WO2018029602A1

WO2018029602A1 - C-3 novel triterpenone with c-28 heterocycle derivatives as hiv inhibitors

Info

Publication number: WO2018029602A1
Application number: PCT/IB2017/054840
Authority: WO
Inventors: Parthasaradhi Reddy BANDI; Rathnakar Reddy KURA; David Krupadanam GAZULA LEVI; Bhaskar Reddy KASIREDDY
Original assignee: Hetero Labs Limited
Priority date: 2016-08-08
Filing date: 2017-08-08
Publication date: 2018-02-15

Abstract

The present invention relates to C-3 novel triterpenone with C-28 heterocycle compounds of formula (I): and pharmaceutically acceptable salts thereof, wherein R₁, W, ring X and ring Y are as defined in formula (I). The present invention comprising compound of formula (I) and related compounds, compositions are useful for therapeutic treatment of viral diseases, particularly HIV mediated diseases.

Description

C-3 NOVEL TRITERPENONE WITH C-28 HETEROCYCLE DERIVATIVES AS

HIV INHIBITORS

This application claims the benefit of Indian provisional application no 201641027007 filed on 8^th August 2016 which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to C-3 novel triterpenone with C-28 heterocycle derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.

BACKGROUND OF THE INVENTION

The Human Immunodeficiency Virus (HIV) has now been established as the causative agent of the Acquired Immunodeficiency Syndrome (AIDS) for over 20 years (Science 1983, 220, 868-871; N.Eng.J.Med.1984, 311, 1292-1297). AIDS is characterized by the destruction of the immune system, particularly of CD4+T-cells. HIV is a retrovirus, and the HIV life cycle encompasses several crucial steps, starting from the attachment of the virus to the host cell membrane and finishing with the release of progeny virons from the cell.

The natural compound betulinic acid, isolated from Syzygium clavifolium and several other plant species was found to possess anti-HIV activity. Chemical modifications were undertaken by several research groups in an attempt to identify potent anti-HIV agents by making semi-synthetic analogs of betulinic acid, leading to the discovery of bevirimat as a compound with a novel mechanism of action (J. Nat. Prod. 199457(2): 243-7; J. Med. Chem. 1996, 39(5), 1016). Further studies shown that bevirimat acts by disrupting Gag processing (Proc. Natl. Acad. Sci. USA 2003, 100(23): 13555-60; Antimicrob. Agents. Chemother. 2001, 45(4), 1225-30; J.Virol. 2004, 78(2): 922-9; J. Biol. Chem. 2005, 280(51): 42149-55; J. Virol. 2006, 80(12), 5716-22) and to be a first-in-class maturation inhibitor with a potent activity against HIV-1. Bevirimat went up to phase 2 clinical trials, in clinic despite optimal plasma concentrations, not all patients given bevirimat have a robust viral load reduction. It was reported that non-respondant patients had more frequent base line Gag polymorphisms near the capsid SP-1 cleavage site than responders. (HIV gag polymorphism determines treatment response to bevirimat. XVII international HIV drug resistance work shop June 10- 14, 2008, Sitges, Spain).

Encouraged by these developments, medicinal chemists started exploring betulinic acid derivatives and related compounds intensively for their therapeutic activities. For example, WO 2014/093941 describes pharmaceutical compositions of betulin derivatives; WO 2013/117137 describes lupane triterpenoids derivatives and pharmaceutical use thereof; WO 2013/020245 describes carbonyl derivatives of betulin; WO 2009/082818 describes preparation of C21-keto lupane derivatives for the treatment of HIV infections; WO 2011/100308 describes preparation of betulin derivatives for treatment of HIV-1; WO 2013/090664 describes preparation of betulin derivatives for the treatment of HIV.

Some additional references disclose betulinic acid related compounds. For example, WO 2007/141383 describes betulin derivatives as antifeedants for plant pests; US 6670345 describes use of betulinic acid and its derivatives for inhibiting cancer growth and process for the manufacture of betulinic acid; WO 2002/091858 describes anxiolytic marcgraviaceae compositions containing betulinic acid, betulinic acid derivatives, and methods of preparation and use; WO 2000/046235 describes preparation of novel betulinic acid derivatives for use as cancer growth inhibitors; WO 2007/141392 describes cosmetic and pharmaceutical compositions comprising betulonic acid and betulin derivatives; and Pharmaceutical Chemistry Journal, 2002, 36(9), 29-32 describes synthesis and anti-inflammatory activity of new acylated betulin derivatives.

Given the fact of the world wide epidemic level of AIDS, there is a strong continued need for new effective drugs for treatment of HIV infected patients, disease conditions and/or disorders mediated by HIV by discovering new compounds with novel structures and/or mechanism of action(s).

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to the compounds of the formula (I):

Formu a I wherein,

HOOC

(wherein R_b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);

W is absent, NR₂ or CR₃R₄;

R₂ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aminoalkyl;

R₃ and R4 are independently selected from hydrogen, halogen, alkyl, hydroxyl; or R₃ and R₄ are taken together with the carbon atom to which they are attached to form an oxo group;

ring X is substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituents are alkyl, aminoalkyl or alkylaminoalkyl; and

ring Y is absent, or substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl; wherein the substituents are independently selected from one or more halo, alkyl, alkoxy, haloalkyl, alkoxyalkoxy, heterocyclyloxy, haloalkoxy, amino, aminoalkyl, hydroxyalkyl, thioalkyl, -OH, -N0₂, -SH, -CN, or -C(0)OH, an analog thereof; or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.

In another aspect, the present invention relates to pharmaceutical composition comprising C-3 novel triterpenone with C-28 heterocycle derivatives and related compounds of formula (I) and processes for preparing thereof.

In yet another aspect, the present invention relates to C-3 novel triterpenone with C- 28 heterocycle derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention relates to C-3 novel triterpenone with C-28 heterocycle derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.

Each embodiment is provided by way of explanation of the invention, and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus it is intended that the present invention include such modifications and variations and their equivalents. Other objects, features, and aspects of the present invention are disclosed in, or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not to be construed as limiting the broader aspects of the present invention.

In one embodiment, unds of formula (I):

HOOC^O^{^}^" (wherein R_b is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);

W is absent, NR₂ or CR₃R₄;

R₃ and R4 are independently selected from hydrogen, halogen, alkyl, hydroxyl; or R₃ and R₄ taken together with the carbon atom to which they are attached to form an oxo group; ring X is substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituents are alkyl, aminoalkyl or alkylaminoalkyl; and

In another embodiment, the present invention relates to compounds of formula (IA):

wherein,

W is absent, NR₂ or CR₃R₄;

In yet another embodiment, the present invention relates to compounds of formula

(IB):

wherein, ring X is substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; wherein the substituents are alkyl, aminoalkyl or alkylaminoalkyl; and

It should be understood that the formula (I), (IA) and (IB) structurally encompasses all stereoisomers, including enantiomers, diastereomers, racemates, and combinations thereof which may be contemplated from the chemical structure of the genus described herein.

It should be understood that the formula (I), (IA) and (IB) structurally encompasses all tautomers.

Also contemplated that the prodrugs of the compounds of the formula (I) includes esters of the compounds.

The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

Accordin to one embodiment, there is provided a compound of formula (I), wherein

According to another embodiment, there is provided a compound of formula (I), wherein W is absent.

According to yet another embodiment, there is provided a compound of formula (I), wherein W is -CH₂.

According to yet another embodiment, there is provided a compound of formula (I), wherein X is substituted or unsubstituted heteroaryl.

According to yet another embodiment, there is provided a compound of formula (I), wherein X is substituted or unsubstituted imidazole; when substituted the substituent is N, N- dimethylethan amine.

According to yet another embodiment, there is provided a compound of formula (I), wherein X is oxadiazole.

According to yet another embodiment there is provided a compound of formula (I), wherein Y is substituted or unsubstituted aryl. According to yet another embodiment there is provided a compound of formula (I), wherein Y is substituted or unsubstituted phenyl; when substituted the substituents are chloro and fluoro.

In certain embodiments, the compounds of formula (I) can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. The present invention is meant to include all suitable isotopic variations of the compounds of generic formula (I). For example, different isotopic forms of hydrogen (H) include protium ( 1H) and deuterium ( 2 H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half -life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.

Isotopically-enriched compounds of formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates. In one embodiment, a compound of formula (I) has one or more of its hydrogen atoms replaced with deuterium.

The representative compounds according to the present invention including the compounds disclosed in the experimental section are illustrative in nature only and are not intended to limit to the scope of the invention. (Nomenclature wherever applicable has been generated from ChemBioDraw Ultra 13.0 version).

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l la- pentamethyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane- 1-carboxylic acid (Example 1),

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chlorophenyl)-l,3,4- oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10, 11, 11 a, l ib, 12, 13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1-carboxylic acid (Example 2), (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chlorophenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11, l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-l-carboxylic acid (Example 3),

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-fluorophenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11, l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-l-carboxylic acid (Example 4),

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chlorophenyl)-l-(2- (dimethylamino)ethyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (Example 5), and

Sodium (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((5-(4-chloro phenyl)- l-(2-(dimethylamino)ethyl)- lH-imidazol-2-yl)methyl)- l-isopropyl-5a,5b, 8, 8,11a- pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylate (Example 6), or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combinations of compounds are also contemplated.

In further yet another embodiment, the compounds of formula (I) structurally encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the general formula (I) described herein.

The absolute configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 5%, in particularly less than 2% or 1 % of the other isomers. Thus when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula (I) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of formula (I) is for instance specified as cis isomer, this means that the compound is free of the trans isomer.

In further yet another embodiment, the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, solvates thereof containing an hydroxyl group; wherein hydrogen atom of the hydroxyl group are replaced with (Ci-C₆)alkanoyloxymethyl, l-((Ci-C₆)alkanoyloxy)ethyl, 1 -methyl- l-((Ci- C₆)alkanoyloxy)ethyl, (Ci-C₆)alkoxycarbonyloxymethyl, N-(Ci-C₆)alkoxycarbonyl aminomethyl, succinoyl, (Ci-C₆)alkanoyl, a-amino(Ci-C₄)alkyl, a-amino(Ci-C₄)alkylene- aryl, arylacyl and a-aminoacyl, where each a -aminoacyl group is independently selected from the naturally occurring L-amino acids, or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

In further yet another embodiment, the prodrugs of present invention are the compounds of formula (I) and its pharmaceutically acceptable salts, stereoisomers, hydrates, solvates thereof containing an amine group; wherein one or more hydrogen atoms of the amine group is replaced with (Ci-C₆)alkylcarbonyl, (Ci-C₆)alkoxycarbonyl, aminocarbonyl, (C3-C₆)cycloalkylcarbonyl, benzylcarbonyl and the like.

The present invention also provides a pharmaceutical composition that includes at least one compound according to formula (I) and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound according to formula (I). The compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, or other container.

The compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections.

The present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject one or more compounds described herein in a therapeutically effective amount to treat that infection, specifically in the form of a pharmaceutical composition.

In another aspect, the present invention relates to combinations comprising a compound of the formula (I) and a second therapeutic agent that is an anti-HIV agent, an anti-HCV agent or anti-TB agents.

In another aspect, the present invention relates to pharmaceutical compositions comprising the compound of formula (I) and one or more second anti-HIV agents and their pharmaceutically acceptable salts and stereoisomers thereof.

In another aspect, the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.

The present invention relates to methods of treatment of HIV infection, AIDS, and AIDS-related conditions by administering to a subject a compound of formula (I) and one or more second therapeutic agents selected from the group consisting of Protease inhibitors, Integrase inhibitors, Nucleoside Reverse Transcriptase inhibitors, Non-Nucleoside Reverse Transcriptase Inhibitors, Fusion/Entry inhibitors, Pharmacokinetic enhancers, and combinations thereof.

In another aspect, the present invention relates to combinations comprising a compound of the formula (I) and one or more second anti-HIV agents wherein the second anti-HIV agent is Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir disoproxil Fumarate, Tenofovir Alafenamide Fumarate, Zidovudine, Efavirenz, Elsulfavirine, Etravirine, Nevirapine, Rilpivirine, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, Cobicistat, Saquinavir, Tipranavir, Enfuvirtide, Maraviroc, Fostemsavir, Dolutegravir, Elvitegravir, Raltegravir, Bictegravir, Cabotegravir or a combination thereof.

In another aspect of the present invention provides a method for preventing; ameliorating or treating a HIV mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. The invention further provides a method, wherein the HIV mediated disease, disorder or syndrome is like AIDS, AIDS related complex, or a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss, or a retroviral infection genetically related to AIDS.

Anti HIV inhibitory potential of the compounds of present invention may be demonstrated by any one or more methodologies known in the art, such as by using the assays described in Mossman T, December 1983, Journal of immunological methods, 65 (1- 2), 55-63 and SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.

The following definitions apply to the terms as used herein:

The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.

The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). The term "alkoxy" refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon and hydrogen atoms, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., methyloxy, ethyloxy, n-propyloxy, 1-methylethyloxy (isopropyloxy), n-butyloxy, n-pentyloxy, and 1,1-dimethylethyloxy (t-butyloxy).

The term "alkoxylalkoxy" refers to a straight or branched hydrocarbon chain with oxygen radical consisting carbon atom, hydrogen atom and alkoxy groups, containing saturation or unsaturation, having from one to eight carbon atoms, and which is attached through oxygen atom to the rest of the molecule by a single bond, e.g., 2- (methyloxy)ethyloxy, 2-(ethyloxy)ethyloxy, 2-(n-propyloxy)ethyloxy, and 3- (isopropyloxy)butyloxy.

The term "amine" refers to an organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group these may respectively be called alkylamines and arylamines; amines in which both types of substituent are attached to one nitrogen atom may be called alkylarylamines. Important amines include amino acids, trimethylamine, dimehtylamine, monomethylamine and aniline.

The term "aminoalkyl" refers to any amino derivative of an alkyl radical more specifically ethanaamine, propanamine and the like.

The term "alkylaminoalkyl" (monoalkylaminoalkyl and dialkylaminoalkyl) refers to any alkyl derivative of an aminoalkyl radical, more specifically mono methylaminoethyl, dimethylaminoethyl, dimethylaminopropyl and the like.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.

The term "aryl" refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.

The term "haloalkyl" refers to alkyl group (as defined above) is substituted with one or more halogens. A monohaloalkyl radical, for example, may have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms. Examples of haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluoro chloromethyl, dichloro fluoromethyl, difluoroethyl, difluoropropyl and the like.

The term "haloalkoxy" is used herein refers alkoxy group, as defined above, wherein one or more of the alkoxy group's hydrogen atoms is independently replaced with a halogen. Illustrative examples of haloalkoxy include, but are not limited to, -OCF₃, -OCHF₂, -OCH₂F, CF₃CF₂O-, -OCH₂CF₃ and -OCH₂CH₂CI; similar comments apply to other halogen- substituted radicals.

The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, tetrazoyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

The term "heteroarylalkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with a heteroaryl group as defined above. Heteroaryl moieties include but are not limited to pyridine- 1 -ylmethyl, pyridine-2-yl ethyl, and pyrimidine-1 -yl methyl. A heteroarylalkyl group can be unsubstituted or substituted with one or more suitable groups. The term "heterocyclyloxy" refers to the group -O-heterocycyl.

The term "hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3- dihydroxypropyl, 1 -(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl.

The term "substituted" refers to 1-3 substituents on the same position or on different positions with the same groups or different groups. Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted guanidine.

The term "thioalkyl" refers to a chemical functional group where a sulfur atom (S) is bonded to an alkyl group. Examples of thioalkyl groups are thiomethyl and thioethyl, thiomethoxymethyl, thiocyclohexyl, thiopropene, thiochloromethyl.

The term "stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereo centers. Stereoisomers include enantiomers and diastereomers.

The term "tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as but are not limited to, enol-keto, imine-enamine tautomers, or the like or the Tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring - NH- moiety and a ring =N- moiety or the like such as but are not limited to, pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

The term "regioisomer" or "positional isomer" refer to that have the same carbon skeleton and the same functional groups but differ from each other in the location of the functional groups on or in the carbon chain. The term "prodrug" denotes a derivative of a compound, which derivative, when administered to warm -blooded animals, e.g. humans, is converted into the compound (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced. For example, a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester. When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term "treating" or "treatment" of a state, disease, disorder or condition includes:

(1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;

(2) inhibiting the state, disease, disorder or condition, i.e., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or subclinical symptom thereof; or

(3) relieving the state, disease, disorder or condition, i.e., causing regression of the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms.

The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).

A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.

The compounds of the present invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of the present invention are capable of existing in stereoisomeric forms (e.g., diastereomers, enantiomers, racemates, and combinations thereof). With respect to the overall compounds described by the Formula (I), the present invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present invention may be separated from one another by the methods known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.

Pharmaceutically acceptable solvates includes hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art.

PHARMACEUTICAL COMPOSITIONS

The pharmaceutical compositions provided in the present invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Specifically, the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to treat viral infection in a subject.

The subjects contemplated include, for example, a living cell and a mammal, including human. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, or other container.

Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene. The carrier or diluent may include a sustained release material, such as, for example, glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick-, sustained-, or delayed-release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy, 20^th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampule, capsule, or sachet. When the carrier serves as a diluent, it may be a solid, semi- solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.

The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.

The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is specifically suitable.

Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Exemplary carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

A typical tablet that may be prepared by conventional tableting techniques.

Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, specifically aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

METHODS OF TREATMENT

The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by viral infections. The connection between therapeutic effect and antiviral is illustrated. For example, PCT publication Nos. WO 01//07646, WO 01/65957, or WO 03/037908; US publication Nos. US 4,598,095 or US 2002/0068757; EP publication Nos. EP 0989862 or EP 0724650; Bioorganic & Medicinal Chemistry Letters, 16, (6), 1712-1715, 2006; and references cited therein, all of which are incorporated herein by reference in their entirety and for the purpose stated.

The present invention further provides a method of treating a disease, condition and/or disorder mediated by viral infections in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.

Diseases, conditions, and/or disorders that are mediated by viral infections are believed to include, but are not limited to, ΗΓ infection, HBV, HCV, a retroviral infection genetically related to HIV, AIDS, inflammatory disease, respiratory disorders (including adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), multiple sclerosis, rheumatoid arthritis, graft rejection (in particular but not limited to kidney and lung allografts), endometriosis, type I diabetes, renal diseases, chronic pancreatitis, inflammatory lung conditions, chronic heart failure and bacterial infections (in particular but not limited to tuberculosis).

The compounds of the present invention may obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the available drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than antiviral can be avoided or declined.

METHODS OF PREPARATION

The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in below schemes. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereoisomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

Compounds of the present invention can be synthesized from naturally occurring Betulin. Key intermediates required for synthesizing analogues are either commercially available or can be prepared by the methods published in the literature. For example, the key intermediates in the present invention were prepared by modifying the procedures published in Journal of organic chemistry 2010, 75, 1285-1288; Journal of organic chemistry 2000, 65, 3934-3940; Tetrahedron: asymmetry 2008, 19, 302-308; or Tetrahedron: asymmetry 2003, 14, 217-223.

Another embodiment of the present invention provides process for preparation of the compounds of general formula (I) are set forth in the below generalized schemes. One of skill in the art will recognize that below generalised schemes can be adapted to produce the compounds of general formula (I) and pharmaceutically acceptable salts of compounds of general formula (I) according to the present invention. Wherein all symbols/variables are as defined earlier unless otherwise stated.

General Synthetic Procedures:

Scheme-1:

The compounds of formula (I) (wherein, W is absent, rings X and Y are same as defined above) can be prepared as described in Scheme 1. The C-3 & C-28 di hydroxy compounds of formula (i) can be protected in different ways like

(a) With a suitable ester forming reagents such as anhydrides with or without addition of base or solvent or catalyst under heating conditions or

(b) with a suitable ester forming reagents such as anhydrides, acid halides or mixed anhydrides or the like in the presence of a base such as triethylamine (TEA) or N,N- diisopropylethylamine (DIPEA) or pyridine or the like in the solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or toluene or the like with or without addition of catalyst such as 4-(Dimethylamino)pyridine (DMAP) under heating conditions or the like to give the C-3 & C-28 di hydroxy protected compounds of formula (ii) (Pi and P₂ are protecting groups such as acetyl, benzyl or the like).

The compounds of formula (ii) can be converted to the ring-E ene compounds of formula (iii) in the presence of hydrogen bromide (HBr) in acetic acid (AcOH), acetic acid (AcOH) and acetic anhydride (Ac₂0) in solvents such as toluene or benzene or xylene or the like. The ring-E ene compounds of formula (iii) can be converted to the ring-E enone compounds of formula (iv) in the presence of sodium dichromate dihydrate (Na₂Cr₂0₇.2H₂0), sodium acetate (NaOAc), acetic acid (AcOH) and acetic anhydride (Ac₂0) in solvents such as toluene or benzene or the like. The ring-E enone compounds of formula

(iv) can be selectively deprotected at C-28 to give the C-28 hydroxy compounds of formula

(v) in the presence of potassium hydroxide (KOH) or the like in the combination of solvents such as toluene: ethanol (EtOH) (1: 1) or with reagent like Aluminium isopropoxide

[Al(OCH(CH₃)₂)₃] in solvent such as 2-propanol or the like. The C-28 hydroxy compounds of formula (v) can be converted to the C-28 aldehyde compounds of formula (vi) in the presence of pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Dess-Martin periodinane (DMP) or Swern oxidation conditions in solvents such as dichloromethane (DCM) or the like. The C-28 aldehyde compounds of formula (vi) can be converted to the C- 28 acid compounds of formula (vii) in the presence of oxidizing agents such as sodium chlorite (NaC10₂) or the like in the presence of scavenger such as 2-methyl-2-butene or the like in the presence of a buffer such as sodium dihydrogen phosphate (NaH₂P0₄) or the like in the combination of solvents such as tert-butanol (t-BuOH), tetrahydrofuran (THF) and water (H₂0) or the like. The C-28 acid compounds of formula (vii) can be converted to the ester compounds of formula (ix) by reacting with compounds of formula (viii) in the presence of a base such as triethylamine (TEA) or Ν,Ν-diisopropylethylamine (DIPEA) or the like in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or the like. The substituted ester compounds of formula (ix) can be converted to the substituted imidazole compounds of formula (x) under heating conditions in the presence of reagents such as ammonium acetate (NH₄OAc) or the like in the solvents such as benzene or toluene or the like.

The C-3 hydroxy compounds of formula (xi) can be achieved by deprotection at C-3 acetyl compounds of formula (x) in the presence of inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as methanol (MeOH), tetrahydrofuran (THF) and water (H₂0) or the like. The C-3 hydroxy compounds of formula (xi) can be converted to the C-3 ester compounds of formula (xiii) by reacting with anhydrides of compounds of formula (xii)a or the acid compounds of formula (xii) (scheme-3) in different ways like

(a) The coupling of compounds of formula (xii)a and (xi) can be achieved in the presence of catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as toluene or benzene or the like under reflux conditions.

(b) The coupling of compounds of formula (xii) and (xi) can be achieved in the presence of Yamaguchi reagent like 2,4,6-trichlorobenzoyl chloride or the like in the presence of a base such as triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA) or the like and a catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or the like.

(c) The coupling of compounds of formula (xii) and (xi) can be achieved in the presence of coupling reagents such as l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) or the like with catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as dichloromethane (DCM) or N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) or the like.

The Acid of compounds of formula (I) can be prepared by deprotection of esters of compounds of formula (xiii) in different ways like

(a) The ester group in compounds of formula (xiii) can be deprotected in the presence of catalyst such as palladium on carbon (10% Pd/C) and hydrogen source such as ammonium formate (HCOONH₄) or hydrogen gas (H₂) or the like in the solvents such as ethyl acetate (EtOAc) or methanol (MeOH) or the combination of ethyl acetate (EtOAc): methanol (MeOH) (1 : 1) or the like.

(b) The ester group in compounds of formula (xiii) can be hydrolyzed in the presence of aqueous solution of inorganic bases such as potassium carbonate (K₂C0₃) or sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the solvents such as combination of methanol (MeOH) and Tetrahydrofuran (THF) or the like.

Scheme-2:

The compounds of formula (I) (wherein, W is absent, and X and Y are same as defined above) can be prepared as described in Scheme 2. The C-28 acid compounds of formula (vii) can be converted to the C-28 acid chloride of compounds of formula (xiv) in the presence of reagents such as thionyl chloride (SOCl₂) or oxalyl chloride (COCl)₂ and catalytic amount of DMF or the like in solvents such as dichloromethane (DCM) or chloroform (CHCI₃) or the like. The C-28 acid chloride of compounds of formula (xiv) can be coupled with hydrazine hydrate in solvents such as dichloromethane (DCM) or the like to give the C-28 acyl hydrazides of compounds of formula (xv). The C-28 acyl hydrazides of compounds of formula (xv) can be converted to the diacyl dihydrazides of compounds of formula (xvi) in different ways like

(a) The C-28 acyl hydrazides of compounds of formula (xv) can be coupled with acids of compounds of formula (xv)a in the presence of coupling reagents such as l-Ethyl-3- (3-dimethylaminopropyl)carbodiimide (EDCI) and 1-Hydroxybenzotriazole hydrate (HOBt) or N-[(Dimethylamino)-lH- l,2,3-triazolo-[4,5-^]pyridin- l-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide (HATU) or Ν,Ν,Ν',Ν'- Tetramethyl-0-(lH-benzotriazol- l-yl)uronium hexafluorophosphate (HBTU) or the like in the presence of bases such as triethylamine (TEA) or N,N- diisopropylethylamine (DIPEA) or the like in solvents such as N,N- dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) or the like.

(b) The C-28 acyl hydrazides of compounds of formula (xv) can be coupled with acid chlorides obtained from corresponding acids of compounds of formula (xv)a in the presence of bases such as triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA) or the like in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or the like.

The diacyl dihydrazides of compounds of formula (xvi) can be converted to the alkyl, aryl or heteroaryl substituted 1,3,4-oxadiazoles of compounds of formula (xvii) in the presence of reagents like /?ara-Toluenesulfonyl chloride or the like in the presence of bases such as triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA) or the like in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or the like. The C-3 hydroxy compounds of formula (xviii) can be achieved by deprotection at C-3 acetyl compounds of formula (xvii) in the presence of inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as methanol (MeOH), tetrahydrofuran (THF) and water (H₂0) or the like. The C-3 hydroxy compounds of formula (xviii) can be converted to the C-3 ester compounds of formula (xix) by using the anhydride of compounds of formula (xii)a or the acid of compounds of formula (xii) in different ways like

(a) The coupling of compounds of formula (xii)a and (xviii) can be achieved in the presence of catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as toluene or benzene or the like under reflux conditions.

(b) The coupling of compounds of formula (xii) and (xviii) can be achieved in the presence of Yamaguchi reagent like 2,4,6-trichlorobenzoyl chloride or the like in the presence of bases such as triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA) or the like and catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or the like.

(c) The coupling of compounds of formula (xii) and (xviii) can be achieved in the presence of coupling reagents such as l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) or the like with catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as dichloromethane (DCM), N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) or the like.

The Acid of compounds of formula (I) can be prepared by deprotection of ester of compounds of formula (xix) in different ways like

(a) ester (xix) deprotection in the presence of catalyst such as palladium on carbon (10% Pd/C) and hydrogen source such as ammonium formate (HCOONH₄) or hydrogen gas (¾) or the like in solvents such as ethyl acetate (EtOAc) or methanol (MeOH) or the combination of ethyl acetate (EtOAc): methanol (MeOH) (1 : 1) or the like.

(b) ester (xix) can be hydrolyzed in the presence of aqueous solution of inorganic bases such as potassium carbonate (K₂CO₃) or sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as methanol (MeOH) and Tetrahydrofuran (THF) or the like.

Scheme-3:

The compounds of formula (I) (wherein, X and Y are same as defined above) can be prepared as described in Scheme 3. The acid of compounds of formula (xx) can be converted to the esters of compounds of formula (xxi) by reacting with compounds of formula (viii) in the presence of bases such as triethylamine (TEA) or Ν,Ν-diisopropylethylamine (DIPEA) or the like in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or the like. The esters of compounds of formula (xxi) can be converted to the cyclized compounds of formula (xxii) under refluxing conditions in the presence of reagents such as ammonium acetate (NH₄OAc) or the like in the solvents such as benzene or toluene or the like.

The C-3 hydroxy compounds of formula (xxiii) can be achieved by deprotection of C-

3 acetyl group of compounds of formula (xxii) in the presence of inorganic bases such as sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the combination of solvents such as methanol (MeOH), tetrahydrofuran (THF) and water (¾0) or the like. The C-3 hydroxy compounds of formula (xxiii) can be converted to the C-3 ester compounds of formula (xxiv) by using the anhydride compounds of formula (xii)a or the acid compounds of formula (xii) in different ways like

(a) The coupling of compounds of formula (xii)a and (xxiii) can be achieved in the presence of catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as toluene or benzene or the like under reflux conditions.

(b) The coupling of compounds of formula (xii) and (xxiii) can be achieved in the presence of Yamaguchi reagent like 2,4,6-trichlorobenzoyl chloride or the like in the presence of bases such as triethylamine (TEA) or N,N-diisopropylethylamine (DIPEA) and catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) or the like.

(c) The coupling of compounds of formula (xii) and (xxiii) can be achieved in the presence of coupling reagents such as l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) or the like with catalyst such as 4-(Dimethylamino)pyridine (DMAP) in solvents such as dichloromethane (DCM) or N,N-dimethylformamide (DMF) or tetrahydrofuran (THF) or the like.

The Acid of compounds of formula (xxv) can be prepared by deprotection of ester of compounds of formula (xxiv) in different ways like

(a) ester (xxiv) deprotection in the presence of catalyst such as palladium on carbon (10% Pd/C) and hydrogen source such as ammonium formate (HCOONH₄) or hydrogen gas (H₂) or the like in the solvents such as ethyl acetate (EtOAc) or methanol (MeOH) or the combination of ethyl acetate (EtOAc): methanol (MeOH) (1: 1) or the like.

(b) ester (xxiv) can be hydrolyzed in the presence of aqueous solution of inorganic bases such as potassium carbonate (K₂CO₃) or sodium hydroxide (NaOH) or potassium hydroxide (KOH) or the like in the solvents such as methanol (MeOH) and Tetrahydrofuran (THF) or the like.

Salts of compounds of formula (I) can be prepared by reacting compounds of formula (xxv) with bases like NaOH or KOH or the like in the combination of solvents such as methanol (MeOH), water (H₂0), and ethyl acetate (EtOAc) or ethanol (EtOH), water (H₂0) and ethyl acetate (EtOAc) or the like.

The abbreviations used in the entire specification may be summarized herein below with their particular meaning: 1H NMR (Proton Nuclear Magnetic Resonance); Hz (hertz); MHz (megahertz); CDCI₃ (Deuterated chloroform); DMSO-d₆ (Deuterated Dimethylsulfoxide); CD₃OD (Deuterated methanol); DMSO (Dimethylsulfoxide); δ (delta); ppm (parts per million); s (singlet); d (doublet); dd (doublet of doublets); m (multiplet); q (quartet); J (coupling constant); JAB (coupling constant); ml or mL (millilitre); °C (degree Celsius); mol (mole(s)); mmol (millimole(s)); M (molar); N (Normal); mg (milligram(s)); g (gram(s)); mm (millimetre(s)); Ac₂0 (acetic anhydride); DIPEA (N,N- Diisopropylethylamine); % (percentage); EtOH (ethanol); EtOAc (Ethyl acetate); H or H₂ (hydrogen); HC1 (Hydrochloric acid); h or hr (hours); HPLC (High-performance liquid chromatography); ESI-MS (Electrospray ionization mass spectrometry); m/z (mass-to-charge ratio); M+H⁺ (parent mass spectrum peak plus H⁺); M+Na⁺ (parent mass spectrum peak plus sodium^"1"); min (Minutes); mM (millimolar); NaOH (Sodium hydroxide); N₂ (Nitrogen); TEA (triethylamine); TLC (Thin Layer Chromatography); THF (Tetrahydrofuran); H₂0 (water); tert (tertiary); t (triplet); IC (Inhibitory concentration), nM (Nano molar); pH (Pouvoir hydrogen); DCM (dichloromethane); DMF (Ν,Ν-dimethylformamide); DMAP (4- (Dimethylamino)pyridine); eq (equivalent(s)); Ltr or L (Litre(s)); NaH₂P0₄ (Sodium dihydrogen phosphate); AcOH (Acetic acid); ABq (AB quartet); MTBE (Methyl tert-butyl ether); HBr (Hydrogen bromide); NaHC0₃ (Sodium bicarbonate); Na₂S0₄ (Sodium sulfate); 1,2-DCE (1,2-dichloroethane); HBTU (0-(Benzotriazol-l-yl)-N,N,N',N'- tetramethyluroniumhexafluorophosphate); KOH (Potassium hydroxide); MeOH (methanol); EDCI (l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide); br.s. (Broad singlet); NaC10₂ (sodium chlorite); NaOCl (sodium hypochlorite); t-BuOH (tert-butanol), K₂C0₃ (potassium carbonate); HATU (N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-^]pyridin-l-ylmethylene]-N- methylmethanaminiumhexafluorophosphate N-oxide); NH₄OAc (ammonium acetate)

EXPERIMENTAL

The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions.

EXAMPLES

Example 1: Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl- 5a.5b.8.8.11a-pentamethyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3.3a.4.5.5a.5b.6.7.7a.8.9. 10J 1 J laJ lbJ2J3 J3a-octadecahydro-2H-cyclopentaralchrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane-l-carboxylic acid:

Step 1: Synthesis of ((lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-9-acetoxy-5a,5b,8,8, lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-3a -cyclopenta[a]chrysen-3a-yl)methyl acetate:

A mixture of (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-3a-(hydroxymethyl)- 5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)icosahydro-lH-cyclopenta[a]chrysen-9-ol (231 g, 0.521 mol, 1.0 eq) and acetic anhydride (1.98 Ltr) were stirred at 140 °C for about 1.5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled down to room temperature and then stirred at 0 °C for about 30 minutes. The obtained solid was filtered and dried under vacuum to afford the title compound (266 g, yield: 96.5%) as an off-white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 4.68 (s, 1H), 4.59 (s, 1H), 4.50-4.43 (m, 1H), 4.25 (d, 7 = 11.1 Hz, 1H), 3.85 (d, 7 = 11.1 Hz, 1H), 2.50-2.40 (m, 1H), 2.07 (s, 3H), 2.04 (s, 3H), 2.0-1.04 (m, 23H), 1.68 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.88-0.75 (m, 10H). Step 2: Synthesis of ((3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-2,3,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-3aH- cyclopenta[a]chrysen-3a-yl)methyl acetate:

HBr in acetic acid (532 ml, 33%), was added to a suspension of ((lR,3aS,5aR,5bR, 7aR,9S,l laR,l lbR,13aR,13bR)-9-acetoxy-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl) icosahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate (step 1, 266 g, 0.505 mol, 1.0 eq) in toluene (532 mL), Ac₂0 (532 mL) and acetic acid (532 mL) previously heated at 105 °C. The reaction mixture was stirred and heated at this temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooling down to room temperature, quenched with sodium acetate. The resulting reaction mixture was evaporated to dryness. The pale brownish residue was taken up in DCM and the organic phase was washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was washed with ethanol : dichloromethane (9:1) and dried under vacuum to obtain the desired product (190 g, yield: 71.42%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 4.52-4.45 (m, 1H), 4.03 (d, 7 = 10.8 Hz, 1H), 3.98 (d, 7 = 11.1 Hz, 1H), 3.19-3.08 (m, 1H), 2.46-2.38 (m, 1H), 2.28-2.22 (m, 2H), 2.05 (s, 3H), 2.04 (s, 3H), 2.0-1.83 (m, 2H), 1.78-1.61 (m, 6H), 1.57-1.44 (m, 3H), 1.43-1.08 (m, 8H), 1.06 (s, 3H), 1.02-0.86 (m, 12H), 0.84 (s, 3H), 0.83 (s, 3H), 0.78 (m, 1H). Step 3: Synthesis of ((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro- 3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate:

To a stirred solution of ((3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octa decahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate (step 2, 190 g, 0.361 mol, 1.0 eq) in toluene (2438 mL) was added AcOH (3.23 Ltr), Ac₂0 (785 mL), sodium dichromate dihydrate (129.26 g, 0.433 mol, 1.2 eq) and sodium acetate (169.36 g, 2.065 mol, 5.71 eq). The reaction mixture was stirred and heated at 60 °C for overnight. TLC indicated starting material was consumed and the desired product was observed. After cooling down, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed successively with water, saturated solution of sodium carbonate and brine solution. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was triturated with methanol, cooled to 0 °C, the precipitates formed were collected by filtration and dried under vacuum to afford the title compound (156 g, yield: 80%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 4.49 (dd, = 10.5, 6.3 Hz, 1H), 4.33 (d, = 10.8 Hz, 1H), 4.06 (d, = 10.8 Hz, 1H), 3.22-3.12 (m, 1H), 2.86 (dd, = 12.3, 3.3 Hz, 1H), 2.39 (d, J = 18.6 Hz, 1H), 2.05 (s, 3H), 2.0 (s, 3H), 1.98-0.75 (m, 40H). Step 4: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(hydroxymethyl)-l-isopropyl -5 a, 5b, 8, 8, 1 la-pentamethyl-2-oxo-3,3a,4, 5, 5 a, 5b, 6, 7,7a,8,9,10,ll,lla,llb,12,13,l 3 a -octa decahydro-2H-cyclopenta[a ]chrys -9-yl acetate:

To a stirred solution of ((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a -octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)methyl acetate (step 3, 156 g, 0.288 mol, 1.0 eq) in a mixture of ethanol (4.45 Ltr) : toluene (4.45 Ltr) (1: 1) was added potassium hydroxide (18.85 g, 0.336 mol, 1.16 eq). The reaction mixture was stirred vigorously at room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was neutralized with aqueous IN HC1 to pH~7 and evaporated to dryness. The obtained residue was taken up in water and a small amount of acetone. The precipitates formed were collected by filtration, washed with water and dried in vacuo to afford the title compound (107.5 g, yield: 75%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 4.49 (dd, = 10.5, 6.0 Hz, 1H), 3.73 (d, = 10.8 Hz, 1H), 3.66 (d, = 10.8 Hz, 1H), 3.25-3.14 (m, 1H), 2.78 (dd, = 12.3, 3.3 Hz, 1H), 2.44 (d, = 18.6 Hz, 1H), 2.05 (s, 3H), 1.98-1.17 (m, 23H), 1.13 (s, 3H), 1.10-1.0 (m, 1H), 0.95 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.80 (m, 1H).

Step 5: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-formyl-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro- 2H-cyclopenta[a ]chrysen-9-yl acetate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(hydroxymethyl)- l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 4, 63 g, 126.5 mmol, 1.0 eq) in DCM (1.5 Ltr) was added pyridinium chlorochromate (81.5 g, 379.5 mmol, 3.0 eq) and silicagel (80 g). The reaction mixture was stirred at room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM .The combined organic layer was washed with saturated sodium bicarbonate solution followed by brine solution. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was stirred with ethanol at room temperature for about 1 hour. The obtained solid was filtered and dried under vacuum to afford the title compound (42 g, yield: 67%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 9.31 (s, 1H), 4.49 (dd, J = 10.2, 6.0 Hz, 1H), 3.32-3.22 (m, 1H), 2.55 (dd, J = 12.6, 3.0 Hz, 1H), 2.43-2.34 (m, 2H), 2.10-2.0 (m, 2H), 2.05 (s, 3H), 1.97-1.80 (m, 2H), 1.80- 1.60 (m, 3H), 1.53-1.05 (m, 16H), 1.03 (s, 3H), 0.94 (s, 3H), 0.90 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.79 (m, 1H).

Step 6: Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro- 3aH-cyclopenta[a ] chrysene-3a-carboxylic acid:

To a stirred solution of (3a ?,5a ?,5b ?,7a ?,95,l la ?,l lb ?,13a5)-3a-formyl-l-isopropyl -5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octa decahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 5, 15 g, 30.24 mmol, 1.0 eq) in t- butanol (150 mL), THF (75 mL) and 2-methyl 2-butene (9.3 ml) at 0 °C was added slowly a solution of NaC10₂ (27.2 g, 302.4 mmol, 10.0 eq) and NaH₂P0₄ (36.2 g, 302.4 mmol, 10.0 eq) dissolved in water (75 mL). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with ethyl acetate, organic layer was separated and washed with water. The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound (10.0 g, 64.59%) as a white solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 12.63 (s, 1H), 4.39 (dd, 7 = 11.1, 4.8 Hz, 1H), 3.21-3.12 (m, 1H), 2.73-2.64 (m, 1H), 2.45-2.38 (m, 1H), 2.34-2.26 (m, 1H), 2.17-2.10 (m, 1H), 2.05 (s, 3H), 1.95-1.03 (m, 23H), 0.98 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H), 0.80 (s, 6H); ESI-MS: m/z 513.39 (M+H)⁺.

Step 7: Synthesis of 2-oxo-2-phenylethyl (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-acetoxy- l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,

13a-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a -octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid (step 6, 4.0 g, 7.81 mmol, 1.0 eq) in DCM (50 mL) at 0 °C was added DIPEA (3.02 g, 23.43 mmol, 3.0 eq) followed by 2- bromo-l-phenylethan-l-one (1.71 g, 8.59 mmol, 1.1 eq). The reaction mixture was allowed to stir at room temperature for about 16 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (150 mL) and extracted with DCM (3x100 mL). The combined organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 20% EtOAc in hexane as an eluent to afford the title compound (3.5 g, yield: 71%) as a solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.90 (d, = 7.2 Hz, 2H), 7.65-7.61 (m, 1H), 7.53-7.45 (m, 2H), 5.38, 5.25 (ABq, /AB = 15.9 Hz, 2H), 4.50 (dd, = 10.2, 6.6 Hz, 1H), 3.30-3.19 (m, 1H), 3.03 (dd, = 12.3, 2.7 Hz, 1H), 2.74 (d, = 18.6 Hz, 1H), 2.58-2.52 (m, 1H), 2.20 (d, = 18.6 Hz, 1H), 2.05 (s, 3H), 2.04-1.0 (m, 22H), 1.15 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.89-0.80 (m, 7H); ESI-MS: m/z 653.39 (M+Na)⁺. Step 8: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:

To a stirred solution of 2-oxo-2-phenylethyl (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)- 9-acetoxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l l,l la, l ib, 12,13, 13a-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylate (step 7, 3.5 g, 5.55 mmol, 1.0 eq) in toluene (35 mL) was added ammonium acetate (4.27 g, 55.55 mmol, 10.0 eq). The reaction mixture was heated to reflux for about 16 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (100 mL) and extracted with DCM (3x100 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 30% EtOAc in hexane as an eluent to afford the title compound (1.5 g, 44.2% yield) as a solid. 1H NMR (300 MHz, CDC1₃): δ ppm 14.3 (br.s., 1H), 7.87 (m, 2H), 7.37-7.32 (m, 4H), 4.50-4.42 (m, 1H), 3.26 (m, 1H), 2.53-2.20 (m, 4H), 2.04 (s, 3H), 1.95-1.0 (m, 25H), 0.93 (s, 3H), 0.88-0.73 (m, 10H); ESI-MS: m/z 611.40 (M+H)⁺.

Step 9: Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9-hydroxy-l-isopropyl-5a,5b,8, 8,lla-pentamethyl-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb, 12,13,13a-octadecahydro-2H-cyclopenta[a Jchrysen -2 -one:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8, 8,l la-pentamethyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l, l la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 8, 0.6 g, 0.982 mmol, 1.0 eq) in MeOH (4 mL), THF (2 mL) and H₂0 (1 mL) at 0 °C was added NaOH (0.393 g, 9.82 mmol, 10.0 eq). The reaction mixture was allowed to stir at room temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (20 ml) and pH adjusted to 6.0 with IN HC1 and extracted with DCM (3x50 mL). The combined organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 40% EtOAc in hexane as an eluent to afford the title compound (0.5 g, yield: 89%) as a solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 11.71 (s, 1H), 7.74 (d, J = 7.5 Hz, 2H), 7.52 (s, 1H), 7.40-7.28 (m, 2H), 7.20-7.10 (m, 1H), 3.28-3.17 (m, 1H), 3.02-2.92 (m, 1H), 2.90-2.80 (m, 1H), 2.75- 2.65 (m, 1H), 2.32-2.25 (m, 2H), 2.18-2.02 (m, 1H), 2.02-1.0 (m, 21H), 0.94 (s, 3H), 0.86 (s, 3H), 0.76 (s, 3H), 0.73 (s, 3H), 0.62 (m, 4H); ESI-MS: m/z 591.38 (M+Na)⁺.

Step 10: Synthesis of 1 -benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b, 8,8,lla-pentamethyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,ll, lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclo butane -1,3 -dicarboxy late:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-hydroxy-l- isopropyl-5a,5b,8,8,l la-pentamethyl-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6,7,7a,8, 9,10,11,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (step 9, 0.6 g, 1.056 mmol, 1.0 eq) in toluene (10 mL) was added DMAP (0.256 g, 2.112 mmol, 2.0 eq) followed by (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic 2,4,6- trichlorobenzoic anhydride (prepared as described in WO 2013160810 A2, 0.695 g, 1.478 mmol, 1.4 eq). The reaction mixture was refluxed for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure, diluted with water (100 mL) and extracted with DCM (3x50 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the title compound (crude wt: 0.4 g) as a solid, which is used as such for next step without further purification. ESI-MS: m/z 813.47 (M+H)⁺.

Step 11: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-l-isopropyl-5a,5b, 8,8,lla-pentamethyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,ll, lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane-1 -carboxylic acid:

To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2- dimethylcyclobutane-l,3-dicarboxylate (step 10, 0.4 g, 0.492 mmol, 1.0 eq) in EtOAc (10 mL) and MeOH (10 mL) was added 10% Pd/C (0.3 g) followed by ammonium formate (0.155 g, 2.46 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for about 2 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with ethyl acetate (20 mL), filtered through celite pad and washed with ethyl acetate (200 mL). The combined filtrate was washed with water (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silicagel column chromatography by using 60% ethyl acetate in hexanes as an eluent to afford the title compound (150 mg, yield: 42%) as an off-white solid. 1H NMR (300 MHz, CD₃OD): δ ppm 7.68 (d, = 7.2 Hz, 2H), 7.41-7.20 (m, 4H), 4.47-4.39 (m, 1H), 3.23-3.20 (m, 1H), 3.10-2.98 (m, 1H), 2.86-2.73 (m, 3H), 2.53-2.40 (m, 2H), 2.38 (m, 1H), 2.30-1.90 (m, 5H), 1.85-1.22 (m, 21H), 1.19 (s, 3H), 1.07 (s, 3H), 1.01 (s, 3H), 0.95- 0.83 (m, 9H), 0.81 (m, 1H); ESI-MS: m/z 723.45 (M+H)⁺; HPLC: 91.3%.

Example 2: Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- chlorophenyl)-L3,4-oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo-3,3aA5, 5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H-cvclopentaralchrvsen-9-yl)oxy)

Step 1: Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(chlorocarbonyl)-l-isopropyl -5 a, 5b, 8, 8, 1 la-pentamethyl-2-oxo-3,3a,4, 5, 5 a, 5b, 6, 7,7a,8,9,10,ll,lla,llb,12,13,l 3 a -octa decahydro-2H-cyclopenta[a ]chrysen-9-yl acetate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l- isopropyl-5a,5b,8, 8,1 la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a -octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid (Example 1-step 6, 5.0 g, 9.76 mmol, 1.0 eq) in DCM (100 mL) at 0 °C was added oxalyl chloride (6.2 g, 48.8 mmol, 5.0 eq) and DMF (0.1 mL). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, followed by co- distilled with toluene (2x30 mL). The obtained crude compound (5.0 g) was used as such for next step without further purification.

Step 2: Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(hydrazinecarbonyl)-l- isopropyl-5a, 5b, 8, 8, 1 la-pentamethyl-2-oxo-3, 3 a, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,l 3, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(chlorocarbonyl)- l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 1, 5.0 g, 9.41 mmol, 1.0 eq) in DCM (25 mL) at 0 °C was slowly added hydrazine hydrate (0.945 g, 18.82 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for about 14 hours. The reaction mixture was evaporated under reduced pressure and diluted with water (50 mL). The precipitates formed were collected by filtration, washed with water (2x50 mL), followed by hexane (50 mL) and dried under vacuum to afford the title compound (2.0 g, yield: 40%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 4.50 (dd, = 9.9, 6.0 Hz, 1H), 3.30-3.15 (m, 1H), 2.80-2.50 (m, 2H), 2.40-2.10 (m, 2H), 2.07 (s, 3H), 2.10-1.0 (m, 25H), 1.0-0.80 (m, 13H); ESI-MS: m/z 549.46 (M+Na)⁺. Step 3: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(2-(4-chlorobenzoyl) hydrazine-l-carbonyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8, 9,10,ll,lla,llb,12,13,13 -octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:

To a stirred solution of 4-chlorobenzoic acid (0.593 g, 3.8 mmol, 1.0 eq) in DMF (20 mL) was added HATU (1.87 g, 4.94 mmol, 1.3 eq) followed by DIPEA (3.37 mL, 19.0 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for about 15 minutes, then (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(hydrazinecarbonyl)-l-isopropyl-

5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 2, 2.0 g, 3.8 mmol, 1.0 eq) was added and stirred at room temperature for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (60 mL) and extracted with ethyl acetate (2x20 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 30% ethyl acetate in hexane as an eluent to afford the title compound (2.0 g, yield: 80%) as an off-white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 8.59 (br.s., 1H), 7.90-7.70 (m, 2H), 7.50-7.40 (m, 2H), 4.53-4.45 (m, 1H), 3.29 (m, 1H), 3.10-3.0 (m, 1H), 2.84-2.78 (m, 1H), 2.73-2.53 (m, 1H), 2.43-2.20 (m, 1H), 2.05 (s, 3H), 1.99-1.0 (m, 25H), 1.0-0.77 (m, 13H).

Step 4: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4-chlorophenyl)-l,3,4- oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10, 11 ,11 a,l lb, 12,13,13a-octadecahydro-2H-cyclopenta[a] ' chrysen-9-yl acetate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(2-(4-chloro benzoyl)hydrazine-l-carbonyl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 3, 3.1 g, 4.6 mmol, 1.0 eq) in DCM (50 mL) was added TEA (1.93 mL, 13.8 mmol, 3.0 eq) followed by /?ara-toluene sulfonyl chloride (1.1 g, 5.98 mmol, 1.3 eq). The reaction mixture was stirred at room temperature for about 14 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (30 mL) and extracted with DCM (2x20 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 2% methanol in dichloromethane as an eluent to afford the title compound (1.1 g, yield: 37%) as an off-white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.93 (d, = 8.4 Hz, 2H), 7.49 (d, = 8.4 Hz, 2H), 4.48 (dd, = 10.8, 5.7 Hz, 1H), 3.35-3.25 (m, 1H), 2.84-2.75 (m, 2H), 2.64 (d, = 18.6 Hz, 1H), 2.41 (d, = 18.9 Hz, 1H), 2.24-2.10 (m, 1H), 2.05 (s, 3H), 2.0-1.03 (m, 21H), 1.01 (s, 3H), 0.96 (s, 3H), 0.89-0.78 (m, 10H); ESI-MS: m/z 669.36 (M+Na)⁺.

Step 5: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4-chlorophenyl)-l,3,4- oxadiazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b,8,8,lla-pentamethyl-3,3a,4,5,5a,5b,6, 7,7a,8,9,

10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chloro phenyl)-l,3,4-oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 4, 1.1 g, 1.7 mmol, 1.0 eq) in MeOH (10 mL), THF (5 mL), and H₂0 (2.5 mL) was added NaOH (0.68 g, 17.0 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (20 mL) and extracted with DCM. The combined organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 2% methanol in dichloromethane as an eluent to afford the title compound (0.41 g, yield: 40%) as a white solid. 1H NMR (300 MHz, CDCI₃): δ ppm 7.93 (d, = 8.7 Hz, 2H), 7.49 (d, = 8.4 Hz, 2H), 3.35-3.17 (m, 2H), 2.85-2.70 (m, 2H), 2.64 (d, = 18.6 Hz, 1H), 2.40 (d, = 18.9 Hz, 1H), 2.33-2.10 (m, 1H), 2.0-1.15 (m, 20H), 1.02-0.89 (m, 10H), 0.84 (s, 3H), 0.75 (s, 3H), 0.73-0.67 (m, 1H); ESI-MS: m/z 627.31 (M+Na)⁺. Step 6: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4- chlorophenyl)-l,3,4-oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chloro phenyl)-l,3,4-oxadiazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (step 5, 0.6 g, 0.99 mmol, 1.0 eq) in toluene (20 mL) was added (lS,3R)-3-((benzyloxy)carbonyl)- 2,2-dimethylcyclobutane-l-carboxylic 2,4,6-trichlorobenzoic anhydride (prepared as described in WO 2013160810 A2, 0.697 g, 1.49 mmol, 1.5 eq), followed by DMAP (0.241 g, 1.98 mmol, 2.0 eq). The reaction mixture was stirred and refluxed for about 24 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (20 mL) and extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 30% EtOAc in hexane as an eluent to afford the title compound (0.6 g, yield: 72%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.93 (d, = 8.4 Hz, 2H), 7.49 (d, = 8.7 Hz, 2H), 7.35 (m, 5H), 5.17-5.07 (m, 2H), 4.50-4.40 (m, 1H), 3.32-3.22 (m, 1H), 2.88-2.60 (m, 5H), 2.43-1.83 (m, 5H), 1.82-0.90 (m, 20H), 1.34 (s, 3H), 1.01 (s, 3H), 0.96 (s, 6H), 0.86 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.78 (m, 1H); ESI-MS: m/z 871.55 (M+Na)⁺.

Step 7: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(5-(4-chloro phenyl)-l,3,4-oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy) carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:

To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- chlorophenyl)-l,3,4-oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 6, 0.6 g, 0.7 mmol, 1.0 eq) in MeOH (10 niL), THF (5 niL) and H₂0 (5 niL) was added K₂C0₃ (0.586 g, 4.2 mmol, 6.0 eq). The reaction mixture was stirred at room temperature for about 24 hours. The reaction mixture was evaporated under reduced pressure, diluted with water and extracted with DCM. The combined organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 2% methanol in dichloromethane as an eluent to afford the title compound (0.12 g, yield: 24%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.93 (d, = 8.4 Hz, 2H), 7.49 (d, = 8.4 Hz, 2H), 4.46 (dd, = 11.1, 4.5 Hz, 1H), 3.37-3.23 (m, 1H), 2.88-2.50 (m, 5H), 2.41 (d, = 18.6 Hz, 1H), 2.22-1.85 (m, 4H), 1.82-1.17 (m, 20H), 1.37 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.90-0.77 (m, 10H); ESI-MS: m/z 781.47 (M+Na)⁺; HPLC: 99.8%.

Example 3: Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- chlorophenyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo-3,3aA5,5a, 5b,6,7 Ja,8,9J0J lJ laJ lbJ2J3 J3a-octadecahydro-2H-cyclopentaralchrysen-9-yl)oxy)

Step 1: Synthesis of 2-(4-chlorophenyl)-2-oxoethyl (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-

9-acetoxy-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla, llb,12,13,13a-octadecahydr -3aH-cyclopenta[a]chrysene-3a-carboxylate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a -octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid (Example 1-step 6, 13.0 g, 25.39 mmol, 1.0 eq) in DCM (1300 mL) was added DIPEA (13.15 mL, 76.17 mmol, 3.0 eq) followed by 2-bromo-l-(4-chlorophenyl)ethan-l-one (5.94 g, 25.39 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-20% ethyl acetate in hexane as an eluent to afford the title compound (10.0 g, yield: 59.2%) as an off-white solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 7.95 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 5.48 (s, 2H), 4.40 (dd, / = 11.1, 4.8 Hz, 1H), 3.26-3.15 (m, 1H), 2.89-2.80 (m, 1H), 2.64 (d, = 18.6 Hz, 1H), 2.42-2.32 (m, 1H), 2.25 (d, = 18.6 Hz, 1H), 2.0 (s, 3H), 1.99-1.11 (m, 22H), 1.03 (s, 3H), 0.92 (s, 3H), 0.88 (s, 3H), 0.84 (m, 1H), 0.80 (s, 6H); ESI-MS: m/z 687.32 (M+Na)⁺.

Step 2: Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(5-(4-chlorophenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b, 8,8,1 la-pentamethyl-2-oxo-3,3a,4, 5, 5a,5b,6,7, 7a,8,9, 10,11, lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:

To a stirred solution of 2-(4-chlorophenyl)-2-oxoethyl (3aR,5aR,5bR,7aR,9S,l laR, HbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9, 10,11,1 la,l lb, 12,13, 13a-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylate (step 1, 10.0 g, 15.0 mmol, 1.0 eq) in toluene (100 mL) was added ammonium acetate (11.57 g, 150.0 mmol, 10.0 eq). The reaction mixture was heated to reflux for about 48 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure and diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-30% ethyl acetate in hexane as an eluent to obtain the title compound (8.0 g, yield: 82.88%) as a white solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 11.78 (s, 1H), 7.77 (d, = 8.7 Hz, 2H), 7.59 (s, 1H), 7.38 (d, = 8.7 Hz, 2H), 4.37 (dd, = 10.5, 5.1 Hz, 1H), 3.27-3.18 (m, 1H), 2.85-2.75 (m, 1H), 2.70-2.65 (m, 1H), 2.32-2.25 (m, 1H), 2.23-2.05 (m, 1H), 2.05 (s, 3H), 1.98-1.87 (m, 2H), 1.82-1.0 (m, 20H), 0.95 (s, 3H), 0.90-0.74 (m, 13H); ESI-MS: m/z 667.36 (M+Na)⁺. Step 3: Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(5-(4-chlorophenyl)-lH- imidazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b,8,8,lla-pentamethyl-3,3a,4,5,5a,5b,6, 7,7a,8,9, 10,11,11 a,l lb, 12, 13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chloro phenyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 2, 8.0 g, 12.40 mmol, 1.0 eq) in MeOH (200 mL), THF (100 mL), and H₂0 (50 mL) was added NaOH (4.96 g, 124.0 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure and diluted with EtOAc. The organic layer was washed with water, dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-40% EtOAc in hexane as an eluent to obtain the title compound (7.0 g, yield: 94%) as a white solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 11.78 (s, 1H), 7.76 (d, = 8.4 Hz, 2H), 7.59 (s, 1H), 7.38 (d, = 8.4 Hz, 2H), 3.25-3.18 (m, 1H), 3.05-2.92 (m, 1H), 2.85-2.78 (m, 1H), 2.75-2.60 (m, 1H), 2.28 (m, 1H), 2.18-2.02 (m, 1H), 2.0-1.80 (m, 2H), 1.70-1.0 (m, 20H), 0.95 (s, 3H), 0.85 (s, 3H), 0.75 (s, 6H), 0.63 (m, 4H); ESI-MS: m/z 603.29 (M+H)⁺.

Step 4: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4- chlorophenyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) ( lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chloro phenyl)-lH-imidazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (step 3, 1.0 g, 1.658 mmol, 1.0 eq) in toluene (10 mL) at 0 °C was added DMAP (1.0 g, 8.29 mmol, 5.0 eq) followed by (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic 2,4,6-trichlorobenzoic anhydride (prepared as described in WO 2013160810 A2, 1.16 g, 2.487 mmol, 1.5 eq). The reaction mixture was warmed to room temperature and heated to reflux for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-25% ethyl acetate in hexane as an eluent to obtain the title compound (0.5 g, yield: 35.58%) as a white solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 11.78 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.59 (s, 1H), 7.40-7.35 (m, 7H), 5.11, 5.05 (ABq, JAB = 12.3 Hz, 2H), 4.38-4.31 (m, 1H), 3.30-3.15 (m, 1H), 2.98-2.90 (m, 1H), 2.88-2.77 (m, 2H), 2.77-2.60 (m, 2H), 2.40-2.30 (m, 2H), 2.22-1.98 (m, 2H), 1.98-1.0 (m, 27H), 0.95 (s, 3H), 0.88-0.70 (m, 13H).

Step 5: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,nbR,13aS)-3a-(5-(4-chloro phenyl)-lH midazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl) -2,2-dimethylcyclobutane-l-carboxylic acid:

To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- chlorophenyl)- lH-imidazol-2-yl)-l-isopropyl-5a,5b, 8,8,1 la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 4, 0.4 g, 0.472 mmol, 1.0 eq) in MeOH (4 mL), THF (2 mL), and H₂0 (2 mL) was added K₂C0₃ (1.3 g, 9.44 mmol, 20.0 eq). The reaction mixture was stirred at room temperature for about 48 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water, acidified with 2N HC1 up to pH~5 and extracted with 10% methanol in DCM. The combined organic extracts were washed with water, dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 0-5% methanol in dichloromethane as an eluent to obtain the title compound (0.1 g, yield: 28%) as a white solid. 1H NMR (300 MHz, CD₃OD): δ ppm 7.68 (d, = 8.4 Hz, 2H), 7.38-7.34 (m, 3H), 4.47- 4.39 (m, 1H), 3.03-2.95 (m, 1H), 2.88-2.73 (m, 3H), 2.53-2.42 (m, 1H), 2.36 (m, 2H), 2.15- 1.90 (m, 4H), 1.82-1.50 (m, 6H), 1.50-1.18 (m, 18H), 1.06 (s, 3H), 1.01 (s, 3H), 0.98-0.80 (m, 12H); ESI-MS: m/z 757.58 (M+H)⁺; HPLC: 90.7%.

Example 4: Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- fluorophenyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8 J la-pentamethyl-2-oxo-3,3aA5,5a, 5b,6,7 ,7a,8,9,10,l l,l la,l lbJ2J3 J3a-octadecahvdro-2H-cvclopentaralchrvsen-9-yl)oxy)

Step 1: Synthesis of 2-(4-fluorophenyl)-2-oxoethyl (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-9- acetoxy-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla, llb,12,13,13a-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylate:

stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a -octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid (Example 1-step 6, 8.0 g, 15.62 mmol, 1.0 eq) in DCM (80 mL) was added DIPEA (8.25 mL, 46.86 mmol, 3.0 eq) followed by 2-bromo-l-(4-fluorophenyl)ethan-l-one (3.72 g, 17.18 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for about 16 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (100 mL) and extracted with DCM (3x300 mL). The combined organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The crude compound was purified by silicagel column chromatography by using 30% EtOAc in hexane as an eluent to obtain the title compound (8.0 g, yield: 79%) as a solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.97-7.90 (m, 2H), 7.20-7.13 (m, 2H), 5.35, 5.21 (ABq, _AB = 16.2 Hz, 2H), 4.53-4.46 (m, 1H), 3.30-3.18 (m, 1H), 3.05-2.97 (m, 1H), 2.74 (d, = 18.9 Hz, 1H), 2.59- 2.50 (m, 1H), 2.21 (d, = 18.9 Hz, 1H), 2.1-2.0 (m, 2H), 2.05 (s, 3H), 2.0-1.0 (m, 20H), 1.14 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.87-0.80 (m, 7H); ESI-MS: m/z 671.49 (M+Na)⁺.

Step 2: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4-fluorophenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b, 8,8,1 la-pentamethyl-2-oxo-3,3a,4, 5, 5a,5b,6,7, 7a,8,9, 10,11, lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:

To a stirred solution of 2-(4-fluorophenyl)-2-oxoethyl (3aR,5aR,5bR,7aR,9S,l laR, HbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9, 10,11,1 la,l lb, 12,13, 13a-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxylate (step 1, 8.0 g, 12.34 mmol, 1.0 eq) in toluene (100 mL) was added ammonium acetate (9.5 g, 123.4 mmol, 10.0 eq). The reaction mixture was heated to reflux for about 30 hours. The reaction mixture was evaporated under reduced pressure, diluted with water and extracted with DCM (3x300 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 30% EtOAc in hexane as an eluent to obtain the title compound (2.62 g, yield: 33.8%) as a solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.71 (m, 2H), 7.18 (s, 1H), 7.12-7.03 (m, 2H), 4.47 (dd, = 10.5, 5.1 Hz, 1H), 3.35-3.22 (m, 1H), 3.02-2.92 (m, 1H), 2.65-2.55 (m, 1H), 2.51-2.36 (m, 1H), 2.35-2.17 (m, 1H), 2.05 (s, 3H), 2.10-1.90 (m, 3H), 1.82-0.90 (m, 22H), 0.90-0.78 (m, 13H); ESI-MS: m/z 629.44 (M+H)⁺.

Step 3: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4-fluorophenyl)-lH- imidazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b,8,8,lla-pentamethyl-3,3a,4,5,5a,5b,6, 7,7a,8,9, 10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-fluoro phenyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 2, 2.0 g, 3.18 mmol, 1.0 eq) in MeOH (20 mL), THF (10 mL), and H₂0 (5 mL) was added NaOH (1.91 g, 47.77 mmol, 15.0 eq). The reaction mixture was stirred at room temperature for about 6 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water and extracted with EtOAc (3x100 mL). The combined organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 40% EtOAc in hexane as an eluent to obtain the title compound (1.2 g, yield: 64%) as a solid.

Step 4: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4-fluoro phenyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2- dimethylcyclobutane- -dicarboxylate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-fluoro phenyl)-lH-imidazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-3,3a,4,5,5a,5b, 6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (step 3, 1.2 g, 2.04 mmol, 1.0 eq) in toluene (12 mL) was added DMAP (0.746 g, 6.12 mmol, 3.0 eq) followed by (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic 2,4,6- trichlorobenzoic anhydride (prepared as described in WO 2013160810 A2, 1.73 g, 3.68 mmol, 1.8 eq). The reaction mixture was heated to reflux for about 16 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water and extracted with DCM (3x100 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 40% EtOAc in hexane as an eluent to obtain the title compound (1.0 g, yield: 59%) as a solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.73-7.67 (m, 2H), 7.35 (m, 5H), 7.18 (s, 1H), 7.07 (t, J = 8.7 Hz, 2H), 5.15, 5.09 (ABq, AB = 12.6 Hz, 2H), 4.44 (dd, J = 11.1, 3.9 Hz, 1H), 3.32-3.22 (m, 1H), 2.90-2.72 (m, 3H), 2.72-2.58 (m, 2H), 2.58-2.12 (m, 2H), 2.12-1.90 (m, 4H), 1.77-1.02 (m, 22H), 0.99 (s, 3H), 0.96 (s, 3H), 0.92-0.77 (m, 13H); ESI-MS: m z 831.57 (M+H)⁺.

Step 5: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-(5-(4-fluoro phenyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl) -2,2-dimethylcyclo butane -1 -carboxylic acid:

To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- fluorophenyl)- lH-imidazol-2-yl)-l-isopropyl-5a,5b, 8, 8, l la-pentamethyl-2-oxo-3,3a,4, 5, 5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 4, 0.4 g, 0.48 mmol, 1.0 eq) in EtOAc (5 mL) and MeOH (5 mL) was added 10% Pd/C (0.2 g) followed by ammonium formate (0.152 g, 2.40 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for about 3 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with ethyl acetate (20 mL), filtered through celite pad and washed with ethyl acetate (200 mL). The filtrate was washed with water (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silicagel column chromatography by using 2-5% methanol in dichloromethane as an eluent to obtain the title compound (130 mg, yield: 36%) as an off- white solid. 1H NMR (300 MHz, CD₃OD): δ ppm 7.72-7.66 (m, 2H), 7.28 (s, 1H), 7.09 (t, = 8.7 Hz, 2H), 4.47-4.0 (m, 1H), 3.40-3.33 (m, 1H), 3.05-2.96 (m, 1H), 2.88-2.73 (m, 3H), 2.53-2.42 (m, 1H), 2.36 (m, 2H), 2.15-1.91 (m, 4H), 1.82-1.10 (m, 22H), 1.10-0.83 (m, 19H); ESI-MS: m/z 741.48 (M+H)⁺; HPLC: 98.2%.

Example 5: Preparation of (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- chlorophenyl)- 1 -(2-(dimethylamino)ethyl)- lH-imidazol-2-yl)- 1 -isopropyl-5a,5b,8,8 J la- pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadecahvdro-2H- cyclopentaralchrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:

Step 1: Synthesis of (3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(5-(4-chlorophenyl)-l-(2- (dimethylamino)ethyl)-lH midazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b,8,8 la^entamethyl- 3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen- 2-one:

To a stirred solution of 50% NaH (0.457 g, 9.948 mmol, 3.0 eq) in DMF (10 mL) was added (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chlorophenyl)-lH-imidazol-2-yl)-9- hydroxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12, 13,13a-octadecahydro-2H-cyclopenta[a]chrysen-2-one (Example 3-step 3, 2.0 g, 3.316 mmol, 1.0 eq) dissolved in DMF (10 mL), followed by 2-chloro-N,N-dimethylethan-l -amine hydrochloride (0.573 g, 3.98 mmol, 1.2 eq) was neutralized with TEA (0.57 mL, 3.98 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layer was washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 4% methanol in dichloromethane as an eluent to obtain the title compound (1.52 g, yield: 68%) as a solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 7.75 (d, = 8.4 Hz, 2H), 7.68 (s, 1H), 7.40 (d, = 8.4 Hz, 2H), 3.80-3.70 (m, 2H), 3.27-3.16 (m, 2H), 3.02-2.92 (m, 2H), 2.40-2.32 (m, 2H), 2.13 (s, 6H), 2.10-1.92 (m, 2H), 1.89-1.18 (m, 21H), 0.97 (m, 4H), 0.86 (m, 4H), 0.71 (s, 3H), 0.68 (s, 3H), 0.61 (s, 3H); ESI-MS: m/z 674.55 (M+H)⁺.

Step 2: Synthesis of 1-benzyl 3-((3aR,5aR,5bR, 7aR,9S,llaR,llbR,13aS)-3a-(5-(4-chloro phenyl)-l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3, 3 a, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H-cyclo penta[a] chrysen-9-yl) -2,2-dimethylcyclobutane-l,3-dicarboxylate:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chloro phenyl)- l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)-9-hydroxy-l-isopropyl-5a,5b, 8,8,1 la- pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclo penta[a]chrysen-2-one (step 1, 1.5 g, 2.22 mmol, 1.0 eq) in DCM (15 mL) at 0 °C was added triethyl amine (1.6 ml, 11.10 mmol, 5.0 eq), DMAP (0.135 g, 1.11 mmol, 0.5 eq), (lS,3R)-3- ((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (prepared as described in WO 2011007230 A2, 0.69 g, 2.66 mmol, 1.2 eq) and 2,4,6-trichlorobenzoyl chloride (0.5 mL, 3.10 mmol, 1.4 eq). The reaction mixture was removed from the ice bath and was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with DCM, washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 4% methanol in dichloromethane as an eluent to obtain the title compound (1.53 g, yield: 75%) as a solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 7.75 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H), 7.43-7.31 (m, 7H), 5.11, 5.05 (ABq, JAB = 12.3 Hz, 2H), 4.38-4.30 (m, 1H), 3.72-3.70 (m, 2H), 3.28-3.17 (m, 1H), 3.0-2.70 (m, 5H), 2.56 (m, 1H), 2.42-2.25 (m, 2H), 2.22-2.16 (m, 1H), 2.13 (s, 6H), 2.10-0.90 (m, 28H), 0.90-0.69 (m, 17H); ESI-MS: m/z 918.71 (M+H)⁺.

Step 3: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,nbR,13aS)-3a-(5-(4-chloro phenyl)-! -(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,lla-penta methyl-2-oxo-3, 3 a, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H-cyclo penta[a ]chrysen-9-yl )oxy )carbonyl)-2,2-dimethylcyclobutane-l -carboxylic acid:

To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4- chlorophenyl)-l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b, 8,8,1 la- pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 2, 1.5 g, 1.632 mmol, 1.0 eq) in MeOH (15 mL), THF (7 mL) and H₂0 (7 mL) was added K₂C0₃ (4.5 g, 32.64 mmol, 20.0 eq). The reaction mixture was stirred at room temperature for about 48 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, acidified with 2N HCl to pH~4.0 and extracted with 10% methanol in dichloromethane. The combined organic layer was washed with water, dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography, followed by recrystallization over acetonitrile gave the title compound (0.1 g, yield: 8%) as a white solid. 1H NMR (300 MHz, DMSO-d₆): δ ppm 12.1 (s, 1H), 7.75 (d, = 8.4 Hz, 2H), 7.68 (s, 1H), 7.40 (d, = 8.4 Hz, 2H), 4.37-4.30 (m, 1H), 3.82-3.68 (m, 2H), 3.27-3.17 (m, 1H), 3.02-2.92 (m, 1H), 2.83- 2.72 (m, 2H), 2.59-2.40 (m, 3H), 2.36-2.23 (m, 2H), 2.13 (s, 6H), 2.09-1.98 (m, 1H), 1.92- 1.78 (m, 2H), 1.68-1.05 (m, 24H), 0.99 (s, 3H), 0.90 (s, 3H), 0.89-0.73 (m, 10H), 0.69 (s, 3H).

Example 6: Preparation of Sodium (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- ((5-(4-chlorophenyl)-l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)methyl)-l-isopropyl-5a, 5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-octadeca hvdro-2H-cvclopentaralchrvsen-9-yl)oxy)carbonyl)-2,2-dimethylcvclobutane-l-carboxylate:

Step 1: Synthesis of 2-(4-chlorophenyl)-2-oxoethyl 2-((3aS,5aR,5bR, 7aR,9S,l laR,l lbR,l 3aS)

-9-acetoxy-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla, llb,12,13,13a-octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)acetate:

To a stirred solution of 2-((3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-9-acetoxy-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a -octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)acetic acid (prepared as described in WO 2013117137 Al, 3.0 g, 5.7 mmol, 1.0 eq) in DCM (40 mL) was added DIPEA (4.04 mL, 22.8 mmol, 4.0 eq), followed by 2-bromo-l-(4-chlorophenyl)ethan-l-one (1.59 g, 6.84 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3x60 mL). The combined organic extracts were washed with water (40 mL), dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 25- 30% EtOAc in hexane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (2.55 g, yield: 66%) as an off-white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.82 (d, = 8.7 Hz, 2H), 7.46 (d, = 8.4 Hz, 2H), 5.23 (s, 2H), 4.49 (dd, = 10.5, 6.0 Hz, 1H), 3.22-3.18 (m, 1H), 2.91 (dd, = 11.7, 3.6 Hz, 1H), 2.86-2.62 (m, 3H), 2.10 (d, = 19.2 Hz, 1H), 2.05 (s, 3H), 2.03-1.81 (m, 4H), 1.81-1.58 (m, 4H), 1.56-0.99 (m, 18H), 0.94 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.81 (m, 1H); ESI-MS: m/z 701.44 (M+Na)⁺.

Step 2: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-((5-(4-chlorophenyl)-lH- imidazol-2-yl)methyl)-l-isopropyl-5a,5b,8,8,lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8, 9,10,ll,lla,llb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate:

To a stirred solution of 2-(4-chlorophenyl)-2-oxoethyl 2-((3aS,5aR,5bR,7aR,9S,l laR, HbR,13aS)-9-acetoxy-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-2,3,4,5,5a,5b,6,7,7a,8,9, 10,11,1 la,l lb, 12,13, 13a-octadecahydro-3aH-cyclopenta[a]chrysen-3a-yl)acetate (step 1, 2.5 g, 3.68 mmol, 1.0 eq) in toluene (30 mL) was added Ammonium acetate (NH₄OAc) (5.67 g, 73.69 mmol, 20.0 eq). The reaction mixture was heated to reflux for about 36 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (50 mL) and extracted with ethyl acetate (3x75 mL). The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using 40-50% EtOAc in hexane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (1.0 g, yield: 41%) as an off-white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.58 (d, = 8.1 Hz, 2H), 7.30 (d, = 8.4 Hz, 2H), 7.09 (s, 1H), 4.50 (dd, = 10.2, 6.0 Hz, 1H), 3.20-3.09 (m, 2H), 3.04 (m, 2H), 2.55 (d, = 18.9 Hz, 1H), 2.18-2.10 (m, 1H), 2.06 (s, 3H), 2.0-1.85 (m, 3H), 1.84-1.71 (m, 2H), 1.71-1.62 (m, 3H), 1.61-1.0 (m, 18H), 0.95 (s, 6H), 0.89-0.81 (m, 7H); ESI-MS: m/z 659.47 (M+H)⁺.

Step 3: Synthesis of (3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-((5-(4-chlorophenyl)-lH- imidazol-2-yl)methyl)-9-hydroxy-l-isopropyl-5a,5b,8,8,lla-pentamethyl-3,3a,4,5,5a,5b,6, 7, 7a,8,9,10,ll,lla,llb,12,1 -octadecahydro-2H-cyclopenta[a]chrysen-2-one:

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((5-(4-chloro phenyl)-lH-imidazol-2-yl)methyl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a, 5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (step 2, 1.0 g, 1.51 mmol, 1.0 eq) in MeOH (10 mL), THF (5 mL) and H₂0 (2.5 mL) at 0 °C was added NaOH (1.21 g, 30.3 mmol, 20.0 eq). The reaction mixture was removed from the ice bath and was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (15 mL), and extracted with DCM (3x30 mL). The combined organic extracts were washed with water (10 mL), brine solution (5 mL), dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography by using 2-3% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (0.75 g, yield: 80.6%) as an off white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.58 (d, = 8.4 Hz, 2H), 7.32 (d, = 8.4 Hz, 2H), 7.12 (s, 1H), 3.28-3.21 (m, 1H), 3.20-3.0 (m, 4H), 2.58 (d, J = 18.9 Hz, 1H), 2.18-2.10 (m, 1H), 2.03-1.76 (m, 5H), 1.73-1.04 (m, 22H), 1.0 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.80 (s, 3H), 0.77-0.72 (m, 1H); ESI-MS: m/z 617.43 (M+H)⁺.

Step 4: Synthesis of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,l 3aS)-3a-((5-(4-chlorophenyl)-l -(2- (dimethylamino)ethyl)-lH midazol-2-yl)methyl)-9-hydroxy-1 sopropyl-5a,5b,8,8,lla-penta methyl-3, 3a,4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H-cyclopenta[a ] chrysen-2-one:

To a stirred suspension of 60% NaH (0.146 g, 3.64 mmol, 3.0 eq) in DMF (5 mL) at 0 °C under nitrogen atmosphere was added (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((5- (4-chlorophenyl)- lH-imidazol-2-yl)methyl)-9-hydroxy- l-isopropyl-5a,5b,8,8, 1 la-penta methyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a] chrysen-2-one (step 3, 0.75 g, 1.21 mmol, 1.0 eq) dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for about 30 minutes, then cooled to 0 °C and then added 2-chloro-N,N-dimethylethan- 1 -amine hydrochloride (0.209 g, 1.45 mmol, 1.2 eq) in TEA (0.2 mL, 1.45 mmol, 1.2 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride solution (5 mL), diluted with water (10 mL) and extracted with ethyl acetate (3x25 mL). The combined organic extracts were washed with water (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography by using 6-7% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (0.55 g, yield: 66%) as an off white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.63 (d, = 8.4 Hz, 2H), 7.28 (d, = 8.4 Hz, 2H), 7.11 (s, 1H), 3.93 (t, J = 6.9 Hz, 2H), 3.26-3.06 (m, 3H), 2.96-2.87 (m, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.52 (d, = 18.6 Hz, 1H), 2.27 (s, 6H), 2.22 (m, 1H), 2.10-1.83 (m, 5H), 1.83-1.16 (m, 17H), 1.05-0.96 (m, 10H), 0.92 (s, 3H), 0.80-0.72 (m, 4H); ESI-MS: m z 688.53 (M+H)⁺.

Step 5: Synthesis of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-((5-(4-chloro phenyl)-l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)methyl)-l-isopropyl-5a,5b,8,8 pentamethyl-2-oxo-3,3a,4,5,5a,5b,6, 7,7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro-2H- cyclopenta[a] chrysen- -yl) ( 1 R,3S )-2,2-dimethylcyclobutane-l ,3 -dicarboxylate :

To a stirred solution of (3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((5-(4-chloro phenyl)- l-(2-(dimethylamino)ethyl)- lH-imidazol-2-yl)methyl)-9-hydroxy- l-isopropyl-5a,5b, 8,8,1 la-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-2-one (step 4, 0.55 g, 0.8 mmol, 1.0 eq) in DCM (20 mL) at 0 °C was added triethyl amine (0.323 g, 3.2 mmol, 4.0 eq), DMAP (0.048 g, 0.4 mmol, 0.5 eq), (lS,3R)-3-((benzyloxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (prepared as described in WO 2011007230 A2, 0.314 g, 1.2 mmol, 1.5 eq) and 2,4,6-trichlorobenzoyl chloride (0.292 g, 1.2 mmol, 1.5 eq). The reaction mixture was removed from the ice bath and was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was evaporated under reduced pressure, diluted with water (5 mL) and extracted with DCM (3x10 mL). The combined organic extracts were washed with 0.5N HC1 (5 mL), water (5 mL) and brine solution (5 mL). The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography by using 2-3% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to obtain the title compound (0.5 g, yield: 67%) as an off-white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.63 (d, = 8.4 Hz, 2H), 7.38-7.33 (m, 5H), 7.28 (d, = 7.2 Hz, 2H), 7.11 (s, 1H), 5.15, 5.10 (ABq, 2H), 4.46 (dd, = 11.4, 4.8 Hz, 1H), 3.94 (t, = 6.9 Hz, 2H), 3.20-3.07 (m, 2H), 2.94 (m, 2H), 2.87-2.74 (m, 2H), 2.70-2.45 (m, 4H), 2.28 (s, 6H), 2.22 (m, 1H), 2.10-1.90 (m, 6H), 1.80- 1.04 (m, 21H), 1.04-0.90 (m, 12H), 0.88-0.80 (m,7H); ESI-MS: m/z 932.69 (M+H)⁺.

Step 6: Synthesis of (lR,3S)-3-((((3aR,5aR,5bR, 7aR,9S,llaR,nbR,13aS)-3a-((5-(4-chloro phenyl)-! -(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)methyl)-l-isopropyl-5a,5b,8,8,lla- pentamethyl-2-oxo-3, 3 a, 4, 5, 5 a, 5b, 6, 7, 7a,8,9,10,ll,lla,llb,12,13,l 3a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid:

To a stirred solution of 1-benzyl 3-((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((5- (4-chlorophenyl)-l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)methyl)-l-isopropyl-5a,5b,8, 8,1 la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro- 2H-cyclopenta[a]chrysen-9-yl) (lR,3S)-2,2-dimethylcyclobutane-l,3-dicarboxylate (step 5, 0.5 g, 0.53 mmol, 1.0 eq) in MeOH (10 mL) and THF (10 mL) was added aqueous 2.5N KOH solution (1.6 mL, 3.97 mmol, 7.5 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (3 mL), cooled to 0 °C, ptl adjusted to 6.0 with IN HC1 and extracted with DCM (3x10 mL). The combined organic extracts were washed with water (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography by using 4-5% methanol in dichloromethane gradient, followed by recrystallization over acetonitrile gave the title compound (0.250 g, yield: 55%) as an off white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.62 (d, = 8.4 Hz, 2H), 7.28 (d, = 7.2 Hz, 2H), 7.11 (s, 1H), 4.48 (dd, J = 11.4, 4.8 Hz, 1H), 4.04-3.96 (m, 2H), 3.20-3.06 (m, 2H), 2.95 (m, 2H), 2.83-2.73 (m, 2H), 2.73-2.65 (m, 2H), 2.63-2.55 (m, 1H), 2.44 (d, = 18.6, 1H), 2.33 (s, 6H), 2.29-2.21 (m, 1H), 2.12-1.97 (m, 5H), 1.84-1.15 (m, 19H), 1.37 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.92-0.81 (m,7H); ESI-MS: m/z 842.68 (M+H)⁺; HPLC: 91.8%.

Step 7: Synthesis of Sodium (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,llaR,llbR,13aS)-3a-((5-(4- chlorophenyl)-l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)methyl)-l-isopropyl-5a,5b,8,8, lla-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7, 7a,8,9,10,ll,lla,llb,12,13,13a-octadecahydro- 2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylate:

To a stirred solution of {IR^S ^ i^^^R ^^S ^^ VoR^aS ^ di-iiS- (4-chlorophenyl)-l-(2-(dimethylamino)ethyl)-lH-imidazol-2-yl)methyl)-l-isopropy

8,1 la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro- 2H-cyclopenta[(3]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid (step 6, 0.250 g, 0.296 mmol, 1.0 eq) in MeOH (4 mL) and water (0.1 mL) was added sodium hydroxide (0.0118 g, 0.296 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for about 2 hours and then distilled out 90% of methanol under reduced pressure. Hexane (5 mL) and ethyl acetate (5 mL) were added to the reaction mixture and stirred at room temperature for overnight. The reaction mixture was filtered, solid was washed with hexane (5 mL), followed by ethyl acetate (5 mL) and then dried under vacuum to obtain the title compound (150 mg, yield: 58.5%) as a white solid. 1H NMR (300 MHz, CDC1₃): δ ppm 7.62 (d, = 8.1 Hz, 2H), 7.25 (d, = 7.8 Hz, 2H), 7.10 (s, 1H), 4.40 (m, 1H), 3.98-3.85 (m, 2H), 3.20-3.02 (m, 2H), 2.99-2.75 (m, 2H), 2.70-2.41 (m, 5H), 2.24 (s, 6H), 2.32-2.15 (m, 2H), 2.10-1.50 (m, 10H), 1.45-1.10 (m, 17H), 1.10-0.97 (m, 19H); ESI-MS: m z 842.19 (M+H)⁺; HPLC: 96.93%; Na⁺ ion content by ion chromatography: 4.75%.

Although the present application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. For example, the following compounds are also included in the scope of the present application and can be prepared by procedure similar to the one described in above synthetic procedures with appropriate variations in reactants, quantities of reagents and reaction conditions.

acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(l-(2-(dimethylamino)ethyl)-5-(4-methoxyphenyl)-lH- imidazol-2-yl)- l-isopropyl-5a,5b,8,8, 1 la-pentamethyl-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9-

yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(5-(4-chlorophenyl)-l-(2-(methylamino)ethyl)-lH- imidazol-2-yl)- l-isopropyl-5a,5b,8,8, 1 la-pentamethyl-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-3a-(5-(4-(2-methoxyethoxy)phenyl)-lH-

— /° imidazol-2-yl)-5a,5b,8,8,l la-pentamethyl-2-oxo-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- (l-(2-(dimethylamino)ethyl)-5-(4-(2- methoxyethoxy)phenyl)- lH-imidazol-2-yl)- 1-isopropyl- 5a,5b,8,8,l la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(l-(2-aminoethyl)-5-(4-chlorophenyl)-lH-imidazol-2-yl)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3a-(5-(4-(((S)- tetrahydrofuran-3-yl)oxy)phenyl)-lH-imidazol-2-yl)-

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(l-(2-(dimethylamino)ethyl)-5-(4-(((S)-tetrahydrofuran-3- yl)oxy)phenyl)-lH-imidazol-2-yl)-l-isopropyl-

5a,5b,8,8,l la-pentamethyl-2-oxo-

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(5-(4-chloro-2-methoxyphenyl)-lH-imidazol-2-yl)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3a-(5-(4-(((R)- tetrahydrofuran-3-yl)oxy)phenyl)-lH-imidazol-2-yl)-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-

octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(l-(2-(dimethylamino)ethyl)-5-(4-(((R)-tetrahydrofuran-3- yl)oxy)phenyl)-lH-imidazol-2-yl)-l-isopropyl-

5a,5b,8,8,l la-pentamethyl-2-oxo-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-

octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- (5-(4-chloro-2-(2-(pyrrolidin- l-yl)ethoxy)phenyl)- 1H- imidazol-2-yl)- l-isopropyl-5a,5b,8,8, 1 la-pentamethyl-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(5-(4-chloro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- o octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(5-(4-chloro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- o octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- ((5-(4-chloro-2-methoxyphenyl)-l-(2- (dimethylamino)ethyl)-lH-imidazol-2-yl)methyl)-l-

0 isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3a-(5-phenyl- 1 ,3 ,4-oxadiazol-2-yl)-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9- o

yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

CI (5-(4-chlorobenzyl)-l,3,4-oxadiazol-2-yl)-l-isopropyl-

5a,5b,8,8,l la-pentamethyl-2-oxo-

yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(5-(lH-benzo[d]imidazol-2-yl)-l,3,4-oxadiazol-2-yl)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl)-l-isopropyl-

5a,5b,8,8,l la-pentamethyl-2-oxo-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-

0 octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-3a-(5-(5- methylpyrazin-2-yl)-l,3,4-oxadiazol-2-yl)-2-oxo-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a- octadecahydro-2H-cyclopenta[a]chrysen-9-

yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-

(5-(lH-benzo[d]imidazol-6-yl)-l,3,4-oxadiazol-2-yl)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-

yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- (5-(4-chloro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)- l,3,4-oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,l la- pentamethyl-2-oxo-

3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-3a-(5-(4-methoxyphenyl)-l,3,4-oxadiazol-2-yl)-

5a,5b,8,8,l la-pentamethyl-2-oxo-

yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- (5-(4-chloro-2-(2-(pyrrolidin-l-yl)ethoxy)phenyl)- 1,3,4- oxadiazol-2-yl) - 1 -isopropyl-5a,5b ,8 , 8,11 a-pentamethyl-2-

oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb,12,13, 13a- octadeca ydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- (5-(4-chloro-2-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)- l,3,4-oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,l la- pentamethyl-2-oxo-

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-3a-(5-(6- methylpyridin-3-yl)-l,3,4-oxadiazol-2-yl)-2-oxo-

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a- (5-(4-chloro-2-(2-(piperidin- 1 -yl)ethoxy)phenyl)- 1 ,3 ,4- oxadiazol-2-yl) - 1 -isopropyl-5a,5b ,8 , 8,11 a-pentamethyl-2- oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb,12,13,13a-

T octadecahydro-2H-cyclopenta[a]chrysen-9- yl)oxy)carbonyl)-2,2-dimethylcyclobutane- 1 -carboxylic acid

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l- isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3a-(5-

(pyrimidin-2-yl)-l,3,4-oxadiazol-2-yl)-

acid

PHARMACOLOGICAL ACTIVITY

The compounds described herein are tested for their antiviral activity following procedures known to a person of ordinary skill in the art. For example, the following protocols can be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention.

Example 7: Evaluation of compounds antiviral activity:

MT2 cells were infected with HIV-1 strain 92HT599 (15TCID 50/ 30000 cells). The infected cells were plated at the concentration of -30 000 cells per well in 96 well plate. Test compound was added to the micro plate in defined format with the final concentration of DMSO (vehicle) is not more than 1%. Assay was carried out with and without human serum/human serum albumin (HSA 45 mg/ml) for the serum shift. Incubation was carried out in C02 incubator for ~ 96 hours for viral infection. At the end of incubation period an aliquot from each well was taken for p24 estimation. The quantitation of p24 is an index for antiviral activity of the compound. Percent inhibition was calculated with reference to control values (vehicle controls).

P-24 estimation was carried out using Advance biosciences kit as per the procedure detailed by supplier. For 0% and 40% serum binding assay, wherein "A" refers to an IC₅₀ value of less than 10 nM, "B" refers to IC₅₀ value in range of 10.01-50 nM, and "C" refers to IC₅₀ values greater than 50 nM values are set forth in Table- 1.

Table- 1

References:

1. Antiviral methods and protocols (Eds: D Kinchington and R. F. Schinazi) Humana Press Inc., 2000.

2. HIV protocols (Eds: N. L. Michael and J. H. Kim) Humana Press Inc, 1999.

3. DAIDS Virology manual from HIV laboratories, Publication NIH-97-3838, 1997.

4. HIV-1 p24 antigen capture assay, enzyme immunoassay for detection of Human immunodeficiency Virus Type 1 (HIV-1) p24 in tissue culture media - Advanced bio science laboratories, Inc kit procedure.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

1. The compound of the formula (I)

unsubstituted cycloalkyl);

W is absent, NR₂ or CR₃R₄;

2. The compound according to claim 1, is a compound of the formula (IA):

wherein,

W is absent, NR₂ or CR₃R₄;

3. The compound according to claim 1, is a compound of the formula (IB):

wherein,

4. The compound according to claim 1, wherein Ri is

5. The compound according to claim 1, 2 and 4, wherein W is absent.

6. The compound according to claim 1-5, wherein Ring X is substituted or unsubstituted heteroaryl.

7. The compound according to claim 6, wherein heteroaryl is substituted or unsubstituted with one or more alkylaminoalkyl.

8. The compound according to claim 1-7, wherein Ring Y is substituted or unsubstituted aryl.

9. The compound according to claim 8, wherein aryl is substituted or unsubstituted with one or more halo.

10. A compound selected from the group consisting of:

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-l-isopropyl-5a,5b,8,8,l la- pentamethyl-2-oxo-3a-(5-phenyl-lH-imidazol-2-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l l,l la,l lb, 12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclo butane- 1-carboxylic acid,

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chlorophenyl)-l,3,4- oxadiazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10, 11, 11 a, l ib, 12, 13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2- dimethylcyclobutane- 1 -carboxylic acid,

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chlorophenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11, l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane- 1-carboxylic acid,

(lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-fluorophenyl)-lH- imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9, 10,11, l la,l lb,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethyl cyclobutane- 1-carboxylic acid, (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-(5-(4-chlorophenyl)-l-(2- (dimethylamino)ethyl)-lH-imidazol-2-yl)-l-isopropyl-5a,5b,8,8,l la-pentamethyl-2-oxo-3,3a, 4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylic acid, and Sodium (lR,3S)-3-((((3aR,5aR,5bR,7aR,9S,l laR,l lbR,13aS)-3a-((5-(4-chloro phenyl)- l-(2-(dimethylamino)ethyl)-lH-i^

pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,l 1,1 la,l lb, 12,13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)carbonyl)-2,2-dimethylcyclobutane-l-carboxylate, or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, prodrugs, or combination thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1-10 and at least one pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to claim 11, wherein the pharmaceutically acceptable excipient is a carrier or diluent.

13. A method for preventing, ameliorating or treating a viral mediated disease, disorder or syndrome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-10.

14. The method according to claim 13, wherein the viral mediated disease, disorder or syndrome is HIV infection, HBV infection, HCV infection, a retroviral infection genetically related to AIDS, respiratory disorders (including adult respiratory distress syndrome (ARDS)), inflammatory disease, or a combination thereof.

15. A method of treating HIV in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-10.

16. The method according to claim 13 and 15, wherein the subject is a mammal including human.

17. Use of a compound according to any of claims 1-10, in the manufacture of a medicament for the treatment of viral mediated diseases.