composition of the solvent

1) 0.5% CMC-Na + 1% Tween-80 (injection volume: 10 ml/kg):

1 g of sodium carboxymethyl cellulose was accurately weighed and added to a 250 ml solvent bottle, then 150 ml of bidistilled water was added. The mixture was stirred at room temperature for 4 hours with a magnetic stirrer until a homogeneous and clear solution was obtained. 2 ml of Tween-80 was added slowly and the mixture was stirred at room temperature for 3 hours until a homogeneous and clear solution was obtained. The solution was slowly transferred into a 200 ml volumetric flask and bidistilled water was added to a constant volume of 200 ml. The solution was transferred to a 250 ml solvent bottle and stirred for 1 hour with a magnetic stirrer to obtain a homogeneous and clear solution.

2) 30% hydroxypropyl-β-cyclodextrin:

30.6122 g of hydroxypropyl-β-cyclodextrin (purity: 98%) was accurately weighed and added to a 100 ml solvent bottle, then 60 ml of bidistilled water was added. The mixture was vortexed for 3 minutes and sonicated at room temperature for 15 minutes to obtain a homogeneous and clear solution. Bi-distilled water was added to a constant volume of 100 ml, mixed on a vortex mixer for 1 minute and sonicated at room temperature for 5 minutes to obtain a homogeneous and clear solution.

4.3.2 Composition of the test compound

1) 12mg/ml PTZ (dose: 120mg/kg; injected volume: 10ml/kg):

248 mg of PTZ was accurately weighed and added to a 40 ml brown flask, followed by the addition of 20.667 ml of saline. The mixture was vortexed for 2 minutes and sonicated at room temperature for 2 minutes to obtain a homogeneous and clear solution (concentration: 15 mg/mL).

2) 0.3 mg/ml of the compounds of example 5 or example 23 (dose: 3 mg/kg; administration volume: 10 ml/kg):

A certain amount of 0.5% CMC-Na + 1% Tween-8 was taken and added to a flask containing a certain amount of the compounds of example 5 or example 23. The mixture was vortexed for 3 minutes and sonicated at room temperature for 15 minutes to obtain a homogeneous suspension (concentration: 0.3 mg/ml).

4.3.3 Study method

1) The experimental animals were transferred to the operating room for environmental adaptation 1 hour before the study;

2) Animals were randomly assigned to groups, labeled and weighed;

3) The compounds of example 3, example 60, example 61 and example 74 were administered respectively 1 hour before the introduction of PTZ, or 0.5% CMC-Na + 1% Tween-80, the compound of example 3, example 60, example 61 and example 74 administered respectively 0.5 hours prior to PTZ administration;

4) PTZ (120 mg/kg) was administered subcutaneously before the observation of the course of the study, and this time point was considered as the start point of observation;

5) After the administration of PTZ, the animal was immediately placed in the observation box and observed for 30 minutes, and the following were recorded: a) the incubation period of the first clonic seizures, b) the incubation period of the first generalized tonic seizures, c) the number of clonic seizures, d) the number of generalized tonic seizures, e) the time the animal died, 6) if the animal had no 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 convulsions: Generalized clonic convulsions in animals last more than 3 seconds and are accompanied by a fall;

Tonic convulsions: limbs straighten at an angle of 90 ° to the body;

6) Possible side effects caused by the drug after administration have been observed and recorded, and can be divided into four levels:

None: normal

Mild sedation

Moderate sedation

Strong sedative effect

7) The test was carried out from 12:00 to 16:30.

4.4 Adaptation to the environment

The experimental animals were transferred to the operating room for environmental adaptation 1 hour before the study.

4.5 Grouping and introduction

Mice were randomly distributed, labeled and weighed; 10 mice per group. The test compound was administered orally in a volume of 10 ml/kg 30-60 minutes prior to PTZ administration.

4.6 Simulation and PTZ study

PTZ (120 mg/kg) was administered subcutaneously before monitoring the course of the study, and this time point was taken into account as the starting point of observation; after PTZ administration, the animal was immediately placed in the observation box and observed for 30 minutes, and the following were recorded: a) incubation period of the first clonic seizures, b) incubation period of the first generalized tonic seizures, c) number of clonic seizures, d) number of generalized tonic seizures , f) the time when the animal died. If the animal had no seizures during the 30 minute observation period, the incubation period was recorded as 1800 seconds and the number of seizures was recorded as 0.

4.7 Data analysis

All measurement data were expressed as mean ± standard error of the mean (SEM) and analyzed using Prism 6.0 statistical software.

4.7 Findings from the study

4.9 Study results

The compounds of the Examples significantly prolonged the incubation period for clonic seizures and generalized tonic seizures, and reduced the number of clonic seizures and generalized tonic seizures compared with the control group. The compounds of the examples can protect 60-100% of animals from death, significantly prolong the incubation period of death, and have a good antiepileptic effect.

Claims (63)

1. The compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt:

, Where: Z is selected from the group consisting of -CH ₂ - and -CH ₂ NH-; ring A is selected from the group consisting of a 3-8 membered heterocyclyl containing one or two heteroatoms selected from N and S, phenyl and a 5-10 membered heteroaryl containing one to four heteroatoms selected from N, where each of 3-8 membered heterocyclyl, phenyl and 5-10 membered heteroaryl optionally further substituted with one or more substituents selected from the group consisting of C _1-3 alkyl, C _1-3 haloalkyl, halogen, oxo, nitro, cyano, methoxy , cyclopropyl, -(CH ₂ ) _n1 SR ₂₅ , -(CH ₂ ) _n1 C(O)R ₂₅ and -(CH ₂ ) _n1 C(O)OR ₂₅ ; each R ^a is the same or different and each is selected from the group consisting of hydrogen, C _1-3 alkyl, C _1-3 haloalkyl, methoxy, halogen, nitro, cyano, cyclopropyl, -(CH ₂ ) _n1 C (O)R ₂₃ , -(CH ₂ ) _n1 C(O)OR ₂₃ , -(CH ₂ ) _n1 S(O) _m1 R ₂₃ and -(CH ₂ ) _n1 S(O)(NR ₂₃ )R ₂₄ , where each of C _1-3 alkyl and cyclopropyl is optionally further substituted with one or more substituents selected from the group consisting of cyano and hydroxy; R _15a is selected from the group consisting of C _1-3 alkyl, C _1-3 haloalkyl, halogen, cyclopropyl, -(CH ₂ ) _n1 OR ₂₃ and -(CH ₂ ) _n1 SR ₂₃ ; R _16a represents a hydrogen atom; or R _15a and R _16a may form cyclopropyl, where cyclopropyl is optionally further substituted with one or more halogens; R ₂₃ is selected from the group consisting of a hydrogen atom, C _1-3 alkyl and a 3-8 membered heterocyclyl containing one heteroatom selected from N, where the 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen ; R ₂₄ is selected from the group consisting of methyl; R ₂₅ is selected from the group consisting of C _1-3 alkyl and a 3-8 membered heterocyclyl containing one heteroatom selected from N, where the 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen; n ₁ is an integer equal to 0; m ₁ is an integer equal to 0, 1 or 2; And x is an integer equal to 0, 1 or 3, or a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

And

. 2. The compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, which is the compound of formula (IV-A), its stereoisomer or its pharmaceutically acceptable salt:

R _15a , ring A, Z, R ^a and x are as defined in paragraph 1. 3. The compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, which is the compound of formula (V), its stereoisomer or its pharmaceutically acceptable salt:

, Where: R _15a , R _16a , R ^a and x are as defined in paragraph 1. 4. The compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to claim 1 or 3, which is the compound of formula (V-A), its stereoisomer or its pharmaceutically acceptable salt:

, Where: R _15a , R _16a , R ^a and x are as defined in clause 3. 5. The compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, which is the compound of formula (VI), its stereoisomer or its pharmaceutically acceptable salt:

, Where: each R ^d represents a hydrogen atom or a halogen; y is an integer equal to 0 or 1; the ring A, Z, R ^a and x are as defined in item 1. 6. The compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, which is the compound of formula (VI-A), its stereoisomer or its pharmaceutically acceptable salt:

, Where: the ring A, Z, R ^a , R ^d , x and y are as defined in clause 5. 7. The compound of the formula, its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-2 and 5-6, where ring A is selected from the group consisting of:

And

. 8. A compound of any formula, its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-7, where Z is selected from the group consisting of -CH ₂ -; R ^a is selected from the group consisting of hydrogen, halogen, cyano, nitro, C _1-3 alkyl, cyclopropyl, C _1-3 haloalkyl, methoxy, -SR ₂₃ , -C(O)R ₂₃ and -C(O) _OR23 ; R ^d is selected from a hydrogen atom; R ₂₃ is selected from the group consisting of a hydrogen atom, C _1-3 alkyl and a 3-8 membered heterocyclyl containing one heteroatom selected from N, where the 3-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen. 9. A compound of any formula, its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-8, Where: R _15a is selected from the group consisting of C _1-3 alkyl and cyclopropyl; or R _15a and R _16a may form cyclopropyl. 10. The compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-9 selected from the group consisting of:

11. The use of a compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-10 to obtain a drug that activates the GABA _A receptor. 12. The use of a compound of formula (IV), its stereoisomer or its pharmaceutically acceptable salt according to any one of paragraphs. 1-10 for treating a disease associated with the central nervous system (CNS) which is selected from the group consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, spasmodic disorder, memory disorder and/or cognitive disorder, dyskinesia, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder, and/or withdrawal syndrome or tinnitus.