NOVEL C28-ANALOGUES WITH C3-MODIFICATIONS OF TRITERPENE

DERIVATIVES AS HIV INHIBITORS

This application claims the benefit of Indian provisional application no 4180/CHE/2015 filed on 11 ^th August 2015 which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel C28-analogues with C3 -modifications of triterpene 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. 1994, 57(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 2016/001820 disclosed novel betulinic proline imidazole derivatives as HIV inhibitors; WO 2015/198263 disclosed novel betulinic proline substituted derivatives as hiv inhibitors; WO 2014/105926 disclosed novel betulinic acid proline derivatives as HIV inhibitors; WO 2014/130810 disclosed C-3 alkyl and alkenyl modified betulinic acid derivatives useful in the treatment of HIV; WO 2014/123889 disclosed C-19 modified triterpenoids with HIV maturation inhibitory activity; WO 2013/160810 disclosed novel betulinic acid derivatives as HIV inhibitors; WO 2013/169578 disclosed C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity; WO 2013/123019 disclosed C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity; WO 2012/106190 disclosed C-17 and C-3 modified triterpenoids with HIV maturation inhibitory activity; WO 2012/106188 disclosed C-28 amines of C-3 modified betulinic acid derivatives as HIV maturation inhibitors; WO 2011/007230 disclosed lupeol-type triterpene derivatives as antivirals; WO 2011/153319 disclosed modified C-28 amides of modified C-3 betulinic acid derivatives as HIV maturation Inhibitors; WO 2011/153315 disclosed modified C-3 betulinic acid derivatives as HIV maturation inhibitors; WO 2009/100532 disclosed novel 17 β lupane derivatives as anti-HIV agents in an attempt to overcome gag polymorphism issues mentioned above. The patent publication WO 2008/057420 describes extended triterpene derivatives as antiretroviral agents; WO 2008/127364 describes preparation of antiviral compounds and use thereof; WO 2007/141390 describes preparation of betulin derived compounds as antiviral agents; WO 2007/002411 describes antiviral compounds; WO 2006/053255 describes novel betulin derivatives, preparation and use thereof; WO 2006/105356 describes methods of manufacturing bioactive 3-esters of betulinic aldehyde and betulinic acid; US 2004/0204389 describes anti-HIV agents with dual sites of action; Journal of Medicinal Chemistry (2010), 53(1), 178-190 describes structure-activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives; Bioorganic & Medicinal Chemistry Letters (2003), 13(20), 3549-3552 describes lupane triterpenes and derivatives with antiviral activity; Russian Journal of Bioorganic Chemistry (2003), 29(6), 594-600 describes synthesis and antiviral activity of ureides and carbamates of betulinic acid and its derivatives and Journal of Medicinal Chemistry (1996), 39(5), 1056-68 describes betulinic acid derivatives: A new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action.

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; 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

The present invention relates to the compounds of the formula (I):

Formula ₍ i ₎ wherein,

Ri can be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkadienyl, ° , substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl (preferably, pyridine, pyrazine, pyrimidine, oxazole or thiazole) or substituted or unsubstituted fused bicycle (wherein R can be hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl);

R ₂ can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aminoacid, substituted or unsubstituted alkoxy, or substituted or unsubstituted cycloalkyl;

X can be absent, O, S, CH ₂ or NR _a ; (wherein R _a can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or R _a with its nitrogen and adjacent carbon together to form N-contained heterocyclyl (preferably, pyrrolidine, piperidine, piperazine, or morpholine));

R ₃ and R ₄ can be independently selected from hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted aminoacid; and preferably amino acids are substituted by substituted or unsubstituted alkyl, phosphoric acid, or phosphorus prodrugs; or R ₃ and R ₄ can be taken together with the carbon atoms to which they are attached to form a bond or R ₃ and R ₄ can be taken together with the carbon atoms to which they are attached to form cycloalkyl or R ₃ and R ₄ can be taken together with the carbon atoms to which they are attached to form epoxide;

R5 can be hydrogen, C(0) ₂ R _c , or substituted or unsubstituted alkyl; (wherein R _c can be hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl);

R ₆ can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxylalkoxy, or substituted or unsubstituted cycloalkyl;

R ₇ can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;

Z can be absent, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl;

R ₇ and Z can be taken together with the N-atom to which they are attached to form substituted or unsubstituted N-linked heterocyclyl (preferably, azetidine, pyrrolidine, piperidine, piperazine);

R ₈ can be hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted alkoxy,-C(0)-NR _e R _f , or hydroxyalkyl; wherein the substituents can be substituted or unsubstituted aryl, heterocyclyl, alkoxylalkoxy, or aminoalkyl; R _e and R _f can be independently selected from hydrogen, substituted or unsubstituted alkyl; or R _e and R _f can be taken together with the N-atom to which they are attached to form substituted or unsubstituted N-linked heterocyclyl; wherein the substituent is alkyl;

Pharmaceutically acceptable salts of the compounds of the formula (I) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (I) are contemplated.

It should be understood that the formula (I) 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) structurally encompasses all tautomers.

Also contemplated are prodrugs of the compounds of the formula (I), including ester prodrugs.

According to one embodiment, there is provided a compound of formula (I), wherein Ri is benzoic acid.

According to other embodiment, there is provided a compound of formula (I), wherein 'X' is absent.

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₂ is hydrogen.

According to yet another embodiment, there is provided a compound of formula (I), when "X is absent, and R ₂ and R5 are hydrogen"; then R ₃ and R ₄ are taken together with carbon atoms to which they are attached to form a bond.

According to yet another embodiment, there is provided a compound of formula (I), when "X is absent, and R ₂ and R5 are hydrogen"; then R ₃ and R ₄ are taken together with carbon atoms to which they are attached form cycloalkyl (preferably cyclopropyl).

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₆ is hydrogen.

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₇ is hydrogen or alkyl (preferably methyl).

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

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

According to preceding embodiment, the said cycloalkyl is cyclobutyl substituted with one or more alkyl (preferably methyl). According to yet another embodiment, there is provided a compound of formula (I), wherein Z is substituted or unsubstituted cycloalkenyl (preferably, cyclopentenyl).

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₇ and Z are taken together with the N-atom to which they are attached to form substituted or unsubstituted N-linked heterocyclyl (preferably, pyrrolidine, piperidine, azetidine or piperazine).

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₈ is substituted or unsubstituted alkyl (preferably methyl or ethyl), when alkyl is substituted the substituents are aminoalkyl, or alkoxylalkoxy.

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₈ is hydroxylalkyl (preferably hydroxy methane or 1,3-dihydroxy propane).

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₈ is substituted or unsubstituted heteroaryl (preferably, imidazole) when heteroaryl is substituted the substituents are phenyl or 4-fluorophenyl.

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₈ is substituted or unsubstituted alkoxy, (preferably ethoxy); when substituted the substituents are morpholine, or methoxyethoxyl.

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₈ is substituted or unsubstituted heterocyclylalkyl (preferably, -CH ₂ -pyrrolidine or -C(CH ₃ ) ₂ -CH ₂ -piperidine).

According to yet another embodiment, there is provided a compound of formula (I), wherein R ₈ is -C(0)-NR _e R _f .

According to yet another embodiment, there is provided a compound of formula (I), wherein R _e and R _f are hydrogen or alkyl (preferably methyl or isopropyl).

According to yet another embodiment, there is provided a compound of formula (I), wherein R _e and R _f are taken together with the N-atom to which they are attached to form substituted or unsubstituted N-linked heterocyclyl.

According to preceding embodiment, the said N-linked heterocyclyl is substituted or unsubstituted piperidine, when substituted the substituent is alkyl (preferably ethyl).

In a further embodiment, there is provided a method for treating mammals infected with a virus, especially wherein said virus is HIV, comprising administering to said mammal an antiviral effective amount of a compound which is selected from the group of compounds of formula (I), and one or more pharmaceutically acceptable carriers, excipients or diluents. Optionally, the compound of formula (I) can be administered in combination with an antiviral effective amount of another AIDS treatment agent selected from the group consisting of: (a) an AIDS antiviral agent or (b) an anti-infective agent

Another embodiment of the present invention is a pharmaceutical composition comprising one or more compounds of formula (I), and one or more pharmaceutically acceptable carriers, excipients, and/or diluents; and optionally in combination with another AIDS treatment agent selected from the group consisting of: AIDS antiviral agent or anti- infective agent

In another embodiment of the present invention there is provided one or more methods for preparation of the compounds of formula (I).

In one further embodiment, the present invention also encompasses the method(s) of preparation of intermediates used in the preparation of compound of formula (I).

Below are the representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention (Nomenclature has been generated from

ChemBioDraw Ultra 13.0 version):

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)-3a-((S)-2-(5-phenyl-lH-imidazol-2-yl)pyrr olidine-l-carboxamido)-2,3,

3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9- yl)benzoic acid (Example 1);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)-3a-(4-(2-morpholinoethoxy)piperidine-l-ca rboxamido)-2,3,3a,4,5,5a,

5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoic acid (Example 2);

4-(( lR,3aS ,5aR,5bR,7aR, 11 aS , 1 IbR, 13aR, 13bR)-3a-(4-(2-(2-methoxyethoxy)ethoxy) piperidine-l-carboxamido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5, 5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoic acid (Example 3);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3,3-dimethylureido)-5a,5b,8,8, l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l 1,1 la,l lb, 12,13, 13a, 13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoic acid (Example 4);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S)-2,2-dimethyl-3- (piperidine-l-carbonyl)cyclobutyl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l -methyl cyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH- cyclopenta [a]chrysen-9-yl)benzoic acid (Example 5); 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-3a-(3- (2-methyl-l-(piperidin-l-yl)propan-2-yl)ureido)-l-(l-methylc yclopropyl)-2,3,3a,4,5,5a,5b,6, 7, 7a, 8, 11, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoic acid (Example 6);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)-3a-(3-methylureido)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l 1,1 la,l lb, 12,13, 13a, 13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoic acid (Example 7);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl) ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l, 1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoicac id (Example 8);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S)-3-(4-ethylpiperidine -l-carbonyl)-2,2-dimethylcyclobutyl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclo propyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl)benzoic acid (Example 9);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S)-3-(isopropyl carbamoyl)-2,2-dimethylcyclobutyl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclo propyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta [a]chrysen-9-yl)benzoic acid (Example 10);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S)-3-(dimethyl carbamoyl)-2,2-dimethylcyclobutyl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclo propyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta [a] chrysen-9-yl)benzoic acid (Example 11);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lS,4R)-4-(hydroxymethyl) cyclopent-2-en-l-yl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5, 5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoic acid (Example 12);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((S)-2-(4-(4-fluorophenyl)-lH- imidazol-2-yl)pyrrolidine- l-carboxamido)-5a,5b,8,8, 1 la-pentamethyl- 1 -( 1-methylcyclo propyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl)benzoic acid (Example 13);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-(l,3-dihydroxypropan-2- yl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l, 1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoicac id (Example

14) ;

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-hydroxyazetidine-l-carbox amido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l, 1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoicac id (Example

15) ;

4-(( lR,3aS ,5aR,5bR,7aR, 11 aS , 1 IbR, 13aR, 13bR)-3a-(4-(2-(2-methoxyethoxy)ethyl) piperazine-l-carboxamido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5, 5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoic acid (Example 16);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(4-(hydroxymethyl)piperidine-l- carboxamido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a, 8, 11, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoic acid (Example 17);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-l-(l- methylcyclopropyl)-3a-((S)-2-(pyrrolidin-l-ylmethyl)pyrrolid ine-l-carboxamido)-2,3,3a,4,5, 5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoic acid (Example 18);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-3a-((S)- 2-(5-phenyl- lH-imidazol-2-yl)pyrrolidine- 1 -carboxamido)- 1 -(prop- 1 -en-2-yl)-2,3 ,3 a,4,5,5a, 5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoic acid (Example 19);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-3a-(4- (2-morpholinoethoxy)piperidine-l-carboxamido)-l-(prop-l-en-2 -yl)-2,3,3a,4,5,5a,5b,6,7,7a, 8, 11, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoic acid (Example 20);

4-(( lR,3aS ,5aR,5bR,7aR, 11 aS , 1 IbR, 13aR, 13bR)-3a-(4-(2-(2-methoxyethoxy)ethoxy) piperidine-l-carboxamido)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6, 7, 7a, 8, 11, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl) benzoic acid (Example 21);

4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S)-2,2-dimethyl-3- (piperidine-l-carbonyl)cyclobutyl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)-2,3, 3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9- yl)benzoic acid (Example 22), or pharmaceutically acceptable salts, solvates, stereoisomers, including hydrates and prodrugs of compounds are also contemplated.

The present invention also provides a pharmaceutical composition that includes at least one compound as described herein 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 described herein. 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 cure that infection, specifically in the form of a pharmaceutical composition.

The 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 an 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel C28-analogues with C3-modifications of triterpene derivatives and related compounds, which may be used as antiviral particularly as anti-HIV compounds and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers of the derivatives, together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by viral infections, are also provided.

The following definitions apply to the terms as used herein:

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

The term "hydroxy alkyl" refers to any hydroxy derivative of an alkyl radical.

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.

An "alkenyl" group refers to an alkyl group, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond.

An "alkadienyl" group refers to an alkyl group, as defined herein, having at least two carbon-carbon double bonds.

The term "amino acid(s)" refers to a straight or branched hydrocarbon chain containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid and which is attached through the nitrogen atom of the amine group to the rest of the molecule by a single bond, e.g., alanine, valine, isoleucine, leucine, phenylalanine, or tyrosine.

The term "amino alkyl" refers to any amino derivative of an alkyl radical.

The term "cycloalkyl" denotes a non-aromatic mono or polycyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of polycyclic 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 "cycloalkenyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.

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 "epoxide" refers to cyclic ether with a three-membered ring. The basic structure of an epoxide contains an oxygen atom attached to two adjacent carbon atoms of a hydrocarbon.

The term "fused bicycle" refers to a fused ring (i.e., rings which share an adjacent pair of atoms) such as naphthyl and biphenyl.

The terms "heterocyclyl" and "heterocyclic ring" refer to a saturated 3-15 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 "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group 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.

"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.

The term "prodrug" means a compound that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate, or metabolite of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. 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 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). The term "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 stereo isomeric 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 stereo isomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereo isomeric 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 stereo specific 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 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, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

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, for example, capsules, tablets, aerosols, solutions, suspensions, liquids, gels, or products for topical application.

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 SCREENING

Antiviral HIV activity and cytotoxicity of compounds according to present invention can be measured in parallel by following the methods published in the literature.

The cytotoxic effect of compounds can be analyzed by measuring the proliferation of cells using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazlium bromide (MTT) staining. Cells (5 x 10 cells /well) will be incubated in in 96 well plates in the presence or absence of compounds. At the end of treatment, 20μ1 of MTT (5mg/ml in PBS) will be added to each well and incubated for an additional 4 hours at 37°C. The purple -blue MTT formazan precipitate will be dissolved in a triplex reagent containing 10% SDS, 5% isobutanol and 10 mmol/lit HC1. The activity of mitochondria, reflecting cellular growth and viability, will be evaluated by measuring the optical density at 570 nm on micro titer plate.

Action of compounds on replication of HIV in Sup-Tl cells can be determined by the method published by Roda Rani et al., 2006 (Archives of Biochemistry and Biophysics, Volume 456, Issue 1, 1 December 2006, Pages 79-92).

Briefly, lxlO ⁶ Sup-Tl cells with 100% cell viability will be seeded in RPMI 1640, 0.1% FBS four 12 well plates. Increasing concentrations of Epap-1 peptides will be added to the cells and will be infected with HIV1 93 I 101 each at final concentration of virus equivalent to 2 ng of p24 per ml. The infected cells will be incubated at 37 C and 5% C02 incubator for 2 hours. After 2hrs the cells will be pelleted at 350 g for 10 min, supernatant will be discarded and cell will be held with RPMI 1640 containing 10% FBS. The cells will be resuspended in the same medium with increasing concentrations of Epap-1 peptides and will be incubated for 96 hours. The cells will be supplemented with peptides at every 24 hours. The supernatants will be collected after 96 hours and analyzed using P24 antigen capture assay kit (SAIC Fredrick). The infection in the absence of Epap-1 will be considered to be 0% inhibition Azidothymidine (AZT) will be taken as positive control.

Action of compound on virus entry and quantification of virus entered can be done in terms of GFP expression by the following the methods published J. Virol. 72, 6988 (1998) by in Cecilia et al., and Analytical Biochemistry Volume 360, Issue 2, 15 January 2007, Pages 315-317 (Dyavar S. Ravi and Debashis Mitra).

Briefly, cells will be seeded in to wells of 24 well plates 1 day prior to the experiment. The cells will be transfected with Tat-reporter. The virus inoculum will be adjusted to 1,000- 4,000 TCID 50/ ml in assay medium (DMEM,10%FCS,glutamine and antibiotics), 50 μΐ aliquots will be incubated with serial dilutions of compounds (50 μΐ ) for lhr at 37°C. The reporter expression will be quantified at appropriate time calculated inhibitory doses referrers to the concentration of these agents in this preincubation mixture.

Other relevant references useful for screening antiviral HIV activity are: Averett,

D.R.1989. Anti-HIV compound assessment by two novel high capacity assays. J. Virol. Methods 23: 263-276; Schwartz, O., et al.1998; A rapid and simple colorimeric test fror the study of anti HIV agents. AIDS Res. and Human Retroviruses, 4(6):441-447; Daluge, S. M., et al. 1994. 5-Chloro-2',3'-deoxy-3'fluorouridine (935U83), a selective anti human immunodeficiency virus agent with an improved metabolic and toxicological profile; Antimicro. Agents and Chemotherapy, 38(7): 1590-1603; H.Mitsuya and S. Border, Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type lymphadenopathy-associated virus (HLTV-III/LAV) by 2,3'-dideoxynucleosides, Proc. Natl. Acad. Sci. USA,83, 1911-15(1986); Pennington et al., Peptides 1990; Meek T.D et al., Inhibition of HIV-1 protease in infected T-limphocytes by synthetic peptide analogues, Nature, 343, p90 (1990); Weislow et al., J. Natl. Cancer Inst. 81, 577-586, 1989; T. Mimoto et al ., J. Med. Chem., 42, 1789-1802, 1999; Uckun et al 1998, Antimicobial Agents and Chemotherapy 42:383; for P24 antigen assay Erice et al., 1993, Antimicrob. Ag. Chemotherapy 37: 385-383; Koyanagi et al., Int. J. Cancer, 36, 445-451, 1985; Balzarini et al. AIDS (1991), 5, 21-28; Connor et al., Journal of virology, 1996, 70, 5306-5311; Popik et al., Journal of virology, 2002, 76, 4709-4722; Harrigton et al., Journal of Virology Methods, 2000, 88, 111-115; Roos et al.,Virology 2000, 273, 307-315; Fedyuk N.V. et al; Problems of Virology 1992, (3)P135; Mosmann T, December 1983, Journal of immunological methods, 65 (1-2), 55-63 ; SPC Cole, cancer chemotherapy and Pharmacology, 1986, 17, 259-263.

METHODS OF TREATMENT

The present invention provides compounds and pharmaceutical compositions 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, HIV 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 can 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 Scheme- 1. 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.

In a further aspect, the compounds of the present invention 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. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as H ("D"), ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ 0, ¹⁷ 0, ¹⁸ 0, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ C1, ¹²³ I and ¹²⁵ I. Particular isotopes are -CD ₃ or -C(D ₂ )-. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

Compounds of the present invention can be synthesized from naturally occurring Betulinic acid or betulinal. 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.

Formula (j)

[where i ⁿ is benzoic acid & R ₆ is H]

Compounds of formula (I) (wherein, R ₂ , R , R ₄ , R ₅ , X, R ₇ , Rg and Z are same as defined above) can be prepared as described in Scheme 1. The C3 -acetyl compounds of formula 1 (prepared as described in our patent publication WO 2013/160810, P ] & P ₂ are protecting groups such as acetyl, benzyl or the like) can be deprotected to give the C3- hydroxy compounds of formula 2 in the presence of bases such as potassium carbonate (K ₂ C0 ₃ ), sodium carbonate (Na ₂ C0 ₃ ), lithium hydroxide (LiOH), cesium carbonate (Cs ₂ C0 ₃ ) or the like in the solvents such as methanol (MeOH), tetrahydrofuran (THF), acetone or the like. The C3-hydroxy compounds of formula 2 can be converted to give the C3-keto compounds of formula 3 in the presence of oxidising agents such as pyridinium chlorochromate (PCC), oxalyl chloride (COCl ₂ ), Dess-martin reagent or the like in the solvents such as dimethyl sulfoxide (DMSO), dichloromethane (DCM), tetrahydrofuran (THF), acetone or the like in presence of a weak base triethylamine (TEA), N,N- Dnsoprop lethyiarrnne (DIPEA) or the like. The C3-keto compounds of formula 3 can be converted to give the C3-triflate compounds of formula 4 in the presence of N-phenyl-O- ((trifluoromethyl)sulfonyl)-N-(((trifluoromethyl) sulfonyl) oxy)hydroxylamine or the like in the presence of a base such as potassium bis((ximeihylsilyl)amide (KHMDS) or the like in the solvents such as tetrahydrofuran (THF) or the like. The C3-triflate compounds of formula 4 can be converted to give the C3-aryl compounds of formula 6 accomplished via Suzuki coupling with the corresponding boronic acid compounds of formula 5 in the presence of palladium (Pd) catalyst in the solvents such as 1,4-dioxane, propanol, water or the like in presence of bases such as sodium carbonate (Na ₂ C0 ₃ ), potassium carbonate (K ₂ C0 ₃ ) or the like. The selective deprotection and protection of the ester compounds of formula 6 in the C- 28 position can be converted to give the C28-silylated compounds of formula 7 in the presence of tert-butyl dimethyl silane, palladium acetate (Pd(OAc) ₂ ) or the like in the solvents such as dichloromethane (DCM), tetrahydrofuran (THF) or the like in the presence of a weak base triethylamine (TEA) or the like. The C28-silylated compounds of formula 7 can be deprotected in the presence of tetra-n-butyl ammonium fluoride (TBAF) or the like in the solvents such as 1,4-dioxane or the like affords the corresponding C28-carboxylic acid compounds of formula 8 which is converted to the C28-isocyanato compounds of formula 9 in the presence of diphenyl phosphoryl azide or the like in the solvents such as 1,4-dioxane or the like in the presence of a weak base triethylamine (TEA) or the like. The C28-isocyanato compounds of formula 9 can be reacted with the amine compounds of formula 10 (as described in patent publication No's: WO 2014/105926, and WO 2013/160810) to provide the C-28 urea compounds of formula 11 in presence of a weak base triethylamine (TEA), N.N-diisopropyiethylarmne (DIPEA) or the like, in the solvents such as methanol (MeOH), tetrahydrofuran (THF), acetone or the like. The C3-benzoic ester compounds of formula 11 can be deprotected to give the final C3-acid compounds of formula (I) in the presence of a base such as lithium hydroxide (LiOH), lithium diisopropyl amide (LDA), potassium tert-butoxide (t-BuOK) or the like in the solvents such as tetrahydrofuran (THF), water or the like.

The abbreviations used in the entire specification may be summarized herein below with their particular meaning: DIPEA (Ν,Ν-Diisopropylethylamine); °C (degree Celsius); δ (delta); ppm (parts per million); % (percentage); DMSO-d ₆ (Deuterated DMSO); d (Doublet); dd (Doublet of doublet); EtOH (Ethanol); EtOAc (Ethyl acetate); g or gr (gram); H or H ₂ (Hydrogen); HC1 (Hydrochloric acid); h or hr. (Hours); HATU (0-(7-Azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluroniumhexafluoro phosphate); Hz (Hertz); HPLC (High- performance liquid chromatography); mmol (Milli mol); M (Molar); ml (Millilitre); mg (Milli gram); m (Multiplet); mm (Millimetre); MHz (Megahertz); ESI-MS (Electron spray Ionization Mass spectra); min (Minutes); mM (Milli molar); NaOH (Sodium hydroxide); N ₂ (Nitrogen); NMR (Nuclear magnetic resonance spectroscopy); S (Singlet); TEA (Triethyl amine); TLC (Thin Layer Chromatography); THF (Tetrahydrofuran); tert (Tertiary), t (Triplet); IC (Inhibitory concentration), nM (Nano molar); pH (Pouvoir hydrogen); (Boc) ₂ 0 (Di-tert-butyl dicarbonate); DCM (dichloromethane); DMF (Ν,Ν-dimethyl formamide); DMAP (4-(Dimethylamino)pyridine); eq (equivalent); Ltr or L (Liter); CDC1 ₃ (Deuterated chloroform); J (Coupling constant); AcOH (Acetic acid); ABq (AB quartet); K ₂ C0 ₃ (potassium carbonate); Cs ₂ C0 ₃ (Cesium carbonate); NaHC0 ₃ (Sodium bicarbonate); Na ₂ S0 ₄ (Sodium sulphate); MeOH (methanol); EDCI (l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide); HOBt (1-Hydroxybenzotriazole); brs (broad singlet); DCC (Ν,Ν'-dicyclohexylcarbodiimide); Pd/C (palladium in carbon) and Pd(OAc) ₂ (palladium 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 4-(( lR,3aS,5aR,5bR,7aR,l laS.l lbR,13aR,13bR)-5a,5b,8,8,l la- pentamethyl-l-(l-methylcvclopropyl)-3a-((S)-2-(5-phenyl-lH-i midazol-2-yl)pyrrolidine-l- carboxamido)-2,3,3aA5,5a,5b,6,7 Ja,8 J lJ laJ lbJ2J3 J3aJ3b-octadecahydro-lH-cyclo pentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of benzyl (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-9-hydroxy-5a,

5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)icosahydro- 3aH-cyclopenta[a]chrysene-3a- carboxylate:

To a stirred solution of benzyl (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9- acetoxy-5a,5b,8,8, 1 la-pentamethyl- l-(l-methylcyclopropyl)icosahydro-3aH-cyclopenta[a] chrysene-3a-carboxylate (prepared as described in WO 2013/160810 A2, 10 g, 16.6 mmol, 1.0 eq) in THF (100 ml) in Methanol (100 ml) was added potassium carbonate (16.0 g, 116.2 mmol, 7.0 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 filtered through a pad of celite and washed with CH ₂ CI ₂ . The filtrate was evaporated under reduced pressure and the crude was purified by column chromatography by using 30% ethylacetate and hexane as an eluent to afford the desired compound (9.0 g, 96.0%) as a white solid. H ¹ NMR (CDCI ₃ , 300 MHz): δ 7.33 (m, 5H), 5.13-5.02 (q, 2H), 3.20-3.17 (t, 1H), 2.26-2.22 (m, 1H), 2.10-1.99 (m, 1H), 1.93-1.73 (m, 3H), 1.72-1.60 (m, 5H), 1.48-1.44 (m, 3H), 1.40-1.16 (m, 9H), 1.10-1.06 (m, 2H), 0.96 (s, 6H), 0.89 (s, 4H), 0.81 (s, 3H), 0.75 (s, 6H), 0.69-0.66 (m, 1H), 0.40-0.30 (m, 2H) and 0.26-0.17 (m, 2H); Mass: [M+H] ⁺ 561.10 (100%).

Step 2: Synthesis of benzyl (lR,3aS,5aR,5bR, 7aR,llaR,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-l-(l-methylcyclopropyl)-9-oxoicosahydro-3aH-cycl openta[a]chrysene-3a- carboxylate:

Oxalyl chloride (2.02 mL, 24.10 mmol, 1.5 eq) was dissolved into DCM (40 mL), the resulting mixture was cooled to -78°C then added DMSO (3.4 mL, 48.2 mmol, 3.0 eq) in DCM (40 mL) under nitrogen atmosphere and stirred for about 45 minutes. Then added benzyl(lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la-penta methyl- l-(l-methylcyclopropyl)icosahydro-3aH-cyclopenta[a]chrysene- 3a-carboxylate (step 1, 9.0 g, 16.07 mmol, 1.0 eq) in DCM (100 mL) and the mixture was stirred for about 2 hours at -78°C. Triethylamine (11.18 mL, 80.35 mmol, 5.0 eq) was added into the mixture drop wise. The resulting mixture was stirred for about 1 hour at -78°C and about 2 hours at room temperature. The resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated. The crude was purified by column chromatography by using 10% ethylacetate and hexane as an eluent to afford the desired compound (7.0 g, 78.0%) as a white solid. H ¹ NMR (CDC1 ₃ , 300 MHz): δ 7.35-7.32 (m, 5H), 5.13-5.02 (q, 2H), 2.50-2.40 (m, 2H), 2.28 (d, 1H), 2.41-2.10 (m, 1H), 2.00-1.80 (m, 3H), 1.71-1.62 (m, 3H), 1.46-1.12 (m, 15H), 1.06 (s, 3H), 1.02 (s, 3H), 0.96 (s, 3H), 0.91-0.90 (m, 6H), 0.79 (s, 3H), 0.38-0.32 (m, 2H) and 0.31-0.20 (m, 2H); Mass: [M+H] ⁺ 558.20 (100%). Step 3: Synthesis of benzyl (lR,3aS,5aR,5bR, 7aR,llaR,llbR,13aR,13bR)-5a,5b,8, 8,11a- pentamethyl-1 -( 1 -methylcyclopropyl)-9-( ( ( trifluoromethyl )sulfonyl )oxy )-l,2, 3,4,5, 5a,5b, 6, 7, 7a,8, 11,11a,! lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxyla te:

The stirred solution of benzyl (lR,3aS,5aR,5bR,7aR,l laR,l lbR,13aR,13bR)-5a,5b, 8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-9-oxoicosahydro-3aH-c yclopenta[a]chrysene- 3a-carboxylate (step 2, 7.0 g, 12.54 mmol, 1.0 eq) in THF (50 mL) was added KHMDS (75 mL, 25.08 mmol, 2.0 eq) at -78°C under nitrogen atmosphere and stirred for about 30 minutes. Then added N-phenyl-Biss(trifluoromethane)sulfonamide (8.97 g, 37.63 mmol, 3.0 eq) in THF (20 mL) and stirred at same temperature for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with saturated NaCl solution and extracted with DCM. The organic layer was dried with Na ₂ S0 ₄ and concentrated at 30°C below water bath temperature. The crude was purified by column chromatography by using 2% ethylacetate and hexane as an eluent to afford the desired compound (6.0 g, 69.7%) as a white solid. H ¹ NMR (CDCI3, 300 MHz): δ 7.59-7.52 (m, 3H), 7.49 (d, 2H), 7.39-7.33 (m, 4H), 5.58 (d, 1H), 5.55-5.02 (q, 2H), 2.26-2.01 (m, 3H), 1.97-1.90 (m, 1H), 1.88-1.61 (m, 4H), 1.50-1.21 (m, 8H), 1.1 (s, 4H), 1.01 (s, 3H), 0.97 (s, 3H), 0.96-0.85 (m, 8H), 0.78 (s, 3H), 0.40-0.31 (m, 2H) and 0.27-0.19 (m, 2H); Mass: [M+H] ⁺ 690.29 (100%).

Step 4: Synthesis benzyl (lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-9-(4-(methoxy carbonyl)phenyl)-5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclop ropyl)-l,2,3,4,5,5a,5b,6, 7,7a, 8,ll,lla,llb,12,13,13a,13b-octadecahydro-3aH-cyclopenta[a]ch rysene-3a-carboxylate:

To stirred solution of benzyl (lR,3aS,5aR,5bR,7aR,l laR,l lbR,13aR,13bR)-5a,5b,8, 8,11 a-pentamethyl- 1 -( 1 -methylcyclopropyl)-9-(((trifluoromethyl)sulfonyl)oxy)- 1 ,2,3 ,4,5,5a, 5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene-3a- carboxylate (step 3, 2.5 g, 3.62 mmol, 1.0 eq ) in 1,4-dioxane (12.5 mL), 2-Propanol (12.5 mL) and water (7.5 mL) was added K ₃ P0 ₄ and 4-(methoxy carbonyl) benzene boronic acid (0.98 g, 5.43 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. Tetrakiss (triphenylphosphine) palladium (0.25 g, 0.2 mmole, 0.06 eq) was added under nitrogen atmosphere, the reaction mixture was heated to 90°C and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and washed with CH ₂ CI ₂ . The filtrate was evaporated under reduced pressure and the crude was purified by column chromatography by using 4% ethylacetate and hexane as an eluent to afford the desired product (1.0 g, 41.6%) as a white solid. H ¹ NMR (CDC1 ₃ , 300 MHz): δ 7.94 (d, 2H), 7.35 (s, 5H), 7.21 (d, 2H), 5.30 (d, 1H), 5.15-5.07 (q, 2H), 3.90 (s, 3H), 2.27-2.09 (m, 2H), 2.23-2.10 (m, 1H), 2.00 (bs, 1H), 1.83- 1.76 (m, 3H), 1.52-1.33 (m, 9H), 1.29-1.22 (m, 5H), 1.19-1.11 (m, 3H), 0.99-0.97 (m, 5H), 0.92-0.88 (m, 9H), 0.85-082 (m, 3H), 0.41-0.32 (m, 2H) and 0.27-0.18 (m, 2H); Mass: [M+H] ⁺ 676.19 (100%).

Step 5: Synthesis of tert-butyldimethylsilyl (lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-9- (4-(methoxycarbonyl)phenyl)-5a,5b,8,8,lla-pentamethyl-l-(l-m ethylcyclopropyl)-l,2,3,4,5, 5a,5b,6,7, 7a,8, 11,11a,! lb, 12,13, 13a,l 3b-octadecahydro-3aH-cyclopenta[a] chrysene-3a- carboxylate:

The stirred solution of benzyl (lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9-(4- (methoxycarbonyl)phenyl)-5a,5b, 8, 8, l la-pentamethyl-l-(l-methylcyclopropyl)- 1,2,3,4,5, 5a, 5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene-3a- carboxylate (step 4, 1.0 g, 1.47 mmol, 1.0 eq) in DCM (15 mL) was added triethylamine (0.32 mL, 2.35 mmol, 1.6 eq) and tert. butyl dimethylsilane (0.47 mL, 2.95 mmol, 2.0 eq) at room temperature under nitrogen atmosphere then Pd (OAc) ₂ (0.16 g, 7.35 mmol, 0.5 eq) was added to the reaction mixture, heated to 60°C and stirred for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and washed with CH ₂ C1 ₂ . The filtrate was evaporated under reduced pressure and the crude was dissolved in acetic acid (5.2 mL), THF (2.6 mL) and water (1.3 mL) and stirred for about 1 hour at room temperature. The solid was separated, filtered and washed with water to afford the desired product (1.0 g, 98.0%) as a white solid. H ¹ NMR (CDC1 ₃ , 300 MHz): δ 7.94 (d, 2H), 7.21 (d, 2H), 5.31 (d, 1H), 3.91 (s, 3H), 2.25-2.09 (m, 3H), 2.23-2.10 (m, 2H), 2.00 (bs, 1H), 1.83-1.76 (m, 1H), 1.68-1.63 (m, 2H), 1.56 (ds, 4H), 1.51-1.43 (m, 4), 1.36-1.25 (m, 8H), 1.01-0.85 (m, 28H), 0.40-0.31 (m, 2H), 0.26 (s, 6H) and 0.06 (s, 2H); Mass: [M+H] ⁺ 700.10 (100%).

Step 6: Synthesis of (lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-9-(4-(methoxycarbonyl) phenyl)-5a,5b,8,8,lla-pentamethyl-l-(l -methylcyclopropyl)-l,2,3,4,5,5a,5b,6, 7,7a,8,ll,lla, llb,12,13,13a,13b-octadecahydr -3aH-cyclopenta[a]chrysene-3a-carboxylic acid:

To a stirred solution of tert-butyldimethylsilyl(lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclo propyl)-l,2,3,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a] chrysene-3a-carboxylate (step 5, 1.0 g, 1.42 mmol, 1.0 eq) in 1,4-dioxane was added TBAF (1.04 mL, 2.85 mmol, 2.0 eq) at room temperature and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and stirred for about 30 minutes. The solid was separated, filtered and dried under vacuum to afford the desired product (0.7 g, 84.0%) as an off white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 11.93 (bs, 1H), 7.89 (d, 2H), 7.26 (d, 2H), 5.26 (d, 1H), 3.84 (s, 3H), 2.25-2.09 (m, 3H), 1.96 (bs, 1H), 1.78-1.58 (m, 5H), 1.51-1.33 (m, 5H), 1.29-1.12 (m, 6H), 0.99-0.94 (m, 9H), 0.89-0.85 (m, 12H), 0.34 (t, 2H) and 0.22 (t, 2H); Mass: [M+H] ⁺ 586.10 (100%).

Step 7: Synthesis of methyl 4-((lR,3aS, 5aR,5bR, 7aR,llaS, HbR,13aR,13bR)-3a-isocyanato- 5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5 ,5a,5b,6, 7,7a,8,ll,lla,llb,12, 13,13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoa te:

To a stirred solution of (lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9-(4-(methoxy carbonyl)phenyl)-5a,5b,8 ,8, 1 la-pentamethyl- 1 -( 1 -methylcyclopropyl)- 1 ,2,3 ,4,5, 5a,5b, 6,7,7a, 8, 11, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro-3 aH-cyclopenta[a] chry sene-3 a-carboxylic acid (step 6, 0.400 g, 0.68 mmol, 1.0 eq) in 1,4-dioxane (4.0 ml) then added Triethylamine (0.5 mL, 3.4 mmoles, 5.0 eq) at room temperature under nitrogen atmosphere followed by diphenylphosphoryl azide (0.5 mL, 2.04 mmol, 3.0 eq). The reaction mixture was heated to 100°C for about 3 hours. After completion of the reaction (monitored by TLC), solvent was evaporated in vacuo to produce the crude residue (0.397g, 100.0%) which is used as such for next step.

Step 8: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-l-(l-methylcyclopropyl)-3a-((S)-2-(5-phenyl-lH-i midazol-2-yl)pyrrolidine-l- carboxamido )-2,3,3a,4,5, 5 a, 5b,6,7, 7a,8,ll,lla,llb,12,13,13a,l 3b-octadecahydro-l H-cyclo penta[a]chrysen-9-yl)benzoate:

To a stirred solution of 5-phenyl-2-(pyrrolidin-2-yl)-lH-imidazole (prepared as described in WO 2014/105926 Al, 0.438 g, 2.04 mmol, 3.0 eq) in THF (5 mL) then added DIPEA (0.5. mL, 3.4 mmol, 5.0 eq) at room temperature, followed by methyl 4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl-l- (l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH -cyclopenta[a]chrysen-9-yl) benzoate (step 7, 0.397 g, 0.68 mmol, 5.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 35% ethyl acetate and hexane as an eluent to afford the desired compound (0.420 g, 77.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.16 (s, 1H), 7.90 (d, 2H), 7.82 (d, 2H), 7.61 (s, 1H), 7.45-7.14 (m, 5H), 5.29 (d, 1H), 4.70 (t, 1H), 4.41 (s, 1H), 3.85 (s, 3H), 3.57 (t, 1H), 3.44-3.38 (q, 1H), 2.43-2.23 (m, 3H), 2.21-2.13 (m, 1H), 2.03-1.98 (m, 3H), 1.81-1.77 (m, 2H), 1.69-1.61 (m, 3H), 1.53-1.33 (m, 3H), 1.25-1.15 (m, 10H), 1.08 (s, 3H), 1.08-0.66 (m, 14H), 0.66 (s, 3H), 0.28 (q, 1H), 0.09 (d, 1H), 0.23 (t, 1H) and 0.59 (t, 1H); Mass: [M+H] ⁺ 797.06 (100%).

Step 9: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla-penta methyl-l-(l -methylcyclopropyl)-3a-((S)-2-(5-phenyl-lH-imidazol-2-yl)pyr rolidine-l-carbox amido)-2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-oc tadecahydro-lH-cyclopenta [a]chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,

5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-3a-((S)-2-(5-phenyl-l H-imidazol-2-yl) pyrrolidine-l-carboxamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadeca hydro- lH-cyclopenta[a]chrysen-9-yl)benzoate (step 8, 0.420 g, 0.52 mmol, 1.0 eq) in 1,4- Dioxane (5 ml) and water (5 ml), Lithium hydroxide monohydried (0.154 mg, 3.68 mmol, 7.0 eq) was added at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give residue.

The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluted by 5% MeOH and DCM to afford the desired pure compound (0.108 g, 26.0 %) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.82 (s, 1H), 12.16 (s, 1H), 7.88-7.61 (m, 4H), 7.61 (s, 1H), 7.33-7.17 (m, 5H), 5.29 (d, 1H), 4.67 (s, 1H), 4.41 (s, 1H), 3.57 (t, 1H), 3.44-3.38 (q, 1H), 2.43-2.23 (m, 3H), 2.21-2.13 (m, 1H), 2.03-1.98 (m, 3H), 1.81-1.77 (m, 2H), 1.69-1.61 (m, 3H), 1.53-1.33 (m, 3H), 1.25-1.15 (m, 10H), 1.08 (s, 3H), 1.08-0.66 (m, 14H), 0.66 (s, 3H), 0.28 (q, 1H), 0.09 (d, 1H), 0.23 (t, 1H) and 0.59 (t, 1H); Mass: [M+H] ⁺ 783.15 (100%); HPLC: 95.00%.

Example 2: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)-3 a-(4-(2-morpholinoethoxy)piperidine- 1 -carboxamido) -2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cyclopentaral chrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-l-(l-methylcyclopropyl)-3a-(4-(2-morpholinoethox y)piperidine-l-carboxamido) -2, 3, 3 a, 4, 5, 5 a, 5b, 6,7, 7a,8,ll,lla,llb,12,13,l 3 a, 13b-octadecahydro-lH-cyclopenta[a ] chrysen-9-yl)benzoate:

To a stirred solution of 4-(2-(piperidin-4-yloxy)ethyl)morpholine (0.363 g, 1.70 mmol, 2.0 eq) in THF (10 mL) then DIPEA (0.70 mL, 4.26 mmol, 5.0 eq) was added at room temperature followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- isocyanato-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoate (Example 1 - step 7, 0.49 g, 0.85 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 5% methanol and DCM as an eluent to afford the desired compound (0.520 g, 76.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.89 (d, 2H), 7.26 (d, 2H), 5.27 (s, 1H), 4.80 (s, 1H), 3.84 (s, 3H), 3.68-3.53 (m, 10H), 2.94 (m, 5H), 2.45-2.40 (m, 10H), 2.14-2.02 (m, 3H), 1.75 (m, 3H), 1.43-1.23 (m, 12H), 1.03 (s, 3H), 0.97-0.89 (m, 16H), 0.45-0.34 (m, 2H) and 0.25 (t, 2H); Mass: [M+H] ⁺ 798.68 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla-penta methyl-1 -( 1 -methylcyclopropyl)-3a-(4-(2-morpholinoethoxy )piperidine-l -carboxamido )-2, 3, 3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9- yl)benzoic acid: To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a, 5b, 8,8,1 la-pentamethyl- 1-( l-methylcyclopropyl)-3a-(4-(2-morpholinoethoxy)piperidine- 1- carboxamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclo penta[a]chrysen-9-yl) benzoate (step 1, 0.520 g, 0.65 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.192 g, 4.56 mmol, 7.0 eq) at room temperature. Then the reaction mixture was heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction was evaporated directly under vacuum to give residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, recrystallized by ethylacetate to afford the desired pure compound (0.160 g, 31.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.78 (s, 1H), 7.87 (d, 2H), 7.22 (d, 2H), 5.26 (d, 1H), 4.80 (s, 1H), 3.65-3.50 (m, 8H), 2.98-2.80 (m, 3H), 2.45-2.31 (m, 6H), 2.16-1.98 (m, 3H), 1.75-1.70 (m, 4H), 1.48-1.39 (m, 10H), 1.30-1.07 (m, 7H), 1.04 (s, 3H), 0.97 (s, 8H), 0.90 (s, 9H), 0.83 (s, 1H), 0.45-0.32 (m, 2H) and 0.24 (d, 2H); Mass: [M+H] ⁺ 784.64 (100%); HPLC: 93.07%.

Example 3: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(4-(2-(2- methoxyethoxy)ethoxy)piperidine- l-carboxamido)-5a,5b,8,8 J la-pentamethyl- 1-(1 -methyl cvclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cvclo pentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(4-(2-(2- methoxyethoxy )ethoxy )piperidine-l -carboxamido )-5a,5b, 8, 8, 11 a-pentamethyl-1 -( 1 -methyl cyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclo penta[a] chrysen-9-yl)benzoat

To a stirred solution of 4-(2-(2-methoxyethoxy)ethoxy)piperidine (0.188 mL, 1.72 mmol, 2.0 eq) in THF (5 mL) then added DIPEA (0.76 mL, 4.3 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- isocyanato-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoate (Example 1 - step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue, which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 5% methanol and DCM as an eluent to afford the desired compound (0.41 g, 72.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.89 (d, 2H), 7.26 (d, 2H), 5.27 (d, 1H), 4.81 (s, 1H), 3.84 (s, 3H), 3.84-3.52 (m, 2H), 3.52-3.49 (m, 6H), 3.45-3.39 (m, 3H), 3.24 (s, 3H), 2.93-2.82 (m, 2H), 2.39-2.31 (m, 2H), 2.14-1.98 (m, 2H), 1.75-1.70 (m, 3H), 1.66-1.43 (m, 7H), 1.35-1.09 (m, 7H), 1.04 (s, 3H), 0.97 (s, 7H), 0.89 (s, 14H), 0.45-0.32 (m, 2H) and 0.25 (t, 2H); Mass: [M+H] ⁺ 787.19 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(4-(2-(2-methoxy ethoxy)ethoxy )piperidine-l -carboxamido )-5a, 5b, 8, 8, lla-pentamethyl-1 -( 1 -methylcyclo propyl ) -2, 3, 3 a, 4, 5, 5 a, 5b, 6, 7,7a,8,ll,lla,llb,12,13,l 3 a, 13b-octadecahydro-l H-cyclopenta [a]chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (4-(2-(2-methoxyethoxy)ethoxy)piperidine- 1 -carboxamido)-5a,5b,8,8, 11 a-pentamethyl- 1 -( 1 - methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)benzoate (step 1, 0.41 g, 0.60 mmol, 1.0 eq) in THF (4 ml) and water (4 ml) was added Lithium hydroxide monohydried (0.178 g, 4.25 mmol, 7.0 eq) at room temperature. Then the reaction mixture was heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, recrystallized by ethylacetate to afford the desired pure compound (0.300 g, 77.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.84 (s, 1H), 7.86 (d, 2H), 7.22 (d, 2H), 5.26 (d, 1H), 4.81 (s, 1H), 3.66-3.41 (m, 14H), 2.96-2.85 (m, 2H), 2.10 (t, 3H), 1.75 (m, 5H), 1.43-1.35 (m, 6H), 1.27-1.11 (m, 7H), 1.07-0.09 (m, 24H), 0.45-0.34 (m, 2H) and 0.33 (t, 2H); Mass: [M+H] ⁺ 773.59 (100%); HPLC: 96.93%. Example 4: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3,3- dimethylureido)-5a,5b,8,8 J la-pentamethyl-l-(l-methylcvclopropyl)-2,3,3a,4,5,5a,5b,6J,7 a,

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(3,3-dimethyl ureido)-5a,5b,8,8,lla-pentamethyl-l-(l -methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll, lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a]chrysen- 9-yl)benzoate:

To a stirred solution of dimethylamine (0.363 g, 1.70 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.70 mL, 4.26 mmol, 5.0 eq) at room temperature, followed by methyl 4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl-l- (l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH -cyclopenta[a]chrysen-9-yl)benzoate (Example 1-step 7, 0.49 g, 0.85 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue, which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 5% methanol and DCM as an eluent to afford the desired compound (0.520 g, 76.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.44 (d, 2H), 5.26 (d, 1H), 4.45 (s, 1H), 3.84 (s, 3H), 2.97 (s, 6H), 2.88-2.79 (m, 1H), 2.25- 1.99 (m, 4H), 1.80-1.52 (m, 4H), 1.47-1.35 (m, 11H), 1.35-1.21 (m, 5H), 1.19-1.00 (m, 8H), 0.99-0.92 (m, 8H), 0.44-0.31 (m, 2H) and 0.27-0.15 (m, 2H); Mass: [M+H] ⁺ 629.54 (100%). Step 2: Synthesis of 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(3,3-dimethyl ureido)-5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclopropyl)-2, 3,3a,4,5,5a,5b,6, 7,7a,8,ll, lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a]chrysen- 9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3,3-dimethylureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b, 6,7,7a,8, 11 , 1 la, 1 lb, 12, 13, 13a, 13b-octadecahydro- lH-cyclopenta[a]chrysen-9-yl)benzoate (step 1, 0.520 g, 0.65 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.192 g, 4.56 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN

HC1 (P was adjusted to 4). The obtained solid compound was separated, recrystallized by ethylacetate to afford the pure compound (0.160 g, 31.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.46 (s, 1H), 7.873 (d, 2H), 7.23 (d, 2H), 5.26 (d, 1H), 4.45 (s, 1H), 2.77 (s, 6H), 2.39-2.27 (m, 3H), 2.20-1.99 (m, 2H), 1.75-1.69 (m, 3H), 1.47-1.35 (m, 11H), 1.23-1.15 (m, 5H), 1.05 (s, 3H), 0.97 (s, 6H), 0.89 (s, 8H), 0.44-0.32 (0.32 (m, 2H) and 0.25 (m, 2H); Mass: [M+H] ⁺ 615.50 (100%); HPLC: 92.03%.

Example 5: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S)- 2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)ureido)-5a, 5b,8,8 J la-pentamethyl-l-(l- methylcvclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH- cvclopentaralchrvsen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)- 2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)ureido)-5a, 5b,8,8,lla-pentamethyl-l-(l- methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH- cyclopenta [a ]chrysen-9-yl)benzoate:

To a stirred solution of (lS,3R)-3-amino-2,2-dimethylcyclobutyl)(piperidin-l-yl) methanone (prepared as described in WO 2013/160810 A2, 0.36 g, 1.72 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.5 mL, 4.30 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la- pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a, 8,l 1,1 la,l lb, 12,13, 13a,13b- octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoate (Example 1-step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 10% methanol and DCM as an eluent to afford the desired compound (0.500 g, 73.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.26 (d, 2H), 5.99 (d, 1H), 5.26 (d, 2H), 3.84 (s, 3H), 3.84-3.56 (m, 2H), 2.89 (t, 1H), 2.27-1.95 (m, 5H), 1.75-1.70 (m, 4H), 1.52-1.28 (m, 12H), 1.23-1.20 (m, 13H), 1.11 (s, 3H), 1.04 (d, 7H), 0.95 (s, 10H), 0.68 (s, 4H), 0.40-0.38 (m, 2H) and 0.27 (bs, 2H); Mass: [M+H] ⁺ 794.69 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)ureido)-5a,5b,8 ,8,lla-pentamethyl-l-(l -methyl cyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclo penta[a] chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-((lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutyl )ureido)-5a,5b,8,8,l la-penta methyl- l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octa decahydro-lH-cyclopenta [a]chrysen-9-yl)benzoate (step 1, 0.500 g, 0.63 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.185 g, 4.41 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give residue. The residue was diluted with water and acidified with IN HCl (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluting with 10% methanol and DCM to afford the desired pure compound (0.120 g, 24.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.72 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.97 (d, 1H), 5.26 (d, 2H), 3.84-3.56 (m, 2H), 2.89 (t, 1H), 2.27-1.95 (m, 5H), 1.75-1.70 (m, 4H), 1.52-1.28 (m, 12H), 1.23-1.20 (m, 13H), 1.11 (s, 3H), 1.04 (d, 7H), 0.95 (s, 10H), 0.68 (s, 4H), 0.40-0.38 (m, 2H) and 0.27 (bs, 2H); Mass: [M+H] ⁺ 780.65 (100%); HPLC: 89.27%.

Example 6: Preparation of 4-((lR.3aS.5aR.5bR.7aR.l laS.l lbR.13aR.13bR)-5a.5b.8.8.11a- pentamethyl-3a-(3-(2-methyl- 1 -(piperidin- 1 - yl)propan-2- vPureido)- 1 -( 1 -methylcyclopropyl)- 2,3,3a,4,5,5a,5b,6,7 Ja,8 J lJ laJ lbJ2J3 J3aJ3b-octadecahvdro-lH-cvclopentaralchrysen-

Synthesis of l-(2-methyl-2-nitropropyl)piperidine:

To the stirred solution of piperidine (3 g, 35.2 mmol, 1.0 eq), 2-nitropropane (3.2 g, 38.81 mmol, 1.1 eq) are cooled with ice bath then added formaldehyde (37%) (2.5 g, 84.48 mmol, 2.4 eq) and NaOH solution (1.3 mL, 0.5 mol/L) are slowly added dropwise at 10°C. Then the reaction mixture was stirred for about 1 hour at 25°C and about 1 hour at 50°C. TLC indicated starting material was consumed and the desired product was observed. The solution is treated with water, ether and aqueous phase is extracted with water. The combined organic phase is dried over NaS04 and combined with HCl in dioxane (30 mL). The precipitate formed which was filtered and dried in vacuum to afford the desired product (4.0 g, yield: 61.0%) as a white solid. H ¹ NMR (CD ₃ OD, 300 MHz): δ 2.60 (m, 4H), 2.44 (s, 2H), 1.66-1.58 (m, 4H) and 1.42-1.35 (m, 8H); Mass: [M] ⁺ 187.21 (100%).

Step 2: Synthesis of 2-methyl-l -(piperidi -l -yl)propan-2-amine:

To the stirred solution of l-(2-methyl-2-nitropropyl)piperidine (step 1, 4 g, 25.64 mmol, 1.0 eq) in Methanol (100 mL) then added Raney Nickel (2 g, 35.89 mmol, 1.4 eq) and treated with hydrogen (50 psi) at room temperature for about 1 hour. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through celite bed and filtrate was concentrated to afford the desired product (3.3 g, yield: 100%) as a white powder. H ¹ NMR (CD ₃ OD, 300 MHz): δ 7.84 (s, 2H), 2.60 (m, 4H), 2.44 (s, 2H), 1.66-1.58 (m, 4H) and 1.42-1.35 (m, 8H); Mass: [M] ⁺ 157.10 (100%).

Step 3: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-3a-( 3 -(2-methyl-l -(piperidin-l -yl)propan-2-yl)ureido)-l-(l -methylcyclopropyl)- 2,3,3a,4, 5, 5 a, 5b, 6, 7,7a,8,ll,lla,llb,12,13,13a,l 3b-octadecahydro - 1 H-cyclopenta[a ] chrysen-9-yl)benzoate:

To a stirred solution of 2-methyl-l-(piperidin-l-yl)propan-2-amine (step 2, 0.55 g, 2.58 mmol, 3.0 eq) in THF (10 mL) then added DIPEA (0.75 mL, 4.30 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- isocyanato-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoate (Example 1 - step 7, 0.49 g, 0.85 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 50% ethylacetate and hexane as an eluent to afford the desired compound (0.400 g, 64.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.26 (d, 2H), 5.26 (d, 1H), 3.84 (s, 3H), 3.32 (s, 9H), 3.27-3.15 (m, 3H), 2.41-2.99 (m, 5H), 1.81-1.69 (m, 3H), 1.50-1.42 (m, 14H), (m, 7H), 1.04 (s, 3H), 0.97 (s, 7H), 0.89 (s, 10H), 0.45-0.32 (m, 2H) and 0.24-0.22 (m, 2H); Mass: [M+H] ⁺ 740.54 (100%).

Step 4: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla-penta methyl-3a-(3-(2-methyl-l-(piperidin-l-yl)propan-2-yl)ureido) -l-(l-methylcyclopropy

3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9- yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a, 5b,8,8,l la-pentamethyl-3a-(3-(2-methyl-l-(piperidin-l-yl)propan-2-yl )ureido)-l-(l-methyl cyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclo penta[a]chrysen-9-yl)benzoate (step 3, 0.400 g, 0.55 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.162 g, 3.86 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column using 5% methanol and DCM to afford the desired pure compound (0.100 g, 25.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.83 (bs, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.26 (d, 1H), 4.72 (s, 1H), 4.12 (q, 1H), 3.25-3.16 (m, 5H), 2.44-2.32 (m, 3H), 2.16-1.98 (m, 3H), 1.74-1.69 (m, 4H), 1.50-1.49 (m, 16H), 1.23-1.11 (m, 7H), 1.04 (s, 3H), 0.97 (s, 7H), 0.89 (s, 10H), 0.45-0.32 (m, 2H) and 0.24-0.22 (m, 2H); Mass: [M+H] ⁺ 725.50 (100%); HPLC: 90.62%.

Example 7: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la- pentamethyl-l-(l-methylcyclopropyl)-3a-(3-methylureido)-2,3, 3a,4,5,5a,5b,6J,7a,8 ,11,11a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-c vclopentaral chrysen-9- vDbenzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-l-(l-methylcyclopropyl)-3a-(3-methylureido)-2,3, 3a,4,5,5a,5b,6, 7,7a,8,ll,lla, lib, 12, 13,13 a, 13b-octadecahydr -lH-cyclopenta[a ] chrysen-9 -yl )benzoate:

To a stirred solution of methanamine (0.053 g, 1.71 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.7 mL, 4.2 mmol, 5.0 eq) at room temperature followed by methyl 4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl-l- (l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH -cyclopenta[a]chrysen-9-yl)benzoate (Example 1-step 7, 0.500 g, 0.85 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 25% ethylacetate and hexane as an eluent to afford the desired compound (0.450 g, 85.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.43 (d, 2H), 7.25 (d, 2H), 5.75 (d, 1H), 5.23 (s, 2H), 4.04 (s, 3H), 2.17-1.99 (m, 4H), 1.74-1.69 (m, 4H), 1.51-1.37 (m, 11H), 1.27-1.12 (m, 6H), 1.03- (s, 3H), 0.97-0.95 (m, 6H), 0.89 (m, 10H), 0.39- 0.37 (m, 2H) and 0.26-0.22 (m, 2H); Mass: [M+H] ⁺ 615.11 (100%). Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla-penta methyl-l-(l -methylcyclopropyl)-3a-(3-methylureido)-2,3,3a,4,5,5a,5b,6,7 , 7a,8,ll,lla,llb, 12,13,13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)ben zoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a, 5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-3a-(3-methylureido)-2 ,3,3a,4,5,5a,5b,6,7, 7a,8, 11, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoate (step 1, 0.450 g, 0.73 mmol, 1.0 eq) in THF (10 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.215 g, 5.11 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid was separated, filtered and washed with diethyl ether to afford the desired pure compound (0.300 g, 68.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.81 (s, 1H), 7.80 (d, 2H), 7.10 (d, 2H), 5.75 (d, 1H), 5.23 (s, 2H), 2.17-1.99 (m, 4H), 1.74-1.69 (m, 4H), 1.51-1.37 (m, 11H), 1.27-1.12 (m, 6H), 1.03 (s, 3H), 0.97-0.95 (m, 6H), 0.89 (m, 10H), 0.39-0.37 (m, 2H) and 0.26-0.22 (m, 2H); Mass: [M+H] ⁺ 601.52 (100%); HPLC: 97.72%.

Example 8: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-(2- (dimethylamino)ethyl)ureido)-5a,5b,8,8 J la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4, 5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cvclopentaralchrvsen-9-yl) benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-(2- ( dimethylamino )ethyl )ureido )-5a,5b, 8, 8, lla-pentamethyl-1 -( 1 -methylcyclopropyl)-2,3, 3a,4, 5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9-yl) benzoate:

To a stirred solution of Nl,Nl-dimethylethane-l,2-diamine (0.188 niL, 1.72 mmol,

2.0 eq) in THF (5 niL) then added DIPEA (0.76 niL, 4.3 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,

8.1 la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l 1,1 la,l lb, 12,13, 13a, 13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (Example 1-step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 5% methanol and DCM as an eluent to afford the desired compound (0.41 g, 72.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.87 (d, 2H), 7.23 (d, 2H), 5.89 (t, 1H), 5.40 (s, 1H), 5.26 (d, 1H), 5.25 (d, 1H), 3.84 (s, 3H), 3.06 (q, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 2.10 (d, 1H), 1.99 (d, 2H), 1.75 (m, 3H), 1.51 (m, 6H), 1.36-1.12 (m, 9H), 1.03 (s, 3H), 0.97 (d, 6H), 0.88-0.81 (m, 10H), 0.38 (d, 2H) and 0.26 (d, 2H); Mass: [M+H] ⁺ 672.58 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-(2-(dimethyl amino)ethyl)ureido)-5a,5b,8,8,lla-pentamethyl-l-(l -methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3, 3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9- yl) benzoate (step 1, 0.41 g, 0.60 mmol, 1.0 eq) in THF (4 ml) and water (4 ml) was added Lithium hydroxide monohydried (0.178 g, 4.25 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN

HC1 (P was adjusted to 4). The obtained solid compound was separated, recrystallized by ethylacetate to afford the desired pure compound (0.300 g, 77.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.78 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.89 (t, 1H), 5.40 (s, 1H), 5.26 (d, 1H), 5.25 (d, 1H), 3.06 (q, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 2.10 (d, 1H), 1.99 (d, 2H), 1.75 (m, 3H), 1.51 (m, 6H), 1.36-1.12 (m, 10H), 1.03 (s, 3H), 0.97 (d, 6H), 0.88-0.81 (m, 10H), 0.38 (d, 2H) and 0.26 (d, 2H); Mass: [M+H] ⁺ 658.54 (100%); HPLC: 98.07%.

Example 9: Preparation of 4-((lR.3aS.5aR.5bR.7aR.l laS.l lbR.13aR.13bR)-3a-(3-((lR.3S)- 3-(4-ethylpiperidine-l-carbonyl)-2,2-dimethylcvclobutyl)urei do)-5a,5b,8,8 J la-pentamethyl- l-(l-methylcvclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro- lH-cyclopentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)- 3-(4-ethylpiperidine-l-carbonyl)-2,2-dimethylcyclobutyl)urei do)-5a,5b,8,8,lla-pentamethyl- l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro- lH-cyclopenta[a]chrysen-9-yl)benzoate:

To a stirred solution of ((lS,3R)-3-amino-2,2-dimethylcyclobutyl)(4-ethylpiperidin-l- yl)methanone (prepared as described in WO 2013/160810 A2, 0.40 g, 1.72 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.75 mL, 4.30 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8, 8,1 la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l 1,1 la,l lb, 12,13, 13a, 13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoate (Example 1-step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 30% ethylacetate and Hexane as an eluent to afford the desired compound (0.400 g, 57.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.70 (d, 2H), 6.00 (d, 1H), 5.24 (d, 2H), 4.45 (t, 2H), 3.84 (s, 3H), 3.79-2.90 (m, 2H), 2.91 (t, 2H), 2.22-2.06 (m, 3H), 2.03 (t, 2H), 1.75-1.70 (m, 5H), 1.52-1.34 (m, 9H), 1.21 (s, 12H), 1.03-0.83 (m, 25H), 0.69 (d, 3H), 0.40 (d, 2H) and 0.27 (bs, 2H); Mass: [M+H] ⁺ 821.64 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)-3 -(4- ethyl piperidine-l-carbonyl)-2,2-dimethylcyclobutyl)ureido)-5a,5b, 8,8,lla-pentamethyl-l-(l- methyl cyclopropyl ) -2, 3, 3a,4, 5, 5 a, 5b, 6,7, 7a,8,ll,lla,llb,12,13,l 3a, 13b-octadecahydro-lH- cyclopenta [a]chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-((lR,3S)-3-(4-ethylpiperidine-l-carbonyl)-2,2-dimethylcyc lobutyl)ureido)-5a,5b, 8,8,1 la- pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a, 8,l 1,1 la,l lb, 12,13, 13a,13b- octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (step 1, 0.400 g, 0.49 mmol, 1.0 eq) in THF (10 ml) and water (10 ml) was added Lithium hydroxide monohydried (0.145 g, 3.46 mmol, 7.0 eq) at room temperature. Then the reaction mixture was heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluting with 3% methanol and DCM to afford the desired pure compound (0.150 g, 38.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.86 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 6.00 (d, 1H), 5.24 (d, 2H), 4.45 (t, 2H), 3.84-3.68 (m, 2H), 2.91 (t, 2H), 2.22-2.06 (m, 3H), 2.03 (t, 2H), 1.75-1.70 (m, 5H), 1.52-1.34 (m, 9H), 1.21 (s, 12H), 1.03-0.83 (m, 25H), 0.69 (d, 3H), 0.40 (d, 2H) and 0.27 (bs, 2H); Mass: [M+H] ⁺ 808.66 (100%); HPLC: 92.91%.

Example 10: Preparation of 4-((lR.3aS.5aR.5bR.7aR.l laS.l lbR.13aR.13bR)-3a-(3-((lR.3S) -3-(isopropylcarbamoyl)-2.2-dimethylcyclobutyl)ureido)-5a.5b .8.8.1 la-pentamethyl-1 -( 1- methylcvclopropyl)-2.3.3a.4.5.5a.5b.6.7.7a.8.11.11a.l lb.l2.13.13a.l3b-octadecahvdro-lH- cyclopentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)-3 -( isopropylcarbamoyl)-2,2-dimethylcyclobutyl )ureido )-5a, 5b, 8, 8, 1 la-pentamethyl-1 -(1- methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)benzoate:

To a stirred solution of (lS,3R)-3-amino-N-isopropyl-2,2-dimethylcyclobutane-l- carboxamide (prepared as described in WO 2013/160810 A2, 0.315 g, 1.7 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.7 mL, 4.20 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la- pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a, 8,l l,l la,l lb,12,13,13a,13b- octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoate (Example 1-step 7, 0.500 g, 0.84 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 30% ethylacetate and hexane as an eluent to afford the desired compound (0.500 g, 77.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.81 (d, 2H), 7.38 (d, 1H), 7.09 (d, 2H), 6.00 (d, 1H), 5.24 (d, 2H), 3.84 (s, 3H), 3.88-3.82 (m, 1H), 3. 65 (m 2H), 2.33-2.07 (m, 2H), 1.97-1.89 (m, 2H), 1.73 (m 2H), 1.51- 1.35 (m, 10H), 1.23-1.17 (m, 5H), 1.12 (s, 5H), 1.03 (s 10H), 0.98 (d, 6H), 0.89 (s, 10H), 0.70 (s, 3H), 0.39 (d, 2H) and 0.27 (d. 2H); Mass: [M+H] ⁺ 768.69 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,nbR,13aR,13bR)-3a-(3-((lR,3S)-3-(iso propylcarbamoyl)-2,2-dimethylcyclobutyl)ureido)-5a,5b,8,8,ll a-pentamethyl-l-(l -methyl cyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclo penta[a] chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-((lR,3S)-3-(isopropylcarbamoyl)-2,2-dimethylcyclobutyl)ur eido)-5a,5b,8,8,l la-penta methyl- l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octa decahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (step 1, 0.500 g, 0.65 mmol, 1.0 eq) in THF (10 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.191 g, 4.5 mmol, 7.0 eq) at room temperature. Then the reaction mixture was heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, washed with hexane and diethyl ether to afford the desired pure compound (0.250 g, 51.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.82 (s, 1H), 7.81 (d, 2H), 7.38 (d, 1H), 7.09 (d, 2H), 6.00 (d, 1H), 5.24 (d, 2H), 3.88-3.82 (m, 1H), 3. 65 (m 2H), 2.33-2.07 (m, 2H), 1.97-1.89 (m, 2H), 1.73 (m 2H), 1.51-1.35 (m, 10H), 1.23-1.17 (m, 5H), 1.12 (s, 5H), 1.03 (s 10H), 0.98 (d, 6H), 0.89 (s, 10H), 0.70 (s, 3H), 0.39 (d, 2H) and 0.27 (d. 2H); Mass: [M+H] ⁺ 754.63 (100%); HPLC: 91.24%.

Example 11: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S) -3-(dimethylcarbamoyl)-2,2-dimethylcvclobutyl)ureido)-5a,5b, 8,8 J la-pentamethyl-l-d- methylcvclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH- cyclopentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)- 3-( dimethylcarbamoyl)-2,2-dimethylcyclobutyl )ureido )-5a,5b, 8, 8, lla-pentamethyl-1 -(1- methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)benzoate:

To a stirred solution of (lS,3R)-3-amino-N,N,2,2-tetramethylcyclobutane-l- carboxamide (prepared as described in WO 2013/160810 A2, 0.29 g, 1.72 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.7 mL, 4.26 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la- pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a, 8,l 1,1 la,l lb, 12,13, 13a,13b- octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoate (Example 1-step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 10% methanol and DCM as an eluent to afford the desired compound (0.450 g, 72.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.41 (d, 2H), 5.99 (d, 1H), 5.26 (t, 2H), 3.84 (s, 3H), 3.74 (q, 1H), 2.92 (s, 3H), 2.88 (d, 1H), 2.81 (s, 3H), 2.20-1.94 (m, 4H), 1.75 (m, 3H), 1.52-1.48 (m, 10H), 1.23-1.11 (m, 10H), 1.04 (s, 4H), 0.98 (d, 6H), 0.85 (s, 8H), 0.83 (t, 1H), 0.67 (s, 3H), 0.39 (d, 2H) and 0.27 (d, 2H); Mass: [M+H] ⁺ 754.56 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,nbR,13aR,13bR)-3a-(3-((lR,3S)-3-(di methylcarbamoyl)-2,2-dimethylcyclobutyl)ureido)-5a,5b,8,8 la-pentamethyl-l-(l -methyl cyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclo penta[a] chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-((lR,3S)-3-(dimethylcarbamoyl)-2,2-dimethylcyclobutyl)ure ido)-5a,5b,8,8,l la-penta methyl- l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octa decahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (step 1, 0.450 g, 0.59 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.175 g, 4.18 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluting with 10% methanol and DCM to afford the desired pure compound (0.084 g, 19.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.72 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.98 (d, 1H), 5.26 (t, 2H), 3.74 (q, 1H), 2.92 (s, 3H), 2.88 (d, 1H), 2.81 (s, 3H), 2.20-1.94 (m, 4H), 1.75 (m, 3H), 1.52-1.48 (m, 10H), 1.23-1.11 (m, 10H), 1.04 (s, 4H), 0.98 (d, 6H), 0.85 (s, 8H), 0.83 (t, 1H), 0.67 (s, 3H), 0.39 (d, 2H) and 0.27 (d, 2H); Mass: [M+H] ⁺ 740.58 (100%); HPLC: 84.89%.

Example 12: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lS,4R) -4-(hvdroxymethyl)cvclopent-2-en-l-yl)ureido)-5a,5b,8,8 J la-pentamethyl-l-d-methylcyclo propyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cvclopentaral chrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(3-((lS,4R)-4 -(hydroxymethyl)cyclopent-2-en-l -yl)ureido)-5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclo propyl ) -2, 3, 3 a, 4, 5, 5 a, 5b, 6, 7,7a,8,ll,lla,llb,12,13,l 3 a, 13b-octadecahydro-l H-cyclopenta [a]chrysen-9-yl)benzoate:

To a stirred solution of ((lR,4S)-4-aminocyclopent-2-en-l-yl)methanol (procured from Aldrich, 0.25 g, 1.69 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.7 mL, 4.20 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS, HbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a, 4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl) benzoate (Example 1-step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 30% ethylacetate and hexane as an eluent to afford the desired compound (0.400 g, 67.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.26 (d, 2H), 5.84 (t, 2H), 5.63 (d, 1H), 5.26 (d, 2H), 4.62 (t, 1H), 4.53 (d, 1H), 3.84 (s, 3H), 2.61 (s, 2H), 2.27 (q, 5H), 1.75 (d, 3H), 1.51-1.36 (m, 10H), 1.32-1.11 (m, 8H), 1.03 (s, 3H), 1.00 (d, 6H), 0.89 (s, 9H), 0.84 (d, 1H), 0.38 (d, 2H) and 0.26 (d, 2H); Mass: [M+H] ⁺ 754.56 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-((lS,4R)-4- (hydroxymethyl)cyclopent-2-en-l-yl)ureido)-5a,5b,8,8,lla-pen tamethyl-l-(l -methylcyclo propyl ) -2, 3, 3 a, 4, 5, 5 a, 5b, 6, 7,7a,8,ll,lla,llb,12,13,l 3 a, 13b-octadecahydro-l H-cyclopenta [a]chrysen-9-yl) benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-(( lS,4R)-4-(hydroxymethyl)cyclopent-2-en-l-yl)ureido)-5a,5b, 8,8,1 la-pentamethyl- 1-(1- methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH- cyclopenta [a]chrysen-9-yl)benzoate (step 1, 0.400 g, 0.57 mmol, 1.0 eq) in THF (10 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.170 g, 4.02 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluting with 2% methanol and DCM to afford the desired pure compound (0.150 g, 38.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.86 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.84 (t, 2H), 5.63 (d, 1H), 5.25 (t, 2H), 4.62 (t, 1H), 4.53 (d, 1H), 2.61 (s, 2H), 2.27 (q, 5H), 1.75 (d, 3H), 1.51-1.36 (m, 10H), 1.32-1.11 (m, 8H), 1.03 (s, 3H), 1.00 (d, 6H), 0.89 (s, 9H), 0.84 (d, 1H), 0.38 (d, 2H) and 0.26 (d, 2H); Mass: [M+H] ⁺ 683.56 (100%); HPLC: 98.42%.

Example 13: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((S)-2-(4- (4-fluorophenyl)-lH-imidazol-2-yl)pyrrolidine-l-carboxamido) -5a,5b,8,8 J la-pentamethyl- l-(l-methylcvclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro- lH-cvclopentaralchrvsen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-((S)-2-(4-(4- fluorophenyl)-lH midazol-2-yl)pyrrolidine-l-carboxamido)-5a,5b,8,8,lla-pentam ethyl-l- (l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro- lH-cyclopenta[a]chrysen-9-yl)benzoate:

To a stirred solution of (S)-4-(4-fluorophenyl)-2-(pyrrolidin-2-yl)-lH-imidazole

(prepared as described in WO 2014/105926 Al, 0.33 g, 1.40 mmol, 1.7 eq) in THF (10 mL) then added DIPEA (0.74 mL, 4.20 mmol, 5.0 eq) at room temperature, followed by methyl 4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl-l- (l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH -cyclopenta[a]chrysen-9-yl)benzoate (Example 1-step 7, 0.500 g, 0.85 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 10% methanol and DCM as an eluent to afford the desired compound (0.600 g, 85.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.18 (s, 1H), 7.88-7.80 (m, 4H), 7.62 (s, 1H), 7.25-7.12 (m, 4H), 5.29 (d, 1H), 4.68 (t, 1H), 4.35 (s, 1H), 3.85 (s, 3H), 3.56 (t, 1H), 3.45-3.37 (m, 1H), 2.41-2.16 (m, 6H), 2.01-1.92 (m, 2H), 1.81-1.68 (m, 4H), 1.52-1.46 (m, 7H), 1.24 (s, 9H), 1.07 (s, 3H), 1.01 (d, 2H), 0.92 (s, 9H), 0.67 (s, 3H), 0.22 (d, 1H), 0.07 (d, 1H), and 0.06 (d, 2H); Mass: [M+H] ⁺ 754.56 (100%). Step 2: Synthesis of 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((S)-2-(4-(4- fluoro phenyl)-! H-imidazol-2-yl)pyrrolidine-l -carboxamido )-5a,5b, 8,8,1 la-pentamethyl-1 -( 1 - methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH- cyclopenta [a]chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- ((S )-2-(4-(4-fluorophenyl)- 1 H-imidazol-2-yl)pyrrolidine- 1 -carboxamido)-5 a,5b,8 , 8,11 a-penta methyl- l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octa decahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (step 1, 0.600 g, 0.73 mmol, 1.0 eq) in THF (12.5 ml) and water (12.5 ml) was added Lithium hydroxide monohydried (0.216 g, 5.11 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluting with 3% methanol and DCM to afford the desired pure compound (0.170 g, 25.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.81 (s, 1H), 12.18 (s, 1H), 7.88-7.80 (m, 4H), 7.62 (s, 1H), 7.25-7.12 (m, 4H), 5.29 (d, 1H), 4.68 (t, 1H), 4.35 (s, 1H), 3.56 (t, 1H), 3.45-3.37 (m, 1H), 2.41-2.16 (m, 6H), 2.01-1.92 (m, 2H), 1.81-1.68 (m, 4H), 1.52-1.46 (m, 7H), 1.24 (s, 9H), 1.07 (s, 3H), 1.01 (d, 2H), 0.92 (s, 9H), 0.67 (s, 3H), 0.22 (d, 1H), 0.07 (d, 1H) and 0.06 (d, 2H); Mass: [M+H] ⁺ 801.56 (100%); HPLC: 98.33%.

Example 14: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-(l,3-di hydroxypropan-2-yl)ureido)-5a,5b,8,8 J la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5, 5a,5b,6J,7a,8 , 11,1 la, 1 lb,12, 13 J3aJ3b-octadecahvdro-lH-cvclopentaralchrvsen-9-yl) benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-(l,3-di hydroxypropan-2-yl)ureido)-5a,5b,8,8,lla-pentamethyl-l-(l-me thylcyclopropyl)-2,3,3a,4,5, 5a,5b,6,7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl) benzoate:

To a stirred solution of 2-aminopropane-l,3-diol (procured from Aldrich, 0.156 g, 1.72 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.76 mL, 8.61 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-iso cyanato-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l,

11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoate (Example 1 - step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 4% MeOH and DCM as an eluent to afford the desired compound (0.300 g, 53.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.26 (d, 2H), 5.89 (d, 1H), 5.48 (s, 1H), 5.25 (d, 1H), 4.64 (s, 2H), 3.84 (s, 3H), 3.40 (s, 2H), 2.22-1.96 (m, 2H), 1.75-1.69 (m, 3H), 1.51-1.43 (m, 8H), 1.28-1.23 (m, 10H), 1.04 (s, 5H), 0.97-0.95 (m, 6H), 0.89-0.83 (m, 10H), 0.38 (m, 2H) and 0.26 (m, 2H); Mass: [M+H] ⁺ 674.58 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(3-(l,3-dihyd roxy propan-2-yl)ureido)-5a,5b,8,8,lla-pentamethyl-l-(l -methylcyclopropyl)-2,3,3a,4,5,5a,5b, 6,7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-(l,3-dihydroxypropan-2-yl)ureido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen- 9-yl) benzoate (step 1, 0.300 g, 0.45 mmol, 1.0 eq) in THF (10 ml) and water (10 ml) was added Lithium hydroxide monohydried (0.13 g, 3.17 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid was separated, purified by column chromatography by using 6% MeOH and DCM as an eluent to afford the desired compound (0.140 g, 47.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.74 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.90 (d, 1H), 5.49 (s, 1H), 5.26 (d, 1H), 4.64 (s, 2H), 3.40 (s, 2H), 2.22-1.96 (m, 2H), 1.75-1.69 (m, 3H), 1.51-1.43 (m, 8H), 1.28-1.23 (m, 10H), 1.04 (s, 5H), 0.97-0.95 (m, 6H), 0.89-0.83 (m, 10H), 0.38 (m, 2H) and 0.26 (m, 2H); Mass: [M+H] ⁺ 661.54 (100%); HPLC: 93.55%.

Example 15: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-hydroxy azetidine-l-carboxamido)-5a,5b,8,8 J la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a, 5b,6,7 Ja,8 J lJ laJ lbJ2J3 J3aJ3b-octadecahvdro-lH-cvclopentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(3-hydroxy azetidine-l-carboxamido)-5a,5b,8,8,lla-pentamethyl-l-(l-meth ylcyclopropyl)-2,3,3a,4,5,5a, 5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9-yl) benzoate:

To a stirred solution of azetidin-3-ol (procured from Aldrich, 0.187 g, 1.72 mmol, 2.0 eq) in THF (8 mL) then added DIPEA (0.74 mL, 4.3 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8, 8,1 la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l 1,1 la,l lb, 12,13, 13a, 13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (Example 1-step 7, 0.490 g, 0.86 mmol, 1.0 eq) in THF (8 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 60% ethylacetate and hexane as an eluent to afford the desired compound (0.300 g, 54.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.87 (d, 2H), 7.22 (d, 2H), 5.51 (bs, 1H), 5.25 (d, 1H), 4.58 (s, 1H), 4.33 (d, 1H), 4.08 (t, 1H), 3.84 (s, 3H), 3.86 (t, 1H), 3.62 (q, 1H), 3.49 (q, 1H), 2.35 (d, 1H), 2.16-1.97 (m, 2H), 1.74-1.69 (m, 3H), 1.52-1.37 (m, 11H), 1.23-1.14 (m, 6H), 1.06 (s, 3H), 0.97-0.96 (m, 6H), 0.89-0.85 (m, 9H), 0.42-0.34 (m, 2H) and 0.24 (m, 2H); Mass: [M+H] ⁺ 656.61 (10%). Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-hydroxy azetidine -l-carboxamido)-5a,5b,8,8,lla-pentamethyl-l-(l-methylcyclopr opyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3 -hydroxy azetidine- l-carboxamido)-5a,5b,8,8, 1 la-pentamethyl- 1 -( l-methylcyclopropyl)-2, 3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9- yl) benzoate (step 1, 0.300 g, 0.46 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.137 g, 3.27 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid was separated and washed with diethyl ether to afford the desired pure compound (0.62 g, 21.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.76 (s, 1H), 7.87 (d, 2H), 7.22 (d, 2H), 5.51 (bs, 1H), 5.25 (d, 1H), 4.58 (s, 1H), 4.33 (d, 1H), 4.08 (t, 1H), 3.86 (t, 1H), 3.62 (q, 1H), 3.49 (q, 1H), 2.35 (d, 1H), 2.16-1.97 (m, 2H), 1.74-1.69 (m, 3H), 1.52-1.37 (m, 11H), 1.23-1.14 (m, 6H), 1.06 (s, 3H), 0.97-0.96 (m, 6H), 0.89-0.85 (m, 9H), 0.42-0.34 (m, 2H) and 0.24 (m, 2H); Mass: [M+H] ⁺ 643.51 (100%); HPLC: 93.02%.

Example 16: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(4-(2-(2- methoxyethoxy)ethyl)piperazine- 1 -carboxamido)-5a,5b,8,8 J 1 a-pentamethyl- 1 -( 1 -methyl cvclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecarivdro-lH-cyclo pentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate:

To a stirred solution of 2-(2-methoxyethoxy)ethan-l-ol (5.0 g, 14.6 mmol, 1.0 eq) was dissolved in DCM (50 mL), cooled to 0°C then add triethylamine (17.3 mL, 43.8 mmol, 3.0 eq) and stirred for about 10 minutes. Tosylchloride (8.7 g, 16.06 mmol, 1.1 eq) was added at same temperature followed by DMAP (1.5 g, 4.3 mmol, 0.3 eq). The reaction mixture was stirred for about 4 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with DCM and washed with water. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated to gave the crude compound which was purified by column chromatography eluting with 30% ethylacetate and hexane to afford the desired pure compound (7.0 g, 61.0%) as a liquid.

Step 2: Synthesis of tert-butyl 4-(2- -methoxyethoxy)ethyl)piperazine-l-carboxylate:

THF was cooled to 0°C then added NaH (0.8 g, 32.4 mmol, 3.0 eq) followed by tert- butyl piperazine-l-carboxylate (2.0 g, 10.8 mmol, 1.0 eq) and stirred for about 20 minutes. At same temperature 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (step 1, 3.5 g, 12.96 mmol, 1.2 eq) was added, the reaction mixture was allowed to room temperature and the reaction mixture was refluxed for overnight. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice and extracted with ethylacetate. The organic layer was dried with Na ₂ S0 ₄ , filtered and concentrated gave the crude compound which was purified by column chromatography column eluting with 5% MeOH and DCM to afford the desired pure compound (1.2 g, 38.0%) as a liquid.

Step 3: Synthesis of 1 -(2-(2-methoxyethoxy)ethyl)piperazine:

Solution of tert-butyl 4-(2-(2-methoxyethoxy)ethyl)piperazine-l-carboxylate (step 2, 0.500 g, 1.73 mmol, 1.0 eq) in 1,4-dioxane in HC1 and stirred at room temperature for about 4 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo to produce the crude residue (0.320 g, 98.0%), which is used as such for next step. Step 4: Synthesis of methyl 4-{{lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-{4-{2-{2- methoxyethoxy)ethyl)piperazine-l-carboxamido)-5a,5b,8, 8, 1 la-pentamethyl-l-(l -methyl cyclopropyl)-2,3,3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclo penta[a] chrysen-9-yl)benzoate:

To a stirred solution of l-(2-(2-methoxyethoxy)ethyl)piperazine (0.320 mL, 1.7 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.7 mL, 4.6 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-iso cyanato-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7, 7a,8,l l, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoate (Example 1 - step 7, 0.497 g, 0.85 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 5% methanol and DCM as an eluent to afford the desired compound (0.600 g, 91.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.26 (d, 2H), 5.26 (d, 1H), 4.83 (s, 1H), 3.84 (s, 3H), 3.52-3.48 (m, 5H), 3.24 (s, 3H), 3.20 (s, 1H), 2.35 (t, 6H), 2.16-1.98 (m, 3H), 1.74 (m, 3H), 1.43-1.39 (m, 12H), 1.23-1.08 (m, 7H), 1.03 (s, 3H), 0.97 (s, 6H), 0.89 (s, 9H), 0.85 (t, 2H), 0.42-0.32 (m, 2H) and 0.25-0.23 (t, 2H); Mass: [M+H] ⁺ 772.73 (100%). Step 5: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(4-(2-(2-methoxy ethoxy)ethyl)piperazine-l -carboxamido)-5a, 5b, 8, 8, lla-pentamethyl-1 -( 1 -methylcyclopropyl) -2, 3, 3 a, 4, 5, 5 a, 5b, 6,7, 7a,8,ll,lla,llb,12,13,l 3 a, 13b-octadecahydro-lH-cyclopenta[a ] chrysen-9-yl)benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (4-(2-(2-methoxyethoxy)ethyl)piperazine-l-carboxamido)-5a,5b , 8,8,1 la-pentamethyl-l-(l- methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)benzoate (step 4, 0.600 g, 0.77 mmol, 1.0 eq) in THF (10 ml) and water (10 ml) was added Lithium hydroxide monohydried (0.228 g, 5.44 mmol, 7.0 eq) at room temperature. Then the reaction mixture was heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluting with 8% MeOH and DCM to afford the desired pure compound (0.100 g, 17.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.83 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.26 (d, 1H), 4.80 (s, 1H), 3.52-3.48 (m, 5H), 3.24 (s, 3H), 3.20 (s, 1H), 2.35 (t, 6H), 2.16-1.98 (m, 3H), 1.74 (m, 3H), 1.43-1.39 (m, 12H), 1.23-1.08 (m, 7H), 1.03 (s, 3H), 0.97 (s, 6H), 0.89 (s, 9H), 0.85 (t, 2H), 0.42-0.32 (m, 2H) and 0.25-0.23 (t, 2H); Mass: [M+H] ⁺ 758.62 (100%); HPLC: 98.08%. Example 17: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(4-(hydroxy methyl)piperidine-l-carboxamido)-5a,5b,8,8 J la-pentamethyl-l-(l-methylcyclopropyl)-2,3, 3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cvclopentaralchrysen-9- yl) benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(4-(hydroxy methyl)piperidine-l -carboxamido )-5a,5b, 8,8,1 la-pentamethyl-1 -( 1 -methylcyclopropyl)-2,3, 3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9- yl) benzoate:

To a stirred solution of piperidin-4-ylmethanol (0.195 g, 1.6 mmol, 2.0 eq) in THF (5 mL) then added DIPEA (0.8 mL, 4.2 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl- l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro- lH-cyclopenta[a]chrysen-9-yl)benzoate (Example 1-step 7, 0.495 g, 0.85 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 25% ethylacetate and hexane as an eluent to afford the desired compound (0.500 g, 86.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.87 (d, 2H), 7.23 (d, 2H), 5.26 (d, 1H), 4.74 (s, 1H), 4.46 (t, 1H), 4.04-3.85 (m, 2H), 3.84 (s, 3H), 3.24 (t, 2H), 2.72-254 (m, 2H), 2.38-2.31 (m, 1H), 2.16-1.98 (m, 2H), 1.87-1.59 (m, 5H), 1.47-1.35 (m, 11H), 1.24-1.10 (m, 6H), 0.97 (s, 3H), 0.93 (s, 9H), 0.89 (s, 9H), 0.47-0.34 (m, 2H) and 0.24 (m, 2H); Mass: [M+H] ⁺ 699.60 (10%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(4-(hydroxymethyl) piperidine-l-carboxamido)-5a,5b,8,8,lla-pentamethyl-l-(l -methylcyclopropyl)-2,3,3a,4,5, 5a,5b,6,7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl) benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-

(4-(hydroxymethyl)piperidine-l-carboxamido)-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclo propyl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl) benzoate (step 1, 0.500 g, 0.73 mmol, 1.0 eq) in THF (10 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.210 g, 5.10 mmol, 7.0 eq) at room temperature. Then the reaction mixture was heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid was separated, filtered and purified by column chromatography eluting with 3% MeOH and DCM to afford the desired pure compound (0.100 g, 25.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.76 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.26 (d, 1H), 4.74 (s, 1H), 4.46 (t, 1H), 4.04-3.83 (m, 2H), 3.24 (t, 2H), 2.72-254 (m, 2H), 2.38-2.31 (m, 1H), 2.16-1.98 (m, 2H), 1.87-1.59 (m, 5H), 1.47-1.35 (m, 11H), 1.24-1.10 (m, 6H), 0.97 (s, 3H), 0.93 (s, 9H), 0.89 (s, 9H), 0.47-0.34 (m, 2H) and 0.24 (m, 2H); Mass: [M+H] ⁺ 685.56 (100%); HPLC: 96.14%. Example 18: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la- pentamethyl- 1 -( 1 -methylcyclopropyl)-3 a-((S )-2-(pyrrolidin- 1 -ylmethyDpyrrolidine- 1 -carbox amido)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cvclopentaral chrysen -9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-1 -( 1 -methylcyclopropyl)-3a-( (S)-2-(pyrrolidin-l -ylmethyl)pyrrolidine-l -carbox amido)-2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-oc tadecahydro-lH-cyclopenta [a]chrysen-9-yl)benzoate:

To a stirred solution of (R)-l-(pyrrolidin-2-ylmethyl)pyrrolidine (procured from Aldrich, 0.33 mL , 2.1 mmol, 1.5 eq) in THF (5 mL) then added DIPEA (1.2. mL, 7.0 mmol, 5.0 eq) at room temperature, followed by methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR, 13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-2,3,3a,4,5,5a,5b,6, 7, 7a, 8, 11, 11 a, l ib, 12,13, 13 a, 13b-octadecahydro- 1 H-cyclopenta[a] chry sen-9-yl)benzoate (Example 1-step 7, 0.800 g, 1.4 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue which was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 3% MeOH and DCM as an eluent to afford the desired compound (0.800 g, 79.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.90 (d, 2H), 7.27 (d, 2H), 5.26 (d, 1H), 3.84 (s, 3H), 3.73 (s, 1H), 3.15-3.07 (m, 1H), 2.72-2.37 (m, 6H), 2.15-2.08 (m, 1H), 1.90-1.73 (m, 12H), 1.50-1.43 (m, 9H), 1.29-1.13 (m, 9H), 1.07 (s, 3H), 0.98-0.89 (m, 17H) and 0.36-0.25 (m, 4H); Mass: [M+H] ⁺ 738.62 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla-penta methyl-l-(l -methylcyclopropyl)-3a-((S)-2-(pyrrolidin-l-ylmethyl)pyrroli dine-l-carboxamido) -2,3,3a,4,5,5a,5b,6,7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl) benzoic acid:

To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a, 5b,8,8,l la-pentamethyl-l-(l-methylcyclopropyl)-3a-((S)-2-(pyrrolidin -l-ylmethyl) pyrrolidine-l-carboxamido)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadeca hydro- lH-cyclopenta[a] chrysen-9-yl)benzoate (step 1, 0.800 g, 11.0 mmol, 1.0 eq) in THF (8 ml) and water (8 ml) was added Lithium hydroxide monohydried (0.460 g, 110.6 mmol, 10.0 eq) at room temperature. Then the reaction mixture was heated to 100°C for about 4hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction mixture was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 (P was adjusted to 4). The obtained solid compound was separated, purified by column chromatography eluted by 8% MeOH and DCM to afford the desired pure compound (0.300 g, 38.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.56 (s, 1H), 7.87 (d, 2H), 7.23 (d, 2H), 5.26 (d, 1H), 3.80 (s, 1H), 3.15-3.07 (m, 1H), 2.72-2.37 (m, 6H), 2.15-2.08 (m, 1H), 1.90-1.73 (m, 12H), 1.50- 1.43 (m, 9H), 1.29-1.13 (m, 9H), 1.07 (s, 3H), 0.98-0.89 (m, 17H) and 0.36-0.25 (m, 4H); Mass: [M+H] ⁺ 724.65 (100%); HPLC: 94.86%.

Example 19: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la- pentamethyl-3a-((S)-2-(5-phenyl-lH-imidazol-2-yl)pyrrolidine -l-carboxamido)-l-(prop-l-en -2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cvclopentaral chrysen-9-yl)benzoic acid:

Step 1: Synthesis of benzyl (lR,3aS,5aR,5bR, 7aR,9S,llaR,llbR,13aR,13bR)-9-hydroxy-5a, 5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)icosahydro-3aH-cycl openta[a]chrysene-3a- carboxylate:

To a stirred solution of benzyl (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 ] chrysene-3a-carboxylate (prepared as described in WO 2013/160810 A2, 10 g, 16.6 mmol, 1.0 eq) in THF (100 ml) in Methanol (100 ml) was added potassium carbonate (16.0 g, 116.2 mmol, 7.0 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 filtered through a pad of celite and washed with CH ₂ CI ₂ . The filtrate was evaporated under reduced pressure and the crude was purified by column chromatography by using 30% ethylacetate and hexane as an eluent to afford the desired compound (9.0 g, 96.0%) as a white solid. H ¹ NMR (CDCI ₃ , 300 MHz): δ 7.37-7.32 (m, 5H), 5.17-5.06 (q, 2H), 4.71 (s, 1H), 4.59 (s, 1H), 3.21-3.13 (m, 1H), 3.06-2.97 (m, 1H), 2.30-2.25 (m, 1H), 2.21-2.13 (m, 1H), 1.94-1.83 (m, 2H), 1.67 (s, 4H), 1.65-1.56 (m, 2H), 1.54 (s, 3H), 1.52- 1.23 (m, 11H), 1.16-1.00 (m, 2H), 0.95 (d, 6H), 0.89-0.83 (m, 1H), 0.79 (s, 3H), 0.75 (d, 6H), and 0.65-0.64 (m, 1H); Mass: [M] ⁺ 547.10 (100%).

Step 2: Synthesis of benzyl (lR,3aS,5aR,5bR, 7aR,llaR,llbR,13aR,13bR)-5a,5b,8,8,H - pentamethyl-9-oxo-l-(prop-l-en-2-yl)icosahydro-3aH-cyclopent a[a]chrysene-3a- carboxylate:

The Oxalyl chloride (2.03 mL, 27.46 mmol, 1.5 eq) was dissolved into DCM (40 mL). The resulting mixture was cooled to -78°C then added DMSO (3.89 mL, 54.93 mmol, 3.0 eq) in DCM (40 mL) under nitrogen atmosphere and stirred for about 45 minutes. Then added benzyl (lR,3aS,5aR,5bR,7aR,9S,l laR,l lbR,13aR,13bR)-9-hydroxy-5a,5b,8,8,l la-penta methyl- l-(prop-l-en-2-yl)icosahydro-3aH-cyclopenta[a]chrysene-3a-ca rboxylate (step 1, 10.0 g, 18.31 mmol, 1.0 eq) in DCM (70 mL). The mixture was stirred for about 4 hours at -78°C. Triethylamine (12.7 mL, 91.55 mmol, 5.0 eq) was added into the mixture drop wise. The resulting mixture was stirred for about 1 hour at -78°C and about 2 hours at room temperature. The resulting mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated. The crude was purified by column chromatography by using 2% ethylacetate and hexane as an eluent to afford the desired compound (9.0 g, 90.0%) as a white solid. H ¹ NMR (CDCI ₃ , 300 MHz): δ 7.37-7.31 (m, 5H), 5.18-5.06 (q, 2H), 4.72 (s, 1H), 4.59 (s, 1H), 3.06-2.98 (m, 1H), 2.49-2.38 (m, 2H), 2.31-2.16 (m, 2H), 1.95-1.84 (m, 3H), 1.72 (s, 1H), 1.63-1.55 (m, 2H), 1.41-1.21 (m, 15H), 1.13-1.08 (m, 2H), 1.05 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H), 0.90 (s, 3H) and 0.78 (s, 3H); Mass: [M] ⁺ 545.00 (100%). Step 3: Synthesis of benzyl (lR,3aS,5aR,5bR, 7aR,llaR,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-l-(prop-l-en-2-yl)-9-(((trifluoromethyl)sulfonyl )oxy)-l,2,3,4,5,5a,5b,6, 7,7a,8, ll,lla,llb,12,13,13a,13b-octadecahydro-3aH-cyclopenta[a]chry sene-3a-carboxylate:

To the stirred solution of benzyl (lR,3aS,5aR,5bR,7aR,l laR,l lbR,13aR,13bR)-5a,

5b,8,8,l la-pentamethyl-9-oxo-l-(prop-l-en-2-yl)icosahydro-3aH-cyclop enta[a]chrysene-3a- carboxylate (step 2, 8.5.0 g, 15.65 mmol, 1.0 eq) in THF (50 mL) was added KHMDS (93 mL, 46.95 mmol, 3.0 eq) at -78°C under nitrogen atmosphere and stirred for about 30 minutes. Then added N-phenyl-Bis (trifluoro methane) sulfonamide (11.17 g, 31.3 mmol, 2.0 eq) in THF (25 mL) and stirred at same temperature for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was quenched with saturated NaCl solution and extracted with DCM. The organic layer was dried with Na ₂ S0 ₄ and concentrated to 30°C below water both temperature. The crude was purified by column chromatography by using 2% ethylacetate and hexane as an eluent to afford the desired compound (7.5 g, 70.0%) as a white solid. H ¹ NMR (CDC1 ₃ , 300 MHz): δ 7.42-7.32 (m, 5H), 5.55 (d, 1H), 5.18-5.06 (q, 2H), 4.72 (s, 1H), 4.60 (s, 1H), 3.06-2.98 (m, 1H), 2.30-2.10 (m, 3H), 1.95-1.84 (m, 2H), 1.77-1.60 (m, 5H), 1.44-1.44-1.28 (m, 11H), 1.25 (s, 2H), 1.21-1.14 (m, 2H), 1.10 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.88 (s, 3H) and 0.78 (s, 3H); Mass: [M] ⁺ 677.29 (100%).

Step 4: Synthesis of benzyl (lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-9-(4-(methoxy carbonyl)phenyl)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl )-l,2,3,4,5,5a,5b,6,7, 7a,8,ll, lla,llb,12,13,13a,13b-octadecahydro-3aH-cyclopenta[a]chrysen e-3a-carboxylate:

To a stirred solution of benzyl (lR,3aS,5aR,5bR,7aR,l laR,l lbR,13aR,13bR)-5a,5b, 8,8, l la-pentamethyl-l-(prop-l-en-2-yl)-9-(trifluoromethyl)sulfony l)oxy)-l, 2,3,4, 5,5a,5b,6,7, 7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxyla te (step 3, 7.5 g, 11.09 mmol, 1.0 eq ) in 1,4-dioxane (38.0 mL), 2-propanol (38.0 mL) and water (23 mL), was added K ₃ P0 ₄ (7.05 g, 33.27 mmoles, 3.0 eq) and 4-(methoxy carbonyl) benzene boronic acid (2.99 g, 16.63 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. Then tetrakiss (triphenylphosphine) palladium (0.76 g, 0.66 mmole, 0.06 eq) were added under nitrogen atmosphere. The mixture was then heated to 90°C and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and washed with CH ₂ CI ₂ . The filtrate was evaporated under reduced pressure and the crude was purified by column chromatography by using 10% ethylacetate and hexane as an eluent to afford the desired product (6.0 g, 82.0%) as a white solid. H ¹ NMR (CDCI ₃ , 300 MHz): δ 7.93 (d, 2H), 7.38- 7.36 (m, 5H), 7.20 (d, 2H), 5.28 (d, 1H), 5.19-5.07 (q, 2H), 4.73 (s, 1H), 4.60 (s, 1H), 3.90 (s, 3H), 3.08-3.00 (m, 1H), 2.31-2.05 (m, 3H), 1.95-1.85 (m, 2H), 1.81-1.62 (m, 6H), 1.49-1.17 (m, 12H), 0.99-0.97 (m, 14H), and 0.27 (m, 3H); Mass: [M] ⁺ 663.02 (100%).

Step 5: Synthesis of tert-butyldimethylsilyl (lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-9- (4-(methoxycarbonyl)phenyl)-5a,5b,8,8,lla-pentamethyl-l-(pro p-l-en-2-yl)-l,2,3,4,5,5a,5b, 6,7, 7a,8, 11,11 a,l lb, 12, 13,13a,l 3b-octadecahydro-3aH-cyclopenta[a] chrysene-3a- carboxylate:

To the stirred solution of benzyl (lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9-(4- (methoxycarbonyl)phenyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)-l,2,3,4,5,5a,5b,6,7, 7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxyla te (step 4, 6.0 g, 9.06 mmol, 1.0 eq) in DCM (90 mL) was added triethylamine (2 mL, 45.3 mmol, 1.6 eq) and tert. Butyldimethylsilane (3 mL, 18.12 mmol, 2.0 eq) at room temperature under nitrogen atmosphere. Then Pd(OAc) ₂ (1.0 g, 4.53 mmol, 0.5 eq) was added to the reaction mixture, heated to 60°C and stirred for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was filtered through a pad of celite and washed with CH ₂ C1 ₂ . The filtrate was evaporated under reduced pressure, the crude was dissolved in acetic acid (31.2 mL), THF (15 mL), water (6 mL) and stirred for about 1 hour at room temperature. Solid was separated which solid was filtered and washed with water to afford the desired product (6.0 g, 96.0%) as an off white solid. H ¹ NMR (DMS0 ₆ , 300 MHz): δ 7.89 (d, 2H), 7.25 (d, 2H), 5.25 (d, 1H), 4.69 (s, 1H), 4.58 (s, 1H), 3.84 (s, 3H), 2.12-2.03 (m, 3H), 1.78-1.62 (m, 5H), 1.49-1.23 (m, 19H), 0.97- 0.88 (m, 25H), and 0.24 (s, 4H); Mass: [M] ⁺ 687.10 (100%).

Step 6: Synthesis of (lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-9-(4-(methoxycarbonyl) phenyl)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-l,2,3,4 ,5,5a,5b,6,7, 7a,8,ll,lla,llb, 12,13,13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene-3a-car boxylic acid:

To the stirred solution of tert-butyldimethylsilyl (lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)- 1,2,3,4, 5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene -3a-carboxylate (step 5, 6.0 g, 8.74 mmol, 1.0 eq) in 1,4-dioxane (72 niL) was added TBAF (6.08 niL, 17.48 mmol, 2.0 eq) at room temperature, and stirred for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water and stirred for about 30 minutes. The solid was separated which solid was filtered and dried under vacuum to afford the desired product (4.2 g, 84.0%) as an off white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.05 (bs, 1H), 7.89 (d, 2H), 7.25 (d, 2H), 5.25 (d, 1H), 4.70 (s, 1H), 4.70 (s, 1H), 3.84 (s, 3H), 2.97-2.93 (m, 1H), 2.32-2.11 (m, 3H), 1.87-1.70 (m, 2H), 1.65-1.50 (m, 6H), 1.45-1.32 (m, 10H), 1.28-1.20 (m, 4H), 1.07 (s, 3H) and 1.05-1.00 (m, 12H); Mass: [M] ⁺ 573.10 (100%).

Step 7: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-isocyanato- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-2,3,3a,4,5,5a,5 b,6, 7,7a,8,ll,lla,llb,12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate:

To a stirred solution of (lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-9-(4-(methoxy carbonyl)phenyl)-5a,5b,8,8, 1 la-pentamethyl-l-(prop-l-en-2-yl)-l, 2,3,4,5, 5a,5b,6,7,7a,8, 11, l la,l lb, 12,13, 13a,13b-octadecahydro-3aH-cyclopenta[a]chrysene-3a-carboxyli c acid (step 6, 0.500 g, 0.874 mmol, 1.0 eq) in 1,4-dioxane (5.0 ml) then added triethylamine (0.60 mL, 4.37 mmoles, 5.0 eq) at room temperature under nitrogen atmosphere followed by diphenylphosphoryl azide (0.6 mL, 2.62 mmol, 3.0 eq). The reaction mixture was heated to 100°C for about 3 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo to afford the desired product (0.490 g, 98.0%) which is used as such for next step.

Step 8: Synthesis of methyl 4-((!R,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-3a-( (S)-2-( 5 -phenyl- 1 H-imidazol-2-yl )pyrrolidine-l -carboxamido )-l -(prop-1 -en -2-yl)-2,3,3a,4,5,5a,5b,6, 7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl)benzoate:

To a stirred solution of (S)-5-phenyl-2-(pyrrolidin-2-yl)-lH-imidazole (prepared as described in WO 2014/105926 Al, 0.55 g, 2.58 mmol, 3.0 eq) in THF (5 mL) then added DIPEA (0.72 mL, 4.3 mmol, 5.0 eq) at room temperature followed by methyl 4- (lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la-pentamethyl-l- (prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclo penta[a]chrysen-9-yl)benzoate (0.49 g, 0.861 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 40% ethylacetate and hexane as an eluent to afford the desired compound (0.3 g, 44.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.21 (s, 1H), 7.90-7.83 (m, 4H), 7.70 (s, 1H), 7.31- 7.12 (m, 5H), 5.29 (d, 1H), 4.83 (s, 1H), 4.71 (t, 1H), 4.13 (s, 1H), 3.84 (s, 3H), 3.62-3.57 (m, 1H), 3.45-3.35 (m, 1H), 2.63 (d, 3H), 2.43-2.36 (m, 4H), 2.16-1.70 (m, 4H), 1.67 (m, 2H), 1.54-1.39 (m, 6H), 1.31 (s, 5H), 1.27-1.15 (m, 5H), 1.05 (s, 3H) and 0.99-0.85 (m, 14H); Mass: [M] ⁺ 782.96 (100%).

Step 9: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla-penta methyl-3a-((S)-2-(5-phenyl-lH-imidazol-2-yl)pyrrolidine-l -carboxamido)-! -(prop-1 -en-2-yl) -2, 3, 3 a, 4, 5, 5 a, 5b, 6,7, 7a,8, 11,11a,! lb, 12, 13,13 a, 13b-octadecahydro-lH-cyclopenta[a ] chrysen-9-yl)benzoic acid: To a stirred solution of methyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a, 5b,8,8,l la-pentamethyl-3a-((S)-2-(5-phenyl-lH-imidazol-2-yl)pyrrolid ine-l-carboxamido)- l-(prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)benzoate (step 8, 0.3 g, 0.383 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.112 g, 2.68 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction was evaporated directly under vacuum to give residue. The residue was diluted with water and acidified with IN HC1 P was adjusted to 4. Then solid compound was separated which solid purified by column chromatography eluted by 80% EtOAc and hexane to afford the desired pure compound (0.120 g, 40.0 %) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.83 (s, 1H), 12.21 (s, 1H), 7.88-7.85 (m, 4H), 7.71 (s, 1H), 7.33-7.15 (m, 5H), 5.28 (d, 1H), 4.83 (s, 1H), 4.74 (t, 1H), 4.13 (s, 1H), 3.83 (s, 1H), 3.61 (d, 1H), 2.63 (d, 3H), 2.43-2.36 (m, 4H), 2.16-1.70 (m, 4H), 1.67 (m, 2H), 1.54-1.39 (m, 6H), 1.31 (s, 5H), 1.27- 1.15 (m, 5H), 1.05 (s, 3H) and 0.99-0.86 (m, 14H); Mass: [M] ⁺ 769.06 (100%); HPLC: 89.04%.

Example 20: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la- pentamethyl-3a-(4-(2-morpholinoethoxy)piperidine-l-carboxami do)-l-(prop-l-en-2-yl)-2,3, 3a,4,5,5a,5b,6,7 Ja,8 J lJ laJ lbJ2J3 J3aJ3b-octadecahydro-lH-cyclopentaralchrysen-9- vPbenzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-3a-(4-(2-morpholinoethoxy)piperidine-l-carboxami do)-l-(prop-l-en-2-yl)-2,3, 3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9- yl)benzoate:

To a stirred solution of 4-(2-(piperidin-4-yloxy)ethyl)morpholine (0.410 g, 1.93 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.8 mL, 4.83 mmol, 5.0 eq) at room temperature followed by methyl 4-(lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-iso cyanato-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8, l l,l la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (Example 19-step 7, 0.550 g, 0.96 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 35% ethylacetate and hexane as an eluent to afford the desired compound (0.500 g, 66.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.89 (d, 2H), 7.26 (d, 2H), 5.25 (d, 1H), 5.03 (s, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 3.84 (s, 3H), 3.73-3.21 (m, 13H), 2.96-2.82 (m, 2H), 2.43-1.69 (m, 13H), 1.66-1.47 (m, 13H), 1.23 (s, 3H), 1.20 (s, 9H) and 1.17 (s, 9H); Mass: [M] ⁺ 784.18 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla-penta methyl-3a-(4-(2-morpholinoethoxy)piperidine-l-carboxamido)-l -(prop-l-en-2-yl)-2,3,3a,4,5, 5a,5b,6,7, 7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl) benzoic acid:

To a stirred solution of methyl 4-(lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)- 5a,5b,8,8, 1 la-pentamethyl-3a-(4-(2-morpholinoethoxy)piperidine- 1-carboxamido)- l-(prop- 1- en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a] chrysen-9-yl) benzoate (step 1, 0.500 g, 0.63 mmol, 1.0 eq) in THF (10 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.187 g, 4.4 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction was evaporated directly under vacuum to give the residue. The residue was diluted with water and acidified with IN HC1 P was adjusted to 4. Then the solid compound was separated which solid was purified by column chromatographed eluted by 5% MeOH and DCM to afford the desired pure compound (0.200 g, 40.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.15 (s, 1H), 7.87 (d, 2H), 7.22 (d, 2H), 5.24 (d, 1H), 5.04 (s, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 3.73- 3.21 (m, 13H), 2.96-2.82 (m, 2H), 2.43-1.69 (m, 13H), 1.66-1.47 (m, 13H), 1.23 (s, 3H), 1.20 (s, 9H) and 1.17 (s, 9H); Mass: [M] ⁺ 770.21 (100%); HPLC: 97.61%.

Example 21: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(4-(2-(2- methoxyethoxy)ethoxy)piperidine-l-carboxamido)-5a,5b,8,8 J la-pentamethyl-l-(prop-l-en- 2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cyclopentaral

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(4-(2-(2- methoxyethoxy )ethoxy )piperidine-l -carboxamido )-5a,5b, 8, 8, 11 a-pentamethyl-1 -(prop-1 -en- 2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-oct adecahydro-lH-cyclopenta[a] chrysen-9-yl)benzoate:

To a stirred solution of 4-(2-(2-methoxyethoxy)ethoxy)piperidine (0.386 g, 1.72 mmol, 2.0 eq) in THF (5 mL) then added DIPEA (0.742 mL, 4.3 mmol, 5.0 eq) at room temperature followed by methyl 4-(lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- isocyanato-5a,5b,8,8,l la-pentamethyl-l-(prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8, l l,l la, 1 lb, 12,13, 13a,13b-octadecahydro-lH-cyclopenta[a]chrysen-9-yl)benzoate (Example 19-step 7, 0.490 g, 0.861 mmol, 1.0 eq) in THF (5 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 40% ethylacetate and hexane as an eluent to afford the desired compound (0.350 g, 52.0%) as a white solid. H ¹ NMR (DMSO- d ₆ , 300 MHz): δ 7.89 (d, 2H), 7.26 (d, 2H), 5.25 (d, 1H), 5.01 (s, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 4.14 (t, 3H), 3.84 (s, 3H), 3.53 (s, 2H), 3.53 (s, 6H), 3.45 (d, 2H), 3.24 (s, 3H), 2.99-2.81 (m, 3H), 2.43-2.37 (m, 4H), 2.12-1.61 (m, 12H), 1.57-1.15 (m, 11H), 1.04 (s, 3H), 0.95 (s, 6H) and 0.89 (s, 6H); Mass: [M] ⁺ 773.11 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(4-(2-(2-methoxy ethoxy)ethoxy)piperidine-l -carboxamido )-5a,5b, 8, 8, 11 a-pentamethyl-1 -(prop-1 -en-2-yl)-2, 3, 3a,4,5,5a,5b,6, 7,7a,8,ll,lla,llb,12,13,13a,13b-octadecahydro-lH-cyclopenta[ a]chrysen-9- yl)benzoic acid: To a stirred solution of methyl 4-(lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (4-(2-(2-methoxyethoxy)ethoxy)piperidine-l-carboxamido)-5a,5 b, 8,8,1 la-pentamethyl- 1- (prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro-lH-cyclo penta[a]chrysen-9-yl)benzoate (step 1, 0.350 g, 0.453 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.133 g, 3.17 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C for about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction was evaporated directly under vacuum to give residue. The residue was diluted with water and acidified with IN HC1 P was adjusted to 4. Then the solid compound was separated which solid purified by column chromatography eluted by 60% ethylacetate and hexane to afford the desired pure compound (0.190 g, 50.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.81 (s, 1H), 7.86 (d, 2H), 7.21 (d, 2H), 5.24 (d, 1H), 5.01 (s, 1H), 4.72 (s, 1H), 4.58 (s, 1H), 3.74 (t, 1H), 3.53 (s, 6H), 3.45 (d, 2H), 3.24 (s, 3H), 2.99-2.81 (m, 3H), 2.43- 2.37 (m, 4H), 2.12-1.61 (m, 12H), 1.57-1.15 (m, 15H), 1.04 (s, 3H), 0.95 (s, 6H) and 0.89 (s, 6H); Mass: [M] ⁺ 759.27 (100%); HPLC: 93.36%.

Example 22: Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(3-((lR,3S) -2,2-dimethyl-3-(piperidine-l-carbonyl)cvclobutyl)ureido)-5a ,5b,8,8 J la-pentamethyl- 1- (prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l l,l la,l lb,12,13,13a,13b-octadecahvdro-lH-cvclo pentaralchrysen-9-yl)benzoic acid:

Step 1: Synthesis of methyl 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)- 2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)ureido)-5a, 5b,8,8,lla-pentamethyl-l-(prop -l-en-2-yl)-2,3,3a,4,5, 5 a, 5b, 6,7, 7a,8,ll,lla,llb,12,13,13a,l 3b-octadecahydro - 1 H-cyclo penta[a] chrysen-9-yl)benzoate:

To a stirred solution of (lS,3R)-3-amino-2,2-dimethylcyclobutyl)(piperidin-l-yl) methanone (prepared as described in WO 2013/160810 A2, 0.36 g, 1.72 mmol, 2.0 eq) in THF (10 mL) then added DIPEA (0.5 mL, 4.30 mmol, 5.0 eq) at room temperature followed by methyl 4-(lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,l la- pentamethyl-l-(prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadeca hydro- lH-cyclopenta[a]chrysen-9-yl)benzoate (Example 19-step 7, 0.49 g, 0.86 mmol, 1.0 eq) in THF (10 mL). The reaction mixture was allowed to reach room temperature under nitrogen atmosphere and stirred for overnight. After completion of the reaction (monitored by TLC), the solvent was evaporated in vacuo providing a crude residue was diluted with water and extracted with CH ₂ CI ₂ (3x20 ml). The combined organic extracts were dried over Na ₂ S0 ₄ , filtered and evaporated under reduced pressure. The residue was purified by column chromatography by using 10% methanol and DCM as an eluent to afford the desired compound (0.500 g, 73.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 7.87 (d, 2H), 7.22 (d, 2H), 6.05 (d, 1H), 5.41 (s, 1H), 5.24 (d, 1H), 4.70 (s, 1H), 4.59 (s, 1H), 3.84 (s, 3H), 3.76-3.58 (m, 2H), 2.89 (t, 1H), 2.54 (s, 2H), 2.29 (s, 1H), 2.17-1.94 (m, 4H), 1.84-1.71 (m, 2H), 1.66 (s, 4H), 1.61-1.42 (m, 14H), 1.25-1.14 (m, 11H), 1.11 (s, 3H), 1.04 (m, 14H) and 0.80 (s, 3H); Mass: [M] ⁺ 780.65 (100%).

Step 2: Synthesis of 4-((lR,3aS,5aR,5bR, 7aR,llaS,llbR,13aR,13bR)-3a-(3-((lR,3S)-2,2- dimethyl-3-(piperidine-l-carbonyl)cyclobutyl)ureido)-5a,5b,8 ,8,lla-pentamethyl-l-(prop-l- en-2-yl)-2,3,3a,4,5, 5 a, 5b, 6, 7, 7a,8,ll,lla,llb,12,13,13a,l 3b-octadecahydro-l H-cyclopenta [a]chrysen-9-yl) benzoic acid:

To a stirred solution of methyl 4-(lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- (3-(lR,3S)-2,2-dimethyl-3-(piperidine-l-carbonyl)cyclobutyl) ureido)-5a,5b,8,8,l la-penta methyl-l-(prop-l-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,l 1,1 la,l lb, 12,13, 13a,13b-octadecahydro -lH-cyclo penta[a]chrysen-9-yl)benzoate (step 1, 0.500 g, 0.63 mmol, 1.0 eq) in THF (5 ml) and water (5 ml) was added Lithium hydroxide monohydried (0.185 g, 4.41 mmol, 7.0 eq) at room temperature. Then the reaction mixture heated to 100°C foe about 4 hours. TLC indicated starting material was consumed and the desired product was observed. Then the reaction was evaporated directly under vacuum to give residue. The residue was diluted with water and acidified with IN HC1 P was adjusted to 4. Then the solid compound was separated which solid purified by column chromatography eluting with 10% methanol and DCM to afford the desired pure compound (0.120 g, 24.0%) as a white solid. H ¹ NMR (DMSO-d ₆ , 300 MHz): δ 12.83 (s, 1H), 7.87 (d, 2H), 7.22 (d, 2H), 6.05 (d, 1H), 5.41 (s, 1H), 5.24 (d, 1H), 4.70 (s, 1H), 4.59 (s, 1H), 3.76-3.58 (m, 2H), 2.89 (t, 1H), 2.54 (s, 2H), 2.29 (s, 1H), 2.17-1.94 (m, 4H), 1.84-1.71 (m, 2H), 1.66 (s, 4H), 1.61-1.42 (m, 14H), 1.25-1.14 (m, 11H), 1.11 (s, 3H), 1.04 (m, 14H) and 0.80 (s, 3H); Mass: [M] ⁺ 766.60 (100%); HPLC: 93.89%.

PHARMACOLOGICAL ACTIVITY

The compounds described herein can be 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 23: Evaluation of compounds antiviral activity:

MT2 cells were infected with HIV-1 strain 92HT599 (10 TCID 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%. Incubation was carried out in C0 ₂ 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.

Results:

For 0% serum binding assay, wherein "A" refers to an IC ₅₀ value < 10 nM, "B" refers to IC ₅₀ value in range of 10.01-50 nM, and "C" refers to IC ₅₀ value > 50 nM.

For 45 mg/ml HSA serum binding assay, wherein "A" refers to an IC ₅₀ value < 50 nM, "B" refers to IC ₅₀ value in range of 50.01-100 nM, and "C" refers to IC ₅₀ values > 100 nM. The IC ₅₀ (nM) values are set forth in Table- 1.

Table- 1

Example IC50 (nM) Example IC50 (nM)

No. No.

0% 45 mg/ml HSA 0% 45 mg/ml HSA

1 B A 13

A A

2 A A 14

A A

3 A 15

C A A

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.