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Title:
C-3 AND C-17 MODIFIED TRITERPENOIDS AS HIV-1 INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2017/134596
Kind Code:
A1
Abstract:
Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, betulinic acid derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula (I). These compounds are useful for the treatment of HIV and AIDS.

Inventors:
CHEN JIE (US)
CHEN YAN (US)
DICKER IRA B (US)
HARTZ RICHARD A (US)
MEANWELL NICHOLAS A (US)
REGUEIRO-REN ALICIA (US)
SIT SING-YUEN (US)
SIN NY (US)
SWIDORSKI JACOB (US)
VENABLES BRIAN LEE (US)
NOWICKA-SANS BEATA
Application Number:
PCT/IB2017/050568
Publication Date:
August 10, 2017
Filing Date:
February 02, 2017
Export Citation:
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Assignee:
VIIV HEALTHCARE UK (NO 5) LTD (GB)
International Classes:
C07J63/00; A61K31/56; A61K31/575; A61K31/58; A61P31/18; C12N9/50
Domestic Patent References:
WO2015157483A12015-10-15
WO2014123889A12014-08-14
WO2006053255A22006-05-18
WO2009100532A12009-08-20
WO2011007230A22011-01-20
WO2015157483A12015-10-15
Foreign References:
US7354924B22008-04-08
US7745625B22010-06-29
US7365221B22008-04-29
US5679828A1997-10-21
US20050239748A12005-10-27
US20080207573A12008-08-28
US8754068B22014-06-17
US8802661B22014-08-12
US8748415B22014-06-10
US8846647B22014-09-30
US8906889B22014-12-09
US20150291655A12015-10-15
US5413999A1995-05-09
Other References:
KASHIWADA, Y. ET AL., J. MED. CHEM., vol. 39, 1996, pages 1016 - 1017
POKROVSKII, A. G. ET AL.: "Synthesis of derivatives of plant triterpenes and study of their antiviral and immunostimulating activity", KHIMIYA Y INTERESAKH USTOICHIVOGO RAZVITIYA, vol. 9, no. 3, 2001, pages 485 - 491, XP002534916
DRUGS OF THE FUTURE, vol. 24, no. 12, 1999, pages 1355 - 1362
CELL, vol. 9, 29 October 1999 (1999-10-29), pages 243 - 246
DRUG DISCOVERY TODAY, vol. 5, no. 5, May 2000 (2000-05-01), pages 183 - 194
MEANWELL, NICHOLAS A. ET AL, CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT, vol. 6, no. 4, 2003, pages 451 - 461
RICHMAN D.D.: "Update of the drug resistance mutations in HIV-1", TOP HIV, December 2009 (2009-12-01)
MED., vol. 17, no. 5, December 2009 (2009-12-01), pages 138 - 145
STRAY K.M. ET AL: "Mutations in multiple domains of Gag drive the emergence of in vitro resistance to the phosphonate-containing HIV-1 protease inhibitor GS-8374", J VIROL, vol. 87, 2013, pages 454 - 463
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Claims:
CLAIMS

What is claimed is:

1. A compound of Formula I, including pharmaceutically acceptable salts thereof:

wherein Ri is isopropenyl or isopropyl; A is -Ci-e alkyl-ORo; wherein Ro is heteroaryl-Qo;

Qo is selected from the group of -H, -CN, -Ci-6 alkyl, -COOH, -Ph, -OCi-6 alkyl, -halo, - CF3,

Y is selected from the group of -COOR2, -C(0)NR2S02R3, -C(0)NHS02NR2R2, - S02NR2C(0)R2, -tetrazole, and -CONHOH,

wherein n = 1-6;

R2 is -H, -Ci-6 alkyl, -alkylsubstituted Ci-6 alkyl or-arylsubstituted Ci-6 alkyl;

W is absent, or is -CH2- or -CO-;

R3 is -H, -Ci-6 alkyl or -alkylsubstituted Ci-6 alkyl; R4 1S selected from the group of -H, -Ci-6 alkyl, -Ci-6 alkyl-C3-6 cycloalkyl, -Ci-6 substituted -Ci-6 alkyl, -Ci-6 alkyl-Qi, -Ci-6 alkyl-C3-6 cycloalkyl-Qi, aryl, heteroaryl,

, -SO2R7, -SO2NR2R2, and

wherein G is selected from the group of -0-, -SO2- and -NR12-;

wherein Qi is selected from the group of -Ci-6 alkyl, - Ci-6 fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF3, -OR2, -COOR2, -NRsR -CONRsRg and -SO2R7;

R5 is selected from the group of -H, -Ci-6 alkyl, -C3-6 cycloalkyl, -Ci-6 alkylsubstituted alkyl, -Ci-e alkyl-NRsRj. -CORB, -SO2R7 and -SO2NR2R2; with the proviso that R4 or R5 is not -COR5 when W is -CO-; with the further proviso that only one of R4 or R5 is selected from the group

of -CORe, -COCOR6,-S02R7 and -SO2NR2R2;

Re is selected from the group of -H, -Ci-6 alkyl, -Ci-6 alkyl-substitutedalkyl, -C3-6 cycloalkyl, -C3-6 substitutedcycloalkyl-Q2, -Ci-6 alkyl-Q2, -Ci-6 alkyl-substitutedalkyl- Q2,-C3-6 cycloalkyl-Q2, aryl-Q2, -NR13R14, and -OR15; wherein Q2 is selected from the group of aryl, heteroaryl, substituted heteroaryl, - OR2, -COOR2, -NR8R9, SO2R7, -CONHSO2R3, and -CONHSO2NR2R2;

R7 is selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl, -C3-6

cycloalkyl, -CF3, aryl, and heteroaryl;

Rs and R9 are independently selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -Ci-6 alkyl-Q2, and -COOR3, or Rs and R9 are taken together with the adjacent N to form a cycle selected from the group of:

M is selected from the group of -R15, -SO2R2, -SO2NR2R2, -OH and -NR2R12;

V is selected from the group of -CR10R11-, -SO2-, -O- and -NR12-; with the proviso that only one of Rs or R9 can be -COOR3;

Rio and R11 are independently selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl and -C3-6 cycloalkyl;

R12 is selected from the group of -H, -Ci-6 alkyl, -alkylsubstituted Ci-6 alkyl, - CONR2R2, -SO2R3, and -SO2NR2R2; Ri3 and Ri4 are independently selected from the group of -H, -Ci-6 alkyl, -C3-6 cycloalkyl, - Ci-6 substituted alkyl, -Ci-6 alkyl-Q3, -Ci-6 alkyl-C3-6 Cycloalkyl-Q3, and Ci-6 substituted alkyl-Q3;

Q3 is selected from the group of heteroaryl, substituted heteroaryl, -NR2R12, - CONR2R2, -COOR2, -OR2, and -SO2R3;

Ri5 is selected from the group of -Ci-6 alkyl, -C3-6 cycloalkyl, -Ci-6 substituted alkyl, -Ci-6 alkyl-Q3, -Ci-6 alkyl-C3-6 cycloalkyl-Q3 and -Ci-6 substituted alkyl-Q3;

Ri6 is selected from the group of -H, -Ci-6 alkyl, -NR2R2, and -COOR2;

with the proviso that when V is -NR12-; Ri6 is not -NR2R2; and

Ri7 is selected from the group of -H, -Ci-6 alkyl, -COOR3, and aryl.

2. The compound of claim 1, wherein in the Ro group the heteroaryl moiety is selected from the group of

3. The compound of claim 2, wherein Ri is isopropenyl.

4. The compound of claim 3, wherein Y is -COOR2.

5. The compound of claim 4, wherein R2 is -H.

The compound of claim 1, wherein R4 is -Ci-6 alkyl

7. The compound of claim 6, wherein Qi is -NRsRsi.

8. The compound of claim 7, wherein when Rs and R9 are taken together with the adjacent d from the group of:

9. The compound of claim 8, wherein R7 and Ri6 are each selected from the group of -H and -Ci-6 alkyl.

10. The compound of claim 1, wherein Qo is -CN.

11. The compound of claim 1, wherein Ri is isopropenyl, in the Ro group the "heteroaryl" moiety is selected from the group of:

-COOH, R4 is -Ci-6 alkyl-

Qi, Qi is -NR8R9, and Rs and R9 are taken together with the adjacent -N to form

A compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:

-323-

-324-

-325-

-326-

-327-

-328- A compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:

14. A composition which comprises an HIV ameliorating amount of one or more compounds as claimed in claim 1, together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

15. A composition which comprises an HIV ameliorating amount of one or more compounds as claimed in claim 11, together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

16. A composition which comprises an HIV ameliorating amount of one or more compounds as claimed in claim 12, together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

17. A composition which comprises an HIV ameliorating amount of one or more compounds as claimed in claim 13, together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

18. A method for treating a mammal infected with the HIV virus comprising

administering to said mammal an HIV ameliorating amount of a compound as claimed in claim 1, together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

19. A method for treating a mammal infected with the HIV virus comprising

administering to said mammal an HIV ameliorating amount of a compound as claimed in claim 12, together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

20. A method for treating a mammal infected with the HIV virus comprising

administering to said mammal an HIV ameliorating amount of a compound as claimed in claim 13, together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

The triple mutant protein identified as T332S/V362I/pr R41G.

Description:
C-3 AND C-17 MODIFIED TRITERPENOIDS AS HIV-1 INHIBITORS

FIELD OF THE INVENTION

The present invention relates to novel compounds useful against HIV and, more particularly, to compounds derived from betulinic acid and other compounds which are useful as HIV maturation inhibitors, and to pharmaceutical compositions containing same, as well as to methods for their preparation.

BACKGROUND OF THE INVENTION

HIV-1 (human immunodeficiency virus -1) infection remains a major medical problem, with an estimated 45-50 million people infected worldwide at the end of 2010. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include nucleoside reverse transcriptase (RT) inhibitors or approved single pill combinations: zidovudine (or AZT or RETROVIR ® ), didanosine (or VIDEX ® ), stavudine (or ZERIT ® ), lamivudine (or 3TC or EPIVIR ® ), zalcitabine (or DDC or HIVID ® ), abacavir succinate (or ZIAGEN ® ), tenofovir disoproxil fumarate salt (or VIREAD ® ), emtricitabine (or

FTC- EMTRIVA ® ), COMBIVIR ® (contains -3TC plus AZT), TRIZIVIR ® (contains abacavir, lamivudine, and zidovudine), EPZICOM ® (contains abacavir and lamivudine), TRUVADA ® (contains VIREAD ® and EMTRIVA ® ); non-nucleoside reverse transcriptase inhibitors: nevirapine (or VIRAMUNE ® ), delavirdine (or RESCRIPTOR ® ) and efavirenz (or SUSTIVA ® ), ATRIPLA ® (TRUVADA ® + SUSTIVA ® ), and etravirine, and peptidomimetic protease inhibitors or approved formulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, KALETRA ® (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ ® ) and tipranavir (APTIVUS ® ) and cobicistat, and integrase inhibitors such as raltegravir (ISENTRESS ® ), and entry inhibitors such as enfuvirtide (T-20) (FUZEON ® ) and maraviroc (SELZENTRY ® ). Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on viremia and disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented as a consequence of the widespread application of combination therapy. However, despite these impressive results, 30 to 50% of patients may ultimately fail combination drug therapies. Insufficient drug potency, noncompliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV- 1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when sub-optimal drug concentrations are present. Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options. Improved HIV fusion inhibitors and HIV entry coreceptor antagonists are two examples of new classes of anti-HIV agents further being studied by a number of investigators.

HIV attachment inhibitors are a further subclass of antiviral compounds that bind to the HIV surface glycoprotein gpl20, and interfere with the interaction between the surface protein gpl20 and the host cell receptor CD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, and block HIV replication in the first stage of the HIV life cycle. The properties of HIV attachment inhibitors have been improved in an effort to obtain compounds with maximized utility and efficacy as antiviral agents. In particular, U.S. Patent Nos. 7,354,924 and U.S. 7,745,625 are illustrative of HIV attachment inhibitors.

Another emerging class of compounds for the treatment of HIV are called HIV maturation inhibitors. Maturation is the last of as many as 10 or more steps in HIV replication or the HIV life cycle, in which HIV becomes infectious as a consequence of several HIV protease-mediated cleavage events in the gag protein that ultimately results in release of the capsid (CA) protein. Maturation inhibitors prevent the HIV capsid from properly assembling and maturing, from forming a protective outer coat, or from emerging from human cells. Instead, non-infectious viruses are produced, preventing subsequent cycles of HIV infection.

Certain derivatives of betulinic acid have now been shown to exhibit potent anti- HIV activity as HIV maturation inhibitors. For example, US 7,365,221 discloses monoacylated betulin and dihydrobetuline derivatives, and their use as anti-HIV agents. As discussed in the '221 reference, esterification of betulinic acid (1) with certain substituted acyl groups, such as 3',3'-dimethylglutaryl and 3',3'-dimethylsuccinyl groups produced derivatives having enhanced activity (Kashiwada, Y., et al., J. Med. Chem. 39: 1016-1017 (1996)). Acylated betulinic acid and dihydrobetulinic acid derivatives that are potent anti-HIV agents are also described in U.S. Pat. No. 5,679,828. Esterification of the hydroxyl in the 3 carbon of betulin with succinic acid also produced a compound capable of inhibiting HIV-1 activity (Pokrovskii, A. G., et al., "Synthesis of derivatives of plant triterpenes and study of their antiviral and immunostimulating activity," Khimiya y Interesakh Ustoichivogo Razvitiya, Vol. 9, No. 3, pp. 485-491 (2001) (English abstract).

Other references to the use of treating HIV infection with compounds derived from betulinic acid include US 2005/0239748 and US 2008/0207573, as well as

WO2006/053255, WO2009/100532 and WO2011/007230.

One HIV maturation compound that has been in development has been identified as Bevirimat or PA-457, with the chemical formula of C36H56O6 and the IUPAC name of 3 -(3-carboxy-3-methyl-butanoyloxy) lup-20(29)-en-28-oic acid. Reference is also made herein to the applications by Bristol-Myers Squibb entitled

"MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS" USSN 13/151,706 filed on June 2, 2011 (now U.S. 8,754,068) and "C-28 AMIDES OF MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV

MATURATION INHIBITORS" USSN 13/151,722, filed on June 2, 2011 (now U.S. 8,802,661). Reference is also made to the application entitled "C-28 AMINES OF C-3

MODIFIED BETULINIC ACID DERIVATIVES AS HIV MATURATION

INHIBITORS" USSN 13/359,680, filed on January 27, 2012 (now U.S. 8,748,415). In addition, reference is made to the application entitled "C-17 AND C-3 MODIFIED TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY" USSN 13/359,727 filed on January 27, 2012 (now U.S. 8,846,647). Further reference is also made to the application "C-3 CYCLOALKENYL TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY" filed USSN 13/760,726 on February 6, 2013 (now U.S. 8,906,889), as well as to the application entitled "TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY" USSN 14/682, 179 filed on April 9, 2015.

What is now needed in the art are new compounds which are useful as HIV maturation inhibitors, as well as new pharmaceutical compositions containing these compounds. In particular, new compounds are needed that will be effective against emerging genotypic HIV mutants.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I below, including pharmaceutically acceptable salts thereof, their pharmaceutical formulations, and their use in patients suffering from or susceptible to a virus such as HIV. The compounds of Formula I are effective antiviral agents, particularly as inhibitors of HIV. They are useful for the treatment of HIV and AIDS.

One embodiment of the present invention is directed to a compound of Formula I, including pharmaceutically acceptable salts thereof:

wherein Ri is isopropenyl or isopropyl;

A is -Ci-e alkyl-ORo; wherein Ro is heteroaryl-Qo;

Qo is selected from the group of -H, -CN, -Ci-6 alkyl, -COOH, -Ph, -OCi-6

alkyl, -halo, -CF3,

Y is selected from the group

of -COOR2, -C(0)NR 2 S0 2 R3, -C(0)NHS0 2 NR 2 R2, -S0 2 NR 2 C(0)R 2 , -tetrazole, and -CONHOH;

R 2 is -H, -Ci-6 alkyl, -alkylsubstituted Ci-6 alkyl or-arylsubstituted Ci-6 alkyl;

W is absent, or is -CH2- or -CO-; R3 is -H, -Ci-6 alkyl or -alkylsubstituted Ci-6 alkyl;

R4 1S selected from the group of -H, -Ci-6 alkyl, -Ci-6 alkyl-C3-6 cycloalkyl, -Ci-6 substituted -Ci-6 alkyl, -Ci-6 alkyl-Qi, -Ci-6 alkyl-C3-6 cycloalkyl-Qi, aryl, heteroaryl,

, -S0 2 R7, -S0 2 NR 2 R 2 , and

wherein G is selected from the group of -0-, -S0 2 - and -NR12-;

wherein Qi is selected from the group of -Ci-6 alkyl, - Ci-6 fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF3, -OR 2 , -COOR 2 , -NRsR?, -CONRsRg and -S0 2 Rv; R5 is selected from the group of -H, -Ci-6 alkyl, -C3-6 cycloalkyl, -Ci-6 alkylsubstituted alkyl, -Ci-e alkyl-NRsRj. -CORB, -S0 2 Rv and -S0 2 NR 2 R 2 ; with the proviso that R4 or R5 is not -CORe when W is -CO-; with the further proviso that only one of R4 or R5 is selected from the group of -CORe, -COCORe,-S0 2 R7 and -S0 2 NR 2 R 2 ; Re is selected from the group of -H, -Ci-6 alkyl, -Ci-6 alkyl-substituted alkyl, -C3-6 cycloalkyl, -C3-6 substitutedcycloalkyl-Q2, -Ci-6 alkyl-Q2, -Ci-6 alkyl-substitutedalkyl- Q2, -C3-6 cycloalkyl-Q2, aryl-Q2, -NR13R14, and -OR15; wherein Q2 is selected from the group of aryl, heteroaryl, substituted

heteroaryl, -OR2, -COOR2, -NR 8 R 9 , SO2R7, -CONHSO2R3, and -CONHSO2NR2R2;

R7 is selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl, -C3-6

cycloalkyl, -CF3, aryl, and heteroaryl;

Rs and R9 are independently selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -Ci-6 alkyl-Q2, and -COOR3, or Rs and R9 are taken together with the adjacent N to form a cycle selected from the group of:

M is selected from the group of -R15, -SO2R2, -SO2NR2R2, -OH and -NR2R12;

V is selected from the group of -CR10R11-, -SO2-, -O- and -NR12-; with the proviso that only one of Rs or R9 can be -COOR3;

Rio and R11 are independently selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl and -C3-6 cycloalkyl;

R12 is selected from the group of -H, -Ci-6 alkyl, -alkylsubstituted Ci-6 alkyl, - CONR2R2, -SO2R3, and -SO2NR2R2; Ri3 and Ri4 are independently selected from the group of -H, -Ci-6 alkyl, -C3-6 cycloalkyl, - Ci-6 substituted alkyl, -Ci-6 alkyl-Q3, -Ci-6 alkyl-C3-6 Cycloalkyl-Q3, and Ci-6 substituted alkyl-Q 3 ; Q3 is selected from the group of heteroaryl, substituted heteroaryl, -NR2R12,

-CONR2R2, -COOR2, -OR2, and -SO2R3;

Ri5 is selected from the group of -Ci-6 alkyl, -C3-6 cycloalkyl, -Ci-6 substituted alkyl, -Ci-6 alkyl-Q3, -Ci-6 alkyl-C3-6 cycloalkyl-Q3 and -Ci-6 substituted alkyl-Q3;

Ri6 is selected from the group of -H, -Ci-6 alkyl, -NR2R2, and -COOR2;

with the proviso that when V is -NR12-; Ri6 is not -NR2R2; and

Ri7 is selected from the group of -H, -Ci-6 alkyl, -COOR3, and aryl.

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; (b) an anti-infective agent; (c) an immunomodulator; and (d) other HIV entry inhibitors. 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: (a) an AIDS antiviral agent; (b) an anti-infective agent; (c) an immunomodulator; and (d) other HIV entry inhibitors.

In another embodiment of the invention there is provided one or more methods for making the compounds of Formula I herein. Also provided herein are intermediate compounds useful in making the compounds of Formula I herein.

The present invention is directed to these, as well as other important ends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

As used herein, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.

Since the compounds of the present invention may possess asymmetric centers and therefore occur as mixtures of diastereomers, the present disclosure includes the individual diastereoisomeric forms of the compounds of Formula I in addition to the mixtures thereof.

Definitions

Unless otherwise specifically set forth elsewhere in the application, one or more of the following terms may be used herein, and shall have the following meanings:

"H" refers to hydrogen, including its isotopes, such as deuterium.

The term "C^ alkyl" as used herein and in the claims (unless specified otherwise) mean straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like.

"Cj -C 4 fluoroalkyl" refers to F-substituted C 1 -C 4 alkyl wherein at least one H atom is substituted with F atom, and each H atom can be independently substituted by F atom;

"Halogen" or "halo" refers to chlorine, bromine, iodine or fluorine. An "aryl" or "Ar" group refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted. When substituted, the substituent group(s) are preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino and -NR x R y , wherein R x and R y are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- or six-member heteroalicyclic ring. A "heteroaryl" group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Unless otherwise indicated, the heteroaryl group may be attached at either a carbon or nitrogen atom within the heteroaryl group. It should be noted that the term heteroaryl is intended to encompass an N-oxide of the parent heteroaryl if such an N-oxide is chemically feasible as is known in the art. Examples, without limitation, of heteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl, benzimidazolyl, indolyl, isoindolyl, pyrazinyl. diazinyl, pyrazine, triazinyl, tetrazinyl, and tetrazolyl. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thioalkoxy, thiohydroxy, thioaryloxy, thioheteroaryloxy,

thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino, and -NR x R y , wherein R x and R y are as defined above. A "heteroalicyclic" group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. Rings are selected from those which provide stable arrangements of bonds and are not intended to encompass systems which would not exist. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi- electron system. Examples, without limitation, of heteroalicyclic groups are azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-l-yl, morpholinyl, thiomorpholinyl and its S oxides and tetrahydropyranyl. When substituted the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl, amino and -NR x R y , wherein R x and R y are as defined above.

An "alkyl" group refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g., "1-20", is stated herein, it means that the group, in this case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from trihaloalkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, and combined, a five- or six-member heteroalicyclic ring.

A "cycloalkyl" group refers to an all-carbon monocyclic or fused ring (i.e., rings which share and adjacent pair of carbon atoms) group wherein one or more rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene and adamantane. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C- thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalo- methanesulfonamido, trihalomethane sulfonyl, silyl, amidino, guanidino, ureido, phosphonyl, amino and -NR x R y with R x and R y as defined above.

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

A "hydroxy" group refers to an -OH group.

An "alkoxy" group refers to both an -O-alkyl and an -O-cycloalkyl group as defined herein.

An "aryloxy" group refers to both an -0-aryl and an -0-heteroaryl group, as defined herein.

A "heteroaryloxy" group refers to a heteroaryl-0- group with heteroaryl as defined herein. A "heteroalicycloxy" group refers to a heteroalicyclic-O- group with

heteroalicyclic as defined herein.

A "thiohydroxy" group refers to an -SH group. A "thioalkoxy" group refers to both an S-alkyl and an -S-cycloalkyl group, as defined herein.

A "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.

A "thioheteroaryloxy" group refers to a heteroaryl-S- group with heteroaryl as defined herein.

A "thioheteroalicycloxy" group refers to a heteroalicyclic-S- group with heteroalicyclic as defined herein.

A "carbonyl" group refers to a -C(=0)-R" group, where R" is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), as each is defined herein.

An "aldehyde" group refers to a carbonyl group where R" is hydrogen.

A "thiocarbonyl" group refers to a -C(=S)-R" group, with R" as defined herein.

A "keto" group refers to a -CC(=0)C- group wherein the carbon on either sides of the C=0 may be alkyl, cycloalkyl, aryl or a carbon of a heteroaryl or heteroalicyclic group.

A "trihalomethanecarbonyl" group refers to a Z3CC(=0)- group with said Z being a halogen.

A "C-carboxy" group refers to a -C(=0)0-R" groups, with R" as defined herein.

An "O-carboxy" group refers to a R"C(-0)0-group, with R" as defined herein. A "carboxylic acid" group refers to a C-carboxy group in which R" is hydrogen.

A "trihalomethyl" group refers to a -CZ3, group wherein Z is a halogen group as defined herein.

A "trihalomethanesulfonyl" group refers to a groups with Z as defined above.

A "trihalomethanesulfonamido" group refers to a group with Z as defined above and R x being H or (Ci-6)alkyl.

A "sulfinyl" group refers to a -S(=0)-R" group, with R" being (Ci-6)alkyl.

A "sulfonyl" group refers to a -S(=0)2R" group with R" being (Ci-6)alkyl.

A "S-sulfonamido" group refers to a with R x and R Y independently being H or (Ci-6)alkyl.

A "N-sulfonamido" group refers to a R"S(=0)2NRx- group, with Rx being H or (Ci- 6 )alkyl.

A "O-carbamyl" group refers to a -OC(=0)NR R y group, with R x and R Y independently being H or (Ci-6)alkyl. A "N-carbamyl" group refers to a ROC(=0)NR group, with R x and R y independently being H or (Ci-6)alkyl.

A "O-thiocarbamyl" group refers to a -OC(=S)NR x R y group, with R x and R y independently being H or (Ci-6)alkyl.

A "N-thiocarbamyl" group refers to a ROC(=S)NR y - group, with R x and R y independently being H or (Ci-6)alkyl. An "amino" group refers to an -NH2 group.

A "C-amido" group refers to a -C(=0)NR x R y group, with R x and R y independently being H or (Ci-6)alkyl.

A "C-thioamido" group refers to a -C(=S)NR x R y group, with R x and R y independently being H or (Ci-6)alkyl.

A "N-amido" group refers to a R x C(=0)NR y - group, with R x and R y independently being H or (Ci-6)alkyl.

An "ureido" group refers to a -NR x C(=0)NR y R y2 group, with R x , R y , and R y2 independently being H or (Ci-6)alkyl. A "guanidino" group refers to a -R x NC(=N)NR y R y2 group, with R x , R y , and R y2 independently being H or (Ci-6)alkyl.

A "amidino" group refers to a R x R y NC(=N)- group, with R x and R y independently being H or (Ci-6)alkyl.

A "cyano" group refers to a -CN group.

A "silyl" group refers to a -Si(R")3, with R" being (Ci-6)alkyl or phenyl.

A "phosphonyl" group refers to a P(=0)(OR x )2 with R x being (Ci-6)alkyl.

A "hydrazino" group refers to a -NR x NR y R y2 group, with R x , R y , and R y2 independently being H or (Ci-6)alkyl.

A "4, 5, or 6 membered ring cyclic N-lactam" group refers to A "spiro" group is a bicyclic organic group with rings connected through just one atom. The rings can be different in nature or identical. The connecting atom is also called the spiroatom, most often a quaternary carbon ("spiro carbon").

An "oxospiro" or "oxaspiro" group is a spiro group having an oxygen contained within the bicyclic ring structure. A "dioxospiro" or "dioxaspiro" group has two oxygens within the bicyclic ring structure. Any two adjacent R groups may combine to form an additional aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initially bearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be

"participating in a heteroaryl ring double bond", and this refers to the form of double bonds in the two tautomeric structures which comprise five-member ring heteroaryl groups. This dictates whether nitrogens can be substituted as well understood by chemists in the art. The disclosure and claims of the present disclosure are based on the known general principles of chemical bonding. It is understood that the claims do not encompass structures known to be unstable or not able to exist based on the literature.

Pharmaceutically acceptable salts and prodrugs of compounds disclosed herein are within the scope of the invention. The term "pharmaceutically acceptable salt" as used herein and in the claims is intended to include nontoxic base addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and the like. The term

"pharmaceutically acceptable salt" as used herein is also intended to include salts of acidic groups, such as a carboxylate, with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)- aminomethane), or with bases such as piperidine or moφholine.

As stated above, the compounds of the invention also include "prodrugs". The term "prodrug" as used herein encompasses both the term "prodrug esters" and the term "prodrug ethers".

As set forth above, the invention is directed to a compound, including of, which is selected from a compound of Formula

wherein Ri is isopropenyl or isopropyl; A is -Ci-e alkyl-ORo; wherein Ro is heteroaryl-Qo;

Qo is selected from the group of -H, -CN, -Ci-6 alkyl, -COOH, -Ph, -OCi-6 alkyl, -halo, -

Y is selected from the group of -COORi, -C(0)NR2S0 2 R3, -C(0)NHS0 2 NR 2 R2, - S02NR2C(0)R2, -tetrazole, and -CONHOH;

R2 is -H, -Ci-6 alkyl, -alkylsubstituted Ci-6 alkyl or-arylsubstituted Ci-6 alkyl;

W is absent, or is -CH2- or -CO-;

R3 is -H, -Ci-6 alkyl or -alkylsubstituted Ci-6 alkyl; R4 1S selected from the group of -H, -Ci-6 alkyl, -Ci-6 alkyl-C3-6 cycloalkyl, -Ci-6 substituted -Ci-6 alkyl, -Ci-6 alkyl-Qi, -Ci-6 alkyl-C3-6 cycloalkyl-Qi, aryl, heteroaryl,

, -SO2R7, -SO2NR2R2, and

wherein G is selected from the group of -0-, -SO2- and -NR12-;

wherein Qi is selected from the group of -Ci-6 alkyl, - Ci-6 fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF3, -OR2, -COOR2, -NRsR -CONRsRg and -SO2R7;

R5 is selected from the group of -H, -Ci-6 alkyl, -C3-6 cycloalkyl, -Ci-6 alkylsubstituted alkyl, -Ci-e alkyl-NRsRj. -CORB, -SO2R7 and -SO2NR2R2; with the proviso that R4 or R5 is not -COR5 when W is -CO-; with the further proviso that only one of R4 or R5 is selected from the group

of -CORe, -COCOR6,-S0 2 R7 and -SO2NR2R2;

Re is selected from the group of -H, -Ci-6 alkyl, -Ci-6 alkyl-substitutedalkyl, -C3-6 cycloalkyl, -C3-6 substitutedcycloalkyl-Q2, -Ci-6 alkyl-Q2, -Ci-6 alkyl-substitutedalkyl- Q2,-C3-6 cycloalkyl-Q2, aryl-Q2, -NR13R14, and -OR15; wherein Q2 is selected from the group of aryl, heteroaryl, substituted heteroaryl, - OR2, -COOR2, -NR8R9, SO2R7, -CONHSO2R3, and -CONHSO2NR2R2;

R7 is selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl, -C3-6

cycloalkyl, -CF3, aryl, and heteroaryl;

Rs and R9 are independently selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -Ci-6 alkyl-Q2, and -COOR3, or Rs and R9 are taken together with the adjacent N to form a cycle selected from the group of:

M is selected from the group of -R15, -SO2R2, -SO2NR2R2, -OH and -NR2R12;

V is selected from the group of -CR10R11-, -SO2-, -O- and -NR12-; with the proviso that only one of Rs or R9 can be -COOR3;

Rio and R11 are independently selected from the group of -H, -Ci-6 alkyl, -Ci-6 substituted alkyl and -C3-6 cycloalkyl;

R12 1S selected from the group of -H, -Ci-6 alkyl, -alkylsubstituted Ci-6 alkyl, -CONR2R2, -SO2R3, and -SO2NR2R2; Ri3 and Ri4 are independently selected from the group of -H, -Ci-6 alkyl, -C3-6 cycloalkyl, - Ci-6 substituted alkyl, -Ci-6 alkyl-Q3, -Ci-6 alkyl-C3-6 Cycloalkyl-Q3, and Ci-6 substituted alkyl-Q 3 ; Q3 is selected from the group of heteroaryl, substituted heteroaryl, -NR2R12,

-CONR2R2, -COOR2, -OR2, and -SO2R3;

Ri5 is selected from the group of -Ci-6 alkyl, -C3-6 cycloalkyl, -Ci-6 substituted alkyl, -Ci-6 alkyl-Q3, -Ci-6 alkyl-C3-6 cycloalkyl-Q3 and -Ci-6 substituted alkyl-Q3;

Ri6 is selected from the group of -H, -Ci-6 alkyl, -NR2R2, and -COOR2;

with the proviso that when V is -NR12-; Ri6 is not -NR2R2; and

Ri7 is selected from the group of -H, -Ci-6 alkyl, -COOR3, and aryl.

In a preferred embodiment of the invention, Ri is isopropenyl.

It is also preferred that Y is -COOR2. More preferably, R2 in this embodiment is

H.

In another preferred embodiment of the invention, in the Ro group the "heteroaryl moiety is preferably selected from the group of:

It is also preferred that there is no intervening alkyl group or other substituent group between the -O moiety and the Ro group in substituent A. It is further preferred that R4 is -Ci-6 alkyl-Qi .

Also preferred is the embodiment wherein Qi is -NRsRsi.

Additionally, when Rs and R9 are taken together with the adjacent -N to form cycle, the preferred cycle will be selected from the group of:

and O

In some embodiments it is also preferred that Qo is -CN.

In another preferred embodiment, Ri is isopropenyl, in the Ro group the

"heteroaryl" moiety is selected from the group of:

Y is -COOH, R4 is -Ci-6 alkyl-Qi, Qi is -NRsRsi, and Rs and R9 are taken together with the adjacent -N to form a cycle which is selected from the group of:

In this embodiment, it is also preferred that R7 and Ri6 are each -H or -Ci-6 alkyl. Preferred compounds, including pharmaceutically acceptable salts thereof, as part

In another embodiment, preferred compounds, including pharmaceutically acceptable salts thereof, will be the following:

The compounds above represent the mixture of diastereoisomers, and the two individual disastereomers. In certain embodiments, one of the specific diastereomers may be particularly preferred. The compounds of the present invention, according to all the various embodiments described above, may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, and by other means, in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, excipients and diluents available to the skilled artisan. One or more adjuvants may also be included.

Thus, in accordance with the present invention, there is further provided a method of treatment, and a pharmaceutical composition, for treating viral infections such as HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition which contains an antiviral effective amount of one or more of the compounds of Formula I together with one or more pharmaceutically acceptable carriers, excipients or diluents. As used herein, the term "antiviral effective amount" means the total amount of each active component of the composition and method that is sufficient to show a meaningful patient benefit, i.e., inhibiting, ameliorating, or healing of acute conditions characterized by inhibition of HIV infection. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. The terms "treat, treating, treatment" as used herein and in the claims means preventing, inhibiting, ameliorating and/or healing diseases and conditions associated with HIV infection.

The pharmaceutical compositions of the invention may be in the form of orally administrable suspensions or tablets; as well as nasal sprays, sterile injectable

preparations, for example, as sterile injectable aqueous or oleaginous suspensions or suppositories. Pharmaceutically acceptable carriers, excipients or diluents may be utilized in the pharmaceutical compositions, and are those utilized in the art of pharmaceutical preparations. When administered orally as a suspension, these compositions are prepared according to techniques typically known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

The compounds herein set forth can be administered orally to humans in a dosage range of about 1 to 100 mg/kg body weight in divided doses, usually over an extended period, such as days, weeks, months, or even years. One preferred dosage range is about 1 to 10 mg/kg body weight orally in divided doses. Another preferred dosage range is about 1 to 20 mg/kg body weight in divided doses. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Also contemplated herein are combinations of the compounds of Formula I herein set forth, together with one or more other agents useful in the treatment of AIDS. For example, the compounds of this disclosure may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, antiinfectives, or vaccines, such as those in the following non-limiting table: ANTIVIRALS

Drug Name Manufacturer Indication 097 Hoechst/Bayer HIV infection,

AIDS. ARC

(non-nucleoside reverse transcriptase (RT) inhibitor)

Amprenavir Glaxo Wellcome HIV infection,

141 W94 AIDS, ARC

GW 141 (protease inhibitor)

Abacavir (1592U89) Glaxo Wellcome HIV infection, GW 1592 AIDS, ARC

(RT inhibitor) Acemannan Carrington Labs ARC

(Irving, TX)

Acyclovir Burroughs Wellcome HIV infection, AIDS,

ARC

AD-439 Tanox Biosystems HIV infection, AIDS,

ARC

AD-519 Tanox Biosystems HIV infection, AIDS,

ARC

Adefovir dipivoxil Gilead Sciences HIV infection

AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDS

Alpha Interferon Glaxo Wellcome Kaposi's sarcoma,

HIV in combination w/Retrovir

Ansamycin Adria Laboratories ARC

LM 427 (Dublin, OH)

Erbamont

(Stamford, CT)

Antibody which Advanced Biotherapy AIDS, ARC

Neutralizes pH Concepts

Labile alpha aberrant (Rockville, MD)

Interferon

AR177 Aronex Pharm HIV infection, AIDS,

ARC

Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated

diseases

BMS-234475 Bristol-Myers Squibb/ HIV infection,

(CGP-61755) Novartis AIDS, ARC

(protease inhibitor)

CI-1012 Warner-Lambert HIV-1 infection

Cidofovir Gilead Science CMV retinitis,

herpes, papillomavirus

Curdlan sulfate AJI Pharma USA HIV infection

Cytomegalovirus Medlmmune CMV retinitis Immune globin

Cytovene Syntex Sight threatening Ganciclovir CMV

peripheral CMV retinitis

Darunavir Tibotec- J & J HIV infection, AIDS, ARC

(protease inhibitor)

Delaviridine Pharmacia-Upj ohn HIV infection,

AIDS, ARC

(RT inhibitor)

Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV

Ind. Ltd. (Osaka, positive

Japan) asymptomatic ddC Hoffman-La Roche HIV infection, AIDS,

Dideoxycytidine ARC ddl Bristol-Myers Squibb HIV infection, AIDS,

Dideoxyinosine ARC; combination

with AZT/d4T

DMP-450 AVID HIV infection,

(Camden, NJ) AIDS, ARC

(protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection,

(DMP 266, SUSTIVA ® ) AIDS, ARC

(-)6-Chloro-4-(S)- (non-nucleoside RT cyclopropylethynyl- inhibitor)

4(S)-trifluoro- methyl- 1 ,4-dihydro- 2H-3 , 1 -benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection

(Gainesville, GA)

Etravirine Tibotec/ J & J HIV infection, AIDS, ARC

(non-nucleoside reverse transcriptase inhibitor)

Famciclovir Smith Kline herpes zoster,

herpes simplex

GS 840 Gilead HIV infection,

AIDS, ARC

(reverse transcriptase inhibitor)

HBY097 Hoechst Marion HIV infection,

Roussel AIDS, ARC

(non-nucleoside reverse transcriptase inhibitor)

Hypericin VIMRx Pharm. HIV infection, AIDS,

ARC Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC

Interferon alfa-n3 Interferon Sciences ARC, AIDS

Indinavir Merck HIV infection, AIDS,

ARC, asymptomatic HIV positive, also in combination with AZT/ddl/ddC

ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc. diseases Lamivudine. 3TC Glaxo Wellcome HIV infection,

AIDS, ARC

(reverse

transcriptase inhibitor); also with AZT

Lobucavir Bristol-Myers Squibb CMV infection

Nelfinavir Agouron HIV infection,

Pharmaceuticals AIDS, ARC

(protease inhibitor) Nevirapine Boeheringer HIV infection,

Ingleheim AIDS, ARC

(RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor

(Akron, OH)

Peptide T Peninsula Labs AIDS

Octapeptide (Belmont, CA)

Sequence

Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc. infection, other CMV infections

PNU- 140690 Pharmacia Upjohn HIV infection,

AIDS, ARC

(protease inhibitor)

Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection,

Tech (Houston, TX) AIDS, ARC

Ritonavir Abbott HIV infection,

AIDS, ARC

(protease inhibitor) Saquinavir Hoffmann- HIV infection,

LaRoche AIDS, ARC

(protease inhibitor)

Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS. Didehydrodeoxy- ARC

Thymidine

Tipranavir Boehringer Ingelheim HIV infection, AIDS. ARC (protease inhibitor)

Valaciclovir Glaxo Wellcome Genital HSV & CMV

infections

Virazole Viratek/ICN asymptomatic HIV

Ribavirin (Costa Mesa, CA) positive, LAS, ARC

VX-478 Vertex HIV infection, AIDS,

ARC

Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,

ARC, with AZT

Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS,

ARC, Kaposi's

sarcoma, in combination with other therapies

Tenofovir disoproxil, HIV infection,

fumarate salt (VIREAD ® ) AIDS,

(reverse transcriptase inhibitor)

EMTRIVA ® Gilead HIV infection,

(Emtricitabine) (FTC) AIDS,

(reverse transcriptase inhibitor)

COMBIVIR c GSK HIV infection,

AIDS,

(reverse transcriptase inhibitor) Abacavir succinate GSK HIV infection,

(or ZIAGEN ® ) AIDS,

(reverse transcriptase inhibitor)

REYATAZ ® Bristol-Myers Squibb HIV infection

(or atazanavir) AIDs, protease

inhibitor

FUZEON ® Roche / Trimeris HIV infection

(Enfuvirtide AIDs, viral Fusion

inhibitor

LEXIVA ® GSK/Vertex HIV infection

(or Fosamprenavir calcium) AIDs, viral protease

inhibitor

Selzentry

Maraviroc; (UK 427857) Pfizer HIV infection

AIDs, (CCR5 antagonist, in development)

Trizivir ( GSK HIV infection

AIDs, (three drug combination)

Sch-417690 (vicriviroc) Schering-Plough HIV infection

AIDs, (CCR5 antagonist, in development) TAK-652 Takeda HIV infection

AIDs, (CCR5 antagonist, in development) GSK 873140 GSK/ONO HIV infection

(ONO-4128) AIDs, (CCR5 antagonist in development)

Integrase Inhibitor Merck HIV infection

MK-0518 AIDs

Raltegravir

TRUVADA' Gilead Combination of Tenofovir disoproxil fumarate salt (VIREAD ® ) and EMTRIVA' (Emtricitabine)

Integrase Inhibitor Gilead/Japan Tobacco HIV Infection

GS917/JTK-303 AIDs

Elvitegravir in development

Triple drug combination Gilead/Bristol-Myers Squibb Combination of Tenofovir

ATRIPLA disoproxil fumarate salt

(VIREAD ® ), EMTRIVA' (Emtricitabine), and

SUSTIVA ® (Efavirenz)

FESTINAVIR Oncolys BioPharma HIV infection

4'-ethynyl-d4T BMS AIDs

in development CMX-157 Chimerix HIV infection

Lipid conjugate of AIDs

nucleotide tenofovir GSK1349572 GSK HIV infection

Integrase inhibitor AIDs

dolutegravir

S/GSK 1265744 GSK HIV infection Integrase inhibitor AIDs

IMMUNOMODULATORS

Drug Name Manufacturer Indication

AS-101 Wyeth-Ayerst AIDS

Bropirimine Pharmacia Upjohn Advanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC

(Irving, TX)

CL246,738 Wyeth AIDS, Kaposi's

Lederle Labs sarcoma

FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4+ cells

Gamma Interferon Genentech ARC, in combination w/TNF (tumor necrosis factor)

Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz

Stimulating Factor

Granulocyte Hoechst-Roussel AIDS

Macrophage Colony Immunex

Stimulating Factor

Granulocyte Schering-Plough AIDS,

Macrophage Colony combination Stimulating Factor w/AZT

HIV Core Particle Rorer Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination

Interleukin-2 w/AZT

IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in

Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in

Interleukin-2 CD4 cell counts (aldeslukin)

Immune Globulin Cutter Biological Pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human)

IMREG-1 Imreg AIDS, Kaposi's

(New Orleans, LA) sarcoma, ARC, PGL

IMREG-2 Imreg AIDS, Kaposi's

(New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl Merieux Institute AIDS, ARC

Dithio Carbamate

Alpha-2 Schering Plough Kaposi's sarcoma Interferon w/AZT, AIDS

Methionine- TNI Pharmaceutical AIDS, ARC

Enkephalin (Chicago, IL)

MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramy 1 -Tripeptide

Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT

Factor

Re ame Immune Response Immunotherapeutic

Corp. rCD4 Genentech AIDS, ARC

Recombinant

Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids

Recombinant Biogen AIDS, ARC

Soluble Human CD4

Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC,

in combination w/AZT SK&F 106528 Smith Kline HIV infection Soluble T4

Thymopentin Immunobiology HIV infection

Research Institute

(Annandale. NJ)

Tumor Necrosis Genentech ARC, in combination Factor: TNF w/gamma Interferon

ANTI-INFECTIVES

Drug Name Manufacturer Indication

Clindamycin Pharmacia Upjohn PCP

Primaquine

Fluconazole Pfizer Cryptococcal

meningitis.

candidiasis

Pastille Squibb Corp. Prevention of

Nystatin Pastille oral candidiasis

Ornidyl Merrell Dow PCP

Eflornithine

Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim Antibacterial

Trimethoprim/sulfa Antibacterial Piritrexim Burroughs Wellcome PCP treatment

Pentamidine Fisons Corporation PCP prophylaxis

Isethionate for

Inhalation

Spiramycin Rhone-Poulenc Cryptosporidia! diarrhea

Intraconazole Janssen-Pharm. Histoplasmosis;

R51211 cryptococcal

meningitis

Trimetrexate Warner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcoma

Recombinant Human Ortho Pharm. Corp. Severe anemia

Erythropoietin assoc. with AZT

therapy

Recombinant Human Serono AIDS-related

Growth Hormone wasting, cachexia

Megestrol Acetate Bristol-Myers Squibb Treatment of

anorexia assoc.

W/AIDS

Testosterone Alza, Smith Kline AIDS-related wasting

Total Enteral Norwich Eaton Diarrhea and

Nutrition Pharmaceuticals malabsorption

related to AIDS Additionally, the compounds of the disclosure herein set forth may be used in combination with HIV entry inhibitors. Examples of such HIV entry inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194 and Inhibitors of the entry of HIV into host cells. Meanwell, Nicholas A.;

Kadow, John F., Current Opinion in Drug Discovery & Development (2003), 6(4), 451- 461. Specifically the compounds can be utilized in combination with attachment inhibitors, fusion inhibitors, and chemokine receptor antagonists aimed at either the CCR5 or CXCR4 coreceptor. HIV attachment inhibitors are also set forth in US 7,354,924 and US 7,745,625.

It will be understood that the scope of combinations of the compounds of this application with AIDS antivirals, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines is not limited to the list in the above Table but includes, in principle, any combination with any pharmaceutical composition useful for the treatment of AIDS.

Preferred combinations are simultaneous or alternating treatments with a compound of the present disclosure and an inhibitor of HIV protease and/or a non- nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddl. A preferred inhibitor of HIV protease is REYATAZ ® (active ingredient Atazanavir). Typically a dose of 300 to 600 mg is administered once a day. This may be co-administered with a low dose of Ritonavir (50 to 500mgs). Another preferred inhibitor of HIV protease is KALETRA ® . Another useful inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-l-(S)-indanyl)-2(R)-phenylmethyl-4-(S)- hydroxy-5-(l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxami do)-piperazinyl))- pentaneamide ethanolate, and is synthesized according to U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non- nucleoside inhibitors of HIV reverse transcriptase include efavirenz. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddl and/or ddC; (2) indinavir, and any of AZT and/or ddl and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) tenofovir disoproxil fumarate salt and emtricitabine.

In such combinations the compound(s) of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

GENERAL CHEMISTRY (METHODS OF SYNTHESIS)

The present invention comprises compounds of Formula I, their pharmaceutical formulations, and their use in patients suffering from or susceptible to HIV infection. The compounds of Formula I also include pharmaceutically acceptable salts thereof.

Procedures to construct compounds of Formula I and intermediates useful for their synthesis are described after the Abbreviations.

Abbreviations

One or more of the following abbreviations, most of which are conventional abbreviations well known to those skilled in the art, may be used throughout the description of the disclosure and the examples:

RT = room temperature

BHT = 2,6-di-tert-butyl-4-hydroxytoluene

CSA = camphorsulfonic acid

LDA = lithium diisopropylamide

KHMDS = potassium bis(trimethylsilyl)amide

SFC = supercritical fluid chromatography

Quant = quantitative

TBDMS = tert-butyldimethylsilane

PTFE = polytetrafluoroethylene

NMO = 4-methylmorpholine-N-oxide THF = tetrahydrofuran

TLC = thin layer chromatography

DCM = dichloromethane

DCE = dichloroethane

TFA = trifluoroacetic acid

LCMS = liquid chromatograph)' mass spectroscopy

Prep = preparative

HPLC = high performance liquid chromatography

DAST = (diethylamino)sulfur trifluoride

TEA = triethylamine

DIPEA = N,N-diisopropylethylamine

HATU = [0-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate]

DCC = N.N'-dicyclohexylcarbodiimide

DMAP = dimethylaminopyridine

TMS = trimethylsilyl

NMR = nuclear magnetic resonance

DPPA = diphenyl phosphoryl azide

AIBN = azobisisobutyronitrile

TBAF = tetrabutylammonium fluoride

DMF = dimethylformamide

TBTU = 0-(benzotriazol-l-yl)-NNN'N'-tetramethyluronium tetrafluoroborate

Min(s) = minute(s)

h = hour(s)

sat. = saturated

TEA = triethylamine

EtOAc = ethyl acetate

TFA = trifluoroacetic acid

PCC = pyridinium chlorochromate

TLC = thin layer chromatography

TfVNPh = (trifluoromethylsulfonyl)methanesulfonamide

dioxane = 1,4-dioxane

PG = protective group

atm = atmosphere(s) mol = mole(s)

mmol= milimole(s)

mg = milligram(s)

μg = micrograni(s)

μΐ = microliter(s)

micrometer(s)

mm= millimeter(s)

Rpm = revolutions per minute

SM = starting material

TLC = thin layer chromatography

AP = area percentage

Equiv. = equivalent s)

DMP = Dess-Martin periodinane

TMSC1 = trimethylsilyl chloride

TBSC1 = tert-Butyldimethylsilyl chloride

TBSOTf = trimethylsilyl trifluoromethanesulfonate

PhMe = toluene

PhNTf2 = N-Phenyl-bis(trifluoromethanesulfonimide)

S-Phos = 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl

TFDO = methyl(trifluoromethyl)dioxirane

TEMPO = 2.2,6,6-tetramethylpiperidinyloxy

DI = deionized water

The terms "C-3" and '"C-28" refer to certain positions of a triterpene core as numbered in accordance with IUPAC rules (positions depicted below with respect to illustrative triterpene: betulin):

The same numbering is maintained when referring to the compound series in schemes and general descriptions of methods.

EXAMPLES

The following examples illustrate typical syntheses of the compounds of Formula I as described generally above. These examples are illustrative only and are not intended to limit the disclosure in any way. The reagents and starting materials are readily available to one of ordinary skill in the art.

Chemistry

Typical Procedures and Characterization of Selected Examples:

Unless otherwise stated, solvents and reagents were used directly as obtained from commercial sources, and reactions were performed under a nitrogen atmosphere. Flash chromatography was conducted on Silica gel 60 (0.040-0.063 particle size; EM Science supply). ¾ NMR spectra were recorded on Bruker DRX-500f at 500 MHz (or Bruker AV 400 MHz, Bruker DPX-300B, or Varian Gemini 300 at 300 MHz as stated). The chemical shifts were reported in ppm on the δ scale relative to 5TMS = 0. The following internal references were used for the residual protons in the following solvents: CDCb (5H 7.26), CD3OD (δ Η 3.30), acetic-d4 (Acetic Acid d 4 ) (δ Η 11.6, 2.07), DMSO mix or DMSO-D6- CDCb (δ Η 2.50 and 8.25) (ratio 75%:25%), and DMSO-D6 (δ Η 2.50). Standard acronyms were employed to describe the multiplicity patterns: s (singlet), br. s (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b (broad), app (apparent). The coupling constant (J) is in Hertz. All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector with Mass Spectrometry (MS) data determined using a Micromass Platform for LC in electrospray mode.

LCMS Methods

LCMS Method 1 :

Start % B = 0

Final % B = 100

Gradient Time = 2 min

Flow Rate = 1 mL/min

Wavelength = 220 nm

Solvent A = 10% Me OH - 90% H2O - 0.1% TFA

Solvent B = 90% MeOH - 10% H2O - 0.1% TFA

Column = Phenomenex CI 8 2.0 x 30mm 3μιη

LCMS Method 2:

Start % B = 20

Final % B = 100

Gradient Time = 3 min

Flow Rate = 0.6 mL/min

Wavelength = 220 nm

Solvent A = 10% MeOH - 90% H2O - 0.1% TFA Solvent B = 90% MeOH - 10% H 2 0 - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 μιη

LCMS Method 3:

Start % B = 20

Final % B = 100

Gradient Time = 2 min

Flow Rate = 0.6 mL/min

Wavelength = 220 nm

Solvent A = 10% MeOH - 90% H 2 0 - 0.1% TFA Solvent B = 90% MeOH - 10% H 2 0 - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 μιη

LCMS Method 4:

Start % B = 0

Final % B = 100

Gradient Time = 4 min

Flow Rate = 0.8 mL/min

Wavelength = 220 nm

Solvent A = 10% MeOH - 90% H2O - 0.1% TFA

Solvent B = 90% MeOH - 10% H2O - 0.1% TFA

Column = Phenomenex CI 8 2.0 x 50mm 3 μιη

LCMS Method 5:

Start % B = 20

Final % B = 100

Gradient Time = 3 min

Flow Rate = 0.8 mL/min

Wavelength = 220 nm

Solvent A = 10% MeOH - 90% H2O - 0.1% TFA

Solvent B = 90% MeOH - 10% H2O - 0.1% TFA

Column = Phenomenex CI 8 2.0 x 50mm 3 μιη LCMS Method 6:

Start % B = 20

Final % B = 100

Gradient Time = 2 min

Flow Rate = 0.8 niL/min

Wavelength = 220 nm

Solvent A = 10% Me OH - 90% H20 - 0.1% TFA Solvent B = 90% MeOH - 10% H20 - 0.1% TFA Column = Phenomenex C18 2.0 X 50 mm 3 μιη

LCMS Method 7:

Start % B = 20

Final % B = 100

Gradient Time = 2 min

Flow Rate = 0.5 mL/min

Wavelength = 220 nm

Solvent A = 10% MeOH - 90% H20 - 0.1% TFA Solvent B = 90% MeOH - 10% H20 - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 μιη

LCMS Method 8:

Start % B = 20

Final % B = 100

Gradient Time = 2 min

Flow Rate = 0.8 mL/min

Wavelength = 220 nm

Solvent A = 10% MeOH - 90% H20 - 0.1% TFA Solvent B = 90% MeOH - 10% H20 - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 μιη

LCMS Method 9: Start % B = 0

Final % B = 100

Gradient Time = 2 min

Flow Rate = 1.0 mL/min

Wavelength = 220 nm

Solvent A = 5% MeCN - 95% H20 - 10 mM Ammonium Acetate Solvent B = 95% MeCN - 5% H20 - 10 mM Ammonium Acetate Column = PHENOMENEX-LUNA C18 2.0 X 30mm 3 μιη LCMS Method 10:

Start % B = 0

Final % B = 100

Gradient Time = 4 min

Flow Rate = 0.6 mL/min

Wavelength = 220 nm

Solvent A = 10% Me OH - 90% H20 - 0.1% TFA

Solvent B = 90% MeOH - 10% H20 - 0.1 % TFA

Column = Xbridge Phenyl 2.1 X 50 mm 2.5 μιη LCMS Method 11 :

Start % B = 0

Final % B = 100

Gradient Time = 4 min

Flow Rate = 0.8 mL/min

Wavelengtli = 220 nm

Solvent A = 10% MeOH - 90% H20 - 0.1% TFA

Solvent B = 90% MeOH - 10% H20 - 0.1% TFA

Column = Phenomenex C18 2.0 X 50 mm 3 μιη LCMS Method 12:

Start % B = 40

Final % B = 60 Gradient Time = 4 min

Flow Rate = 0.8 mL/min

Wavelength = 254 nm

Solvent A = 10% Me OH - 90% H20 - 0.1% TFA

Solvent B = 90% MeOH - 10% H20 - 0.1% TFA

Column = Xbridge Phenyl 2.1 X 50 mm 2.5 μιη

LCMS Method 13:

Start % B = 35

Final % B = 100

Gradient Time = 4 min

Flow Rate = 0.8 mL/min

Wavelength = 220 nm

Solvent A = 10% MeOH - 90% H20 - 0.1% TFA

Solvent B = 90% MeOH - 10% H20 - 0.1% TFA

Column = Phenomenex C18 2.0 X 50 mm 3 μιη

LCMS Method 14

Conditions: 0% B→ 100% B over 4 minute gradient; hold at 100% B for 1 min Solvent A: 90% water, 10% methanol, 0.1% TFA

Solvent B: 10% water, 90% methanol, 0.1% TFA

Column: Phenomenex Luna CI 8, 3 mm, 2.0 x 50 mm

Flow Rate: 1 mL / min

Detector Wavelength: 220 nm

LCMS Method 15

Conditions: 0% B→ 100% B over 2 minute gradient; hold at 100% B for 1 min Solvent A: 90% water, 10% methanol, 0.1% TFA

Solvent B: 10% water, 90% methanol, 0.1% TFA

Column: Phenomenex Luna C18, 2.0 x 50 mm, 3 um

Flow Rate: 1 mL / min

Detector Wavelength: 220 nm LCMS Method 16

Start %B = 2, Final %B = 98 over 1.5 minute gradient; hold at 98%B for 0.5 min Flow Rate = 0.8 mL / min

Detector Wavelength = 220 nm

Solvent A = 100% water, 0.05% TFA

Solvent B = 100% acetonitrile, 0.05% TFA

Column = Waters Aquity UPLC BEH C18 2.1 X 50 mm 1.7 um

Oven temp = 40 °C

LCMS Method 17

Start %B = 2, Final %B = 98 over 3 minute gradient; hold at 98%B for 1 min Flow Rate = 0.8 mL / min

Detector Wavelength = 220 nm

Solvent A = 100% water, 0.05% TFA

Solvent B = 100% acetonitrile, 0.05% TFA

Column = Waters Aquity UPLC BEH C 18, 2.1 x 50 mm, 1.7 μιη

Oven temp = 40 °C LCMS Method 18

Start %B = 0, Final %B = 100 over 4 minute gradient; hold at 100%B for 1 min Flow Rate = 0.8 mL / min

Detector Wavelength = 220 nm

Solvent A = 95% water, 5% acetonitrile, 10 mM ammonium acetate

Solvent B = 5% water, 95% acetonitrile, 10 mM ammonium acetate

Column = Phenomenex Luna CI 8, 50 x 2 mm, 3 μιη

Oven temp = 40 °C

LCMS Method 19

Start %B = 2, Final %B = 98 over 4 minute gradient; hold at 98%B for 1 min Flow Rate = 0.8 mL / min

Detector Wavelength = 220 nm Solvent A = 100% water, 0.05% TFA

Solvent B = 100% acetonitrile, 0.05% TFA

Column = Waters Aquity UPLC BEH C 18, 2.1 x 50 mm, 1.7 μιη

Oven temp = 40 °C

LCMS Method 20

Start %B = 2, Final %B = 98 over 2 minute gradient; hold at 98%B for 1 min Flow Rate = 0.8 mL / min

Detector Wavelength = 220 nm

Solvent A = 100% water, 0.05% TFA

Solvent B = 100% acetonitrile, 0.05% TFA

Column = Waters Aquity UPLC BEH C 18, 2.1 x 50 mm, 1.7 μιη

Oven temp = 40 °C LCMS Method 21

Start %B = 0, Final %B = 100 over 2 minute gradient; hold at 100%B for 3 min Flow Rate = 0.8 mL / min

Detector Wavelength = 220 nm

Solvent A = 95% water, 5% acetonitrile, 10 mM ammonium acetate

Solvent B = 5% water, 95% acetonitrile, 10 mM ammonium acetate

Column = Phenomenex Luna CI 8, 50 x 2 mm, 3 μιη

Oven temp = 40 °C

Preparative HPLC Methods

Preparative HPLC Method 1

Conditions: 30% B→ 100% B over 20 minute gradient; hold at 100% B for 4 min Solvent A: 5% acetonitrile, 95% water, 0.1% TFA

Solvent B: 95% acetonitrile, 5% water 0.1% TFA

Column: Waters Xbridge 30 x 100 mm, 5 μιη

Flow Rate: 40 mL/min

Detector Wavelength: 220 nm Preparative HPLC Method 2

Conditions: 10% B→ 100% B over 25 minute gradient

Solvent A: 5% acetonitrile, 95% water, 0.1% TFA

Solvent B: 95% acetonitrile, 5% water 0.1% TFA

Column: Waters Sunfire 30 x 150 mm, 5 um

Flow Rate: 40 mL/min

Detector Wavelength: 220 nm Preparative HPLC Method 3

Conditions: 10% B→ 100% B over 20 minute gradient; hold at 100% B for 5 min

Solvent A: 5% acetonitrile, 95% water, 0.1% TFA

Solvent B: 95% acetonitrile, 5% water 0.1% TFA

Column: Waters Sunfire 30 x 150 mm, 5 um

Flow Rate : 40 mL/min

Detector Wavelength: 220 nm

Preparative HPLC Method 4

Conditions: 30% B→ 100% B over 20 minute gradient; hold at 100% B for 5 min Solvent A: 5% acetonitrile, 95% water, 0.1% TFA

Solvent B: 95% acetonitrile, 5% water 0.1% TFA

Column: Waters Sunfire 30 x 150 mm, 5 um

Flow Rate: 40 mL/min

Detector Wavelength: 220 nm

Preparative HPLC Method 5:

Start % B = 20, Final % B = 100 over 10 min gradient, hold at 100% B for 4 min

Flow Rate = 50 ml/min

Wavelength = 220

Solvent Pair = Water - acetonitrile- TFA

Solvent A = 90% Water -10% acetonitrile-0.1% TFA

Solvent B = 10% Water -90% acetonitrile-0.1% TFA

Column = Waters Sunfire CI 8, 5 μπι, 30 x 150 mm Preparative HPLC Method 6

Conditions: 0% B→ 100% B over 20 minute gradient

Solvent A: 10% acetonitrile, 90% water, 0.1% TFA

Solvent B: 90% acetonitrile, 10% water 0.1% TFA

Column: Waters Sunfire C18, 30 x l50 mm, 5 μιη

Flow Rate: 50 mL/min

Detector Wavelength: 220 nm Preparative HPLC Method 7

Conditions: 30% B→ 100% B over 20 minute gradient

Solvent A: 10% acetonitrile, 90% water, 0.1% TFA

Solvent B: 90% acetonitrile, 10% water 0.1% TFA

Column: Waters Sunfire C18, 30 x l50 mm, 5 μπι

Flow Rate: 50 mL/min

Detector Wavelength: 220 nm

Preparative HPLC Method 8

Conditions: 20% B→ 100% B over 15 minute gradient

Solvent A: 10% acetonitrile, 90% water, 0.1% TFA

Solvent B: 90% acetonitrile, 10% water 0.1% TFA

Column: Waters Sunfire C18, 30 x l50 mm, 5 μπι

Flow Rate: 50 mL/min

Detector Wavelength: 220 nm

Preparative MPLC Methods Preparative MPLC Method 1

Conditions: 30% B for 1 column volume, 30%B to 80%B gradient over 7 column volumes, 80%B to 100%B gradient over 0.5 column volumes, 100%B for 2 column volumes

Solvent A = 5% acetonitrile, 95% water, 0.1% TFA Solvent B = 95% acetonitrile, 5% water 0.1% TFA

Column = Redi Sep Gold (150 g)

Flow Rate = 60 mL/min

Detector Wavelength = 220 nm

Preparative MPLC Method 2

Conditions: 30% B for 1 column volume, 30%B to 80%B gradient over 10 column volumes, 100%B for 2 column volumes

Solvent A = 5% acetonitrile, 95% water, 0.1% TFA

Solvent B = 95 % acetonitrile, 5 % water 0.1% TFA

Column = Redi Sep Gold (150 g)

Flow Rate = 60 mL/min

Detector Wavelength = 220 nm Analytical HPLC Methods

Analytical HPLC Method 1

Conditions: 10% B→ 100% B over 15 min gradient; hold at 100% B for 10 min Solvent A: 10% methanol, 90% water, 0.1% TFA

Solvent B : 90% methanol, 10% water, 0.1% TFA

Column: Waters Sunfire C18, 4.6 x l50 mm, 3.5 mm

Flow Rate: 1 mL/min

Detector Wavelength: 220 nm Analytical HPLC Method 2

Conditions: 10% B→ 100% B over 15 min gradient; hold at 100% B for 10 min

Solvent A: 10% methanol, 90% water, 0.1% TFA

Solvent B: 90% methanol, 10% water, 0.1% TFA

Column: Waters Xbridge phenyl, 4.6 x 150 mm, 3.5 mm

Flow Rate: 1 mL/min

Detector Wavelength: 220 nm

Analytical HPLC Method 3 Conditions: 10% B→ 100% B over 15 min gradient; hold at 100% B for 10 min Solvent A: 5% acetonitrile, 95% water, 0.1% TFA

Solvent B: 95% acetonitrile, 5% water, 0.1% TFA

Column: Waters Sunfire C18, 3.0 x l50 mm, 3.5 um

Flow Rate: 0.5 mL / min

Detector Wavelength: 220 nm

Analytical HPLC Method 4

Conditions: 10% B→ 100% B over 15 min gradient; hold at 100% B for 10 min Solvent A: 5% acetonitrile, 95% water, 0.1% TFA

Solvent B: 95% acetonitrile, 5% water, 0.1% TFA

Column: Waters Xbridge phenyl, 3.0 x 150 mm, 3.5 um

Flow Rate: 0.5 mL / min

Detector Wavelength: 220 nm

Preparation of intermediates

Intermediate 1. Preparation of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate.

A mixture of ethyl 4-oxocyclohexanecarboxylate (12.7 g, 75 mmol), ethylene glycol (21 ml, 373 mmol), (lS)-(+)-10-camphorsulfonic acid (0.175 g, 0.75 mmol) and anhydrous toluene (300 mL) was refluxed with a Dean-Stark water trap for 8 hours. The mixture was quenched with 100 mL saturated sodium bicarbonate solution and was vigorously stirred. The separated organic phase was washed with water (100 mL), dried over Na2S04 and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0- 15 % ethyl acetate / hexanes to give the desired product as an oil (15.9 g, 99 %). Ή NMR (400MHz, CHLOROFORM-d) δ 4.13 (q, J=7.2 Hz, 2H), 3.95 (s, 4H), 2.34 (tt, J=10.4, 4.0 Hz, 1H), 1.98 - 1.90 (m, 2H), 1.87 - 1.75 (m, 4H), 1.61 - 1.51 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). Intermediate 2. Preparation of ethyl 8-formyl-l,4-dioxaspiro[4.5]decane-8-carboxylate.

To a solution of ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (21 g, 98 mmol) in THF (150 mL) at -78 °C was added 2M LDA (64 mL, 127 mmol) dropwise. The resulting solution was stirred at -78 °C for 1 h, then in an ice bath for 1.5 h. The reaction mixture was chilled back to -78 °C and molecular sieves were added. Dried ethyl formate (12 mL, 147 mmol) was added dropwise slowly over 1 h. The reaction mixture was stirred at -78 °C for 1 h. The cold bath was removed and the reaction was quenched with a saturated solution of NH4CI in 0.5 N HC1 (250 mL) dropwise. The mixture was extracted with

EtOAc (3 x 200 mL). The combined organic layer was washed with saturated solution of NH4CI in 0.5 N HC1 (200 mL), brine (200 mL), dried over NaiSC , and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-20 % ethyl acetate / hexanes to give the desired product as an oil (9.3 g, 39 %). ¾ NMR (400MHz, CHLOROFORM-d) δ 9.54 (s, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.98 - 3.90 (m, 4H), 2.25 - 2.16 (m, 2H), 2.10 - 2.01 (m, 2H), 1.74 - 1.60 (m, 4H), 1.27 (t, J=7.2 Hz, 3H).

Intermediate 3. Preparation of ethyl 8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate.

To a solution of the ethyl 8-formyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (1.0 g, 4.13 mmol) in EtOH (10 mL) at 0 °C was added NaBH 4 (0.187 g, 4.95 mmol). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated NH4CI (10 mL) and was then diluted with H2O until dissolved. The mixture was extracted with EtOAc (3 x 50 mL), washed with brine (50 mL), dried over Na2S04 and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-25 % ethyl acetate / hexanes to give the desired product as an oil (0.86 g, 85 %). ¾ NMR (400MHz,

CHLOROFORM-d) δ 4.21 (q, J=7.1 Hz, 2H), 3.99 - 3.91 (m, 4H), 3.65 (d, J=6.5 Hz, 2H), 2.19 - 2.11 (m, 2H), 1.68 (dd, J=6.8, 5.5 Hz, 4H), 1.63 - 1.57 (m, 2H), 1.29 (t, J=7.0 Hz, 3H).

Intermediate 4. Preparation of ethyl 8-((benzoyloxy)methyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate.

To a solution of ethyl 8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate (3.0 g, 12.3 mmol) in pyridine (60 mL) was added DMAP (0.3 g, 2.5 mmol). The mixture was heated to 50 °C and benzoic anhydride (3.1 g, 13.5 mmol) was added. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with brine (50 mL), dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-20 % hexane/EtOAc to give the desired product as an oil (4.3 g, 100 %). ¾ NMR (400MHz, CHLOROFORM-d) δ 8.01 (dd, J=8.4, 1.4 Hz, 2H), 7.60 - 7.54 (m, 1H), 7.47 . 7.40 (m, 2H), 4.35 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.99 - 3.92 (m, 4H), 2.36 - 2.23 (m, 2H), 1.76 - 1.63 (m, 6H), 1.24 (t, J=7.2 Hz, 3H).

Intermediate 5. Preparation of (l-(ethoxycarbonyl)-4-oxocyclohexyl)methyl benzoate.

A solution of ethyl 8-((benzoyloxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxyla te (4.3 g, 12.4 mmol) in acetone (120 mL) and 0.5N HC1 (24.8 mL, 12.4 mmol) was stirred at 50 °C overnight. The reaction mixture was neutralized with saturated aqueous NaiCC and partially concentrated in vacuo to remove acetone. The residue was diluted with H2O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed brine (50 mL), dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-30 % hexane/EtOAc to give the desired product as an oil (3.8 g, 100 %). ¾ NMR (400MHz, CHLOROFORM-d) δ 8.01 (d, J=7.6 Hz, 2H), 7.62 - 7.55 (m, 1H), 7.49 - 7.42 (m, 2H), 4.45 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 2.61 - 2.48 (m, 4H), 2.47 - 2.37 (m, 2H), 1.91 - 1.79 (m, 2H), 1.28 (t, J=7.1 Hz, 3H). Intermediate 6. Preparation of (l-(ethoxycarbonyl)-4-

(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -en- 1 -yl)methyl benzoate .

A solution of (l-(ethoxycarbonyl)-4-oxocyclohexyl)methyl benzoate (3.8 g, 12.4 mmol) and l,l, l-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesul fonamide (4.95 g, 13.8 mmol) in THF (120 mL) was cooled to -78 °C. To this solution was added KHMDS (1 M in THF) (16.4 mL, 16.4 mmol). The resulting solution was stirred at -78 °C for 2 h. The reaction was quenched with saturated aqueous NH4CI (50 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-20 % ethyl acetate / hexanes to give the desired product (3.8 g, 69 %) as an oil. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.00 (dd, J=8.4, 1.1 Hz, 2H), 7.62 - 7.56 (m, 1H), 7.49 - 7.44 (m, 2H), 5.80 (td, J=3.2, 1.6 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.21 (qd, J=7.1, 2.1 Hz, 2H), 2.93 - 2.83 (m, 1H), 2.59 - 2.27 (m, 4H), 1.99 - 1.90 (m, 1H), 1.25 (t, J=7.2 Hz, 3H).

Intermediate 7. (1 -(ethoxycarbonyl)-4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)cyclohex-3 -en- 1 -yl)methyl benzoate .

A mixture of (l-(ethoxycarbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)cycloh ex-3-en-l- yl)methyl benzoate (3.8 g, 8.7 mmol), bis(pinacolato)diboron (2.4 g, 9.5 mmol), potassium acetate (2.6 g, 26.0 mmol) and PdCi2(dppf)-CH 2 Cl2 adduct (0.2 g, 0.260 mmol) in 1,4- dioxane (80 mL) was cooled to -78 °C. Three cycles of evacuating the flask and purging with nitrogen were performed. The mixture was stirred at 70 °C for 3 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-20 % ethyl acetate / hexanes to give the desired product (5.8 g, 67 %) as an oil. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.00 (dd, J=8.4, 1.4 Hz, 2H), 7.59 - 7.54 (m, 1H), 7.46 - 7.41 (m, 2H), 6.54 (dt, J=3.6, 1.9 Hz, 1H), 4.44 (d, J=10.8 Hz, 1H), 4.39 (d, J=10.8 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 2.77 - 2.68 (m, 1H), 2.29 - 2.20 (m, 3H), 2.05 - 1.97 (m, 1H), 1.92 - 1.83 (m, 1H), 1.27 (s, 12H), 1.22 (t, J=7.2 Hz, 3H).

Intermediates 8 and 9. Chiral separation of (S)-(l-(ethoxycarbonyl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)methy l benzoate and (R)-(l- (ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)cyclohex-3-en-l- yl)methyl benzoate.

8 9

The racemic mixture was separated by supercritical fluid chromatography (SFC) to give (S)-( 1 -(ethoxycarbonyl)-4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en- 1 - yl)methyl benzoate and (R)-(l-(ethoxycarbonyl)-4-(4,4,5, 5 -tetramethyl- 1,3, 2- dioxaborolan-2-yl)cyclohex-3 -en- 1 -yl)methyl benzoate .

SFC Experimental Details:

Column: ChiralCel OJ-H, 30 x 250mm, 5μιη

Mobile Phase: 5% Me OH / 95% C02

Pressure: 100 bar

Temperature: 40°C

Flow Rate: 70 mL/min

UV: 225 nm

Injection: 0.50 mL (-100 mg/mL in IPA:ACN:MeOH, 2:2: 1)

Fraction Collection: Slope & Level (w/ 6 mL/min MeOH make-up):

Peak 1 window: 3.00' - 4.50'

Peak 2 window: 3.80' - 7.00' Intermediate 10. Preparation of ethyl 8-(((methylsulfonyl)oxy)methyl)- 1,4- dioxaspiro [4.5] decane-8 -carboxylate .

To vacuum dried ethyl 8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate (280 mg, 1.146 mmol) in DCM (2 mL) was added N,N-diisopropylethylamine (0.299 mL, 1.719 mmol) under nitrogen. The clear solution was chilled in an ice bath until cold. To this was added, dropwise, neat methanesulfonyl chloride (0.106 mL, 1.375 mmol) and the resulting solution was stirred in the ice bath and allowed to reach RT overnight. The crude reaction mixture was purified on silica gel column eluted with 50% ethyl acetate / hexanes to give the desired product (304 mg, 82 %). ¾ NMR (400MHz, CHLOROFORM-d) δ 4.26 - 4.17 (m, 4H), 3.97 - 3.93 (m, 4H), 3.00 (s, 3H), 2.24 - 2.15 (m, 2H), 1.73 - 1.61 (m, 6H), 1.29 (t, J=7.2 Hz, 3H).

General Procedure A: Preparation of C-3 ot-substituted cyclohexenecarboxylic acid derivatives.

Step 1 : Preparation of ether.

Step 1-A: To a solution of ethyl 8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate (intermediate 3) (1 eq), reactant Ar-OH (1 eq) and triphenylphosphine (1.2 eq) in THF was added diisopropyl diazene-l,2-dicarboxylate (1.2 eq) dropwise under nitrogen. The resulting solution was stirred at RT for 1 h, then at 50 °C for 3 days. The reaction mixture was diluted with saturated NH4CI, extracted with EtOAc, washed with brine, dried over NaiSC , and concentrated in vacuo. The crude product was purified by silica gel column eluted with ethyl acetate / hexanes to give the desired product.

Step 1-B: A mixture of ethyl 8-(((methylsulfonyl)oxy)methyl)-l,4-dioxaspiro[4.5]decane- 8-carboxylate (1 eq), cesium carbonate (2.15 eq) and Ar-OH (3.5 eq) in acetonitrile was stirred at 85 °C over 48 hours. The inorganic salts were removed by filtration, and the filtrate was washed with water, extracted with ethyl acetate. The combine organic phase was concentrated in vacuo. The crude product was purified by silica gel column eluted with Ethyl acetate / hexanes to give the desired product.

Step 2: Preparation of ketone.

A solution of the product from step 1 (1 eq) and 0.5 N HCl (1 eq) in acetone was stirred at 50 °C for 1-2 days. The reaction mixture was neutralized with saturated aqueous. Na2C03 and partially concentrated in vacuo to remove acetone. The residue was diluted with H2O, extracted with EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with ethyl acetate / hexanes to give the desired ketone.

Step 3: Preparation of triflate.

To a solution of ketone from step 2 (1 eq) and 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl)sulfonyl)-methanesulfonamide (1.1 eq) in THF at -78 °C was added KHMDS (1 M in THF) (1.3 eq). The resulting yellow to orange solution was stirred at -78 °C for 2 h. The reaction was quenched with saturated aqueous NH4CI. The mixture was extracted with EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with ethyl acetate / hexanes to give the desired triflate.

Step 4: Preparation of boronate.

In a pressure vessel, a mixture of triflate from step 3 (1 eq), bis(pinacolato)diboron (1.1 eq), KOAc (2.5 eq) and PdCi2(dppf)-CH2Ci2 adduct (0.03 eq) in 1,4-dioxane was flushed with nitrogen, sealed and heated at 70 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with ethyl acetate / hexanes to give the desired boronate.

Step 5: Preparation of C-3 ot-substituted cyclohexenecarboxylic ester.

A mixture of C3-triflate (1 eq), boronate from step 4 (leq), NaiCC H2O (3 eq) and Pd(Pli3P)4 (0.06 eq) in dioxane and H2O (4 : 1), was flushed with nitrogen, sealed and heated at 70 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and H2O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with ethyl acetate / hexanes to give the desired C-3 ot-substituted cyclohexenecarboxylic ester.

Step 6: Preparation of carboxylic acid.

A solution of ester from step 5 in 1,4-dioxane, MeOH and IN NaOH (2 : 1 : 1) was stirred at 60 -70 °C for 1-2 h. The reaction mixture was purified by reverse phase preparative HPLC to give the final product.

Example 1

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l -carboxylic acid.

Step 1. Preparation of ethyl 8-((pyridin-2-yloxy)methyl)-l,4-dioxaspiro[4.5]d carboxylate.

The title compound was prepared in 83 % yield as an oil, following the procedure described in general procedure A step 1-A, using pyridin-2-ol as reactant. Ή NMR (500MHz, CHLOROFORM-d) δ 8.14 (ddd, J=5.0, 2.0, 0.8 Hz, IH), 7.59 - 7.53 (m, IH), 6.87 (ddd, .7=7.1, 5.1, 0.9 Hz, IH), 6.73 (dt, J=8.4, 0.8 Hz, IH), 4.38 (s, 2H), 4.17 (q, J=7.2 Hz, 2H), 4.01 - 3.93 (m, 4H), 2.35 - 2.24 (m, 2H), 1.79 - 1.67 (m, 6H), 1.23 (t, J=7.1 Hz, 3H). LC/MS m/z 322.10 (M+H) + , 1.93 min (LCMS Method 1). Step 2. Preparation of ethyl 4-oxo-l-((pyridin-2-yloxy)methyl)cyclohexane-l- carboxylate.

The title compound was prepared in 99 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-((pyridin-2-yloxy)methyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.14 (ddd, J=5.1, 1.9, 0.8 Hz, IH), 7.61 - 7.55 (m, IH), 6.90 (ddd, J=7.1, 5.1, 0.9 Hz, IH), 6.74 (dt, J=8.3, 0.8 Hz, IH), 4.45 (s, 2H), 4.24 (q, J=7.0 Hz, 2H), 2.59 - 2.48 (m, 4H), 2.46 - 2.37 (m, 2H), 1.94 - 1.83 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). LC/MS m/z 278.05 (M+H) + , 1.74 min (LCMS Method 1).

Step 3. Preparation of ethyl l-((pyridin-2-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 110 % yield (containing PhNHTf) as an oil, following the procedure described in general procedure A step 3, using ethyl 4-oxo-l-((pyridin-2- yloxy)methyl)cyclohexane-l -carboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 8.14 (ddd, J=5.0, 2.0, 0.8 Hz, IH), 7.62 - 7.55 (m, IH), 6.90 (ddd, J=7.1, 5.1, 0.9 Hz, IH), 6.73 (dt, J=8.3, 0.8 Hz, IH), 5.80 - 5.76 (m IH), 4.45 (d, J=10.3 Hz, IH), 4.39 (d, J=10.3 Hz, IH), 4.18 (qd, J=7.1, 1.3 Hz, 2H), 2.88 - 2.80 (m, IH), 2.56 - 2.25 (m, 4H), 2.02 - 1.93 (m, IH), 1.22 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz,

CHLOROFORM-d) δ -73.87 (s, 3F). /LC/MS m/z 410.00 (M+H) + , 2.24 min (LCMS Method 1). Step 4. Preparation of ethyl l-((pyridin-2-yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 75 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl l-((pyridin-2-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate as reactant. 'H NMR (400MHz, CHLOPvOFORM-d) δ 8.13 (ddd, J=5.0, 2.0, 0.8 Hz, 1H), 7.58 - 7.51 (m, 1H), 6.86 (ddd, J=7.0, 5.1, 0.9 Hz, 1H), 6.71 (dt, J=8.4, 0.8 Hz, 1H), 6.57 - 6.53 (m, 1H), 4.42 (d, J=10.0 Hz, 1H), 4.33 (d, J=10.0 Hz, 1H), 4.14 (qd, J=6.7, 1.4 Hz, 2H), 2.73 (dq, J=18.8, 2.8 Hz, 1H), 2.31 - 2.18 (m, 3H), 2.03 - 1.95 (m, 1H), 1.91 - 1.83 (m, 1H), 1.27 (s, 6H), 1.26 (s, 6H), 1.19 (t, J=7.0 Hz, 3H). LC/MS m/z 388.20 (M+H) + , 2.22 min (LCMS Method 1).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylate.

The title compound was prepared in 71 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl l-((pyridin-2-yloxy)methyl)-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-ene-l-carbo xylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.13 (dd, J=5.1, 1.4 Hz, 1H), 7.55 (ddd, J=8.6, 7.0, 2.0 Hz, 1H), 6.85 (ddd, J=7.0, 5.3, 0.8 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 5.35 (br. s, 1H), 5.18 (d, J=5.5 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 4.47 - 4.37 (m, 2H), 4.14 ((qd, J=6.7, 1.4 Hz, 2H), 3.12 - 2.99 (m, 8H), 2.73 - 2.39 (m, 6H), 2.23 - 0.84 (m, 27H), 1.69 (s, 3H), 1.20 (t, J=7.2 Hz, 3H), 1.05 (s, 3H), 0.96 -0.90 (m, 9H), 0.89 (s, 3H). LC/MS m/z 830.00 (M+H) + , 3.74 min (LCMS Method 2).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid was prepared in 32 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- (1,1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 8.14 (d, J=3.8 Hz, 1H), 7.59 - 7.52 (m, 1H), 6.89 - 6.84 (m, 1H), 6.73 (d, J=8.3 Hz, 1H), 5.35 (br. s, 1H), 5.21 - 5.16 (m, 1H), 4.71 (s, 1H), 4.60 (s, 1H), 4.50 - 4.38 (m, 2H), 3.14 - 2.99 (m, 8H), 2.86 - 2.57 (m, 6H), 2.29 - 0.89 (m, 27H), 1.68 (s, 3H), 1.10 (s, 3H), 0.98 (s, 3H), 0.97 - 0.91 (m, 6H), 0.85 (s, 3H). LC/MS m/z 802.50 (M+H) + , 3.56 min (LCMS Method 2).

Example 2

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl-3 -phenyl- lH-pyrazol-5 - yl)oxy)methyl)cyclohex-3-ene- 1 -carboxylic acid.

Step 1. Preparation of ethyl 8-(((l-methyl-3-phenyl-lH-pyrazol-5-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8-carboxylate .

The title compound was prepared in 99 % yield as an oil, following the procedure described in general procedure A step 1-A, using l-methyl-3-phenyl-lH-pyrazol-5-ol as reactant. 'H NMR (500MHz, CHLOROFORM-d) δ 7.78 - 7.70 (m, 2H), 7.39 (t, J=7.6 Hz, 2H), 7.32 - 7.28 (m, 1H), 5.83 (s, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.12 (s, 2H), 4.01 - 3.94 (m, 4H), 3.67 (s, 3H), 2.37 - 2.26 (m, 2H), 1.80 - 1.65 (m, 6H), 1.31 - 1.26 (m, 3H). LC/MS m/z 401.10 (M+H) + , 2.17 min (LCMS Method 1).

Step 2. Preparation of ethyl l-(((l-methyl-3-phenyl-lH-pyrazol-5-yl)oxy)methyl)-4- oxocy clohexane - 1 -carboxylate .

The title compound was prepared in 81 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((l-methyl-3-phenyl-lH-pyrazol- 5-yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ

7.75 - 7.71 (m, 2H), 7.42 - 7.35 (m, 2H), 7.32 - 7.27 (m, 1H), 5.84 (s, 1H), 4.28 (q, J=7.0 Hz, 2H), 4.19 (s, 2H), 3.68 (s, 3H), 2.63 - 2.51 (m, 4H), 2.48 - 2.39 (m, 2H), 1.92 - 1.81 (m, 2H), 1.30 (t, J=7.2 Hz, 3H). LC/MS m/z 357.15 (M+H) + , 1.99 min (LCMS Method 1). Step 3. Preparation of ethyl l-(((l-methyl-3-phenyl-lH-pyrazol-5-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 68 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl l-(((l-methyl-3-phenyl-lH-pyrazol- 5-yl)oxy)methyl)-4-oxocyclohexane-l-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.75 - 7.71 (m, 2H), 7.41 - 7.35 (m, 2H), 7.32 - 7.29 (m, 1H), 5.84 (s, 1H), 5.83 - 5.79 (m, 1H), 4.25 - 4.10 (m, 4H), 3.67 (s, 3H), 2.92 - 2.82 (m, 1H), 2.59 - 2.25 (m, 4H), 2.00 (ddd, J=13.7, 7.8, 6.4 Hz, 1H), 1.27 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -73.83 (s, 3F). LC/MS m/z 489.20 (M+H) + , 2.30 min (LCMS Method 1).

Step 4. Preparation of ethyl l-(((l-methyl-3-phenyl-lH-pyrazol-5-yl)oxy)methyl)-4- (4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 68 % yield as a wax, following the procedure described in general procedure A step 4, using ethyl l-(((l-methyl-3-phenyl-lH-pyrazol- 5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex- 3-ene-l-carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 7.75 - 7.71 (m, 2H), 7.41 - 7.34 (m, 2H), 7.31 - 7.28 (m, J=7.5 Hz, 1H), 6.57 - 6.53 (m, 1H), 5.83 (s, 1H), 4.23 - 4.11 (m, 4H), 3.65 (s, 3H), 2.76 - 2.67 (m, 1H), 2.32 - 2.12 (m, 3H), 2.03 - 1.86 (m, 2H), 1.27 (s, 12H), 1.23 (t, J=7.0 Hz 3H). LC/MS m/z 467.30 (M+H) + , 3.58 min (LCMS Method 2).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-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)- 1 -((( 1 -methyl-3 -phenyl- lH-pyrazol-5 - yl)oxy)methyl)cyclohex-3-ene-l-carboxylate.

The title compound was prepared in 59 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl l-(((l-methyl-3-phenyl-lH-pyrazol- 5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)cyclohex-3-ene-l- carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.74 - 7.70 (m, 2H), 7.40 - 7.33 (m, 2H), 7.31 - 7.25 (m, IH), 5.83 (s, IH), 5.36 (br. s., IH), 5.19 (d, J=4.8 Hz, IH), 4.71 (d, J=2.0 Hz, IH), 4.59 (s, IH), 4.24 - 4.15 (m, 4H), 3.65 (s, 3H), 3.10 - 2.98 (m, 8H), 2.74 - 2.43 (m, 6H), 2.32 - 1.02 (m, 27H), 1.68 (s, 3H), 1.26 (t, J=7.0 Hz, 3H), 1.06 (s, 3H), 0.97 - 0.91 (m, 9H), 0.86 (s, 3H). LC/MS m/z 909.60 (M+H) + , 3.89 min (LCMS Method 2).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl-3 -phenyl- lH-pyrazol-5 - yl)oxy)methyl)cyclohex-3-ene-l-carboxylic acid was prepared in 81 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl-3 -phenyl- lH-pyrazol-5 - yl)oxy)methyl)cyclohex-3-ene-l-carboxylate as reactant. ¾ NMR (400MHz, METHANOLS) δ 7.73 - 7.68 (m, 2H), 7.40 - 7.34 (m, 2H), 7.31 - 7.26 (m, 1H), 6.04 (s, 1H), 5.37 (br. s., 1H), 5.22 (d, J=4.5 Hz, 1H), 4.76 (s, 1H), 4.65 (s, 1H), 4.31 - 4.23 (m, 2H), 3.64 (s, 3H), 3.20 - 3.04 (m, 8H), 2.92 - 2.61 (m, 6H), 2.24 - 1.10 (m, 27H), 1.73 (s, 3H), 1.16 (s, 3H), 1.06 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.92 (s, 3H). LC/MS m/z 881.55 (M+H) + , 3.77 min (LCMS Method 2) .

Example 3

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl-5 -(trifluoromethyl)- lH-pyrazol-3 - yl)oxy)methyl)cyclohex-3-ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-(((l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate.

The title compound was prepared in 86 % yield as an oil, following the procedure described in general procedure A step 1-A, using l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-ol as reactant. 'H NMR (500MHz, CHLOROFORM-d) δ 5.99 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.19 (s, 2H), 3.96 (t, J=3.0 Hz, 4H), 3.82 (s, 3H), 2.31 - 2.19 (m, 2H), 1.78 - 1.64 (m, 6H), 1.26 (t, J=7.1 Hz, 3H). LC/MS m/z 393.05 (M+H) + , 2.18 min (LCMS Method 1).

Step 2. Preparation of ethyl l-(((l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl)oxy)methyl)-4-oxocyclohexane- 1 -carboxylate .

The title compound was prepared in 98 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxy late as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 5.99 (s, 1H), 4.26 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.82 (d, J=0.8 Hz, 3H), 2.59 - 2.34 (m, 6H), 1.92 - 1.79 (m, 2H), 1.28 (t, J=6.8 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -60.88 (s, 3F). LC/MS m/z 349.15 (M+H) + , 2.08 min (LCMS Method 1).

Step 3. Preparation of ethyl l-(((l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- ene-l-carboxylate.

The title compound was prepared in 70 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl l-(((l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-yl)oxy)methyl)-4-oxocyclohexane-l-carboxylate as reactant. 'H NMR

(400MHz, CHLOROFORM-d) δ 5.99 (s, 1H), 5.79 - 5.76 (m, 1H), 4.29 - 4.16 (m, 4H), 3.81 (d, J=0.8 Hz, 3H), 2.85 - 2.75 (m, 1H), 2.55 - 2.19 (m, 4H), 2.02 - 1.93 (m, 1H), 1.25 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -60.89 (s, 3F), -73.88 (s, 3F). LC/MS m/z 481.10 (M+H) + , 2.32 min (LCMS Method 1).

Step 4. Preparation of ethyl l-(((l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y l)cyclohex-3-ene-l- carboxylate.

The title compound was prepared in 79 % yield as a wax, following the procedure described in general procedure A step 4, using ethyl l-(((l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)c yclohex-3-ene-l-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.55 - 6.51 (m, 1H), 5.97 (s, 1H), 4.25 (d, J=9.3 Hz 1H), 4.19 - 4.13 (m, 3H), 3.81 (d, J=0.8 Hz, 3H), 2.69 (dq, J=19.1, 2.8 Hz, 1H), 2.27 - 2.16 (m, 3H), 2.00 - 1.81 (m, 2H), 1.26 (s, 12H), 1.22 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -60.84 (s, 3F). LC/MS m/z 481.13 (M+Na) + , 2.41min (LCMS Method 1).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl-5 -(trifluoromethyl)- lH-pyrazol-3 - yl)oxy)methyl)cyclohex-3-ene-l-carboxylate.

The title compound was prepared in 88 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl l-(((l-methyl-5-(trifluoromethyl)-lH- pyrazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxab orolan-2-yl)cyclohex-3-ene- 1-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 5.98 (s, 1H), 5.33 (br. s., 1H), 5.17 (d, J=4.8 Hz, 1H), 4.71 (s, 1H), 4.60 (s, 1H), 4.29 - 4.09 (m, 4H), 3.80 (s, 3H), 3.12 - 3.00 (m, 8H), 2.79 - 2.46 (m, 6H), 2.24 - 0.88 (m, 27H), 1.69 (s, 3H), 1.22 (t, J=7.0 Hz, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.96 - 0.89 (m, 6H), 0.85 (s, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -60.83 (s, 3F). LC/MS m/z 901.50 (M+H) + , 3.89 min (LCMS Method 2).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl-5 -(trifluoromethyl)- lH-pyrazol-3 - yl)oxy)methyl)cyclohex-3-ene-l-carboxylic acid was prepared in 56 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl-5 -(trifluoromethyl)- lH-pyrazol-3 - yl)oxy)methyl)cyclohex-3-ene-l-carboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 6.00 (s, 1H), 5.35 (br. s., 1H), 5.19 (d, J=5.8 Hz, 1H), 4.71 (s, 1H), 4.60 (s, 1H), 4.34 - 4.21 (m, 2H), 3.81 (s, 3H), 3.14 - 2.99 (m, 8H), 2.76 - 2.54 (m, 6H), 2.23 - 1.04 (m, 27H), 1.69 (s, 3H), 1.08 (s, 3H), 0.97 (s, 3H), 0.97 - 0.92 (m, 6H), 0.86 (s, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -60.81 (s, 3F). LC/MS m/z 873.45 (M+H) + , 3.73 min (LCMS Method 2). Example 4

Preparation of 2-((l-carboxy-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)methoxy)thiazol e-4-carboxylic acid.

Step 1. Preparation of ethyl 2-((8-(ethoxycarbonyl)-l,4-dioxaspiro[4.5]decan-8- yl)methoxy)thiazole-4-carboxylate.

The title compound was prepared as an oil without further purification, following the procedure described in general procedure A step 1-A, using ethyl 2-hydroxythiazole-4- carboxylate as reactant. LC/MS m/z 400.30 (M+H) + , 2.18 min (LCMS Method 1).

Step 2. Preparation of ethyl 2-((l-(ethoxycarbonyl)-4-oxocyclohexyl)methoxy)thiazole-4 carboxylate.

/r - COOEt

The title compound was prepared in 26 % yield (yield calculated over 2 steps) as a solid, following the procedure described in general procedure A step 2, using crude ethyl 2-((8- (ethoxycarbonyl)-l,4-dioxaspiro[4.5]decan-8-yl)methoxy)thiaz ole-4-carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 7.61 (s, 1H), 4.66 (s, 2H), 4.38 (q, J=7.3 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 2.58 - 2.48 (m, 4H), 2.45 - 2.36 (m, 2H), 1.92 - 1.81 (m, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H). Step 3. Preparation of ethyl 2-((l-(ethoxy carbonyl)-4-

(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-l-yl)methox y)thiazole-4-carboxylate.

The title compound was prepared in 40 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 2-((l-(ethoxycarbonyl)-4- oxocyclohexyl)methoxy)thiazole-4-carboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 7.60 (s, IH), 5.80 - 5.76 (m, IH), 4.66 (d, J=10.0 Hz, IH), 4.60 (d, J=10.3 Hz, IH), 4.38 (q, J=7.0 Hz, 2H), 4.19 (qd, J=7.1, 0.8 Hz, 2H), 2.87 - 2.79 (m, IH), 2.56 - 2.23 (m, 4H), 1.99 - 1.90 (m, IH), 1.38 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.0 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -73.84 (s, 3F). LC/MS m/z 488.15 (M+H) + , 2.41 min (LCMS Method 1).

Step 4. Preparation of ethyl 2-((l-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3 -en- 1 -yl)methoxy)thiazole-4-carboxylate .

The title compound was prepared in 57 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 2-((l-(ethoxycarbonyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -en- 1 -yl)methoxy)thiazole-4-carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 7.58 (s, IH), 6.54 - 6.49 (m, IH),

4.64 (d, J=10.0 Hz, IH), 4.56 (d, J=10.0 Hz, IH), 4.37 (q, J=7.0 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 2.68 (dq, J=19.1, 3.0 Hz, IH), 2.27 - 2.16 (m, 3H), 2.00 - 1.81 (m, 2H), 1.38 (t, J=7.0 Hz, 3H), 1.26 (s, 12H), 1.21 (t, J=7.0 Hz, 3H). LC/MS m/z 466.30 (M+H) + , 2.42 min (LCMS Method 1). Step 5. Preparation of ethyl 2-((4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methoxy)thiazole-4- carboxylate.

The title compound was prepared in 79 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 2-((l-(ethoxycarbonyl)-4-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3 -en- 1 -yl)methoxy)thiazole-4-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.58 (s, IH), 5.33 (br. s., IH), 5.18 (d, J=6.0 Hz, IH), 4.71 (d, J=2.0 Hz, IH), 4.67 - 4.60 (m, 2H), 4.59 (s, IH), 4.37 (q, J=7.0 Hz, 2H), 4.20 - 4.09 (m, 2H), 3.12 - 2.96 (m, 8H), 2.74 - 2.41 (m, 6H), 2.21 - 0.86 (m, 27H), 1.69 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.96 - 0.90 (m, 6H), 0.85 (s, 3H). LC/MS m/z 908.60 (M+H) + , 3.05 min (LCMS Method 3).

Step 6. 2-((l-carboxy-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-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)cyclohex-3-en-l-yl)methoxy)thiazol e-4-carboxylic acid was prepared in 85 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 2-((4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-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)-l-(emoxycarbonyl)cyclohex-3-en-l- yl)methoxy)thiazole-4- carboxylate as reactant. ¾ NMR (500MHz, METHANOL-d 4 ) δ 7.49 (s, 1H), 5.34 (br. s., 1H), 5.21 (d, J=4.7 Hz, 1H), 4.78 (s, 1H), 4.68 (s, 1H), 4.61 - 4.53 (m, 2H), 3.27 - 3.06 (m, 11H), 2.99 - 2.96 (m, 1H), 2.89 - 2.80 (m, 1H), 2.67 - 2.58 (m, 1H), 2.35 - 1.04 (m, 27H), 1.73 (s, 3H), 1.18 (s, 3H), 1.09 (s, 3H), 1.00 - 0.96 (m, 6H), 0.92 (s, 3H). LC/MS m/z 852.50 (M+H) + , 2.86 min (LCMS Method 3).

Example 5

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((4-methyl-l,2,5-thiadiazol-3- yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-(((4-methyl-l,2,5-thiadiazol-3-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8 -carboxylate .

The title compound was prepared in 64 % yield as an oil, following the procedure described in general procedure A step 1-A, using 4-methyl-l,2,5-thiadiazol-3-ol as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 4.43 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.99 - 3.92 (m, 4H), 2.36 (s, 3H), 2.31 - 2.24 (m, 2H), 1.75 - 1.66 (m, 6H), 1.24 (t, J=7.2 Hz, 3H). LC/MS m/z 343.20 (M+H) + , 2.17 min (LCMS Method 1).

Step 2. Preparation of ethyl l-(((4-methyl-l,2,5-thiadiazol-3-yl)oxy)methyl)-4- oxocyclohexane-l-carboxylate.

The title compound was prepared in 81 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((4-methyl-l,2,5-thiadiazol-3- yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 4.51 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.61 - 2.38 (m, 6H), 2.37 (s, 3H), 1.91 - 1.82 (m, 2H), 1.28 (t, J=7.2 Hz, 3H). LC/MS m/z 299.20 (M+H) + , 1.94 min (LCMS Method 1).

Step 3. Preparation of ethyl l-(((4-methyl-l,2,5-thiadiazol-3-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 60 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl l-(((4-methyl-l,2,5-thiadiazol-3- yl)oxy)methyl)-4-oxocyclohexane-l-carboxylate as reactant. Ή NMR (400MHz, CHLOROFORM-d) δ 5.82 - 5.78 (m, IH), 4.52 (d, J=10.3 Hz, IH), 4.47 (d, J=10.3 Hz, IH), 4.26 - 4.12 (m, 2H), 2.90 - 2.82 (m, IH), 2.59 - 2.27 (m, 4H), 2.36 (s, 3H), 2.00 - 1.93 (m, IH), 1.24 (t, J=7.0 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -73.83 (s, 3F). LC/MS m/z 431.15 (M+H) + , 2.41 min (LCMS Method 1).

Step 4. Preparation of ethyl l-(((4-methyl-l,2,5-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 -carboxylate .

The title compound was prepared in 74 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl l-(((4-methyl-l,2,5-thiadiazol-3- yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- ene-l-carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 6.56 - 6.52 (m, IH), 4.51 (d, J=10.0 Hz, IH), 4.44 (d, J=10.0 Hz, IH), 4.16 (qd, J=7.1, 1.1 Hz, 2H), 2.71 (dq, J=19.1, 3.3 Hz, IH), 2.35 (s, 3H), 2.31 - 2.17 (m, 3H), 2.04 - 1.85 (m, 2H), 1.26 (s 12H), 1.21 (t, J=7.0 Hz, 3H). LC/MS m/z 409.25 (M+H) + , 2.45 min (LCMS Method 1). Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((4-methyl-l,2,5-thiadiazol-3- yl)oxy)methyl)cyclohex-3- ene-l-carboxylate.

The title compound was prepared in 73 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl l-(((4-methyl-l,2,5-thiadiazol-3- yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y l)cyclohex-3-ene-l- carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 5.36 (br. s., 1H), 5.19 (d, J=5.3 Hz, 1H), 4.76 (s, 1H), 4.63 (s, 1H), 4.56 - 4.44 (m, 2H), 4.21 - 4.09 (m, 2H), 3.17 - 3.00 (m, 8H), 2.98 - 2.59 (m, 6H), 2.23 - 0.82 (m, 27H), 2.35 (s, 3H), 1.70 (s, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.97 - 0.91 (m, 6H), 0.85 (s, 3H). LC/MS m/z 851.55 (M+H) + , 3.07 min (LCMS Method 3).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((4-methyl-l,2,5-thiadiazol-3- yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid was prepared in 53 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-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)- 1 -(((4-methyl- 1 ,2,5 -thiadiazol-3 -yl)oxy)methyl)cyclohex-3 - ene-l-carboxylate as reactant.

¾ NMR (400MHz, CHLOROFORM-d) δ 5.36 (br. s., 1H), 5.18 (br. s., 1H), 4.74 (br. s., 1H), 4.65 (br. s., 1H), 4.59 - 4.45 (m, 2H), 3.24 - 2.98 (m, 9H), 2.89 - 2.51 (m, 5H), 2.34 (s, 3H), 1.68 (s, 3H), 2.22 - 0.97 (m, 27H), 1.15 (s, 3H), 1.02 (s, 3H), 0.97 - 0.89 (m, 6H), 0.86 (s, 3H). LC/MS m/z 823.55 (M+H) + , 2.85 min (LCMS Method 3).

Example 6

Preparation of l-((( 1,2,5 -thiadiazol-3 -yl)oxy )methyl)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-(((l,2,5-thiadiazol-3-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8-carboxylate .

The title compound was prepared in 92 % yield as an oil, following the procedure described in general procedure A step 1-A, using l,2,5-thiadiazol-3-ol as reactant. Ή NMR (400MHz, CHLOROFORM-d) δ 7.97 (s, 1H), 4.46 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 4.00 - 3.92 (m, 4H), 2.32 - 2.21 (m, 2H), 1.76 - 1.66 (m, 6H), 1.24 (t, J=7.2 Hz, 3H). LC/MS m/z 329.20 (M+H) + , 2.07 min (LCMS Method 1).

Step 2. Preparation of ethyl l-(((l,2,5-thiadiazol-3-yl)oxy)methyl)-4-oxocyclohexane-l- carboxylate.

The title compound was prepared in 80 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((l,2,5-thiadiazol-3- yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.99 (s, 1H), 4.54 (s, 2H), 4.26 (q, J=7.0 Hz, 2H), 2.60 - 2.50 (m, 4H), 2.47 - 2.38 (m, 2H), 1.93 - 1.82 (m, 2H), 1.28 (t, J=7.0 Hz, 3H). LC/MS m/z 285.15 (M+H) + , 1.85 min (LCMS Method 1).

Step 3. Preparation of ethyl l-(((l,2,5-thiadiazol-3-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 34 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl l-(((l,2,5-thiadiazol-3- yl)oxy)methyl)-4-oxocyclohexane-l-carboxylate as reactant. Ή NMR (400MHz,

CHLOROFORM-d) δ 7.99 (s, IH), 5.81 - 5.78 (m, IH), 4.55 (d, J=10.3 Hz, IH), 4.50 (d, J=10.3 Hz, IH), 4.20 (qd, J=7.1, 0.8 Hz, 2H), 2.90 - 2.81 (m, IH), 2.57 - 2.25 (m, 4H), 2.04 - 1.95 (m, IH), 1.24 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ - 73.83 (s, 3F). LC/MS m/z 417.10 (M+H) + , 2.37 min (LCMS Method 1).

Step 4. Preparation of ethyl l-(((l,2,5-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethy l- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 69 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl l-(((l,2,5-thiadiazol-3- yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- ene- 1 -carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 7.96 (s, IH), 6.56 - 6.52 (m, IH), 4.54 (d, J=10.0 Hz, IH), 4.45 (d, J=10.0 Hz, IH), 4.16 (q, J=7.0 Hz, 2H), 2.71 (dq, J=18.9, 3.4 Hz, IH), 2.30 - 2.17 (m, 3H), 2.03 - 1.94 (m, IH), 1.92 - 1.83 (m, IH), 1.26 (s 12H), 1.21 (t, J=7.2 Hz, 3H). LC/MS m/z 395.30 (M+H) + , 2.40 min (LCMS Method 1). Step 5. Preparation of ethyl 1 -(((1,2,5 -thiadiazol-3 -yl)oxy )methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate.

The title compound was prepared in 76 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl l-(((l,2,5-thiadiazol-3- yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y l)cyclohex-3-ene-l- carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.97 (s, 1H), 5.35 (br. s., 1H), 5.18 (d, J=5.0 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 4.58 - 4.49 (m, 2H), 4.16(q, J=7.5 Hz, 2H), 3.13 - 2.98 (m, 8H), 2.76 - 2.43 (m, 6H), 2.22 - 0.82 (m, 27H), 1.69 (s, 3H), 1.22 (t, J=7.2 Hz 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.96 - 0.91 (m, 6H), 0.85 (s, 3H). LC/MS m/z 837.55 (M+H) + , 3.08 min (LCMS Method 3).

Step 6. l-(((l,2,5-thiadiazol-3-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-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)cyclohex-3-ene-l-carboxylic acid was prepared in 56 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 1- (((l,2,5-thiadiazol-3-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a- ((2-(l, l-dioxidothiomo holino)ethyl)amino)-5a,5b,8,8, 1 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.98 (s, 1H), 5.37 (br. s., 1H), 5.19 (br. s., 1H), 4.76 (s, 1H), 4.66 (s, 1H), 4.62 - 4.49 (m, 2H), 3.23 - 3.00 (m, 8H), 2.90 - 2.53 (m, 6H), 2.28 - 0.89 (m, 27H), 1.69 (s, 3H), 1.16 (s, 3H), 1.03 (s, 3H), 0.97 - 0.91 (m, 6H), 0.86 (s, 3H). LC/MS m/z 809.50 (M+H) + , 2.90 min (LCMS Method 3).

Example 7

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -ethyl- 1H- 1 ,2,3 -triazol-5 -yl)oxy)methyl)cyclohex-3 -ene- 1-carboxylic acid.

Step 1. Preparation of ethyl 8-(((l-ethyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8 -carboxylate .

The title compound was prepared in 56 % yield as an oil, following the procedure described in general procedure A step 1-B, using 1 -ethyl- lH-l,2,3-triazol-5-ol as reactant. ¾ NMR (500MHz, CHLOROFORM-d) δ 7.07 (s, 1H), 4.19 (q, J=7.1 Hz, 3H), 4.17 (q, J=7.3 Hz, 2H), 4.10 (s, 2H), 4.01 - 3.92 (m, 4H), 2.33 - 2.24 (m, 2H), 1.76 - 1.61 (m, 6H), 1.44 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H). LC/MS m/z 340.25 (M+Na) + , 1.91 min (LCMS Method 1).

Step 2. Preparation of ethyl l-(((l-ethyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4- oxocy clohexane - 1 -carboxylate .

The title compound was prepared in 86 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((l-ethyl-lH-l,2,3-triazol-5- yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.09 (s, 1H), 4.26 (q, J=7.0 Hz, 2H), 4.18 (q, J=7.5 Hz, 2H), 4.17 (s, 2H), 2.61 - 2.50 (m, 4H), 2.47 - 2.38 (m, 2H), 1.89 - 1.78 (m, 2H), 1.45 (t, J=7.4 Hz, 3H), 1.28 (t, J=7.2 Hz, 3H). LC/MS m/z 296.25 (M+H) + , 1.62 min (LCMS Method 1). Step 3. Preparation of ethyl l-(((l-ethyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 35 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl l-(((l-ethyl-lH-l,2,3-triazol-5- yl)oxy)methyl)-4-oxocyclohexane-l-carboxylate as reactant. Ή NMR (400MHz, CHLOROFORM-d) δ 7.09 (s, 1H), 5.82 - 5.78 (m, 1H), 4.24 - 4.13 (m, 6H), 2.90 - 2.81 (m, 1H), 2.60 - 2.24 (m, 4H), 2.00 - 1.92 (m, 1H), 1.44 (t, J=7.3 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz, CHLOROFORM-d) δ -73.82 (s, 3F). LC/MS m/z 428.20 (M+H) + , 2.15 min (LCMS Method 1).

Step 4. Preparation of ethyl l-(((l-ethyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 -carboxylate .

The title compound was prepared in 57 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl l-(((l-ethyl-lH-l,2,3-triazol-5- yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- ene- 1 -carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.07 (s, 1H), 6.55 - 6.50 (m, 1H), 4.21 - 4.11 (m, 6H), 2.69 (dq, J=19.0, 2.9 Hz, 1H), 2.31 - 2.09 (m, 3H), 2.02 - 1.85 (m, 2H), 1.43 (t, J=7.3 Hz, 3H), 1.27 (s, 12H), 1.22 (t, J=7.2 Hz, 3H). LC/MS m/z 406.20 (M+H) + , 2.22 min (LCMS Method 1).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -ethyl- 1H- 1 ,2,3 -triazol-5 -yl)oxy)methyl)cyclohex-3 -ene- 1 -carboxylate.

The title compound was prepared in 90 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl l-(((l-ethyl-lH-l,2,3-triazol-5- yl)oxy)methyl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)cyclohex-3-ene- 1- carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.07 (s, IH), 5.35 (br. s., IH), 5.18 (d, J=6.0 Hz, IH), 4.70 (s, IH), 4.59 (s, IH), 4.23 - 4.11 (m, 6H), 3.11 - 2.97 (m, 8H), 2.71 - 2.42 (m, 6H), 2.24 - 0.86 (m, 27H), 1.68 (s, 3H), 1.42 (t, J=7.3 Hz, 3H), 1.23 (t, J=7.0 Hz, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.95 - 0.90 (m, 6H), 0.85 (s, 3H).

LC/MS m/z 848.60 (M+H) + , 2.74 min (LCMS Method 3).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -ethyl- IH- 1 ,2,3 -triazol-5 -yl)oxy)methyl)cyclohex-3 -ene- 1-carboxylic acid was prepared in 61 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -ethyl- IH- 1 ,2,3 -triazol-5 -yl)oxy)methyl)cyclohex-3 -ene- 1-carboxylate as reactant.

¾ NMR (400MHz, CHLOROFORM-d) δ 7.10 (s, IH), 5.36 (br. s., IH), 5.18 (br. s., IH), 4.69 (s, IH), 4.59 (s, IH), 4.28 - 4.20 (m, 2H), 4.16 (q, J=7.3 Hz, 2H), 3.13 - 2.99 (m, 8H), 2.82 - 2.55 (m, 6H), 2.24 - 1.00 (m, 27H), 1.68 (s, 3H), 1.43 (t, J=7.3 Hz, 3H), 1.09 (s, 3H), 0.98 (s, 3H), 0.96 - 0.91 (m, 6H), 0.85 (s, 3H). LC/MS m/z 820.55 (M+H) + , 2.86 (LCMS Method 3).

Example 8

Preparation of l-((benzo[d]isothiazol-3-yloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-((benzo[d]isothiazol-3-yloxy)methyl)-l,4- dioxaspiro [4.5] decane-8 -carboxylate .

The title compound was prepared in 26 % yield as an oil, following the procedure described in general procedure A step 1-B, using benzo[d]isothiazol-3(2H)-one as reactant. 'H NMR (500MHz, CHLOROFORM-d) δ 7.88 (dd, J=8.1, 0.9 Hz, 1H), 7.78 (d, J=8.1 Hz, IH), 7.53 (ddd, J=8.2, 7.1, 1.1 Hz, IH), 7.39 (td, J=7.5, 0.8 Hz, IH), 4.63 - 4.59 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 3.97 (t, J=2.6 Hz, 4H), 2.41 - 2.31 (m, 2H), 1.82 - 1.73 (m, 6H), 1.23 (t, J=7.1 Hz, 3H). LC/MS m/z 378.25 (M+H) + , 4.17 min (LCMS Method 4). Step 2. Preparation of ethyl l-((benzo[d]isothiazol-3-yloxy)methyl)-4-oxocyclohexane-l- carboxylate.

The title compound was prepared in 88 % yield as a wax, following the procedure described in general procedure A step 2, using ethyl 8-((benzo[d]isothiazol-3- yloxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.87 (dt, J=8.0, 1.0 Hz, IH), 7.79 (dt, J=8.2, 0.8 Hz, IH), 7.54 (ddd, J=8.2, 7.0, 1.1 Hz, IH), 7.40 (ddd, J=8.0, 7.0, 1.0 Hz, IH), 4.68 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 2.66 - 2.51 (m, 4H), 2.49 - 2.40 (m, 2H), 1.99 - 1.88 (m, 2H), 1.26 (t, J=7.2 Hz, 3H). LC/MS m/z 334.20 (M+H) + , 2.31 min (LCMS Method 1).

Step 3. Preparation of ethyl l-((benzo[d]isothiazol-3-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 64 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl l-((benzo[d]isothiazol-3- yloxy)methyl)-4-oxocyclohexane-l-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.86 (dt, J=8.0, 1.0 Hz, IH), 7.79 (dt, J=8.1, 0.8 Hz, IH), 7.54 (ddd, J=8.2, 7.0, 1.1 Hz, IH), 7.43 - 7.39 (m, IH), 5.83 - 5.79 (m, IH), 4.68 (d, J=10.0 Hz, IH), 4.63 (d, J=10.3 Hz, IH), 4.20 (qd, J=7.2, 2.1 Hz, 2H), 2.97 - 2.88 (m, IH), 2.59 - 2.32 (m, 4H), 2.07 - 1.98 (m, IH), 1.23 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz,

CHLOROFORM-d) δ -73.83 (s, 3F). LC/MS m/z 466.15 (M+H) + , 2.51 min (LCMS Method 1).

Step 4. Preparation of ethyl l-((benzo[d]isothiazol-3-yloxy)methyl)-4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 -carboxylate .

The title compound was prepared in 61 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl l-((benzo[d]isothiazol-3- yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-e ne- 1 -carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 7.85 (dt, J=7.9, 0.9 Hz, IH), 7.76 (dt, J=8.2, 0.8 Hz, IH), 7.52 (ddd, J=8.2, 7.0, 1.1 Hz, IH), 7.42 - 7.37 (m, IH), 6.58 - 6.54 (m. IH), 4.66 (d, J=10.0 Hz, IH), 4.58 (d, J=10.0 Hz, IH), 4.16 (qd, J=7.1, 1.0 Hz, 2H), 2.76 (dq, J=18.9, 2.7 Hz, IH), 2.37 - 2.28 (m, IH), 2.27 - 2.20 (m, 2H), 2.07 - 1.89 (m, 2H), 1.28 - 1.25 (m, 12H), 1.19 (t, J=7.2 Hz, 3H). LC/MS m/z 444.25 (M+H) + , 2.58 min (LCMS Method 1).

Step 5. Preparation of ethyl l-((benzo[d]isothiazol-3-yloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 47 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl l-((benzo[d]isothiazol-3- yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )cyclohex-3-ene-l- carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.87 (d, J=7.8 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.52 (td, J=7.6, 1.1 Hz, 1H), 7.37 (td, J=7.5, 1.0 Hz, 1H), 5.37 (br. s., 1H), 5.20 (d, J=6.0 Hz, 1H), 4.76 (s, 1H), 4.64 (s, 1H), 4.19 - 4.16 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.17 - 3.03 (m, 8H), 2.79 - 2.36 (m, 6H), 2.28 - 0.83 (27H), 1.70 (s, 3H), 1.27 (t, J=7.3 Hz, 3H), 1.08 (s, 3H), 0.99 (s, 3H), 0.99 - 0.95 (m, 6H), 0.85 (s, 3H). LC/MS m/z 886.55 (M+H) + , 3.07 min (LCMS Method 3).

Step 6. l-((benzo[d]isothiazol-3-yloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid was prepared in 21 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 1- ((benzo[d]isothiazol-3-yloxy)methyl)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)- 3a-((2-( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.88 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.40 - 7.33 (m, 1H), 5.39 (br. s., 1H), 5.20 (br. s., 1H), 4.78 (s, 1H), 4.71 (s, 1H), 4.74 - 4.64 (m, 2H), 3.34 - 2.52 (m, 14H), 2.33 - 1.00 (m, 27H), 1.69 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H), 0.98 - 0.91 (m, 6H), 0.87 (s, 3H). LC/MS m/z 858.50 (M+H) + , 2.88 min (LCMS Method 3).

Example 9

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-4-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-((pyridin-4-yloxy)methyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate.

The title compound was prepared in 77 % yield, following the procedure described in general procedure A step 1-A, using 4-hydroxypyridine as reactant. ¾ NMR (500MHz, CHLOROFORM-d) δ 8.46 - 8.41 (m, 2H), 6.81 - 6.77 (m, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.04 (s, 2H), 4.01 - 3.93 (m, 4H), 2.37 - 2.25 (m, 2H), 1.80 - 1.66 (m, 6H), 1.24 (t, J=7.1 Hz, 3H). LC/MS: m/e 322.05 (M+H) + , 2.26 min (LCMS Method 11). Step 2. Preparation of ethyl 4-oxo-l-((pyridin-4-yloxy)methyl)cyclohexane-l- carboxylate.

The title compound was prepared in 64 % yield, following the procedure described in general procedure A step 2, using ethyl 8-((pyridin-4-yloxy)methyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.27 - 8.23 (m, 2H), 6.67 - 6.62 (m, 2H), 3.97 (s, 2H), 3.92 (q, J=7.3 Hz, 2H), 2.43 - 2.31 (m, 4H), 2.27 - 2.17 (m, 2H), 1.77 - 1.66 (m, 2H), 1.07 (t, J=7.3 Hz, 3H). LC/MS: m/e 278.05 (M+H) + , 0.81 min (LCMS Method 8).

Step 3. Preparation of ethyl l-((pyridin-4-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 66 % yield, following the procedure described in general procedure A step 3, using ethyl 4-oxo-l-((pyridin-4- yloxy)methyl)cyclohexanecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM- d) δ 8.47 - 8.44 (m, 2H), 6.83 - 6.79 (m, 2H), 5.82 (t, J=4.1 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 4.17 - 4.07 (m, 2H), 2.91 - 2.82 (m, 1H), 2.59 - 2.47 (m, 1H), 2.45 - 2.25 (m, 4H), 2.09 - 2.00 (m, 2H), 1.25 (t, J=7.2 Hz, 3H). LC/MS: m/e 410.00 (M+H) + , 1.92 min (LCMS Method 8).

Step 4. Preparation of ethyl l-((pyridin-4-yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 59 % yield, following the procedure described in general procedure A step 4, using ethyl l-((pyridin-4-yloxy)methyl)-4-

(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. ¾ NMR

(400MHz, CHLOROFORM-d) δ 8.33 - 8.30 (m, 2H), 6.73 - 6.69 (m, 2H), 6.46 (br. s., 1H), 4.10 - 4.04 (m, 2H), 4.02 - 3.95 (m, 2H), 2.63 (dd, J=19.2, 2.9 Hz, 1H), 2.23 - 2.12 (m, 2H), 2.12 - 2.01 (m, 1H), 1.94 - 1.77 (m, 2H), 1.17 (s, 12H), 1.11 (t, J=7.2 Hz, 3H). LC/MS: m/e 388.10 (M+H) + , 1.90 min (LCMS Method 8).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-4-yloxy)methyl)cycloh ex-3-ene-l-carboxylate.

The title compound was prepared in 34 % yield, following the procedure described in general procedure A step 5, using ethyl l-((pyridin-4-yloxy)methyl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylat e as reactant. LC/MS: m/e 831.45 (M+H) + , 2.54 min (LCMS Method 3). ¾ NMR (400MHz, CHLOROFORM-d) δ 8.42 (d, J=6.0 Hz, 2H), 6.80 (d, J=6.3 Hz, 2H), 5.36 (br. s., 1H), 5.18 (d, J=4.8 Hz, 1H), 4.71 (d, J=1.8 Hz, 1H), 4.59 (s, 1H), 4.20 - 4.06 (m, 4H), 3.12 - 2.97 (m, 8H), 2.74 - 2.51 (m, 4H), 2.51 - 2.40 (m, 1H), 2.31 - 2.12 (m, 4H), 2.11 - 1.98 (m, 3H), 1.98 - 1.80 (m, 5H), 1.80 - 1.62 (m, 2H), 1.69 (s, 3H), 1.62 - 1.37 (m, 10H), 1.37 - 1.17 (m, 4H), 1.26 (t, J=7.2 Hz, 3H), 1.16 - 0.99 (m, 3H), 0.99 - 0.93 (m, 6H), 0.93 - 0.87 (m, 3H), 0.87 - 0.81 (m, 3H).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-4-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid was prepared in 47 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-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)-l-((pyridin-4-yloxy)methyl)cycloh ex-3-enecarboxylate as reactant. ¾ NMR (400MHz, METHANOLS) δ 8.33 (d, J=6.3 Hz, 2H), 6.98 (d, J=5.5 Hz, 2H), 5.38 (br. s., 1H), 5.21 (d, J=5.0 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.65 (s, 1H), 4.28 - 4.12 (m, 2H), 3.24 - 3.00 (m, 8H), 2.94 - 2.72 (m, 5H), 2.66 (d, J=18.1 Hz, 1H), 2.37 - 1.97 (m, 8H), 1.97 - 1.78 (m, 1H), 1.72 (s, 3H), 1.78 - 1.69 (m, 3H), 1.66 - 1.21 (m, 14H), 1.16 (s, 3H), 1.20 - 1.08 (m, 2H), 1.05 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H). LC/MS: m/e 802.45 (M+H) + , 2.50 min (LCMS Method 3). Example 10

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-3-yloxy)methyl)cycloh ex-3-enecarboxylic acid.

Step 1. Preparation of ethyl 8-((pyridin-3-yloxy)methyl)-l,4-dioxaspiro[4.5]d carboxylate.

The title compound was prepared in 84 % yield, following the procedure described in general procedure A step 1-A, using 3-hydroxypyridine as reactant ¾ NMR (500MHz, CHLOROFORM-d) δ 8.30 (d, J=2.7 Hz, 1H), 8.24 (dd, J=4.4, 1.4 Hz, 1H), 7.25 - 7.15 (m, 2H), 4.21 (q, J=7.2 Hz, 2H), 4.05 (s, 2H), 4.00 - 3.93 (m, 4H), 2.38 - 2.25 (m, 2H), 1.83 - 1.66 (m, 6H), 1.32 - 1.22 (m, 3H). LC/MS: m/e 322.10 (M+H) + , 2.534 min (LCMS Method 11). Step 2. Preparation of ethyl 4-oxo-l-((pyridin-3-yloxy)methyl)cyclohexane-l- carboxylate.

The title compound was prepared in 47.8 % yield, following the procedure described in general procedure A step 2, using ethyl 8-((pyridin-3-yloxy)methyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate as reactant. LCMS: m/e 279.00 (M+H) + , 2.079 min (LCMS Method 8). Ή NMR (400MHz, CHLOROFORM-d) δ 8.22 (dd, J=2.6, 0.9 Hz, IH), 8.16 (dd, J=4.3, 1.8 Hz, IH), 7.19 - 7.09 (m, 2H), 4.18 (q, J=7.0 Hz, 2H), 4.07 - 4.04 (m, 2H), 2.55 - 2.41 (m, 4H), 2.38 - 2.28 (m, 2H), 1.88 - 1.75 (m, 2H), 1.19 (t, J=7.2 Hz, 3H).

Step 3. Preparation of ethyl l-((pyridin-3-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 51.9 % yield, following the procedure described in general procedure A step 3, using ethyl 4-oxo-l-((pyridin-3- yloxy)methyl)cyclohexanecarboxylate as reactant. LCMS: m/e 410.00 (M+H) + , 1.983 min (LCMS Method 8). 'H NMR (400MHz, CHLOROFORM-d) δ 8.26 - 8.21 (m, 1H), 8.19 - 8.13 (m, 1H), 7.20 - 7.09 (m, 2H), 5.78 - 5.70 (m, 1H), 4.16 - 4.10 (m, 2H), 4.09 - 4.02 (m, 2H), 2.84 - 2.74 (m, 1H), 2.52 - 2.40 (m, 1H), 2.38 - 2.26 (m, 2H), 2.26 - 2.17 (m, 1H), 2.01 - 1.92 (m, 1H), 1.21 - 1.15 (m, 3H).

Step 4. Preparation of ethyl l-((pyridin-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 88 % yield, following the procedure described in general procedure A step 4, using ethyl l-((pyridin-3-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. LCMS: m/e 388.10 (M+H) + , 1.986 min (LCMS Method 8). Ή NMR (400MHz, CHLOROFORM-d) δ 8.20 (dd, J=2.4, 0.9 Hz, 1H), 8.13 (dd, J=4.0, 2.0 Hz, 1H), 7.18 - 7.10 (m, 2H), 6.52 - 6.45 (m, 1H), 4.16 - 3.95 (m, 4H), 2.71 - 2.60 (m, 1H), 2.26 - 2.03 (m, 3H), 1.96 - 1.79 (m, 2H), 1.20 - 1.18 (m, 12H), 1.14 (t, J=7.2 Hz, 3H). Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((pyridin-3 -yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate and ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-3a-((2- (4-(methylsulfonyl)piperidin- 1 -yl)ethyl)amino)- 1 -(prop- 1 -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)- 1 -((pyridin-3 -yloxy)methyl)cyclohex-3 -enecarboxylate .

The title compounds were prepared in 26.4 % and 28.4 yields respectively, following the procedure described in general procedure A step 5, using ethyl l-((pyridin-3- yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )cyclohex-3-enecarboxylate as reactant.

For ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((pyridin-3 -yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate : LCMS: m/e 830.50 (M+H) + , 2.363 min (LCMS Method 8). ¾ NMR (400MHz,

CHLOROFORM-d) δ 8.28 (d, J=2.0 Hz, 1H), 8.21 (dd, J=4.0, 2.0 Hz, 1H), 7.23 - 7.16 (m, 2H), 5.35 (br. s., 1H), 5.17 (d, J=4.8 Hz, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.59 (s, 1H), 4.15 - 4.09 (m, 4H), 3.14 - 2.96 (m, 8H), 2.91 - 2.48 (m, 6H), 1.68 (s, 3H), 1.05 (s, 3H), 2.29 - 1.00 (m, 30H), 0.97 - 0.89 (m, 9H), 0.86 - 0.81 (m, 3H).

For ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-5a,5b,8,8,l la-pentamethyl-3a- ((2-(4-(methylsulfonyl)piperidin- 1 -yl)ethyl)amino)- 1 -(prop- 1 -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)-l-((pyridin-3-yloxy)methyl)cycloh ex-3-enecarboxylate:

LCMS: m/e 858.55 (M+H) + , 2.454 min (LCMS Method 8). ¾ NMR (400MHz,

CHLOROFORM-d) δ 8.28 (d, J=1.8 Hz, 1H), 8.21 (dd, J=4.0, 1.8 Hz, 1H), 7.20 - 7.16 (m, 2H), 5.35 (br. s., 1H), 5.17 (d, J=4.8 Hz, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.58 (s, 1H), 4.20 - 4.05 (m, 4H), 3.11 (t, J=8.5 Hz, 2H), 2.83 (s, 3H), 2.88-2.76 (m, 1H), 2.2.74 - 2.38 (m, 7H), 1.68 (s, 3H), 1.06 (s, 3H), 2.27 - 0.78 (m, 47H). Step 6. 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-3-yloxy)methyl)cycloh ex-3-enecarboxylic acid was prepared in 68.1 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-3-yloxy)methyl)cycloh ex-3-enecarboxylate as reactant. 1 HNMR(400MHz, CHLOROFORM-d) δ 8.32 (s, 1H), 8.21 (br. s., 1H), 7.23 (br. s., 2H), 5.37 (br. s., 1H), 5.18 (br. s., 1H), 4.71 (s, 1H), 4.60 (s, 1H), 4.23 - 4.08 (m, 2H), 3.16 - 2.99 (m, 8H), 2.89 - 2.57 (m, 6H), 2.33 - 1.79 (m, 9H), 1.68 ( s, 3H), 1.11 ( s, 3H), 0.99 ( s, 3H), 0.96 ( s, 3H), 0.93-0.92 ( m, 3H), 0.86 ( s, 3H), 1.75 - 0.81 (m, 18H). LC/MS: m/e 802.45 (M+H) + , 2.346 min (LCMS Method 8).

Example 11

Preparation of 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-5a,5b,8,8,lla- pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin- 1 -yl)ethyl)amino)- 1 -(prop- 1 -en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-3-yloxy)methyl)cycloh ex-3-enecarboxylic acid.

The title compound was prepared in 4.02 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR, 13aR,13bR)- 5a,5b,8,8,l la-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-l-yl)ethy l)amino)-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)-l-((pyridin-3-yloxy)methyl)cycloh ex-3-enecarboxylate as reactant. LCMS: m/e 830.50 (M+H) + , 2.367 min (LCMS Method 8). ¾ NMR (400MHz, CHLOROFORM-d) δ 8.31 (s, 1H), 8.20 (t, J=2.9 Hz, 1H), 7.22 (d, J=2.3 Hz, 2H), 5.37 (br. s., 1H), 5.18 (d, J=5.5 Hz, 1H), 4.76 - 4.67 (m, 1H), 4.59 (s, 1H), 4.16 (br. s., 2H), 3.13 (t, J=10.2 Hz, 2H), 2.92 - 2.59 (m, 9H), 2.48 (d, J=11.5 Hz, 1H), 2.31 - 1.78 (m, 15H), 1.68 ( s, 3H), 1.12 ( s, 3H), 0.98 ( s, 3H), 0.96 ( s, 3H), 0.93-0.92 ( m, 3H), 0.85 ( s, 3H), 1.71 - 0.77 (m, 18H).

Example 12

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2

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)-l-(((5-methylisothiazol-3-yl)oxy) methyl)cyclohex-3 carboxylic acid.

Step 1. Preparation of ethyl 8-((isothiazol-3-yloxy)methyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate.

The title compound was prepared in 69 % yield, following the procedure described in general procedure A step 1-A, using 5-methylisothiazol-3-ol as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.32 (d, J=1.0 Hz, 1H), 4.37 (br. s, 2H), 4.17 (q, J=7.0 Hz, 2H), 3.95 (s, 4H), 2.47 (d, J=1.0 Hz, 3H), 2.28 - 2.21 (m, 2H), 1.76 - 1.63 (m, 6H), 1.23 (t, J=7.2 Hz, 3H). LC/MS: m/e 342.10 (M+H) + , 3.67 min (LCMS Method 11).

Step 2. Preparation of ethyl l-(((5-methylisothiazol-3-yl)oxy)methyl)-4-oxocyclohexane- 1-carboxylate.

The title compound was prepared in 87 % yield, following the procedure described in general procedure A step 2, using ethyl 8-(((5-methylisothiazol-3-yl)oxy)methyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.34 (s, 1H), 4.48 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.59 - 2.45 (m, 4H), 2.45 - 2.36 (m, 2H), 1.94 - 1.82 (m, 2H), 1.29 (t, J=7.1 Hz, 3H). LC/MS: m/e 298.05 (M+H) + , 2.20 min (LCMS Method 8). Step 3. Preparation of ethyl l-(((5-methylisothiazol-3-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 87 % yield, following the procedure described in general procedure A step 3, using ethyl l-(((5-methylisothiazol-3-yl)oxy)methyl)-4- oxocyclohexanecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.31 (s, 1H), 5.74 (br. s., 1H), 4.43 (d, J=10.3 Hz, 1H), 4.37 (d, J=10.0 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.79 (dd, J=17.8, 2.8 Hz, 1H), 2.46 (s, 3H), 2.43 - 2.17 (m, 4H), 1.97 - 1.86 (m, 1H), 1.22 (t, J=7.3 Hz, 3H). LC/MS: m/e 430.2 (M+H) + , 2.20 min. Step 4. Preparation of ethyl l-(((5-methylisothiazol-3-yl)oxy)methyl)-4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 -carboxylate .

The title compound was prepared in 32 % yield, following the procedure described in general procedure A step 4, using ethyl l-(((5-methylisothiazol-3-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. ¾ NMR

(400MHz, CHLOROFORM-d) δ 6.51 - 6.45 (m, 1H), 6.26 (d, J=1.0 Hz, 1H), 4.42 - 4.37 (m, 1H), 4.33 - 4.26 (m, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.69 - 2.58 (m, 1H), 2.42 (d, J=1.0 Hz, 3H), 2.22 - 2.12 (m, 3H), 2.02 (s, 1H), 1.95 - 1.87 (m, 1H), 1.82 - 1.74 (m, 1H), 1.22 (d, J=2.0 Hz, 12H), 1.16 (t, J=7.2 Hz, 3H). Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((5 -methylisothiazol-3 -yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylate.

The title compound was prepared in 43 % yield, following the procedure described in general procedure A step 5, using ethyl 1 -(((5 -methylisothiazol-3 -yl)oxy)methyl)-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxyl ate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.30 (d, J=1.0 Hz, 1H), 5.33 (br. s., 1H), 5.17 (d, J=5.8 Hz, 1H), 4.70 (s, 2H), 4.58 (d, J=1.5 Hz, 2H), 4.49 - 4.43 (m, 1H), 4.42 - 4.36 (m, 1H), 4.17 - 4.12 (m, 2H), 3.13 - 2.96 (m, 8H), 2.73 - 2.62 (m, 2H), 2.62 - 2.52 (m, 2H), 2.50 - 2.41 (m, 1H), 2.46 (d, J=1.0 Hz, 3H), 2.22 - 2.10 (m, 8H), 2.10 - 1.97 (m, 3H), 1.96 - 1.65 (m, 4H), 1.68 (s, 3H), 1.64 - 1.37 (m, 7H), 1.37 - 1.23 (m, 6H), 1.20 (t, J=7.1 Hz, 3H), 1.16 - 0.98 (m, 5H), 0.98 - 0.81 (m, 9H). LC/MS: m/e 850.55 (M+H) + , 2.99 min (LCMS Method 3).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((5 -methylisothiazol-3 -yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylic acid was prepared in 36 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((5 -methylisothiazol-3 -yl)oxy)methyl)cyclohex-3 - enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.36 (d, J=0.8 Hz, 1H), 5.37 (br. s., 1H), 5.30 - 5.10 (m, 1H), 4.79 (s, 1H), 4.72 (s, 1H), 4.51 (d, J=10.0 Hz, 1H), 4.45 (dd, J=10.0, 3.5 Hz, 1H), 3.39 (d, J=12.3 Hz, 1H), 3.28 - 2.87 (m, 11H), 2.86 - 2.57 (m, 2H), 2.49 (d, J=0.8 Hz, 3H), 2.31 - 1.83 (m, 12H), 1.83 - 1.67 (m, 2H), 1.71 (s, 3H), 1.67 - 1.23 (m, 13H), 1.16 (s, 3H), 1.13 - 1.02 (m, 2H), 1.06 (s, 3H), 0.97 (m, 3H), 0.93 (m, 3H), 0.88 (s, 3H). LC/MS: m/e 822.60 (M+H) + , 2.83 min (LCMS Method 3).

Example 13

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl- lH-tetrazol-5 -yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylic acid.

Step 1. Preparation of ethyl 8-(((l-methyl-lH-tetrazol-5-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8 -carboxylate .

The title compound was prepared in 82 % yield, following the procedure described in general procedure A step 1-A, using 1 -methyl- lH-tetrazol-5-ol as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 4.57 (s, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.97 - 3.92 (m, 4H), 3.77 (s, 3H), 2.29 - 2.21 (m, 1H), 2.18 - 2.10 (m, 1H), 1.76 - 1.63 (m, 6H), 1.24 (t, J=7.2 Hz, 3H). LC/MS: m/e 327.20 (M+H) + , 2.15 min (LCMS Method 3).

Step 2. Preparation of ethyl l-(((l-methyl-lH-tetrazol-5-yl)oxy)methyl)-4- oxocyclohexane-l-carboxylate.

The title compound was prepared in 91 % yield, following the procedure described in general procedure A step 2, using ethyl 8-(((l-methyl-lH-tetrazol-5-yl)oxy)methyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 4.67 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.79 (s, 3H), 2.61 - 2.36 (m, 6H), 1.92 - 1.75 (m, 2H), 1.28 (t, J=7.3 Hz, 3H). LC/MS: m/e 283.15 (M+H) + , 3.01 min (LCMS Method 10). Step 3. Preparation of ethyl l-(((l-methyl-lH-tetrazol-5-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 29 % yield, following the procedure described in general procedure A step 3, using ethyl l-(((l-methyl-lH-tetrazol-5-yl)oxy)methyl)-4- oxocyclohexanecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 5.80 - 5.72 (m, 1H), 4.70 - 4.57 (m, 2H), 4.22 - 4.15 (m, 2H), 3.77 (s, 3H), 2.89 - 2.81 (m, 1H), 2.50 - 2.23 (m, 4H), 1.97 - 1.88 (m, 1H), 1.25 (t, J=7.2 Hz, 3H). LC/MS: m/e 415.25 (M+H) + , 2.51 min (LCMS Method 3). Step 4. Preparation of ethyl l-(((l-methyl-lH-tetrazol-5-yl)oxy)methyl)-4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 -carboxylate .

The title compound was prepared in 90 % yield, following the procedure described in general procedure A step 4, using ethyl 1-(((1 -methyl- lH-tetrazol-5 -yl)oxy )methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. ¾ NMR

(400MHz, CHLOROFORM-d) δ 6.54 - 6.40 (m, 1H), 4.64 (d, J=9.8 Hz, 1H), 4.56 (d, J=9.8 Hz, 1H), 4.17 - 4.10 (m, 2H), 3.74 (s, 3H), 2.72 - 2.63 (m, 1H), 2.34 - 2.11 (m, 3H), 2.00 - 1.92 (m, 1H), 1.88 - 1.80 (m, 1H), 1.23 (s, 12H), 1.21 (t, J=7.2 Hz 3H). LC/MS: m/e 393.35 (M+H) + , 4.06 min (LCMS Method 10).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl- lH-tetrazol-5-yl)oxy)methyl)cycloh< carboxylate

The title compound was prepared in 56 % yield, following the procedure described in general procedure A step 5, using ethyl l-(((l-methyl-lH-tetrazol-5-yl)oxy)methyl)-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxyl ate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 5.33 (br. s., 1H), 5.17 (d, J=5.8 Hz, 1H), 4.70 (d, J=2.0 Hz, 1H), 4.58 (d, J=1.3 Hz, 1H), 4.20 - 4.10 (m, 4H), 3.75(s, 3H), 3.12 - 2.97 (m, 8H), 2.76 - 2.40 (m, 6H), 2.26 - 0.87 (m, 27H), 1.68 (s, 3H), 1.21 (t, J=7.2 Hz, 3H), 1.04 (s, 3H), 0.95 (s, 3H), 0.94 - 0.87 (m, 6H), 0.84 (s, 3H). LC/MS: m/e 835.60 (M+H) + , 2.82 min (LCMS Method 3). Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl- lH-tetrazol-5 -yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylic acid was prepared in 74 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- (1,1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -methyl- lH-tetrazol-5 -yl)oxy)methyl)cyclohex-3 - enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 5.37 (br. s., 1H), 5.20 (t, J=6.4 Hz, 1H), 4.79 - 4.61 (m, 4H), 3.79 (s, 2H), 3.26 - 2.98 (m, 10H), 2.82 (d,

J=9.3 Hz, 4H), 2.76 - 2.55 (m, 1H), 2.33 - 2.11 (m, 1H), 2.08 (s, 3H), 2.11 - 1.82 (m, 8H), 1.70 (s, 3H), 1.65 - 1.37 (m, 10H), 1.36 - 1.22 (m, 4H), 1.16 (s, 3H), 1.11 - 1.01 (m, 2H), 1.03 (s, 3H), 0.98 (s, 1.5H), 0.97 (s, 1.5H), 0.94 (s, 1.5H), 0.93 (s, 1.5H), 0.87 (s, 3H). LC/MS: m/e 807.60 (M+H) + , 2.90 min (LCMS Method 3). Example 14

Preparation of 4-((l ,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-oxo-4,5-dihydro-l,2,4-thia diazol-3- yl)oxy)methyl)cyclohex-3-ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-(((5-(methylthio)-l,2,4-thiadiazol-3-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8 -carboxylate .

The title compound was prepared in 90 % yield, following the procedure described in general procedure A step 1-A, using 5-(methylthio)-l,2,4-thiadiazol-3-ol as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 4.45 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 3.98 - 3.91 (m, 4H), 2.68 (s, 3H), 2.31 - 2.21 (m, 2H), 1.77 - 1.66 (m, 6H), 1.24 (t, J=7.2 Hz, 3H). LC/MS: m/e 375.10 (M+H) + , 2.50 min (LCMS Method 3). Step 2. Preparation of ethyl l-(((5-(methylthio)-l,2,4-thiadiazol-3-yl)oxy)methyl)-4- oxocy clohexanecarboxylate .

The title compound was prepared in 100 % yield, following the procedure described in general procedure A step 2, using ethyl 8-(((5-(methylthio)-l,2,4-thiadiazol-3- yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 4.53 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 2.58 - 2.48 (m, 4H), 2.44 - 2.35 (m, 2H), 1.96 - 1.86 (m, 2H), 1.28 (t, J=7.2 Hz, 3H). LC/MS: m/e 331.05 (M+H) + , 2.32 min (LCMS Method 3).

Step 3. Preparation of ethyl l-(((5-(methylthio)-l,2,4-thiadiazol-3-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 55 % yield, following the procedure described in general procedure A step 3, using ethyl l-(((5-(methylthio)-l,2,4-thiadiazol-3- yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 5.74 (td, J=3.1, 1.8 Hz, IH), 4.50 (d, J=10.3 Hz, IH), 4.45 (d, J=10.3 Hz, 1H),4.15 (q, J=7.0 Hz, 2H), 2.84 - 2.75 (m, IH), 2.65 (s, 3H), 2.51 - 2.19 (m, 4H), 2.02 - 1.94 (m, IH), 1.21 (t, J=7.2 Hz, 3H). Step 4. Preparation of ethyl l-(((5-(methylthio)-l,2,4-thiadiazol-3-yl)oxy)methyl)-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxyl ate.

The title compound was prepared in 39 % yield, following the procedure described in general procedure A step 4 for 7 h, using ethyl l-(((5-(methylthio)-l,2,4-thiadiazol-3- yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.50 (dt, J=3.5, 1.8 Hz, IH), 4.49 (d, J=10.0 Hz, IH), 4.40 (d, J=10.0 Hz, IH), 4.11 (q, J=7.0 Hz, 2H), 2.72 - 2.64 (m, IH), 2.64 (s, 3H), 2.28 - 2.16 (m, 3H), 1.98 - 1.81 (m, 2H), 1.23 (s, 12H), 1.17 (t, J=7.2 Hz, 3H).

LC/MS: m/e 441.25 (M+H) + , 2.92 min (LCMS Method 3).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-(methylthio)-l,2,4-thiadia zol-3- yl)oxy)methyl)cyclohex-3 -enecarboxylate .

The title compound was prepared, following the procedure described in general procedure A step 5 at 90 °C for 4 h, using ethyl l-(((5-(methylthio)-l,2,4-thiadiazol-3- yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y l)cyclohex-3-enecarboxylate as reactant. LC/MS: m/e 883.55 (M+H) + , 3.11 min (LCMS Method 3).

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-oxo-4,5-dihydro-l,2,4-thia diazol-3- yl)oxy)methyl)cyclohex-3-ene-l-carboxylic acid was prepared in 10 % yield, following the procedure described in general procedure A step 6, using ethyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-(methylthio)-l,2,4-thiadia zol-3- yl)oxy)methyl)cyclohex-3-enecarboxylate as reactant. Ή NMR (400MHz,

CHLOROFORM-d) δ 4.80 (s, 1H), 4.76 - 4.69 (m, 1H), 4.60 -4.50 (m, 2H), 3.35 - 3.01 (m, 10H), 3.01 - 2.78 (m, 4H), 2.67 - 2.51 (m, 4H), 2.51 - 2.36 (m, 5H), 2.36 - 2.14 (m, 2H), 1.81 - 1.75 (m, 2H), 1.72 (s, 3H), 1.75 - 1.68 (m, 2H), 1.68 - 1.34 (m, 11H), 1.27 (s, 3H), 1.26 (s, 3H), 1.20 (s, 3H), 1.08 (s, 3H), 1.13 - 1.03 (m, 4H), 0.94 (s, 3H). LC/MS: m/e 825.50 (M+H) + , 2.78 min (LCMS Method 3). Example 15 Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((thiazol-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid.

Step 1 : Preparation of ethyl 8-((thiazol-2-yloxy)methyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate.

The title compound was prepared in 35 % yield, following the procedure described in general procedure A step 1-A, using thiazol-2-ol as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.39 (d, J=5.5 Hz, IH), 6.03 (d, J=5.3 Hz, IH), 4.09 (q, J=7.3 Hz, 2H), 3.86 (s, 4H), 3.76 (s, 2H), 2.11 - 2.03 (m, 2H), 1.68 - 1.46 (m, 6H), 1.20 (t, J=7.2 Hz, 3H). LC/MS m/z 328.10 (M+H) + , 2.09 min (LCMS Method 3).

Step 2. Preparation of ethyl 4-oxo-l-((thiazol-2-yloxy)methyl)cyclohexane-l-carboxylate.

The title compound was prepared in 80 % yield, following the procedure described in general procedure A step 2, using ethyl 8-((thiazol-2-yloxy)methyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) □ 6.47 (d, J=5.5 Hz, IH), 6.13 (d, J=5.5 Hz, IH), 4.28 (q, J=7.0 Hz, 2H), 3.97 (s, 2H), 2.55 - 2.35 (m, 6H), 1.89 - 1.77 (m, 2H), 1.34 (t, J=7.2 Hz, 3H). MS m/z 284.20 (M+H) + , 1.72 min (LCMS Method 3). Step 3. Preparation of ethyl l-((thiazol-2 -yloxy)methyl)-4-

(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 22 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 4-oxo-l-((thiazol-2- yloxy)methyl)cyclohexane-l -carboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 6.43 (d, J=5.5 Hz, IH), 6.11 (d, J=5.3 Hz, IH), 5.73 (td, J=3.4, 1.5 Hz, IH), 4.16 (qd, J=7.2, 2.6 Hz, 2H), 3.90 (s, 2H), 2.74 - 2.64 (m, IH), 2.45 - 2.39 (m, 2H), 2.33 - 2.20 (m, 2H), 1.85 - 1.76 (m, IH), 1.25 (t, J=7.2 Hz, 3H). MS m/z 416.20 (M+H) + , 2.75 min (LCMS Method 3).

Step 4. Preparation of ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-((thiazol- 2- yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 71 % yield, following the procedure described in general procedure A step 4, using ethyl l-((thiazol-2-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. ¾ NMR

(400MHz, CHLOROFORM-d) δ 6.49 - 6.46 (m, 1H), 6.45 (d, J=5.3 Hz, 1H), 6.06 (d, J=5.3 Hz, 1H), 4.12 (qd, J=7.2, 2.6 Hz, 2H), 3.86 (s, 2H), 2.63 - 2.54 (m, 1H), 2.31 - 1.99 (m, 4H), 1.60 (ddd, J=13.0, 9.0, 5.6 Hz, 1H), 1.23 (s, 12H), 1.22 (t, J=7.2 Hz, 3H). MS m/z 394.30 (M+H) + , 2.65 min (LCMS Method 3).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((thiazol-2-yloxy)methyl)cycloh ex-3-enecarboxylate.

The title compound was prepared in 30 % yield as a solid, following the procedure described in general procedure A step 5, using

(lR,3aS,5aR,5bR,7aR,l laR,l lbR,13aR,13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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 trifluoromethanesulfonate and ethyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l-((thiazol-2-yloxy)methyl)cyclohex -3-enecarboxylate as reactants. 'H NMR (400MHz, CHLOROFORM-d) δ 6.46 (d, J=5.5 Hz, 1H), 6.06 (d, J=5.3 Hz, 1H), 5.30 (br. s., 1H), 5.18 - 5.13 (m, 1H), 4.70 (d, J=2.0 Hz, 1H), 4.58 (s, 1H),

4.11 (q, J=7.3 Hz, 2H), 3.96 - 3.84 (m, 2H), 3.11 - 2.97 (m, 8H), 2.74 - 2.42 (m, 6H), 2.22 - 0.85 (m, 27H), 1.67 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.04 (s, 3H), 0.94 (s, 3H), 0.93 - 0.86 (m, 6H), 0.83 (s, 3H). MS m/z 836.65 (M+H) + , 2.98 min (LCMS Method 3). Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((thiazol-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid was prepared in 68 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((thiazol-2-yloxy)methyl)cycloh ex-3-enecarboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 6.70 (d, J=5.5 Hz, 1H), 6.08 (d, J=5.5 Hz, 1H), 5.42 - 5.28 (m, 1H), 5.20 (dd, J=16.2, 4.9 Hz, 1H), 4.78 (s, 1H), 4.69 (s, 1H), 4.19 - 4.01 (m, 1H), 4.02 - 3.85 (m, 1H), 3.29 (d, J=15.8 Hz, 1H), 3.24 - 2.95 (m, 7H), 2.85 (d, J=10.8 Hz, 2H), 2.61 (d, J=16.6 Hz, 1H), 2.43 (d, J=15.1 Hz, 1H), 2.31 -

2.12 (m, 8H), 2.12 - 1.85 (m, 6H), 1.85 - 1.75 (m, 1H), 1.70 (s, 3H), 1.75 - 1.60 (m, 2H), 1.59 - 1.21 (m, 12H), 1.17 (s, 3H), 1.13 - 1.01 (m, 2H), 1.04 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.86 (s, 3H). LC/MS: m/e 808.55 (M+H) + , 1.832 min (LCMS Method 3).

Example 16

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -phenyl- 1H- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-(((l-phenyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8 -carboxylate .

The title compound was prepared following the procedure described in general procedure A step 1-A, using l-phenyl-lH-l,2,3-triazol-5-ol as reactant. This material was carried forward to the next step without purification. LC/MS: m/e 388.20 (M+H) + , 2.32 min (LCMS Method 3).

Step 2. Preparation of ethyl 4-oxo-l-(((l-phenyl-lH-l,2,3-triazol-5- yl)oxy)methyl)cyclohexanecarboxylate .

The title compound was prepared in 9 % yield, following the procedure described in general procedure A step 2, using ethyl 8-(((l-phenyl-lH-l,2,3-triazol-5-yl)oxy)methyl)- l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 7.66 - 7.59 (m, 2H), 7.53 - 7.45 (m, IH), 7.45 - 7.36 (m, 2H), 7.20 (s, IH), 4.22 (s, 2H), 4.15 (q, J=7.1 Hz, 2H), 2.53 - 2.42 (m, 4H), 2.40 - 2.30 (m, 2H), 1.83 - 1.71 (m, 2H), 1.15 (t, J=7.2 Hz, 3H). LC/MS: m/e 388.20 (M+H) + , 2.32 min (LCMS Method 3).

Step 3. Preparation of ethyl l-(((l-phenyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate .

The title compound was prepared in 144 % yield, following the procedure described in general procedure A step 3, using ethyl 4-oxo- 1-(((1 -phenyl- IH- 1,2,3 -triazol-5- yl)oxy)methyl)cyclohexanecarboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 7.69 - 7.63 (m, 2H), 7.54 - 7.48 (m, 2H), 7.46 - 7.40 (m, IH), 7.22 (s, IH), 5.80 - 5.75 (m, IH), 4.29 (d, J=9.0 Hz, IH), 4.22 (d, J=8.8 Hz, IH), 4.17 - 4.11 (m, 2H), 2.87 - 2.79 (m, IH), 2.56 - 2.44 (m, IH), 2.42 - 2.22 (m, 3H), 1.97 - 1.89 (m, IH), 1.17 (t, J=7.2 Hz, 3H). LC/MS: m/e 476.25 (M+H) + , 2.65 min (LCMS Method 3). Step 4. Preparation of ethyl l-(((l-phenyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)cyclohex-3 -enecarboxylate .

The title compound was prepared in 91 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 1-(((1 -phenyl- lH-1, 2,3 -triazol-5- yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.68 - 7.63 (m, 2H), 7.50 - 7.43 (m, 2H), 7.41 - 7.35 (m, IH), 7.19 (s, IH), 6.49 (dt, J=3.5, 1.8 Hz, IH), 4.25 (d, J=8.8 Hz, IH), 4.19 (d, J=8.8 Hz, IH), 4.08 (qd, J=7.1, 1.0 Hz, 2H), 2.69 - 2.60 (m, IH), 2.28 - 2.05 (m, 3H), 1.98 - 1.90 (m, IH), 1.88 - 1.81 (m, IH), 1.23 (s, 12H), 1.12 (t, J=7.2 Hz, 3H). LC/MS: m/e 454.35 (M+H) + , 2.63 min (LCMS Method 3). Step 4. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -phenyl- IH- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- enecarboxylate.

4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -phenyl- IH- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid was prepared in 58 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-(((1 -phenyl- lH-1, 2,3 -triazol-5- yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-y l)cyclohex-3-enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.71 - 7.65 (m, 2H), 7.51 - 7.44 (m, 2H), 7.41 - 7.35 (m, IH), 7.19 (s, IH), 5.32 (br. s., IH), 5.15 (d, J=4.8 Hz, IH), 4.68 (d, J=2.0 Hz, IH), 4.57 (s, IH), 4.30 - 4.20 (m, 2H), 4.09 (q, J=7.3 Hz, 2H), 3.09 - 2.96 (m, 8H), 2.71 - 2.38 (m, 6H), 2.25 - 0.86 (m, 27H), 1.66 (s, 3H), 1.14 (t, J=7.2 Hz, 3H), 1.03 (s, 3H), 0.94 (s, 3H), 0.93 - 0.87 (m, 6H), 0.83 (s, 3H). Step 6. The title compound was prepared in 20% yield as a solid, following the procedure described in general procedure A step 5, using ethyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -phenyl- IH- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.79 - 7.70 (m, 2H), 7.53 - 7.46 (m, 2H), 7.43 - 7.37 (m, IH), 7.26 - 7.22 (m, IH), 5.36 (br. s., IH), 5.18 (t, J=5.5 Hz, IH), 4.70 (s, IH), 4.61 (s, IH), 4.38 - 4.23 (m, 2H), 3.09 - 2.92 (m, 8H), 2.90

- 2.80 (m, 2H), 2.78 - 2.54 (m, 4H), 2.31 - 2.10 (m, 4H), 2.04 - 1.80 (m, 6H), 1.73 (d, J=11.3 Hz, IH), 1.67 (s, 3H), 1.54 (d, J=17.8 Hz, 3H), 1.49 - 1.35 (m, 6H), 1.35 - 1.15 (m, 5H), 1.11 (s, 3H), 1.14 - 1.02 (m, 2H), 1.00 (s, 3H), 0.97 - 0.94 (m, IH), 0.96 (s, 3H), 0.93

- 0.92 (m, 3H), 0.85 (s, 3H). LC/MS: m/e 868.65 (M+H) + , 2.83 min (LCMS Method 3).

Example 17

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -isopropyl- 1H- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-(((l-isopropyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-l,4- dioxaspiro [4.5] decane-8 -carboxylate .

The title compound was prepared in 43 % yield as a semi-solid, following the procedure described in general procedure A step 1-B at 105 °C, using l-isopropyl-lH-l,2,3-triazol-5- ol as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.06 (s, 1H), 4.59 (spt, J=6.8 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 4.00 - 3.91 (m, 4H), 2.33 - 2.24 (m, 2H), 1.76 - 1.65 (m, 6H), 1.51 (d, J=6.8 Hz, 6H), 1.24 (t, J=7.2 Hz, 3H). LC/MS: m/e 354.30 (M+H) + , 3.33 min (LCMS Method 11).

Step 2. Preparation of ethyl l-(((l-isopropyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4- oxocy clohexane - 1 -carboxylate .

The title compound was prepared in 91 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((l-isopropyl-lH-l,2,3-triazol-5- yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.02 (s, IH), 4.50 (spt, J=6.8 Hz, IH), 4.17 (q, J=7.0 Hz, 2H), 4.11 (s, 2H), 2.52 - 2.40 (m, 4H), 2.38 - 2.28 (m, 2H), 1.82 - 1.71 (m, 2H), 1.43 (d, J=7.0 Hz, 6H), 1.19 (t, J=7.2 Hz, 3H). LC/MS: m/e 354.30 (M+H) + , 1.96 min (LCMS Method 3). Step 3. Preparation of ethyl l-(((l-isopropyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate .

The title compound was prepared in 97 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 1 -(((1-isopropyl-lH- 1,2,3 -triazol-5- yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 7.04 (s, IH), 5.79 - 5.73 (m, IH), 4.53 (spt, J=6.8 Hz, IH), 4.19 - 4.04 (m, 4H), 2.88 - 2.76 (m, IH), 2.55 - 2.21 (m, 4H), 1.92 (ddd, J=13.7, 7.9, 6.3 Hz, IH), 1.47 (d, J=6.8 Hz, 6H), 1.20 (t, J=7.2 Hz, 3H). 19 F NMR (376MHz,

CHLOROFORM-d)□ -73.94 (s, 3F). LC/MS: m/e 442.20 (M+H) + , 2.64 min (LCMS Method 3). Step 4. Preparation of ethyl l-(((l-isopropyl-lH-l,2,3-triazol-5-yl)oxy)methyl)-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxyl ate.

The title compound was prepared in 100 % yield, following the procedure described in general procedure A step 4, using ethyl l-(((l-isopropyl-lH-l,2,3-triazol-5- yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3- enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.02 (s, 1H), 6.48 (dt, J=3.3, 1.7 Hz, 1H), 4.53 (spt, J=6.8 Hz, 1H), 4.16 - 4.06 (m, 4H), 2.69 - 2.60 (m, 1H), 2.28 - 2.05 (m, 3H), 1.98 - 1.81 (m, 2H), 1.46 (dd, J=6.8, 2.3 Hz, 6H), 1.22 (s, 12H), 1.17 (t, J=7.2 Hz, 3H). LC/MS: m/e 420.30 (M+H) + , 2.65 min (LCMS Method 3).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -isopropyl- 1H- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- enecarboxylate.

The title compound was prepared in 100 % yield, following the procedure described in general procedure A step 5, using ethyl l-(((l-isopropyl-lH-l,2,3-triazol-5- yl)oxy)memyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl )cyclohex-3-enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.05 (s, 1H), 5.33 (br. s., 1H), 5.16 (d, J=4.8 Hz, 1H), 4.68 (s, 1H), 4.56 (s, 1H), 4.56 (spt, J=6.7 Hz, 1H), 4.20 - 4.09 (m, 4H), 3.11 - 2.93 (m, 8H), 2.71 - 2.36 (m, 6H), 2.30 - 0.86 (m, 27H), 1.66 (s, 3H), 1.49 (d, J=6.3 Hz, 6H), 1.21 (t, J=7.2 Hz, 3H), 1.04 (s, 3H), 0.94 (s, 3H), 0.93 - 0.87 (m, 6H), 0.83 (s, 3H). LC/MS: m/e 862.73 (M+H) + , 2.35 min (LCMS Method 1). Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -isopropyl- 1H- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid was prepared in 45 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR, 13aR,13bR)- 3a-((2-( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((( 1 -isopropyl- 1H- 1 ,2,3-triazol-5-yl)oxy)methyl)cyclohex-3- enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 7.12 (d, J=2.3 Hz, 1H), 5.36 (br. s., 1H), 5.19 (d, J=4.3 Hz, 1H), 4.72 (s, 1H), 4.63 (s, 1H), 4.67 - 4.52 (h, J=6.8 Hz, 1H), 4.32 - 4.10 (m, 2H), 3.20 - 2.89 (m, 8H), 2.87 - 2.68 (m, 3H), 2.68 - 2.53 (m, 1H), 2.34 - 2.21 (m, 1H), 2.21 - 1.85 (m, 11H), 1.85 - 1.73 (m, 1H), 1.71 - 1.65 (m. 1H), 1.68 (s, 3H), 1.51 (d, J=6.5 Hz, 6H), 1.64 - 1.36 (m, 9H), 1.36 - 1.19 (m, 4H), 1.14 (s, 3H), 1.07 (br. s., 2H), 1.01 (s, 3H), 0.97 - 0.96 (m, 4H), 0.94 - 0.89 (m, 3H), 0.87 (s, 3H). LC/MS: m/e 834.69 (M+H) + , 2.32 min (LCMS Method 1).

Example 18

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-(prop-l-en-2-yl)isothiazol -3-yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid.

Step 1. Preparation of ethyl 8-((isothiazol-3-yloxy)methyl)-l,4-dioxaspiro[4.5]d carboxylate.

The title compound was prepared in 36 % yield, following the procedure described in general procedure A step 1-A, using isothiazol-3(2H)-one as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.42 (d, J=4.8 Hz, IH), 6.57 (d, J=4.8 Hz, IH), 4.42 (s, 2H), 4.17 (q, J=7.0 Hz, 2H), 3.99 - 3.93 (m, 4H), 2.31 - 2.20 (m, 2H), 1.75 - 1.65 (m, 6H), 1.23 (t, J=7.2 Hz, 3H). LC/MS: m/e 328.20 (M+H) + , 3.59 min (LCMS Method 12).

Step 2. Preparation of ethyl 8-(((5-(2-hydroxypropan-2-yl)isothiazol-3-yl)oxy)methyl)- 1 ,4-dioxaspiro [4.5] decane- 8 -carboxylate .

To a solution of ethyl 8-((isothiazol-3-yloxy)methyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate (100 mg, 0305 mmol) in THF (2 mL) under nitrogen at -78 °C was added a 2M solution of LDA (0.305 mL, 0.611 mmol). It was stirred at -78 °C for 20 minutes before it was added neat propan-2-one (0.045 mL, 0.611 mmol). Stirring continued for another 30 minutes at -78 °C. The reaction was quenched with a half-saturated ammonium chloride in 0.5M HC1, extracted with ethyl acetate and concentrated in vacuo. The crude mixture was purified by silica gel column eluted with 0-45 % EtOAc / hexanes to give the desired product as an oil (83 mg, 70 %). ¾ NMR (400MHz,

CHLOROFORM-d) δ 6.35 (s, 1H), 4.32 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.91 (s, 4H), 2.84 (s, 1H), 2.26 - 2.12 (m, 2H), 1.72 - 1.61 (m, 6H), 1.58 (s, 6H), 1.19 (t, J=7.2 Hz, 3H). LC/MS: m/e 386.20 (M+H) + , 2.75 min (LCMS Method 13). Step 3. Preparation of ethyl l-(((5-(2-hydroxypropan-2-yl)isothiazol-3-yl)oxy)methyl)-4- oxocy clohexanecarboxylate .

The title compound was prepared in 100 % yield, following the procedure described in general procedure A step 2 using ethyl 8-(((5-(2-hydroxypropan-2-yl)isothiazol-3- yl)oxy)methyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz CHLOROFORM-d) δ 6.36 (s, 1H), 4.41 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 2.99 (s, 1H), 2.52 - 2.41 (m, 4H), 2.39 - 2.29 (m, 2H), 1.88 - 1.75 (m, 2H), 1.59 (s, 6H), 1.23 (t, J=7.0 Hz, 3H). LC/MS: m/e 342.15 (M+H) + , 2.03 min (LCMS Method 3).

Step 4. Preparation of ethyl l-(((5-(prop-l-en-2-yl)isothiazol-3-yl)oxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 22 % yield, following the procedure described in general procedure A step 3 using ethyl l-(((5-(2-hydroxypropan-2-yl)isothiazol-3- yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. ¾ NMR (400MHz,

CHLOROFORM-d) δ 6.50 (s, IH), 5.76 (td, J=3.3, 1.8 Hz, IH), 5.45 (s, IH), 5.18 (s, IH), 4.47 (d, J=10.0 Hz, IH), 4.41 (d, J=10.0 Hz, IH), 4.19 (qd, J=7.1, 0.8 Hz, 2H), 2.85 - 2.77 (m, IH), 2.53 - 2.22 (m, 4H), 2.09 (s, 3H), 1.98 - 1.90 (m, IH), 1.24 (t, J=7.2 Hz, 3H). LC/MS: m/e 456.10 (M+H) + , 2.76 min (LCMS Method 3).

Step 5. Preparation of ethyl l-(((5-(prop-l-en-2-yl)isothiazol-3-yl)oxy)methyl)-4-(4,4,5, 5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-ene- 1 -carboxylate .

The title compound was prepared in 78 % yield, following the procedure described in general procedure A step 4 using ethyl l-(((5-(prop-l-en-2-yl)isothiazol-3-yl)oxy)methyl)-

4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxyla te as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.55 - 6.50 (m, IH), 6.49 (s, IH), 5.43 (s, IH), 5.14 (s, IH), 4.46 (d, J=10.0 Hz, IH), 4.37 (d, J=10.0 Hz, IH), 4.15 (q, J=7.0 Hz, 2H), 2.74 - 2.64 (m, IH), 2.28 - 2.16 (m, 3H), 2.09 (s, 3H), 2.01 - 1.80 (m, 2H), 1.26 (s, 12H), 1.21 (t, J=7.2 Hz, 3H). LC/MS: m/e 434.20 (M+H) + , 2.79 min (LCMS Method 3).

Step 6. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-(prop-l-en-2-yl)isothiazol -3-yl)oxy)methyl)cyclohex-3- enecarboxylate.

The title compound was prepared in 42 % yield, following the procedure described in general procedure A step 5 using ethyl l-(((5-(prop-l-en-2-yl)isothiazol-3-yl)oxy)methyl)- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en ecarboxylate as reactant. Ή NMR (400MHz, CHLOROFORM-d) δ 6.51 (s, IH), 5.44 (s, IH), 5.35 (br. s., IH), 5.19 (br. s., IH), 5.17 (s, IH), 4.76 (s, IH), 4.71 (s, IH), 4.51 - 4.38 (m, 2H), 4.21 - 4.12 (m, 2H), 3.41 - 2.92 (m, 11H), 2.78 - 2.54 (m, 3H), 2.22 - 0.89 (m, 27H), 2.09 (s, 3H), 1.69 (s, 3H), 1.23 (t, J=7.2 Hz, 3H), 1.13 (s, 3H), 1.04 (s, 3H), 0.96 - 0.91 (m, 6H), 0.87 (s, 3H). LC/MS: m/e 876.60 (M+H) + , 3.01 min (LCMS Method 3).

Step 7. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-(prop-l-en-2-yl)isothiazol -3-yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid was prepared in 56 % yield, following the procedure described in general procedure A step 6 using ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR, 13bR)- 3a-((2-( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((5-(prop-l-en-2-yl)isothiazol -3-yl)oxy)methyl)cyclohex-3- enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 6.55 (s, 1H), 5.47 (s, 1H), 5.37 (br. s., 1H), 5.21 (d, J=5.3 Hz, 1H), 5.19 (s, 1H), 4.79 (s, 1H), 4.73 (s, 1H), 4.56 - 4.50 (m, 1H), 4.50 - 4.43 (m, 1H), 3.40 (d, J=11.8 Hz, 1H), 3.29 - 2.91 (m, 10H), 2.80 - 2.72 (m, 1H), 2.72 - 2.62 (m, 1H), 2.34 - 2.09 (m, 6H), 2.11 (s, 3H), 2.09 - 1.97 (m, 4H), 1.97 - 1.83 (m, 2H), 1.83 - 1.68 (m, 2H), 1.71 (s, 3H), 1.67 - 1.37 (m, 12H), 1.37 - 1.23 (m, 1H), 1.15 (s, 3H), 1.13 - 1.03 (m, 2H), 1.06 (s, 3H), 0.98 - 0.97 (m, 3H), 0.95 - 0.93 (m, 3H), 0.89 (s, 3H). LC/MS: m/e 848.50 (M+H) + , 3.05 min (LCMS Method 3).

Example 19

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((pyridazin-3 -yloxy)methyl)cyclohex-3 -ene- 1 -carboxylic acid.

Step 1. Preparation of ethyl 8-((pyridazin-3-yloxy)methyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate.

To the solution of ethyl 8-(hydroxymethyl)-l,4-dioxaspiro[4.5]decane-8-carboxylate (300 mg, 1.23 mmol) in DMF (6 mL) at 0 °C was added potassium tert-butoxide (1.84 mL, 1.84 mmol) followed by 3-chloropyridazine (211 mg, 1.84 mmol). The resulting suspension was stirred at 0 °C then warmed to RT overnight. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water, dried over sodium sulfate, and concentrated in vacuo to give crude product. LC/MS: m/e 323.20 (M+H) + , 2.09 min (LCMS Method 7).

Step 2. Preparation of ethyl 4-oxo-l-((pyridazin-3-yloxy)methyl)cyclohexanecarboxylate.

The title compound was prepared in 70 % yield, following the procedure described in general procedure A step 2 using ethyl 8-((pyridazin-3-yloxy)methyl)-l,4- dioxaspiro[4.5]decane-8-carboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.82 (dd, J=4.5, 1.3 Hz, IH), 7.37 (dd, J=9.0, 4.5 Hz, IH), 6.96 (dd, J=8.9, 1.4 Hz, IH), 4.64 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 2.57 - 2.28 (m, 6H), 1.92 - 1.82 (m, 2H), 1.28 (t, J=7.2 Hz, 3H). LC/MS: m/e 279.15 (M+H) + , 1.71 min (LCMS Method 7). Step 3. Preparation of ethyl l-((pyridazin-3-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate .

The title compound was prepared in 39 % yield, following the procedure described in general procedure A step 3 using ethyl 4-oxo-l-((pyridazin-3- yloxy)methyl)cyclohexanecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM- d) δ 8.82 (dd, J=4.5, 1.3 Hz, IH), 7.36 (dd, J=9.0, 4.5 Hz, IH), 6.94 (dd, J=9.0, 1.3 Hz, IH), 5.75 (td, J=3.1, 1.8 Hz, IH), 4.62 (d, J=10.5 Hz, IH), 4.59 (d, J=10.5 Hz, IH), 4.18 - 4.11 (m, 2H), 2.88 - 2.79 (m, IH), 2.53 - 2.23 (m, 4H), 1.97 - 1.90 (m, IH), 1.21 (t, J=7.2 Hz, 3H). LC/MS: m/e 411.15 (M+H) + , 2.66 min (LCMS Method 7).

Step 4. Preparation of ethyl l-((pyridazin-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3 -enecarboxylate .

The title compound was prepared in 43 % yield, following the procedure described in general procedure A step 4 using ethyl l-((pyridazin-3-yloxy)methyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.78 (dd, J=4.5, 1.3 Hz, IH), 7.32 (dd, J=8.9, 4.4 Hz, IH), 6.91 (dd, J=8.9, 1.4 Hz, IH), 6.49 (dt, J=3.7, 1.8 Hz, IH), 4.62 (d, J=10.3 Hz, IH), 4.53 (d, J=10.5 Hz, IH), 4.07 (q, J=7.0 Hz, 2H), 2.72 - 2.64 (m, IH), 2.27 - 2.08 (m, 3H), 1.98 - 1.80 (m, 2H), 1.21 (s, 12H), 1.21 (t, J=7.3 Hz, 3H). LC/MS: m/e 389.25 (M+H) + , 2.74 min (LCMS Method 7).

Step 5. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridazin-3-yloxy)methyl)cycl ohex-3-enecarboxylate.

The title compound was prepared following the procedure described in general procedure A step 5 using ethyl l-((pyridazin-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. The crude material was taken directly into the next step without purification.

Step 6. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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] chry sen-9-yl) - 1 -((pyridazin-3 -y loxy)methyl)cy clohex-3 -ene - 1 -carboxylic acid was prepared in 22 % yield as a solid, following the procedure described in general procedure A step 6 using ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridazin-3-yloxy)methyl)cycl ohex-3-enecarboxylate as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 9.09 (d, J=4.5 Hz, 1H), 7.74 (dd, J=9.0, 4.5 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 5.38 (br. s., 1H), 5.21 (t, J=5.6 Hz, 1H), 4.79 (s, 1H), 4.72 (s, 1H), 4.76 - 4.64 (m, 2H), 3.39 (d, J=12.5 Hz, 1H), 3.25 - 3.02 (m, 9H), 3.02 - 2.86 (m, 2H), 2.86 - 2.62 (m, 2H), 2.32 - 2.06 (m, 5H), 2.06 - 1.84 (m, 6H), 1.82 - 1.67 (m, 2H), 1.71 (s, 3H), 1.66 - 1.35 (m, 10H), 1.35 - 1.20 (m, 4H), 1.17 (s, 3H), 1.14 - 1.04 (m, 2H), 1.05 (s, 3H), 0.97 - 0.95 (m, 3H), 0.92 - 0.91 (m, 3H), 0.87 (s, 3H).

LC/MS: m/e 803.48 (M+H) + , 2.27 min (LCMS Method 1).

General Procedure B: Preparation of (R) ot-substituted cyclohexenecarboxylic acid derivatives.

Step 1. Preparation of ((R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(ethoxycarbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate .

A mixture of (lR,3aS,5aR,5bR,7aR,l laR,l lbR, 13aR, 13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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 trifluoromethanesulfonate (1 eq), (R)-(l-(ethoxycarbonyl)-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)met hyl benzoate (1.2 eq), NaiCOs (3 eq) and Pd(Ph 3 P) 4 (0.06 eq) in 1,4-dioxane and HiO (4 : 1) was flushed with nitrogen, sealed and heated at 70 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-35 % Ethyl acetate / hexanes to give the desired product (68 % yield) as a solid. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.01 (dd, J=8.4, 1.4 Hz, 2H), 7.60 - 7.53 (m, 1H), 7.47 - 7.40 (m, 2H), 5.36 (br. s., 1H), 5.20 (dd, J=6.0, 1.8 Hz, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.60 (s, 1H), 4.49 - 4.39 (m, 2H), 4.18 (qd, J=7.2, 1.4 Hz, 2H), 3.13 - 2.98 (m, 8H), 2.73 - 2.43 (m, 6H), 2.27 - 0.89 (m, 27H), 1.69 (s, 3H), 1.25 - 1.20 (m, 3H), 1.07 (s, 3H), 0.97 (br. s., 3H), 0.96 (br. s., 3H), 0.94 (s, 3H), 0.87 (s, 3H). LC/MS m/z 857.65 (M+H) + , 2.43 min (LCMS Method 1).

Step 2. Preparation of ethyl (R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- (l,l-dioxidomiomoφholino)ethyl)amino)-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)- 1 -(hydroxymethyl)cyclohex-3 -ene- 1 -carboxylate .

A suspension of ((R)-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 lbR, 13aR, 13bR)-3a-((2-( 1, 1 - dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate (1 eq) and IN NaOH (1 eq) in MeOH and THF was stirred at RT for 2 days. The mixture was neutralized with IN HC1 and the solvent was removed in vacuo. The residue was taken into CH2CI2, washed with H2O followed by brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified on silica gel eluted with ethyl acetate / hexanes to give the desired product (85 % yield) as a solid. Ή NMR (400MHz, CHLOROFORM-d) δ 5.32 (br. s., 1H), 5.18 (d, J=4.8 Hz, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.60 (s, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.69 (br. s., 2H), 3.12 - 2.98 (m, 8H), 2.72 - 2.43 (m, 6H), 2.28 - 0.89 (m, 27H), 1.70 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.07 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H). LC/MS m/z 753.65 (M+H) + , 3.79 min (LCMS Method 2).

Step 3. Preparation of (R) ot-methyl ether.

To a solution of ethyl (R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(hydroxymethyl)cyclohex-3-ene-l -carboxylate (1 eq) and Ar-X (2 eq) in DMF was added KOtBu (2 eq) at 0 °C. The resulted mixture was warmed to RT and stirred overnight. The reaction mixture was diluted with EtAOc, washed with water, dried over Na2S04, and concentrated in vacuo to give crude product which was used in the next step without further purification.

Step 4: Preparation of (R) ot-substituted cyclohexenecarboxylic acid.

A solution of (R) a-methyl ether from Step 3 in 1,4-dioxane, MeOH and IN NaOH (2 : 1 1) was stirred at 50 °C. The reaction mixture was purified by reverse phase preparative HPLC to give the final product.

Example 20

Preparation of (R)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid.

Step 1 - 2: General procedure B. Step 3. Preparation of ethyl (R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((pyridin-2-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in General procedure B step 3, using 2-chloropyridine as reactant. LC/MS m/z 830.55 (M+H) + , 3.56 min (LCMS Method 5).

Step 4. (R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -((pyridin-2-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylic acid was prepared in 41 % yield (2 steps) as a solid, following the procedure described in General procedure B step 4 for 6 h, using ethyl (R)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylate as reactant. ¾ NMR (500MHz, CHLOROFORM-d) δ 8.21 (dd, J=5.3, 1.4 Hz, IH), 7.70 (ddd, J=8.6, 7.0, 2.0 Hz, IH), 6.98 (ddd, J=7.1, 5.3, 0.8 Hz, IH), 6.84 (d, J=8.4 Hz, IH), 5.37 (br.s., 1H),5.20 (dd,J=6.1, 1.7 Hz, IH), 4.78 (s, lH),4.71(s, IH), 4.49 (d,J=9.9 Hz, IH), 4.45 (d,J=9.9Hz, IH), 3.38 - 3.31 (m, IH), 3.25 - 3.00 (m, 9H), 2.98 -2.85 (m, 2H), 2.79 (dt,J=10.9, 5.6 Hz, IH), 2.70 - 2.62 (m, IH), 2.28 - 1.86 (m, 11H), 1.76-1.07 (m, 16H), 1.70 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H). LC/MS m/z 802.45 (M+H) + , 3.34 min (LCMS Method 5).

Example 21

Preparation of (R)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyrimidin-4-yloxy)methyl)cycl ohex-3 -ene- 1 -carboxylic acid.

Step 1 - 2: General procedure B.

Step 3. Preparation of ethyl (R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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] chry sen-9-yl)- 1 -((pyrimidin-4-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in General procedure B step 3, using 4-chloropyrimidine as reactant. LC/MS m/z 831.55 (M+H) + , 3.45 min (LCMS Method 5).

Step 4. (R)-4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyrimidin-4-yloxy)methyl)cycl ohex-3-ene-l-carboxylic acid was prepared in 31 % yield (2 steps) as a solid, following the procedure described in General procedure B step 4 for 4 h, using ethyl (R)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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] chry sen-9-yl)- 1 -((pyrimidin-4-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate as reactant. ¾ NMR (500MHz, CHLOROFORM-d) δ 8.95 (s, 1H), 8.57 (d, J=6.4 Hz, 1H), 6.96 (dd, J=6.3, 0.9 Hz, 1H), 5.38 (br. s., 1H), 5.21 (d, J=4.6 Hz, 1H), 4.78 (s, 1H), 4.70 (s, 1H), 4.66 (s, 2H), 3.37 - 3.31 (m, 1H), 3.23 - 3.01 (m, 9H), 2.97 - 2.86 (m, 2H), 2.80 (dt,J=10.6, 5.6 Hz, 1H), 2.69 - 2.62 (m, 1H), 2.30 - 1.87 (m, 11H), 1.76- 1.01 (m, 16H), 1.70 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H). LC/MS m/z 725.50 (M+H) + , 3.23 min (LCMS Method 5).

Example 22

Preparation of (R)-l-(((3-chloropyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-2: General procedure B.

Step 3. Preparation of ethyl (R)-l-(((3-chloropyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in General procedure B step 3, using 2,3-dichloropyridine as reactant. LC/MS m/z 864.45 (M+H) + , 3.83 min (LCMS Method 5).

Step 4. (R)-l-(((3-chloropyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid was prepared in 69 % yield (2 steps) as a solid, following the procedure described in General procedure B step 4 for 6 h, using ethyl (R)-l-(((3-chloropyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as reactant. ¾ NMR (500MHz, CHLOROFORM-d) δ 8.04 (dd, J=4.9, 1.7 Hz, 1H), 7.64 (dd, J=7.6, 1.5 Hz, 1H), 6.87 (dd, J=7.6, 5.0 Hz, 1H), 5.38 (br. s., 1H), 5.21 (d, J=4.6 Hz, 1H), 4.77 (s, 1H), 4.71 (s, 1H), 4.54 (d, J=10.4 Hz, 1H), 4.51 (d, J=10.2 Hz, 1H), 3.43 - 3.36 (m, 1H), 3.25 - 3.01 (m, 9H), 2.99 - 2.87 (m, 2H), 2.75 (td, J=10.9, 5.7 Hz, 1H), 2.69 - 2.62 (m, 1H), 2.30 - 1.85 (m, 11H), 1.76 - 1.07 (m, 16H), 1.69 (s, 3H), 1.16 (s, 3H), 1.04 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H). LC/MS m/z 836.45 (M+H) + , 3.48 min (LCMS Method 5). Example 23

Preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 - 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-2: General procedure B.

Step 3. Preparation of ethyl (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 97 % yield as a solid, following the procedure described in General procedure B step 3, using 2-fluoronicotinonitrile as reactant. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.33 (dd, J=5.0, 2.0 Hz, IH), 7.87 (dd, J=7.4, 1.9 Hz, IH), 7.00 - 6.95 (m, IH), 5.37 (br. s., IH), 5.19 (d, J=4.8 Hz, IH), 4.71 (d, J=2.0 Hz, IH), 4.60 (s, IH), 4.57 - 4.53 (m, 2H), 4.18 (qd, J=7.2, 2.6 Hz, 2H), 3.12 - 2.99 (m, 8H), 2.76 - 2.41 (m, 6H), 2.28 - 0.90 (m, 27H), 1.69 (s, 3H), 1.27 (t, J=7.2 Hz, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H). LC/MS m/z 855.60 (M+H) + , 4.03 min (LCMS Method 2).

Step 4. (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid was prepared in 67 % yield as a solid, following the procedure described in General procedure B step 3 at RT for 2 days, using ethyl (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-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)cyclohex-3-ene-l-carboxylate as reactant. ¾ NMR (400MHz, METHANOLS) δ 8.37 (dd, J=5.0, 2.0 Hz, IH), 8.06 (dd, J=7.5, 1.8 Hz, IH), 7.10 (dd, J=7.5, 5.0 Hz, IH), 5.37 (br. s., IH), 5.22 (dd, J=6.0, 1.5 Hz, IH), 4.85 (s, IH), 4.76 (t, J=1.5 Hz, IH), 4.63 - 4.55 (m, 2H), 3.27 - 3.07 (m, 11 H), 2.91 (ddd, J=14.4, 10.0, 4.6 Hz, IH), 2.79 - 2.61 (m, 2H), 2.32 - 1.09 (m, 27H), 1.77 (s, 3H), 1.17 (s, 3H), 1.12 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H). LC/MS m/z 827.60 (M+H) + , 3.70 min (LCMS Method 2). Example 24

Preparation of (R)-l-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

The title compound was a side product formed during Step 4 of the preparation of ethyl (R)- 1 -(((3-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-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)cyclohex-3-ene-l-carboxylate. The material was isolated in 14 % yield as a solid. Ή NMR (400MHz, METHANOL-d 4 ) δ 8.40 (dd, J=7.8, 2.0 Hz, IH), 8.29 (dd, J=5.0, 2.0 Hz, IH), 7.13 (dd, J=7.7, 4.9 Hz, IH), 5.37 (br. s., IH), 5.21 (d, J=4.5 Hz, IH), 4.83 (s, IH), 4.72 (s, IH), 4.64 (d, J=10.3 Hz, IH), 4.53 (d, J=10.5 Hz, IH), 3.28 - 3.03 (m, 11H), 3.01 - 2.90 (m, IH), 2.84 - 2.68 (m, 2H), 2.37 - 1.06 (m, 27H), 1.75 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H). LC/MS m/z 845.60 (M+H) + , 3.66 min (LCMS Method 2) . General Procedure C: Preparation of (S) ot-substituted cyclohexenecarboxylic acid derivatives.

Step 1. Preparation of ((S)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l - dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(ethoxycarbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate .

The title compound was prepared in 86% of yield as a solid, following the procedure described in General procedure B step 1, using (S)-(l-(ethoxycarbonyl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)methy l benzoate instead of (R)- ( 1 -(ethoxycarbonyl)-4-(4,4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3 -en- 1 - yl)methyl benzoate as the reactant. LC/MS m/z 857.50 (M+H) + , 3.055 min ( LCMS Method 3). ¾ NMR (400MHz, CHLOROFORM-d) δ 8.07 - 7.90 (m, 2H), 7.64 - 7.52 (m, 1H), 7.49 - 7.37 (m, 2H), 5.37 (br. s., 1H), 5.21 (dd, J=6.0, 1.8 Hz, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.61 (d, J=1.3 Hz, 1H), 4.52 - 4.37 (m, 2H), 4.25 - 4.16 (m, 2H), 3.15 - 3.00 (m, 8H), 2.78 - 2.53 (m, 5H), 2.51 - 2.42 (m, 1H), 2.34-2.23 (m, 1H), 1.70 ( s, 3H), 1.07 ( s, 3H), 0.99 ( s, 3H), 0.97 ( s, 3H), 0.93 ( s, 3H), 0.87 ( s, 3H), 2.22 - 0.80 (m, 29H).

Step 2. Preparation of ethyl (S)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR, 13aR, 13bR)-3a-((2- (l,l-dioxidomiomoφholino)ethyl)amino)-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)- 1 -(hydroxymethyl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 94% of yield as a solid, following the procedure described in General procedure B step 2, using ((S)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate instead of ((R)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate as the reactant. LC/MS m/z 753.55 (M+H) + , 2.754 min ( LCMS Method 3). ¾NMR (400MHz, CHLOROFORM-d) δ 5.30 (s, IH), 5.16 (d, J=5.0 Hz, IH), 4.72 (s, IH), 4.61 (s, IH), 4.23 - 4.12 (m, 2H), 3.67 (s, 2H), 3.28 - 2.65 (m, 13H), 2.54 (d,J=16.1 Hz, IH), 1.68 ( s, 3H), 1.09 ( s, 3H), 0.98 ( s, 3H), 0.96 ( s, 3H), 0.89 ( s, 3H), 0.85 ( s, 3H), 2.23 - 0.78 (m, 30H).

Step 3. Preparation of ethyl (S)-l-((aryloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

To a solution of ethyl (S)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(hydroxymethyl)cyclohex-3-ene-l -carboxylate (1 eq) in DMF at -78 °C was added KOtBu (2 eq). The resulted mixture was stirred for 20 minutes before the addition of Ar-X (2 eq). Then the reaction was warmed to RT and stirred overnight. The reaction mixture was diluted with EtAOc, washed with water, dried over Na2S04, and concentrated in vacuo to give crude product which was either used in next step without further purification or purified by silica gel chromatography using ethyl acetate/hexanes as eluents.

Step 4. Preparation of (S)-l-((aryloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

A solution of ethyl (S)-l-((aryloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylate from Step 3 in 1,4-dioxane, MeOH and IN NaOH (2: 1 : 1) was stirred at 50 °C for 2-18 hours. The reaction mixture was then purified by reverse phase preparative HPLC to give the final product.

Example 25

Preparation of (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-2: General procedure C step 1-2. Step 3. Preparation of ethyl (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in General procedure C step 3, using 2-chloronicotinonitrile as the reactant. LC/MS m/z 855.50 (M+H) + , 3.004 min (LCMS Method 3). Step 4. (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yl)- 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)cyclohex-3-ene-l-carboxylic acid was prepared in 29 % yield (over 2 steps) as a solid, following the procedure described in General procedure C step 4 for 7 h, using ethyl (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 827.50 (M+H) + , 3.393 min (LCMS Method 7). 'H NMR (400MHz, METHANOLS) δ 8.40 (dd, J=5.1, 1.9 Hz, IH), 8.08 (dd, J=7.5, 2.0 Hz, IH), 7.12 (dd, J=7.5, 5.0 Hz, IH), 5.39 (br. s., IH), 5.25 - 5.21 (m, IH), 4.85 (s, IH), 4.76 (s, IH), 4.62 (d, J=10.3 Hz, IH), 4.58 (d, J=10.3 Hz, IH), 3.31 - 3.18 (m, 8H), 3.16 - 3.12 (m, 2H), 3.12 - 3.07 (m, IH), 3.02 - 2.87 (m, IH), 2.80 (td, J=l 1.0, 5.5 Hz, IH), 2.73 - 2.63 (m, 2H), 2.37 - 2.27 (m, IH), 2.26 - 2.01 (m, 8H), 1.97 - 1.91 (m, IH), 1.88 - 1.75 (m, 2H), 1.78 (s, 3H), 1.72 - 1.44 (m, 10H), 1.42 - 1.31 (m, IH), 1.20 (s, 3H), 1.27 - 1.09 (m, 3H), 1.13 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).

Alternatively, Example 28 can be prepared using the following procedure:

Step 1 : Preparation of (S)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yl)- 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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylic acid, HC1. To a flask containing a suspension of (R)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- ((2-(l, l-dioxidothiomo holino)ethyl)amino)-5a,5b,8,8, 1 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)-l-(fluoromethyl)cyclohex-3-enecar boxylic acid (4.08 g, 5.61 mmol) prepared as described in WO 2015157483 in 1,4-dioxane (50.0 inL) was added tetrabutylammonium hydroxide (55% in water) (26.5 g, 56.1 mmol). The flask was attached to reflux condensor and was heated in an oil bath at 100 °C. After 8.5 days of heating, LC/MS showed the reaction was complete. The mixture was cooled to rt and was transferred to a graduated addition funnel. Upon standing in the addition funnel, two distinct layers formed. The bottom layer containing the product was split in half based on the graduation of the funnel. Half of the material was made acidic by adding IN HC1. The solids that formed were collected by filtration and were washed with water. The solids were then triturated with ether and collected by filtration. The solids were washed with ether then allowed to dry on the filter paper. The title product was isolated as a white solid (1.95g, 2.56 mmol, 45.6% yield, 91% if calculated as half of the mixture). LCMS: m/e 725.4 (M+H) + , 1.15 min (method 16).

Step 2. To a suspension of (S)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yl)- 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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylic acid, HC1 (1.95 g, 2.56 mmol) in THF (30 mL) was added KHMDS (0.91M in THF) (9.0 mL, 8.19 mmol). The mixture was stirred for 5 minutes, then 2-fluoronicotinonitrile (1.0 g, 8.19 mmol) was added. After 2.5h an aliquot was removed. LC/MS showed the reaction was complete. The reaction mixture was diluted with IN HC1 (30 mL) then was extracted with ethyl acetate (3 x 75 mL). The organic layers were washed with sat. aq. NaCl, and dried over magnesium sulfate. The drying agent was removed by filtration. The drying agent did not filter well, so it is likely that solid precipitated while standing at rt, so the solid filter cake was stirred with ethyl acetate, then with dichloromethane, then filtered again. The combined filtrates were concentrated under reduced pressure. The residue was triturated with ether and the solids that formed were collected by filtration and washed with ether. The residue was dissolved in methanol and was purified by reverse phase chromatography using a 275g Isco Redisep gold CI 8 column and a 20%B-80%A to 100%B gradient where A was 90% water, 10% acetonitrile with 0.1% TFA buffer and B was 10% water, 90% acetonitrile with 0.1% TFA buffer. The fractions containing the product were combined and concentrated under reduced pressure to give (S)-l-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR,13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-enecarboxylic acid, TFA (1.50g, 1.59 mmol, 62%) as a white solid. LCMS: m/e 827.4 (M+H) + , 1.32 min (method 16).

Example 26

Preparation of (S)-l-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

The title compound was prepared as a side product in 7 % yield (over 2 steps) as a solid, following the procedure described in General procedure C Step 4 for 7 h, using ethyl (S)- l-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR, 13bR)- 3a-((2-( 1 , 1 -dioxido1hiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 845.55 (M+H-H 2 0) + , 3.349 min (LCMS Method 7). 'H NMR (400MHz, METHANOL- d 4 ) 5 8.42 (dd, J=7.5, 2.0 Hz, 1H), 8.31 (dd, J=4.8, 2.0 Hz, 1H), 7.16 (dd, J=7.5, 5.0 Hz, 1H), 5.40 (br. s., 1H), 5.24 (d, J=4.5 Hz, 1H), 4.86 (br. s., 1H), 4.76 (s, 1H), 4.66 - 4.62 (d, J=10.5 Hz, 1H), 4.57 - 4.53 (d, J=10.5 Hz, 1H), 3.30 - 3.17 (m, 7H), 3.12 (d, J=17.3 Hz, 3H), 2.96 - 2.92 (m, 1H), 2.81 - 2.71 (m, 2H), 2.45 - 2.30 (m, 1H), 2.25 - 2.12 (m, 5H), 2.12 - 2.00 (m, 3H), 1.92 - 1.67 (m, 6H), 1.78 (s, 3H), 1.67 - 1.41 (m, 10H), 1.26 - 1.06 (m, 3H), 1.20 (s, 3H), 1.13 (s, 3H), 1.02 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H).

Example 27

Preparation of (R)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((3-(methoxycarbonyl)pyridin-2 -yl)oxy)methyl)cyclohex-3- ene-l-carboxylic acid.

The title compound was prepared as a side product in 0.6 % yield (over 2 steps) as a solid, following the procedure described in General procedure B step 4 for 15 h, using ethyl (R)-

1- (((3-cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR, 13bR)- 3a-((2-( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 860.65 (M+H) + , 2.93 min (LCMS Method 7). 'H NMR (400MHz, METHANOLS) δ 8.30 (dd, J=5.0, 2.0 Hz, IH), 8.17 (dd, J=7.5, 2.0 Hz, IH), 7.06 (dd, J=7.5, 5.0 Hz, IH), 5.39 (br. s., IH), 5.25 - 5.21 (m, IH), 4.85 (s, IH), 4.75 (s, IH), 4.57 - 4.47 (m, 2H), 3.89 (s, 3H), 3.30 - 3.17 (m, 8H), 3.16 - 3.07 (m, 3H), 3.02 - 2.90 (m, IH), 2.81 (td, J=11.0, 5.4 Hz, IH), 2.73 - 2.63 (m, IH), 2.36 - 2.00 (m, 9H), 2.00 - 1.90 (m, IH), 1.90 - 1.75 (m, 3H), 1.77 (s, 3H), 1.75 - 1.34 (m, 12H), 1.26 - 1.09 (m, 2H), 1.20 (s, 3H), 1.12 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H). Example 28

Preparation of (S)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((6-methoxypyridin-2-yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylic acid.

Step 1 - 2: General procedure C step 1-2.

Step 3. Preparation of ethyl (S)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((6-fluoropyridin-2-yl)oxy)met hyl)cyclohi

carboxylate.

The title compound was prepared as a solid, following the procedure described in General procedure C step 3, using 2,6-difluoropyridine as the reactant. LC/MS m/z 848.50 (M+H) + , 3.031 min (LCMS Method 3).

Step 4. (S)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((6-methoxypyridin-2-yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylic acid was prepared in 3.7 % yield (over 2 steps) as a solid, following the procedure described in General procedure C step 4 for 15 h, using ethyl (S)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((6-fluoropyridin-2-yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylate as the reactant. LC/MS: m/e 832.50 (M+H) + , 3.267 min (LCMS Method 7). ¾ NMR (500MHz, METHANOLS) δ 7.54 (t, J=7.9 Hz, IH), 6.32 (d, J=2.9 Hz, IH), 6.30 (d, J=2.9 Hz, IH), 5.38 (br. s., IH), 5.29 - 5.15 (m, IH), 4.85 (s, IH), 4.76 (s, IH), 4.485 - 4.345 (m, 2H), 3.89 (s, 3H), 3.30 - 3.17 (m, 8H), 3.17 - 3.07 (m, 3H), 2.94 (ddd, J=14.5, 10.2, 4.7 Hz, IH), 2.78 (td, J=l 1.0, 5.4 Hz, IH), 2.67 - 2.60 (m, IH), 2.30 (d, J=18.2 Hz, IH), 2.22 - 2.09 (m, 3H), 2.09 - 2.00 (m, 2H), 1.96 - 1.66 (m, 8H), 1.78 (s, 3H), 1.66 - 1.43 (m, 10H), 1.43 - 1.29 (m, 2H), 1.29 - 1.09 (m, IH), 1.19 (s, 3H), 1.13 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).

Example 29

Preparation of (S)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yl)- 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)- 1 -(((6-fluoropyridin-2-yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylic acid.

The title compound was prepared in 69.8 % of yield (2 steps) as a solid, following the procedure described in General procedure C step 4 for 7 h, using ethyl (S)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((6-fluoropyridin-2-yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylate as the reactant. LC/MS: m/e 820.45 (M+H) + , 3.136 min (LCMS Method 7). ¾ NMR (500MHz, ACETONE-de) δ 7.85 (q, J=8.1 Hz, IH), 6.71 (dd, J=8.0, 1.3 Hz, IH), 6.61 (dd, J=7.8, 2.3 Hz, IH), 5.42 - 5.35 (m, IH), 5.23 (dd, J=6.2, 1.8 Hz, IH), 4.79 (d, J=1.2 Hz, IH), 4.68 (d, J=1.4 Hz, IH), 4.46 (d, J=10.2 Hz, IH), 4.41 (d, J=10.2 Hz, IH), 3.43 - 3.24 (m, 8H), 3.23 - 3.12 (m, 5H), 3.12 - 3.05 (m, 3H), 3.02 (td, J=10.8, 5.7 Hz, IH), 2.70 - 2.61 (m, IH), 2.38 - 2.16 (m, 4H), 2.17 - 2.01 (m, 3H), 1.95 - 1.84 (m, 2H), 1.84 - 1.68 (m, 2H), 1.74 (s, 3H), 1.64 (d, J=16.8 Hz, IH), 1.61 - 1.42 (m, 8H), 1.40 - 1.22 (m, 1H), 1.26 (s, 3H), 1.23 - 1.11 (m, 2H), 1.13 (s, 3H), 1.02 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H).

Example 30

Preparation of (S)-l-(((4-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 - 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-2: General procedure C step 1-2.

Step 3. Preparation of ethyl (S)-l-(((4-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 - 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in General procedure C step 3, using 2-fluoroisonicotinonitrile as the reactant. LC/MS m/z 855.50 (M+H) + , 3.048 min (LCMS Method 3).

Step 4. (S)-l-(((4-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid was prepared in 30.5 % yield (over 2 steps) as a solid, following the procedure described in General procedure C step 4 for 7 h, using ethyl (S)-l-(((4-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 845.55 (M+H) + , 3.048 min (LCMS Method 7). 'H NMR (400MHz, CHLOROFORM-d) δ 8.02 (d, J=5.3 Hz, 1H), 7.12 (d, J=5.3 Hz, 1H), 6.97 (s, 1H), 5.16 (br. s., 1H), 5.00 (d, J=5.5 Hz, 1H), 4.58 (br. s., 1H), 4.48 (br. s., 1H), 4.35 - 4.18 (m, 2H), 3.25 - 2.65 (m, 18H), 2.47 (d, J=17.1 Hz, 1H), 2.14 - 1.64 (m, 10H), 1.52 - 1.48 (m, 2H), 1.50 (s, 3H), 1.45 - 1.03 (m, 10H), 0.98 (s, 3H), 0.88 - 0.84 (m, 2H), 0.86 (s, 3H), 0.78 (s, 3H), 0.73 (s, 3H), 0.68 (s, 3H). Example 31

Preparation of (S)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid.

Step 1-2: General procedure C step 1-2.

Step 3. Preparation of ethyl (S)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -((pyridin-2-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in General procedure C step 3, using 2-bromopyridine as the reactant. LC/MS m/z M+l=830.55. 2.822 min (LCMS Method 3). Step 4. (S)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid was prepared in 22.9 % yield (over 2 steps) as a solid, following the procedure described in General procedure C step 4 for 7 h, using ethyl (S)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 802.45 (M+H) + , 2.824 min (LCMS Method 3). ¾ NMR

(400MHz, CHLOROFORM-d) δ 8.21 (dd, J=5.1, 1.4 Hz, IH), 7.69 (ddd, J=8.6, 7.0, 1.8 Hz, IH), 6.97 (td, J=6.2, 0.9 Hz, IH), 6.83 (d, J=8.5 Hz, IH), 5.38 (br. s., IH), 5.21 (d, J=4.5 Hz, IH), 4.80 (s, IH), 4.72 (s, IH), 4.51 (d, J=10.0 Hz IH), 4.46 (d, J=10.0 Hz IH), 3.37 - 3.34 (m, IH), 3.25 - 3.10 (m, 7H), 3.10 - 3.01 (m, 2H), 3.00 - 2.87 (m, 2H), 2.82 (dt, J=10.9, 5.6 Hz, IH), 2.73 (d, J=15.3 Hz, IH), 2.35 - 2.13 (m, 4H), 2.13 - 1.88 (m, 7H), 1.81 - 1.67 (m, 2H), 1.71 (s, 3H), 1.66 - 1.26 (m, 13H), 1.18 (s, 3H), 1.13 - 1.03 (m, IH), 1.06 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H).

Example 32

Preparation of (S)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -((pyrazin-2-yloxy)methyl)cyclohex-3-ene- 1 -carboxylic acid.

Step 1-2: General procedure C step 1-2. Step 3. Preparation of ethyl (S)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -((pyrazin-2-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in General procedure C step 3, using 2-fluoropyrazine as the reactant. LC/MS m/z M+l=831.55. 2.922 min (LCMS Method 3).

Step 4. (S)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -((pyrazin-2-yloxy)methyl)cyclohex-3-ene- 1 -carboxylic acid was prepared in 77.0 % yield (over 2 steps) as a solid, following the procedure described in General procedure C step 4 for 9 h, using ethyl (S)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyrazin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 803.42 (M+H) + , 2.38 min (LCMS Method 1). ¾ NMR (400MHz, CHLOROFORM-d) δ 8.27 (br. s., 2H), 8.17 (br. s., IH), 5.39 (br. s., IH), 5.22 (d, J=4.8 Hz, IH), 4.79 (s, IH), 4.73 (s, IH), 4.62 - 4.48 (dd, J=10.5, 17.3 Hz, 2H), 3.44 - 3.32 (m, IH), 3.30 - 2.89 (m, 11H), 2.84 - 2.64 (m, 2H), 2.38 - 1.83 (m, 11H), 1.83 - 1.67 (m, 2H), 1.71 (s, 3H), 1.68 - 1.37 (m, 10H), 1.38 - 1.22 (m, 2H), 1.16 (s, 3H), 1.13 - 1.03 (m, 2H), 1.06 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.89 (s, 3H). General Procedure D: Preparation of a-pyridin-2-yloxy cyclohexenecarboxylic acid derivatives.

Step 1. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino-

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)- 1 -((pyridin-2-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylate .

A mixture of (lR,3aS,5aR,5bR,7aR,l laR,l lbR, 13aR, 13bR)-3a-amino-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 trifluoromethane sulfonate (1 eq), ethyl 1- ((pyridin-2-yloxy)methyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxa borolan-2-yl)cyclohex-3-ene- 1-carboxylate (leq), Na 2 C0 3 (3 eq) and Pd(Ph 3 P)4 (0.06 eq) in 1,4-dioxane and HiO (4 : 1), was flushed with nitrogen, sealed and heated at 70 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-55 % ethyl acetate / hexanes to give the desired product (57 % yield) as a solid. ¾ NMR (400MHz, CHLOROFORM-d) δ 8.13 (dd, J=5.0, 1.5 Hz, 1H), 7.58 - 7.52 (m, 1H), 6.86 (ddd, J=7.2, 5.1, 0.8 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.35 (br. s., 1H), 5.19 (d, J=5.8 Hz, 1H), 4.73 (d, J=2.3 Hz, 1H), 4.60 (dd, J=2.3, 1.3 Hz, 1H), 4.48 - 4.37 (m, 2H), 4.18 - 4.11 (m, 2H), 2.70 - 2.62 (m, 1H), 2.54 (td, J=10.9, 5.3 Hz, 1H), 2.29 - 0.84 (m, 27H), 1.69 (s, 3H), 1.20 (t, J=7.2 Hz, 3H), 1.07 (s, 3H), 0.96 (s, 3H), 0.97 - 0.91 (m, 6H), 0.86 (s, 3H). LC/MS m/z 669.60 (M+H) + , 2.82 min (LCMS Method 3).

Step 2: Preparation of C-17 amine derivative.

To a solution of ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino- 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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylate (1 eq) and aldehyde (2 eq) in DCE was added titanium (IV) isopropoxide (2 eq). The mixture was stirred at RT for 1 h. Sodium triacetoxyborohydride (2 eq) was added and the mixture was stirred at RT overnight. The reaction was quenched with saturated aqueous Na2C03. The resulting slurry was extracted with dichloromethane, washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with ethyl acetate / hexanes to give the desired product.

Step 3: Preparation of carboxylic acid.

A solution of the ester from step 2 in 1,4-dioxane, MeOH and IN NaOH (2: 1 : 1) was stirred at 60 -70 °C. The reaction mixture was purified by reverse phase preparative HPLC to give the final product.

Example 33

Preparation of 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(4-hydrox y-l,l- dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)amino)-5a,5b,8,8,l la-pentamethyl-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)- 1 -((pyridin-2-yloxy)methyl)cyclohex-3-ene- 1 -carboxylic acid.

Step 1 : General procedure D step 1.

Step 2. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2-(4- hydroxy-1, l-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)amino)-5a,5b,8,8 , 1 la- pentamethyl-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)-l-((pyridin-2-yl oxy)methyl)cyclohex-3- ene- 1 -carboxylate.

The title compound was prepared in 78 % yield as a solid, following the procedure described in general procedure D step 2, using 2-(4-hydroxy-l, l-dioxidotetrahydro-2H- thiopyran-4-yl)acetaldehyde as reactant. Ή NMR (400MHz, CHLOROFORM-d) 5 8.12 (dd, J=5.0, 1.5 Hz, 1H), 7.57 - 7.52 (m, 1H), 6.85 (ddd, J=7.0, 5.1, 0.9 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.34 (br. s., 1H), 5.18 (d, J=5.8 Hz, 1H), 4.73 (d, J=1.8 Hz, 1H), 4.61 (s, 1H), 4.48 - 4.36 (m, 2H), 4.18 - 4.08 (m, 4H), 3.57 - 3.43 (m, 2H), 2.91 - 2.61 (m, 5H), 2.50 (td, J=10.7, 5.5 Hz, 1H), 2.24 - 0.88 (31H), 1.68 (s, 3H), 1.19 (t, J=7.2 Hz, 3H), 1.03 (s, 3H), 0.96 (s, 3H), 0.95 - 0.90 (m, 6H), 0.85 (s, 3H). LC/MS m/z 845.60 (M+H) + , 3.59 min (LCMS Method 4).

Step 3. 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(4-hydroxy-l,l- dioxidotetrahydro-2H-miopyran-4-yl)ethyl)amino)-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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylic acid was prepared in 76 % yield as a solid, following the procedure described in general procedure D step 3 at 60° C for 12 h, using ethyl 4-

(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2-(4-hydroxy- 1 , 1 -dioxidotetrahydro- 2H-thiopyran-4-yl)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-ene-l-carboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 8.29 (br. s., lH), 7.96 (t, J=7.0 Hz, 1H), 7.17 (br. s., 1H), 7.04 (d, J=8.3 Hz, 1H), 5.35 (br. s., 1H), 5.18 (d, J=5.3 Hz, 1H), 4.75 (s, 1H), 4.69 (s, 1H), 4.53 - 4.39 (m, 2H), 3.58 - 3.35 (m, 2H), 3.21 (br. s., 2H), 2.97 - 2.84 (m, 2H), 2.76 - 2.62 (m, 2H), 2.58 - 2.44 (m, 1H), 2.34 - 1.04 (m, 32H), 1.68 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 0.95 - 0.91 (m, 6H), 0.87 (s, 3H). LC/MS m/z 817.55 (M+H) + , 5.51 min (LCMS Method 4).

General Procedure E. Preparation of ot-substituted cyclohexenecarboxylic acid derivatives via alkylation of a-methyl alcohol.

Step 1. Preparation of (4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(ethoxycarbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate .

A mixture of (lR,3aS,5aR,5bR,7aR,l laR,l lbR, 13aR, 13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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 trifluoromethanesulfonate (1 eq), (l-(ethoxycarbonyl)-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-l-yl)met hyl benzoate (1.05 eq), Na 2 C0 3 HiO (3 eq) and Pd(Ph3P) 4 (0.06 eq) in 1,4-dioxane and H2O (4 : 1) was flushed with nitrogen, sealed and heated at 70 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and H2O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine dried over NaiSC , and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0 - 60 % ethyl acetate / hexanes to give the desired product as a solid (67 % yield). ¾ NMR (400MHz, CHLOROFORM-d) δ 8.01 (dd, J=8.2, 1.1 Hz, 2H), 7.59 - 7.53 (m, 1H), 7.46 - 7.40 (m, 2H), 5.36 (br. s., 1H), 5.20 (d, J=5.5 Hz, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.59 (s, 1H), 4.48 - 4.39 (m, 2H), 4.21 - 4.14 (m, 2H), 3.12 - 2.98 (m, 8H), 2.73 - 2.53 (m, 5H), 2.50 - 2.42 (m, 1H),

2.31 - 0.81 (m, 27H), 1.69 (s, 3H), 1.22 (t, J=7.2 Hz, 3H), 1.06 (s, 3H), 0.96 (s, 3H), 0.98 - 0.92 (m, 6H), 0.86 (s, 3H). LC/MS: m/e 857.50 (M+H) + , 2.91 min (LCMS Method 3).

Step 2: . Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2- (1,1 -dioxidothiomo holino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(hydroxymethyl)cyclohex-3 -ene- 1 -carboxylate .

A suspension of 4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 lbR, 13aR, 13bR)-3a-((2-( 1, 1 - dioxidothiomoφholino)e1hyl)amino)-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)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate (1 eq) and IN NaOH (1 eq) in MeOH and THF was stirred at RT for 1 day. The mixture was neutralized with saturated aqueous citric acid and the solvent was removed in vacuo. The residue was taken into EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo to give the desired product (99% yield) as a solid without further purification. LC/MS m/z 753.70 (M+H) + , 2.85 min (LCMS Method 3).

Step 3. Preparation of ot-substituted cyclohexenecarboxylic ester.

To a solution of ethyl -4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(hydroxymethyl)cyclohex-3-ene-l -carboxylate (1 eq) and Ar-X (2 eq) in DMF was added KOtBu (2 eq). The resulting mixture was warmed to RT and stirred overnight. The reaction mixture was diluted with EtAOc, washed with water, dried over Na2S04, and concentrated in vacuo to give crude product which was used in next step without further purification.

Step 4. Preparation of ot-substituted cyclohexenecarboxylic acid.

A solution of ot-methyl ether from step 4 in 1,4-dioxane, MeOH and IN NaOH (2 : 1 : 1) was stirred at 50 °C. The reaction mixture was purified by reverse phase preparative HPLC to give the final product.

Example 34

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-((pyrimidin-2-yloxy)methyl)cycl ohex-3-ene-l-carboxylic acid.

Step 1-2: General procedure E. Step 3. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -((pyrimidin-2-yloxy)methyl)cyclohex-3-ene- 1 -carboxylate .

The title compound was prepared as crude product, following the procedure described in general procedure E step 3, using 2-bromopyrimidine as reactant. LC/MS m/z 831.60 (M+H) + , 2.76 min (LCMS Method 3).

Step 4. 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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] chry sen-9-yl)- 1 -((pyrimidin-2-yloxy)methyl)cyclohex-3 -ene- 1 -carboxylic acid was prepared in 11 % yield as a solid, following the procedure described in general procedure E step 4, using ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR, 13aR,13bR)-3a-((2- (l,l-dioxidothiomoφholino)ethyl)amino)-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)-l-((pyrimidin-2-yloxy)methyl)cycl ohex-3-enecarboxylate as reactant. 'H NMR (400MHz, CHLOROFORM-d) δ 8.62 (d, J=4.8 Hz, 2H), 7.10 (t, J=4.9 Hz, 1H), 5.39 (br. s., 1H), 5.21 (d, J=4.5 Hz, 1H), 4.78 (s, 1H), 4.72 (s, 1H), 4.64 - 4.54 (m, 2H), 3.39 (br. d, J=13.1 Hz, 1H), 3.27 - 3.03 (m, 9H), 3.03 - 2.89 (m, 2H), 2.80 - 2.70 (m, 1H), 2.33 - 2.06 (m, 4H), 2.06 - 2.02 (m, 6H), 2.02 - 1.85 (m, 4H), 1.81 - 1.67 (m, 2H), 1.71 (s, 3H), 1.67 - 1.37 (m, 10H), 1.37 - 1.25 (m, 2H), 1.16 (s, 3H), 1.12 - 1.03 (m, 1H), 1.06 (s, 3H), 0.98 - 0.97 (m, 3H), 0.95 - 0.94 (m, 3H), 0.89 (s, 3H). LC/MS: m/e 803.50 (M+H) + , 2.80 min (LCMS Method 3).

Example 35

Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(((7-methoxyisoquinolin- 1 -yl)oxy)methyl)cyclohex-3 -ene- 1 -

Step 1-2: General procedure E. Step 3. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(((7-methoxyisoquinolin- 1 -yl)oxy)methyl)cyclohex-3 - enecarboxylate.

The title compound was prepared as crude product, following the procedure described in general procedure E step 3, using l-chloro-7-methoxyisoquinoline as reactant. LC/MS: m/e 910.65 (M+H) + , 2.98 min (LCMS Method 3).

Step 4: 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(((7-methoxyisoquinolin- 1 -yl)oxy)methyl)cyclohex-3 -ene- 1 - carboxylic acid was prepared in 39 % yield as a solid, following the procedure described in general procedure E step 4, using ethyl 4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8,lla-pentamethyl -l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(((7-methoxyisoquinolin- 1 -yl)oxy)methyl)cyclohex-3 - enecarboxylate as reactant. LC/MS: m/e 882.60 (M+H) + , 2.83 min (LCMS Method 3). Example 36

Preparation of l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 - 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-2: General procedure E.

Step 3. Preparation of ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate.

The title compound was prepared in 41 % yield, following the procedure described in general procedure E step 3, using 2-chloronicotinonitrile as reactant. Ή NMR (400MHz, CHLOROFORM-d) δ 8.31 (dd, J=5.0, 1.8 Hz, 1H), 7.86 (dd, J=7.5, 2.0 Hz, 1H), 6.97 (dd, J=7.4, 5.1 Hz, 1H), 5.34 (br. s., 1H), 5.17 (d, J=5.0 Hz, 1H), 4.69 (d, J=1.8 Hz, 1H), 4.57 (br. s., 1H), 4.53 (s, 2H), 4.21 - 4.12 (m, 2H), 3.10 - 2.97 (m, 8H), 2.74 - 2.40 (m, 6H), 2.28 - 0.82 (m, 27H), 1.67 (s, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.04 (s, 3H), 0.94 (s, 3H), 0.93 - 0.88 (m, 6H), 0.84 (s, 3H). LC/MS: m/e 855.60 (M+H) + , 3.08 min (LCMS Method 7).

Step 4. l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid was prepared in 33 % yield, following the procedure described in general procedure E step 3 at RT, using ethyl l-(((3- cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-enecarboxylate as reactant. ¾ NMR (400MHz, METHANOL-d 4 )□ 8.41 - 8.38 (m, 1H), 8.08 (dd, J=7.5, 1.8 Hz, 1H), 7.12 (dd, J=7.7, 5.1 Hz, 1H), 5.39 (br. s., 1H), 5.23 (d, J=4.8 Hz, 1H), 4.85 (s, 1H), 4.75 (s, 1H), 4.63 (dd, J=3.8, 10.5 Hz, 1H), 4.58 (d, J=10.3 Hz, 1H), 3.30 - 3.17 (m, 8H), 3.17 - 3.07 (m, 3H), 2.99 - 2.89 (m, 1H), 2.80 (td, J=l 1.0, 5.4 Hz, 1H), 2.72 - 2.64 (m, 1H), 2.40 - 2.23 (m, 1H), 2.23 - 2.15 (m, 2H), 2.15 - 2.01 (m, 7H), 1.99 - 1.90 (m, 1H), 1.90 - 1.76 (m, 3H), 1.78 (s, 3H), 1.76 - 1.64 (m, 2H), 1.63 - 1.41 (m, 9H), 1.41 - 1.29 (m, 1H), 1.24 - 1.18 (m, 1H), 1.20 (s, 3H), 1.18 - 1.10 (m, 1H), 1.13 (s, 3H), 1.025 - 1.015 (m, 3H), 0.98 (s, 3H), 0.95 (s, 3H). LC/MS: m/e 827.65 (M+H) + , 3.12 min (LCMS Method 7).

General procedure F. Preparation of a-substituted cyclohexenecarboxylic acid derivatives via silyl carboxylate.

Step 1. Preparation of (l-((benzyloxy)carbonyl)-4-oxocyclohexyl)methyl benzoate.

To a solution of benzyl l-(hydroxymethyl)-4-oxocyclohexanecarboxylate (4.3 g, 16.4 mmol) in pyridine (20 mL) was added benzoic anhydride (4.45 g, 19.7 mmol) followed by DMAP (2.00 g, 16.4 mmol). The resulting solution was stirred at 55 °C for 2 hours. The reaction mixture was diluted with 50 mL of ethyl acetate and was washed with 0.5 N HCl to pH = 4. The organic layer was dried over Na2S04 and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-50 % ethyl acetate / hexanes to give the desired product as an oil (3.3 g, 49 %).

¾ NMR (400MHz, CHLOROFORM-d) δ 7.92 (d, J=7.8 Hz, 2H), 7.65 - 7.54 (m, 1H), 7.44 . 7.37 (m 5 2H), 7.35 - 7.27 (m, 5H), 5.25 (s, 2H), 4.46 (s, 2H), 2.63 - 2.35 (m, 6H), 1.86 (td, J=12.4, 5.0 Hz, 2H).

Step 2. Preparation of (l-((benzyloxy)carbonyl)-4- (((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -en- 1 -yl)methyl benzoate .

To a solution of (l-((benzyloxy)carbonyl)-4-oxocyclohexyl)methyl benzoate (4.2 g, 11.5 mmol) and 1, 1,1 -trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)-methanesul fonamide (4.5 g, 12.6 mmol) in THF (50 mL) at -78 °C was added KHMDS (1 M in THF) (14.9 mL, 14.9 mmol). The resulting yellow solution was stirred at -78 °C for 2 h. The reaction was quenched with saturated aqueous NH4CI. The mixture was extracted with EtOAc, washed with brine, dried over NaiSCU, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-15 % ethyl acetate / hexanes to give the desired triflate as an oil (3.6 g, 63 %). ¾ NMR (400MHz, CHLOROFORM-d) δ 7.92 (d, J=7.8 Hz, 2H), 7.62 - 7.55 (m, 1H), 7.42 (t, J=7.5 Hz, 2H), 7.35 - 7.27 (m, 5H), 5.80 (br. s., 1H), 5.26 - 5.14 (m, 2H), 4.50 - 4.41 (m, 2H), 2.90 (dd, J=17.9, 2.4 Hz, 1H), 2.57 - 2.28 (m, 4H), 2.02 - 1.91 (m, 1H).

Step 3. Preparation of (l-((benzyloxy)carbonyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-3 -en- 1 -yl)methyl benzoate .

A mixture of (l-((benzyloxy)carbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)c yclohex-3-en- l-yl)methyl benzoate (3.32 g, 6.66 mmol), bis(pinacolato)diboron (1.71 g, 6.73 mmol), KOAc (1.64 g, 16.7 mmol)) and PdCl2(dppf)-CH 2 Ci2 adduct (0.16 g, 0.2mmol) in 1,4- dioxane (30 mL) was flushed with nitrogen, sealed and heated at 70 °C for 20 h. The mixture was diluted with water (150 mL) and extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-20 % ethyl acetate / hexanes to give the desired boronate as an oil (2.2 g, 69 %). ¾ NMR (400MHz, CHLOROFORM-d) δ 7.90 (d, J=8.1 Hz, 2H), 7.58 - 7.51 (m, 1H), 7.42 - 7.36 (m, 2H),

7.32 - 7.22 (m, 5H), 6.54 (br. s., 1H), 5.16 (s, 2H), 4.48 - 4.36 (m, 2H), 2.75 (d, J=17.6 Hz, 1H), 2.32 - 2.19 (m, 3H), 2.07 - 2.00 (m, 1H), 1.92 - 1.86 (m, 1H), 1.27 (s, 12H). LC/MS: m/e 499.20 (M+Na) + , 3.10 min (LCMS Method 7). Step 4. Preparation of (4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR,13bR)-3a-amino-l- (buta-2,3-dien-2-yl)-5a,5b,8,8, 1 la-pentamethyl- 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)- 1 -((benzyloxy)carbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate .

A mixture of (lR,3aS,5aR,5bR,7aR,l laR,l lbR, 13aR, 13bR)-3a-amino-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 trifluoromethane sulfonate (2.4 g, 4.3 mmol), ( 1 -((benzyloxy)carbonyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-en- 1 - yl)methyl benzoate (2.05 g, 4.3 mmol), Na 2 C0 3 HiO (1.60 g, 12.9 mmol) and Pd(Ph 3 P)4 (0.3 g, 0.26 mmol) in 1,4-dioxane (100 mL) and H2O (25 mL) was flushed with nitrogen, sealed and heated at 70 °C for 2 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by silica gel column eluted with 0-55 % ethyl acetate / hexanes to give the desired C-3 ot- substituted cyclohexenecarboxylic ester (1.8 g, 55 %). ¾ NMR (400MHz,

CHLOROFORM-d) δ 7.91 (d, J=7.0 Hz, 2H), 7.58 - 7.51 (m, 1H), 7.42 - 7.35 (m, 2H), 7.33 - 7.28 (m, 2H), 7.26 - 7.22 (m, 3H), 5.34 (br. s., 1H), 5.21 - 5.11 (m, 3H), 4.73 (s, 1H), 4.60 (br. s., 1H), 4.51 - 4.39 (m, 2H), 2.71 (d, J=17.3 Hz, 1H), 2.54 (td, J=10.9, 5.1 Hz, 1H), 2.25 - 0.92 (m, 27H), 1.69 (s, 3H), 1.13 - 0.85 (m, 15H). LC/MS: m/e 758.70 (M+H) + , 3.24 min (LCMS Method 7). Step 5. Preparation of (1 -((benzyloxy)carbonyl)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3 -en- 1 -yl)methyl benzoate .

A suspension of (4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-amino- 5a,5b,8,8, l 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -((benzyloxy)carbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate (1.6 g, 2.11 mmol), 4-(2-chloroethyl)thiomorpholine 1, 1-dioxide hydrochloride (1.5 g, 6.33 mmol), sodium iodide (0.35 g, 2.32 mmol) and K3PO4 (2.24 g, 10.55 mmol) in acetonitrile (20 mL) was flushed with N2, sealed and heated at 100 °C for 15 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL), dried over Na2S04, and concentrated in vacuo. The crude product was purified on silica gel column eluted with 25-60% EtOAc/hexane to give the desired product (1.3 g, 67 % yield). ¾ NMR (400MHz, CHLOROFORM-d) δ 7.92 (d, J=7.8 Hz, 2H), 7.58 - 7.51 (m, 1H), 7.43 - 7.36 (m, 2H), 7.31 (d, J=4.6 Hz, 2H), 7.25 (d, J=4.4 Hz, 3H), 5.35 (br. s., 1H), 5.22 - 5.12 (m, 3H), 4.71 (s, 1H), 4.60 (br. s., 1H), 4.45 (q, J=10.7 Hz, 2H), 3.15 - 2.99 (m, 8H), 2.78 - 2.42 (m, 6H), 2.23 - 0.81 (m, 27H), 1.69 (s, 3H), 1.07 - 0.79 (m, 15H).

LC/MS: m/e 919.60 (M+H) + , 3.27 min (LCMS Method 7). Step 6. Preparation of benzyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(hydroxymethyl)cyclohex-3 -ene- 1 -carboxylate .

To a solution of (l-((benzyloxy)carbonyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)methyl benzoate (1.0 g, 1.09 mmol) in MeOH (15 mL) was added IN NaOH (1.09 mL, 1.09 mmol). The mixture was stirred at RT for 12 h, neutralized with saturated aqueous citric acid and the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with brine, dried over Na2S04, and concentrated in vacuo to give the desired product (56% yield with trace amount methyl ester by product) without further purification. LC/MS: m/e 815 (M+H) + , 4.803 min (LCMS Method 7). For methyl ester: LC/MS: m/e 739.55 (M+H) + , 4.615 min (LCMS Method 7).

Step 7. Preparation of benzyl l-((aryloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate.

To a solution of benzyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-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)-l-(hydroxymethyl)cyclohex-3-ene-l -carboxylate (1 eq) in DMF at -78 °C was added KOtBu (2 eq). The resulted mixture was stirred for 20 minutes before the addition of Ar-X (2 eq). Then the reaction was warmed to RT and stirred overnight. The reaction mixture was diluted with EtOAc, washed with water, dried over Na2S04, and concentrated in vacuo to give crude product which was either used in next step without further purification or purified by silica gel chromatography with ethyl acetate/hexanes as eluents.

Step 8. Preparation of tert-butyldimethylsilyl l-((aryloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3 -ene- 1 -carboxylate .

To a solution of the crude product ( 1 eq) from general procedure F, step 7 in DCE (3 mL) was added TEA (1.6 eq), t-Butyldimethylsilane (2.0 eq), and palladium acetate (0.25 eq). The mixture was flushed with N2 for 5 minutes and then heated at 60 °C for 2-6 hours. The reaction mixture was cooled to room temperature and was filtered through a pad of celite and silica gel and washed with 50 % EtOAc in hexanes, then with dichloromethane. The filtrate was concentrated under reduced pressure and the crude product obtained was used in the next step without additional purification.

Step 9. Preparation of l-((aryloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

To a solution of the crude product ( 1 eq ) from general procedure F, step 8 in THF (3 mL) was added a solution of TBAF (1.6 eq) in THF. The resulting mixture was stirred for 2 hours. The solution was purified by reverse phase preparative HPLC. Fractions containing the desired product were collected and dried to afford the desired l-((aryloxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid. Example 37

Preparation of l-(((4-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-6: General procedure F steps 1-6

Step 7. Preparation of benzyl l-(((4-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 - 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 22% yield as a solid, following the procedure described in general procedure F, step 7, using 2-fluoroisonicotinonitrile as the reactant. LC/MS m/z M+l=917.65, 4.765 min (LCMS Method 7).

Step 8. Preparation of tert-butyldimethylsilyl l-(((4-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in general procedure F, step 8, using benzyl l-(((4-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS m/z M+l=941.75, 3.467 min (LCMS Method 7). Step 9. l-(((4-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8,lla-pentamethyl -l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid was prepared in 10.7% yield as a solid, following the procedure described in general procedure F, step 9, using tert- butyldimethylsilyl l-(((4-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 827.60 (M+H) + , 3.00 min (LCMS Method 7). 'HNMR (400MHz, CHLOROFORM-d) δ 8.31 (d,J=5.0Hz, IH), 7.21 (dd,J=5.1, 1.1 Hz, IH), 7.14 (s, IH), 5.36 (br. s., IH), 5.21 (d, J=4.8 Hz, IH), 4.84 (s, IH), 4.75 (s, IH), 4.52 (dd, J=4.3, 10.3 Hz, IH), 4.45 (dd, J=1.8, 10.3 Hz, IH), 3.28 - 3.15 (m, 8H),3.14 - 3.06 (m, 4H), 2.98 - 2.87 (m, IH), 2.76 (td,J=ll.l, 5.4 Hz, IH), 2.45 - 2.58 (m, IH), 2.35 - 2.21 (d, J=8.5 Hz, IH), 2.21 - 1.98 (m, 8H), 1.92- 1.73 (m, 2H), 1.77 (s, 3H), 1.73-1.41 (m, 11H), 1.40- 1.28 (m, 2H), 1.27- 1.08 (m, 2H), 1.18 (s, 3H), 1.11 (s, 3H), 1.00-0.99 (m, 3H), 0.96 (s, 3H), 0.93 (s, 3H). Example 38

Preparation of l-(((5-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-6: General procedure F steps 1-6

Step 7. Preparation of benzyl l-(((5-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared in 35.5% yield as a solid, following the procedure described in general procedure F, step 7, using 6-fluoronicotinonitrile as the reactant. LC/MS m/z M+l=917.65, 3.136 min (LCMS Method 7). Step 8: Preparation of tert-butyldimethylsilyl l-(((5-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylate.

The title compound was prepared as a solid, following the procedure described in general procedure F, step 8, using benzyl l-(((5-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS m/z M+l=941.70, 3.311 min (LCMS Method 7).

Step 9. l-(((5-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid was prepared in 10.5 % of yield as a solid, following the procedure described in general procedure F, step 9, using tert-butyldimethylsilyl l-(((5-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8,lla-pentamethyl -l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 827.55 (M+H) + , 3.049 min (LCMS Method 7). 'HNMR (400MHz, METHANOLS) δ 8.52 (d,J=2.3 Hz, IH), 7.96 (dd,J=8.8, 2.3 Hz, IH), 6.92 (d,J=8.8 Hz, IH), 5.35 (br. s., IH), 5.21 (d, J=4.5 Hz, IH), 4.84 (s, IH), 4.75 (s, IH), 4.56 (dd, J=2.8, 10.5 Hz, IH), 4.49 (d,J=10.5 Hz, IH), 3.28 - 3.15 (m, 8H), 3.14-3.06 (m, 3H), 2.93 (dt,J=14.2, 5.2 Hz, IH), 2.81 - 2.71 (m, IH), 2.67 - 2.57 (m, IH), 2.35 - 2.21 (m, IH), 2.21 - 1.97 (m, 10H), 1.92 - 1.72 (m, 5H), 1.77 (s, 3H), 1.72 - 1.39 (m, 11H), 1.39 - 1.20 (m, IH), 1.20 - 1.07 (m, IH), 1.18 (s, 3H), 1.11 (s, 3H), 1.02- 0.98 (m, IH), 0.96 (s, 3H), 0.93 (s, 3H).

Example 39

Preparation of l-(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

Step 1-6: General procedure F steps 1-6

Step 7. Preparation of benzyl l-(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 - 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in general procedure F, step 7, using 6-chloropicolinonitrile as the reactant. LC/MS m/z

M+l=917.65, 3.083 min (LCMS Method 7). Step 8. Preparation of tert-butyldimethylsilyl l-(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in general procedure F, step 8, using benzyl l-(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS m/z M+l=941.70, 3.516 min (LCMS Method 7).

Step 9. l-(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid was prepared in 17.6 % of yield as a solid, following the procedure described in general procedure F, step 9, using tert-butyldimethylsilyl l-(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yl)- 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)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 827.55 (M+H) + , 3.003 min (LCMS Method 7). Ή NMR (400MHz, METHANOLS) δ 7.84 (dd, J=8.5, 7.3 Hz, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 5.38 (br. s., 1H), 5.24 (d, J=6.0 Hz, 1H), 4.86 (s, 1H), 4.76 (s, 1H), 4.59 - 4.53 (m, 1H), 4.48 - 4.43 (m, 1H), 3.30 - 3.17 (m, 8H), 3.09 - 3.17 (m, 3H), 2.98 - 2.89 (m, 1H), 2.78 (td, J=10.9, 5.5 Hz, 1H), 2.65 (br. d, J=15.8 Hz, 1H), 2.37 - 2.00 (m, 9H), 1.94 - 1.74 (m, 5H), 1.79 (s, 3H), 1.74 - 1.44 (m, 11H), 1.44 - 1.29 (m, 2H), 1.26 - 1.10 (m, 2H), 1.20 (s, 3H), 1.13 (s, 3H), 1.03 - 1.02 (m, 3H), 1.00 - 0.99 (m, 3H), 0.95 (s, 3H).

Example 40

Preparation of 1 -(((6-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

Step 1. Preparation of methyl l-(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -ene- 1 -carboxylate .

The title compound was prepared as a solid, following the procedure described in general procedure F, step 7, using 6-chloropicolinonitrile and methyl 4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-(hydroxymethyl)cyclohex-3-ene-l -carboxylate instead of benzyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-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)-l-(hydroxymethyl)cyclohex-3-ene-l -carboxylateas the reactants . LC/MS m/z M+ 1 =841.60, 3.164 min (LCMS Method 7) .

Step 2. l-(((6-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid was prepared in a yield of 19.9% as a solid, following the procedure described in general procedure E, step 4, using methyl 1 -(((6-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylate as the reactant. LC/MS: m/e 845.60 (M+H) + , 2.931 min (LCMS Method 7). 'H NMR (400MHz, METHANOLS) δ 7.84 (dd, J=8.3, 7.3 Hz, 1H), 7.72 (dd, J=7.3, 0.8 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 5.39 (br. s., 1H), 5.23 (d, J=4.3 Hz, 1H), 4.87 (s, 1H), 4.77 (s, 1H), 4.61 - 4.56 (m, 1H), 4.55 - 4.50 (m, 1H), 3.25 (d, J=8.8 Hz, 5H), 3.20 (br. s., 2H), 3.17 - 3.09 (m, 3H), 2.97 - 2.87 (m, 1H), 2.77 (d, J=5.3 Hz, 1H), 2.68 (d, J=13.6 Hz, 1H), 2.41 - 1.99 (m, 9H), 1.94 - 1.68 (m, 6H), 1.79 (s, 3H), 1.68 - 1.44 (m, 9H), 1.43 - 1.30 (m, 3H), 1.29 - 1.11 (m, 2H), 1.19 (s, 3H), 1.13 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).

Preparation of 4-(methylsulfonyl)cyclohexanone.

To a solution of (methylsulfonyl)ethene (10.0 g, 94 mmol) in benzene (50 mL) was added (buta-l,3-dien-2-yloxy)trimethylsilane (14.07 g, 99 mmol) and hydroquinone (20 mg, 0.182 mmol). The mixture was degassed several times at -78 °C prior to heating. The contents were sealed and heated at 105 °C for 48 hours. The reaction was analyzed by NMR in CDCI3 that showed about 10% of the vinyl sulfone residue. Additional (buta-1,3- dien-2-yloxy)trimethylsilane (4 mL) was added and heating resumed for another 48 hours. NMR analysis again at 72 hrs time point showed further reduction of the amount of vinyl sulfone (-3%). The sample from the NMR tube was combined the reaction mixture and evaporated to a thick gum under vacuum at room temperature (-19 °C). The mixture was rediluted with acetone (250 mL) resulting in the formation of a clear solution. The mixture was chilled in an ice bath until cold. 4 mL of 0.25 N HCl (pre-chilled in the same ice-bath) was added resulting in the formation a cloudy mixture, which became clear after 15 minutes of stirring at 0 °C, and then returned to a cloudy state in another 10 minutes, it remained turbid for the rest of stirring period. A 50 aliquot was removed, flash dried into a film, and was analyzed by NMR in CDC . NMR showed -7% of vinyl sulfone relative to the desired product. The acetone solution was filtered through a short bed of silica gel type-H after a total reaction time of about one hour, and was then washed with more acetone. The filtrate was concentrated on the rotovapor at 19 °C bath temperature. The crude product was sub-divided into two parts, 7.75 gm each, for purification. The product was purified by column chromatography on silica gel (30% ethyl acetate→ 100% ethyl acetate in hexanes; two 330 g columns) to afford 4-(methylsulfonyl)cyclohexanone (16.7 g, 100% yield) as a white solid: ¾ NMR (400MHz, CHLOROFORM-d) δ 3.29 (tt, J=11.0, 3.9 Hz, 1H), 2.94 (s, 3H), 2.73 - 2.62 (m, 2H), 2.58 - 2.37 (m, 4H), 2.15 (qd, J=11.9, 4.5 Hz, 2H).

Preparation of 2-(czs-l-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde and 2-(trans- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde .

(29% yield) (43% yield)

0 3 , NMO 0 3 , NMO

then Me 2 S then Me 2 S

CH 2 CI 2 /MeOH CH 2 CI 2 /MeOH

Step 2a Step 2b

Step 1. Preparation of (czs)- l-allyl-4-(methylsulfonyl)cyclohexanol and (fr ra)-l-allyl-4- (methylsulfonyl)cyclohexanol.

To a solution of 4-(methylsulfonyl)cyclohexanone (1.03 g, 5.84 mmol) in THF (40 mL) at 0 °C was added via cannula allylmagnesium bromide (7.60 mL, 7.60 mmol). The reaction mixture was stirred at 0 °C for 30 min. The reaction was quenched by the addition of saturated NH4CI solution (25 mL). The mixture was transferred to a separatory funnel and the aqueous layer was extracted with ethyl acetate (5 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (70% ethyl acetate with 1% methanol/30% hexanes→ 100% ethyl acetate with 1% methanol; 40 g column) to afford (czs)- l-allyl-4-(methylsulfonyl)cyclohexanol (374 mg, 1.713 mmol, 29% yield) as a white solid and (zra«s)-l-allyl-4-(methylsulfonyl)cyclohexanol (551 mg, 2.52 mmol, 43% yield) as a colorless oil. (czs)-l-allyl-4-(methylsulfonyl)cyclohexanol:

¾ NMR (400MHz, CDCb) δ 5.96 - 5.79 (m, 1H), 5.26 - 5.21 (m, 1H), 5.18 (ddt, J=17.1, 2.1, 1.2 Hz, 1H), 2.85 (s, 3H), 2.80 (tt, J=12.5, 3.6 Hz, 1H), 2.25 (d, J=7.5 Hz, 2H), 2.15 - 2.07 (m, 2H), 1.97 (qd, J=13.0, 3.8 Hz, 2H), 1.88 - 1.81 (m, 2H), 1.52 - 1.42 (m, 2H); 13 C NMR (100MHz, CDCh) δ 132.50, 120.02, 69.06, 62.26, 47.86, 36.85, 35.67, 21.13. The structure of (czs)- l-allyl-4-(methylsulfonyl)cyclohexanol was confirmed by X-ray crystallography.

(fra«s)-l-allyl-4-(methylsulfonyl)cyclohexanol:

¾ NMR (400MHz, CDCb) δ 5.88 (ddt, J=17.2, 10.1, 7.4 Hz, 1H), 5.28 - 5.16 (m, 2H), 2.98 - 2.91 (m, 1H), 2.90 (s, 3H), 2.35 (d, J=7.5 Hz, 2H), 2.23 - 2.14 (m, 2H), 2.02 - 1.93 (m, 2H), 1.90 - 1.78 (m, 2H), 1.57 - 1.46 (m, 2H); 13 C NMR (100MHz, CDCb) δ 132.62, 120.19, 69.20, 62.41, 48.00, 36.98, 35.83, 21.29.

Step 2a. Preparation of 2-((c/5)-l-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde .

(fra«s)-l-Allyl-4-(methylsulfonyl)cyclohexanol (3.4 g, 15.57 mmol) was dissolved in CH2CI2 (160 mL) and MeOH (32.0 mL) in a 500 mL round bottom flask. N- Methylmorpholine-N-oxide (ΝΜΟ) (2.189 g, 18.69 mmol) was added and the mixture was cooled to -78 °C [Schwartz, C, Raible, J., Mott, K., Dussault, P. H. Org. Lett. 2006, 8, 3199 - 3201]. Ozone was bubbled through the reaction mixture until the solution was saturated with ozone (turned into a blue color) and several minutes thereafter (total time 25 min). Nitrogen was then bubbled through the reaction mixture until the disappearance of the blue color. Dimethyl sulfide (11.52 mL, 156 mmol) was then added and the reaction mixture was stirred at 0 °C for 16 h. The mixture was concentrated under vacuum. The product was purified by column chromatography on silica gel (50% ethyl acetate with 1% methanol/50% hexanes→ 95% ethyl acetate with 1% methanol/5% hexanes; 330 g column) to afford 2-((ls,4s)-l-hydroxy-4-

(methylsulfonyl)cyclohexyl)acetaldehyde (3.31 g, 15.03 mmol, 96% yield) as a white solid: ¾ NMR (400MHz, CHLOROFORM-d) δ 9.87 (t, J=l . l Hz, 1H), 2.85 (s, 3H), 2.82 - 2.76 (m, 1H), 2.67 (d, J=1.3 Hz, 2H), 2.13 - 1.98 (m, 6H), 1.50 - 1.38 (m, 2H); 13 C NMR (101MHz, CHLOROFORM-d) δ 202.5, 68.9, 61.9, 54.9, 36.8, 35.9, 20.8.

Step 2b. Preparation of 2-((fr «5)-l-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde.

(lr,4r)-l-Allyl-4-(methylsulfonyl)cyclohexanol (2 g, 9.16 mmol) was dissolved in CH2CI2 (80 mL) and MeOH (16.00 mL) in a 500 mL round bottom flask. N- Methylmorpholine-N-oxide (ΝΜΟ) (1.288 g, 10.99 mmol) was added and the mixture was cooled to -78 °C [Schwartz, C, Raible, J., Mott, K., Dussault, P. H. Org. Lett. 2006, 8, 3199 - 3201]. Ozone (excess) was bubbled through the reaction mixture until the solution was saturated with ozone (turned into a blue color) and several minutes thereafter (total time 25 min). Nitrogen was then bubbled through the reaction mixture until the disappearance of the blue color. Dimethyl sulfide (6.78 mL, 92 mmol) was then added and the reaction mixture was stirred at 0 °C for 16 h. The mixture was concentrated under vacuum. The product was purified by column chromatography on silica gel (70% ethyl acetate with 5% methanol/30% hexanes→ 100% ethyl acetate with 5% methanol; 220 g column) to afford 2-((lr,4r)-l-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehy de (1.58 g, 7.17 mmol, 78% yield) as a white solid: ¾ NMR (400MHz, CHLOROFORM-d) δ 9.82 (t, J=1.8 Hz, 1H), 2.99 - 2.88 (m, 1H), 2.85 (s, 3H), 2.67 (d, J=1.8 Hz, 2H), 2.20 - 2.10 (m, 2H), 2.06 - 1.98 (m, 2H), 1.74 (dtd, J=14.0, 10.6, 3.5 Hz, 2H), 1.61 - 1.50 (m, 2H); 13 C NMR (101MHz, CHLOROFORM-d) δ 202.4, 70.0, 59.3, 50.3, 38.2, 34.9, 21.1. Example Al . Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR, 13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)-l-((pyridin-2-yl oxy)methyl)cyclohex-3- enecarboxylic acid.

Step 1. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- pentamethyl-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)-l-((pyridin-2-yl oxy)methyl)cyclohex-3- enecarboxylate.

A mixture of ethyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-enecarboxylate (65 mg, 0.097 mmol), 2-((ls,4s)-l -hydroxy -4-(methylsulfonyl)cyclohexyl)acetaldehyde (47.1 mg, 0.214 mmol), and borane-2-picoline complex (22.86 mg, 0.214 mmol) in MeOH (1 mL) and acetic acid (0.2 mL) was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (10 mL) and saturated aqueous sodium carbonate solution (2 mL). The aqueous layer was extracted with dichloromethane (4 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (10% 9: 1 acetone:methanol/90% hexanes→ 65% 9: 1 acetone: methanol/35% hexanes; 24 g column, λ = 220 nm) to afford ethyl 4-((l ,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-((ls,4R)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-enecarboxylate (69 mg, 81% yield) as a colorless solid: Ή NMR (500MHz, CHLOROFORM-d) 5 8.15 (dd, J=5.0, 1.8 Hz, IH), 7.56 (ddd, J=8.5, 6.9, 2.0 Hz, IH), 6.87 (td, J=6.1, 0.7 Hz, IH), 6.73 (d, J=8.4 Hz, IH), 5.37 (br. s., IH), 5.20 (d, J=6.1 Hz, IH), 4.75 (d, J=1.5 Hz, IH), 4.62 (s, IH), 4.50 - 4.44 (m, IH), 4.43 - 4.37 (m, IH), 4.21 - 4.10 (m, 2H), 2.85 (s, 3H), 2.84 - 2.67 (m, 4H), 2.55 (td, J=10.8, 5.5 Hz, IH), 2.22 - 0.88 (m, 43H), 1.70 (s, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.87 (s, 3H); LC/MS m/e 873.7 [(M+H) + , calcd for C53H81N2O6S 873.6], t R = 4.67 min (LCMS Method 14).

Step 2. A solution of ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)-l-((pyridin-2-yl oxy)methyl)cyclohex-3- enecarboxylate (65 mg, 0.074 mmol) in dioxane (1 mL) and MeOH (0.5 mL) was treated with sodium hydroxide (0.372 mL, 0.744 mmol, 2M aq). The reaction mixture was heated at 50 °C for 3 h and then at 60 °C for 6 h. The mixture was cooled to room temperature, and was partially neutralized by the addition of 2 N HC1 (200 uL). The mixture was filtered through a syringe filter, and was purified by reverse phase HPLC (Preparative HPLC Method 1). The product (61.7 mg) contained an impurity (ca. 6%). The product was repurified by reverse phase HPLC (Preparative HPLC Method 2). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2-((ls,4R)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,lla-pentam ethyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-enecarboxylic acid, TFA (48.4 mg, 67% yield) as a white amorphous solid: Ή NMR (500MHz, Acetic Acid- d 4 )5 8.29 (dd,J=5.3, 1.7 Hz, 1H), 7.90 - 7.82 (m, 1H), 7.13 - 7.08 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.41 (br. s., 1H), 5.26 (d, J=5.8 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 4.56 - 4.50 (m, 1H), 4.49 - 4.44 (m, 1H), 3.48 - 3.34 (m, 2H), 3.09 - 2.99 (m, 1H), 2.96 (s, 3H), 2.89 - 2.79 (m, 1H), 2.72 (d,J=16.0Hz, 1H), 2.32 - 1.32 (m, 35H), 1.75 (s, 3H), 1.17 (s, 3H), 1.13 (d, J=7.5 Hz, 2H), 1.09 (s, 3H), 1.02 (d, J=3.7 Hz, 3H), 0.99 (d, J=3.7 Hz, 3H), 0.95 (s, 3H); LC/MS m/e 845.6 [(M+H) + , calcd for CsiHvvNiOeS 845.6], t R = 4.36 min (LCMS Method 14); HPLC (Analytical HPLC Method 1): fe = 18.86 min; HPLC (Analytical HPLC Method 2): fe = 20.24 min.

Example A2. Preparation of 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2- ((lr,4S)-l-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino) -5a,5b,8,8,lla- pentamethyl-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)-l-((pyridin-2-yl oxy)methyl)cyclohex-3- enecarboxylic acid.

Step 1. Preparation of ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2- ((lr,4S)-l-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino) -5a,5b,8,8,lla- pentamethyl-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)-l-((pyridin-2-yl oxy)methyl)cyclohex-3- enecarboxylate.

A mixture of ethyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-enecarboxylate (65 mg, 0.097 mmol), 2-((lr,4r)-l -hydroxy -4-(methylsulfonyl)cyclohexyl)acetaldehyde (47.1 mg, 0.214 mmol), and borane-2-picoline complex (22.86 mg, 0.214 mmol) in MeOH (1 mL) and acetic acid (0.2 mL) was stirred at room temperature for 16 h. The reaction was not complete. Additional 2-((lr,4r)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)acetaldehyde (21 mg, 0.097 mmol, 1 eq) was then added and 1 h later borane-2-picoline complex (10 mg, 0.097 mmol, 1 eq) was added to the reaction mixture and the mixture was stirred at room temperature for 3 h. The mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (10 mL) and saturated aqueous sodium carbonate solution (2 mL). The aqueous layer was extracted with dichloromethane (4 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (10% 9: 1 acetone:methanol/90% hexanes→ 65% 9: 1 acetone: methanol/35% hexanes; 24 g column, λ = 220 nm) to afford ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-enecarboxylate (42.4 mg, 50% yield) as a colorless foam: Ή NMR (500MHz, CHLOROFORM-d) δ 8.14 (dd, J=5.0, 1.8 Hz, 1H), 7.61 - 7.54 (m, 1H), 6.87 (ddd, J=7.0, 5.1, 0.8 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.36 (br. s., 1H), 5.20 (d, J=6.0 Hz, 1H), 4.72 (d, J=1.4 Hz, 1H), 4.60 (s, 1H),

4.51 - 4.44 (m, 1H), 4.43 - 4.36 (m, 1H), 4.21 - 4.10 (m, 2H), 2.99 - 2.91 (m, 1H), 2.89 (s, 3H), 2.83 - 2.76 (m, J=12.1 Hz, 1H), 2.72 - 2.62 (m, 2H), 2.59 - 2.51 (m, 1H), 2.21 - 0.88 (m, 43H), 1.69 (s, 3H), 1.21 (t, J=7.1 Hz, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.87 (s, 3H); LC/MS m/e 873.7 [(M+H) + , calcd for CsaHsiNiOeS 873.6], t R = 4.62 min (LCMS Method 14).

Step 2. A solution of ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2- ((lr,4S)-l-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino) -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)-l-((pyridin-2-yl oxy)methyl)cyclohex-3- enecarboxylate (42 mg, 0.048 mmol) in dioxane (1 mL) and MeOH (0.5 mL) was treated with sodium hydroxide (0.361 mL, 0.721 mmol, 2 M aq). The reaction mixture was heated at 60 °C for 24 h. Additional sodium hydroxide (0.120 mL, 0.240 mmol, 5 eq, 2 M aq) was added and the reaction mixture was heated at 70 °C for 8 h. The reaction was complete. The mixture was cooled to room temperature, and was partially neutralized by the addition of 2 N HC1 (400 uL). The mixture was filtered through a syringe filter, and was purified by reverse phase HPLC (Preparative HPLC Method 3). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford 4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)-l-((pyridin-2-yloxy)methyl)cycloh ex-3-enecarboxylic acid, TFA (31.3 mg, 67% yield) as a white amorphous solid. Ή NMR (500MHz, Acetic Acid- d 4 ) δ 8.30 - 8.25 (m, 1H), 7.85 - 7.78 (m, 1H), 7.10 - 7.04 (m, 1H), 6.95 (dd, J=8.5, 0.6 Hz, 1H), 5.41 (br. s., 1H), 5.26 (d, J=6.0 Hz, 1H), 4.83 (s, 1H), 4.72 (s, 1H), 4.55 - 4.49 (m, 1H), 4.48 - 4.43 (m, 1H), 3.46 - 3.37 (m, 1H), 3.36 - 3.28 (m, 1H), 3.18 - 3.10 (m, 1H), 2.98 (s, 3H), 2.91 - 2.81 (m, 1H), 2.71 (d, J=16.3 Hz, 1H), 2.32 - 1.32 (m, 35H), 1.75 (s, 3H), 1.16 - 1.12 (m, 2H), 1.14 (s, 3H), 1.09 (s, 3H), 1.02 (d, J=3.7 Hz, 3H), 0.99 (d, J=3.2 Hz, 3H), 0.94 (s, 3H); LC/MS m/e 845.6 [(M+H) + , calcd for CsiHvvNiOeS 845.6], t R = 4.33 min (LCMS Method 14); HPLC (Analytical HPLC Method 1): fe = 18.86 min; HPLC (Analytical HPLC Method 2): = 20.48 min.

Example A3. Preparation of (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylic acid.

Step 1. Preparation of ((S)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(ethoxycarbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate .

To a flask containing (lR,3aS,5aR,5bR,7aR,l laR,l lbR, 13aR, 13bR)-3a-amino- 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 trifluoromethanesulfonate (1.00 g, 1.79 mmol) was added (R)- ( 1 -(ethoxycarbonyl)-4-(4,4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3 -en- 1 - yl)methyl benzoate (1.337 g, 3.23 mmol), potassium phosphate tribasic (1.52 g, 7.17 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos) (0.055 g, 0.134 mmol) and palladium(II) acetate (0.020 g, 0.090 mmol). The mixture was diluted with 1,4-dioxane (25 mL) and water (6.25 mL), then was flushed with N2 and heated at 75 °C for 16 h. The mixture was cooled to rt. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 75 mL). The organic layers were washed with brine (150 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50% ethyl acetate with 4% MeOH and 0.8% ammonium hydroxide/50% hexanes→ 70% ethyl acetate with 4% MeOH and 0.8% ammonium hydroxide/30% hexanes, 120 g column) to afford ((S)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino-5a,5b,8,8, l 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate (1.15 g, 92% yield) as an off-white solid: Ή NMR (400MHz, CHLOROFORM-d) δ 8.06 - 8.00 (m, 2H), 7.62 - 7.55 (m, 1H), 7.49 - 7.41 (m, 2H), 5.38 (br. s., 1H), 5.22 (dd, J=6.3, 1.8 Hz, 1H), 4.75 (d, J=2.0 Hz, 1H), 4.62 (dd, J=2.3, 1.3 Hz, 1H), 4.52 - 4.40 (m, 2H), 4.20 (qd, J=7.2, 2.1 Hz, 2H), 2.70 (d, J=18.3 Hz, 1H), 2.56 (td, J=10.9, 5.3 Hz, 1H), 2.35 - 1.95 (m, 6H), 1.91 - 1.81 (m, 1H), 1.78 - 1.13 (m, 20H), 1.71 (s, 3H), 1.24 (t, J=7.3 Hz, 3H), 1.09 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H); LC/MS m/e 696.7 [(M+H) + , calcd for C46H 65 N04 696.5], t R = 2.60 min (LCMS Method 15). Step 2. Preparation of (S)-ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a- amino-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)- 1 -(hydroxymethyl)cyclohex-3 -enecarboxylate .

To a solution of ((S)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino- 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)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate (1.07 g, 1.537 mmol) in THF (10 mL) and MeOH (1 mL) was added sodium hydroxide (1.691 mL, 1.691 mmol). The reaction mixture was stirred at r.t. for 14 h. The solid was removed by filtration. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCC solution (10 mL)/water (10 mL). The aqueous layer was extracted with 5% methanol in ethyl acetate (5 x 25 mL). The combined organic layers were washed with brine (10 mL). The brine wash was reextracted with 5% methanol in ethyl acetate. The combined organic layers were dried over MgS04, filtered, and concentrated to afford (S)-ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a- amino-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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylate (0.535 g, 59% yield) as a white solid. The crude product was used directly in the next step. Ή NMR (400MHz, CHLOROFORM-d) δ 5.34 (t, J=3.8 Hz, IH), 5.20 (dd, J=6.1, 1.9 Hz, IH), 4.75 (d, J=2.0 Hz, IH), 4.63 (d, J=1.3 Hz, IH), 4.21 (q, J=7.0 Hz, 2H), 3.70 (s, 2H), 2.62 - 2.51 (m, 2H), 2.23 - 2.15 (m, 2H), 2.09 - 1.92 (m, 4H), 1.83 - 1.12 (m, 21H), 1.72 (s, 3H), 1.30 (t, J=7.2 Hz, 3H), 1.09 (s, 3H), 0.99 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H); LC/MS (ESI) mle 614.6 [(M+H) + , calcd for CsgHeiNOsNa 614.5], fe = 4.28 min (LCMS Method 14).

Step 3. Preparation of (S)-ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a- amino-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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate.

To a solution of (S)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- amino-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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylate (495 mg, 0.836 mmol) and 2-fluoronicotinonitrile (204 mg, 1.673 mmol) in THF (7 mL) and DMF (1 mL) at 0 °C was added potassium fert-butoxide (1.004 mL, 1.004 mmol). The cooling bath was removed and the reaction mixture was stirred at 20 °C for 1.5 h. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCC solution (15 mL). The aqueous layer was extracted with ethyl acetate (4 x 25 mL). The combined organic layers were washed with brine (15 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (50% of a 5% methanol in ethyl acetate solution/50% hexanes→ 100% of a 5% methanol in ethyl acetate solution; 40 g column) to afford (S)-ethyl 4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-5a,5b,8,8,l la-pentamethyl-1- (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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (344 mg, 59% yield) as an off-white solid: ¾ NMR (400MHz,

CHLOROFORM-d) δ 8.34 (dd, J=5.0, 2.0 Hz, 1H), 7.88 (dd, J=7.5, 2.0 Hz, 1H), 6.99 (dd,J=7.5, 5.0Hz, 1H), 5.38 (br. s., 1H), 5.21 (dd,J=6.1, 1.6Hz, 1H), 4.75 (d,J=2.3 Hz, 1H), 4.62(dd,J=2.1, 1.4 Hz, 1H), 4.57 (s, 2H), 4.25 - 4.15 (m, 2H), 2.78 - 2.68 (m, 1H), 2.56 (td,J=10.9, 5.1 Hz, 1H), 2.35 - 1.89 (m, 6H), 1.79 - 1.11 (m, 21H), 1.71 (s, 3H), 1.27 (t,J=6.8 Hz, 3H), 1.09 (s, 3H), 0.99 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H);

LC/MS (ESI) mle 694.7 [(M+H) + , calcd for C45H64N3O3694.5], fe = 4.52 min (LCMS Method 14).

Step 4. Preparation of (S)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-((ls,4R)-l- hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,lla-pentam ethyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate.

(S)-Ethyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a- 5a,5b,8,8,lla-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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (150 mg, 0.216 mmol) and 2-((ls,4s)-l -hydroxy -4- (methylsulfonyl)cyclohexyl)acetaldehyde (76 mg, 0.346 mmol) were dissolved in MeOH (1.6 mL) and acetic acid (0.32 mL). Borane-2-picoline complex (37.0 mg, 0.346 mmol) was added and the mixture was stirred at room temperature for 14 h. The mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (3 mL) and sodium carbonate solution (2 mL). The aqueous layer was extracted with ethyl acetate (5 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate with 5% methanol/70% hexanes→ 100% ethyl acetate with 5% methanol; 24 g column, 25 min gradient) to afford (S)-ethyl l-(((3- cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)cyclohex-3-enecar boxylate (134.6 mg, 69% yield) as a white foam: ¾ NMR (500MHz, CHLOROFORM-d) δ 8.34 (dd, J=5.0, 2.0 Hz, 1H), 7.88 (dd, J=7.6, 1.9 Hz, 1H), 6.99 (dd, J=7.5, 5.0 Hz, 1H), 5.37 (br. s., 1H), 5.20 (dd, J=6.2, 1.6 Hz, 1H), 4.74 (d, J=1.5 Hz, 1H), 4.61 (s, 1H), 4.56 (s, 2H), 4.24 - 4.15 (m, 2H), 2.85 (s, 3H), 2.83 - 2.67 (m, 4H), 2.55 (td, J=10.9, 5.6 Hz, 1H), 2.31 - 0.88 (m, 37H), 1.70 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H); LC/MS (ESI) mle 898.7 [(M+H) + , calcd for C54H80N3O6S 898.6], fe = 4.44 min (LCMS Method 14). Step 5. To a solution of (S)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylate (123 mg, 0.137 mmol) in dioxane (4 mL) and MeOH (2 mL) was added lithium hydroxide (2 mL, 2.00 mmol, 1 M aq). The mixture was heated at 60 °C for 12.5 h. Only a small amount of starting material was detected by LC/MS (LCMS Method 16). The reaction was stopped at this point due to competing hydrolysis of the nitrile group to the corresponding amide. The mixture was cooled to room temperature and was partially neutralized by the addition of 6 N HCl (250 μί). The mixture was then filtered through a syringe filter, and was purified by reverse phase HPLC (5 injections) (Preparative HPLC Method 4). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford (S)-l-(((3- cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)cyclohex-3-enecar boxylic acid, TFA (51.6 mg, 38% yield) as a white amorphous solid: ¾ NMR (500MHz, Acetic Acid-d4) δ 8.42 (dd, J=5.1, 1.9 Hz, IH), 8.05 (dd, J=7.6, 1.9 Hz, IH), 7.11 (dd, J=7.6, 5.1 Hz, IH), 5.43 (s, IH), 5.27 (d, J=4.7 Hz, IH), 4.83 (s, IH), 4.72 (s, IH), 4.68 - 4.61 (m, 2H), 3.47 - 3.33 (m, 2H), 3.08 - 2.99 (m, IH), 2.96 (s, 3H), 2.90 - 2.81 (m, IH), 2.74 (d, J=15.6 Hz, IH), 2.38 - 1.13 (m, 37H), 1.75 (s, 3H), 1.18 (s, 3H), 1.09 (s, 3H), 1.03 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H); LC/MS (ESI) m/e 870.6 [(M+H) + , calcd for C52H76N3O6S 870.5], t R = 1.31 min (LCMS Method 16); HPLC (Analytical HPLC Method 3): fe = 12.19 min; HPLC

(Analytical HPLC Method 4): fa = 1 1.64 min.

Alternate route for the preparation of Example A3

Preparation of (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4-

(methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylic acid.

Step 1. Preparation of ((S)-l-(ethoxycarbonyl)-4-

((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-((ls,4R) -l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,lla-pentam ethyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3 -en- 1 -yl)methyl benzoate .

((S)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-amino-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)- 1 -(ethoxycarbonyl)cyclohex-3 -en- 1 - yl)methyl benzoate (7.63 g, 10.96 mmol), and 2-((ls,4s)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)acetaldehyde (3.86 g, 17.54 mmol) were dissolved in MeOH (30 mL) and acetic acid (6 mL). Borane-2-picoline complex (1.876 g, 17.54 mmol) was added and the mixture was stirred at room temperature for 14 h. The mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (50 mL) and sodium carbonate solution (50 mL). The aqueous layer was extracted with ethyl acetate (7 x 100 mL). The combined organic layers were washed with brine (25 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate with 5% methanol/70% hexanes → 100% ethyl acetate with 5% methanol; 330 g column, 30 min gradient) to afford ((S)-l- (ethoxycarbonyl)-4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l- hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-en-l-yl)methyl benzoate (8.81 g, 89% yield) as a white solid: ¾ NMR (500MHz, CHLOROFORM-d) δ 8.06 - 8.00 (m, 2H), 7.61 - 7.54 (m, 1H), 7.50 - 7.42 (m, 2H), 5.37 (br. s., 1H), 5.21 (dd, J=6.2, 1.6 Hz, 1H), 4.75 (d, J=1.8 Hz, 1H), 4.62 (s, 1H), 4.47 - 4.41 (m, 2H), 4.24 - 4.16 (m, 2H), 2.85 (s, 3H), 2.83 - 2.65 (m, 4H), 2.55 (td, J=10.9, 5.6 Hz, 1H), 2.33 - 2.23 (m, 1H), 2.20 - 1.03 (m, 36H), 1.70 (s, 3H), 1.24 (t, J=7.1 Hz, 3H), 1.05 (s, 3H), 0.99 - 0.87 (m, 12H); LC/MS (ESI) m/e 900.4 [(M+H) + , calcd for CssHsiNOvS 900.6], t R = 4.55 min (LCMS Method 14). Step 2. Preparation of (S)-4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)-l-(hydroxymethyl )cyclohex-3- enecarboxylic acid.

To a solution of ((S)-l-(ethoxycarbonyl)-4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-en-l-yl)methyl benzoate (8.00 g, 8.89 mmol) in 1,4-dioxane (160 mL) and methanol (80 mL) in a pressure vessel was added lithium hydroxide (89 mL, 89 mmol). The vessel was sealed and the mixture was heated at 65 °C (internal temperature) for 16 h. The reaction mixture was cooled to room temperature and was partially neutralized by the addition of 4 N HC1 (15.5 mL, 7 eq). The mixture was then concentrated. The crude product was taken up in dioxane (40 mL)/methanol (20 mL)/water (5 mL) and was made acidic by the addition of TFA (dropwise until acidic). The suspension became a solution. The solution contained some suspended solid matter. It was passed through a short plug of sand followed by filtration through a syringe filter. The product was then purified by reverse phase MPLC on a CI 8 Redi Sep Gold column (150 g) on the biotage (Preparative MPLC Method 1, 6 injections). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford (S)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylic acid, TFA (6.57 g, 84% yield) as a white amorphous solid. The product was then dried further under vacuum in a vacuum dessicator with dryrite. ¾ NMR (500MHz, CHLOROFORM-d) δ 8.54 (br. s., 1H), 8.02 (br. s., 1H), 5.34 (br. s., 1H), 5.23 - 5.16 (m, 1H), 4.78 (s, 1H), 4.70 (s, 1H), 3.76 (s, 2H), 3.22 (d, J=3.1 Hz, 2H), 2.86 (s, 3H), 2.83 - 2.68 (m, 2H), 2.59 (d, J=15.3 Hz, 1H), 2.47 - 2.34 (m, 1H), 2.26 - 1.06 (m, 36H), 1.71 (s, 3H), 1.09 (s, 3H), 1.03 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H); LC/MS (ESI) m/e 768.4 [(M+H) + , calcd for C46H74NOeS 768.5], fe = 3.85 min. (LCMS Method 14).

Step 3. To a solution of (S)-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-((2- ((ls,4R)-l-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino) -5a,5b,8,8, 1 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)-l-(hydroxymethyl )cyclohex-3- enecarboxylic acid, TFA (5.92 g, 6.71 mmol) in THF (80 mL) at 0 °C was added sodium hydride (2.147 g, 53.7 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 15 min. The mixture was cooled to 0 °C and 2- fluoronicotinonitrile (3.28 g, 26.8 mmol) in THF (10 mL) was added via cannula. The reaction mixture was stirred at 0 °C for 1.5 h. The reaction was quenched by the addition of acetic acid (3.84 mL, 67.1 mmol, 10 eq). The solution was directly injected on a column and was purified by column chromatography on silica gel (5% methanol in CH2CI2 to elute the high Rf material and then 12% methanol in CH2CI2 to elute the product. 6.70 g of product was obtained. The product was then purified further by reverse phase MPLC on a C18 Redi Sep Gold column (150 g) on the biotage (Preparative MPLC Method 2, 5 injections). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4-

(methylsulfonyl)cyclohexyl)ethyl)amino)-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, 1 la, 1 lb, 12, 13, 13a, 13b-octadecahydro- 1H- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (5.06 g, 5.14 mmol) as a white amorphous solid.

The product (TFA salt) was then dissolved in MeCN/FhO (60/40) and was slowly passed through an AG l-x2 ion exchange resin chloride form (Bio-Rad 100-200 mesh cat # 140- 1241, prewashed with 90% acetonitrile/10% water). 140 grams of resin was used. The fractions containing product were combined and the organic solvent was removed on the rotovapor and water was frozen and placed on the lyophilizer to afford (S)-l-(((3- cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-

(( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)cyclohex-3-enecar boxylic acid, HC1 (4.26 g, 66% yield) as a white amorphous solid: ¾ NMR (500MHz, Acetic Acid-d4) δ 8.42 (dd, J=5.1, 1.9 Hz, 1H), 8.05 (dd, J=7.6, 1.9 Hz, 1H), 7.11 (dd, J=7.6, 5.1 Hz, 1H), 5.43 (br. s., 1H), 5.27 (d, J=4.6 Hz, 1H), 4.89 (s, 1H), 4.73 (s, 1H), 4.69 - 4.60 (m, 2H), 3.45 - 3.33 (m, 2H), 3.13 (td, J=10.8, 5.1 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.97 (s, 3H), 2.74 (d, J=15.1 Hz, 1H), 2.61 - 2.53 (m, 1H), 2.38 - 1.13 (m, 36H), 1.76 (s, 3H), 1.20 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H); LC/MS (ESI) m/e 870.3 [(M+H) + , calcd for C52H76N3O6S 870.5], t R = 4.56 min (LCMS Method 14); HPLC (HPLC Method 3): fe = 13.13 min; HPLC (HPLC Method 4): fe = 12.46 min. Example A4. Preparation of (S)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylic acid.

Step 1. Preparation of (S)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethy l)amino)-5 a, 5b , 8 , 8 , 11 a-pentamethy 1- 1 -(prop- 1 - 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)cyclohex-3-enecarboxylate.

(S)-Ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino- 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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (150 mg, 0.216 mmol) and 2-((lr,4r)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)acetaldehyde (76 mg, 0.346 mmol) were dissolved in MeOH (1.6 mL) and acetic acid (0.32 mL). Borane-2-picoline complex (37.0 mg, 0.346 mmol) was added and the mixture was stirred at room temperature for 16 h. The mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (5 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate with 5% methanol/70% hexanes→ 100% ethyl acetate with 5% methanol; 24 g column) to afford (S)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylate (131 mg, 68% yield) as a white foam: ¾NMR (400MHz, CHLOROFORM-d) δ 8.33 (dd, J=5.0, 2.0 Hz, 1H), 7.87 (dd, J=7.5, 2.0 Hz, 1H), 6.98 (dd, J=7.4, 5.1 Hz, 1H), 5.37 (br. s., 1H), 5.20 (d, J=4.5 Hz, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.60 (s, 1H), 4.56 (s, 2H), 4.24 - 4.15 (m, 2H), 2.99 - 2.89 (m, 1H), 2.88 (s, 3H), 2.83 - 2.61 (m, 3H), 2.55 (td, J=10.8, 5.5 Hz, 1H), 2.31 - 1.02 (m, 37H), 1.69 (s, 3H), 1.27 (q, J=7.2 Hz, 3H), 1.06 (s, 3H), 0.98 (s, 6H), 0.92 (s, 3H), 0.87 (s, 3H); LC/MS mle 898.7 [(M+H) + , calcd for C54H79N3O6S 898.6], t R = 4.44 min (LCMS Method 14).

Step 2. To a solution of (S)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4-

(methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylate (131 mg, 0.146 mmol) in dioxane (4 mL) and MeOH (2 mL) was added lithium hydroxide (2 mL, 2.00 mmol, 1 M aq). The mixture was heated at 60 °C for 10.5 h. Only a small amount of starting material was detected by LC/MS (LCMS Method 16). The reaction was stopped at this point. The mixture was cooled to room temperature and was partially neutralized by the addition of 6 N HC1 (250 μί). The mixture was then filtered through a syringe filter, and was purified by reverse phase HPLC (5 injections) (Preparative HPLC Method 4). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford (S)-l- (((3-cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- ((2-(( lr,4S)- l-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8, 8, 11a- 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)cyclohex-3-enecar boxylic acid, TFA (69 mg, 48% yield) as a white amorphous solid: ¾ NMR (400MHz, Acetic Acid-d 4 ) δ 8.43 (dd, J=5.0, 2.0 Hz, 1H), 8.06 (dd, J=7.5, 2.0 Hz, 1H), 7.12 (dd, J=7.5, 5.3 Hz, 1H), 5.44 (br. s., 1H), 5.27 (d, J=4.8 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 4.69 - 4.61 (m, 2H), 3.43 - 3.29 (m, 2H), 3.20 - 3.10 (m, 1H), 2.99 (s, 3H), 2.91 - 2.81 (m, J=9.0 Hz, 1H), 2.74 (d, J=17.6 Hz, 1H), 2.40 - 1.33 (m, 37H), 1.76 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H); LC/MS (ESI) m/e 870.7 [(M+H) + , calcd for C52H75N3O6S 870.5], t R = 2.37 min (LCMS Method 15); HPLC (Analytical HPLC Method 3): fe = 16.00 min; HPLC (Analytical HPLC Method 4): fe = 13.90 min.

Example A5. Preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4-

(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8, l la-pentamethyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah yd] cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid.

Step 1. Preparation of ((R)-4-((lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-amino- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(ethoxycarbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate .

To a flask containing (lR,3aS,5aR,5bR,7aR,l laR,l lbR, 13aR, 13bR)-3a-amino- 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 trifluoromethanesulfonate (2.2 g, 3.94 mmol) was added (S)-(l- (ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)cyclohex-3-en-l- yl)methyl benzoate (2.94 g, 7.10 mmol), potassium phosphate tribasic (3.35 g, 15.78 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-Phos) (0.121 g, 0.296 mmol) and palladium(II) acetate (0.044 g, 0.197 mmol). The mixture was diluted with 1,4- dioxane (60 mL) and water (15 mL) and was flushed with N2 and heated at 75 °C for 16 h. The mixture was cooled to rt. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were washed with brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel The residue was purified by column chromatography on silica gel (50% ethyl acetate with 4% MeOH and 0.8% ammonium hydroxide/50% hexanes→ 70% ethyl acetate with 4% MeOH and 0.8% ammonium hydroxide/30% hexanes, 220 g column) to afford ((R)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino-5a,5b,8,8, l 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate (2.47 g, 90% yield) as an off-white solid: Ή NMR (400MHz, CHLOROFORM-d) δ 8.05 - 8.00 (m, 2H), 7.61 - 7.55 (m, 1H), 7.45 (t, J=7.7 Hz, 2H), 5.38 (br. s., 1H), 5.25 - 5.19 (m, 1H), 4.75 (s, 1H), 4.62 (s, 1H), 4.46 (q, J=10.8 Hz, 2H), 4.19 (q, J=7.0 Hz, 2H), 2.74 - 2.66 (m, 1H), 2.56 (td, J=10.9, 5.1 Hz, 1H), 2.29 - 1.96 (m, 6H), 1.87 (dt, J=12.9, 6.2 Hz, 1H), 1.78 - 1.11 (m, 20H), 1.71 (s, 3H), 1.24 (t, J=7.3 Hz, 3H), 1.09 (s, 3H), 0.98 (br. s., 3H), 0.97 (br. s., 3H), 0.95 (s, 3H), 0.89 (s, 3H); LC/MS m/e 696.7 [(M+H) + , calcd for C46H 65 N04 696.5], t R = 2.55 min (LCMS Method 15).

Step 2. Preparation of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR, 13bR)-3a- amino-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)- 1 -(hydroxymethyl)cyclohex-3 -enecarboxylate .

To a solution of ((R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino- 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)- 1 -(ethoxycarbonyl)cyclohex-3-en- 1 -yl)methyl benzoate (1.20 g, 1.724 mmol in THF (10 mL) and MeOH (1 mL) was added sodium hydroxide (1.897 mL, 1.897 mmol). The reaction mixture was stirred at r.t. for 14 h. The solid was removed by filtration. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCC solution (10 mL)/water (10 mL). The aqueous layer was extracted with 5% methanol in ethyl acetate (5 x 25 mL). The combined organic layers were washed with brine (10 mL). The brine wash was reextracted with 5% methanol in ethyl acetate. The combined organic layers were dried over MgS04, filtered, and concentrated to afford (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR, 1 laS, 1 lbR, 13aR, 13bR)-3a- amino-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, 1 la, 1 lb, 12, 13, 13a, 13b-octadecahydro- 1H- cyclopenta[a]chrysen-9-yl)-l-(hydroxymethyl)cyclohex-3-eneca rboxylate (450 mg, 44% yield) as a white solid. The crude product was used directly in the next step. ¾ NMR (400MHz, CHLOROFORM-d) δ 5.34 (br. s., IH), 5.20 (dd, J=6.0, 1.8 Hz, IH), 4.75 (d, J=2.0 Hz, IH), 4.62 (s, IH), 4.20 (q, J=7.2 Hz, 2H), 3.70 (s, 2H), 2.62 - 2.51 (m, 2H), 2.21 - 2.14 (m, 2H), 2.10 - 1.94 (m, 4H), 1.82 - 1.12 (m, 21H), 1.71 (s, 3H), 1.29 (t, J=7.2 Hz, 3H), 1.09 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.89 (s, 3H); LC/MS (ESI) m/e 614.6 [(M+H) + , calcd for C39H 6 iN0 3 Na 614.5], t R = 4.27 min (LCMS Method 14).

Step 3. Preparation of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR, 13bR)-3a- amino-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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate.

To a solution of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- amino-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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylate (412 mg, 0.696 mmol) and 2-fluoronicotinonitrile (170 mg, 1.392 mmol) in THF (7 mL) and DMF (1 mL) at 0 °C was added potassium fert-butoxide (0.835 mL, 0.835 mmol). The cooling bath was removed and the reaction mixture was stirred at 20 °C for 1.5 h. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCC solution (15 mL). The aqueous layer was extracted with ethyl acetate (4 x 25 mL). The combined organic layers were washed with brine (15 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (50% of a 5% methanol in ethyl acetate solution/50% hexanes→ 100% of a 5% methanol in ethyl acetate solution; 40 g column) to afford (R)-ethyl 4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-5a,5b,8,8,l la-pentamethyl-1- (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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (365 mg, 0.526 mmol, 76% yield) as an off-white solid: Ή NMR

(400MHz, CHLOROFORM-d) δ 8.34 (dd, J=5.0, 2.0 Hz, IH), 7.88 (dd, J=7.4, 1.9 Hz, IH), 6.99 (dd,J=7.5, 5.0 Hz, IH), 5.38 (br. s., IH), 5.21 (dd,J=6.3, 1.8 Hz, IH), 4.74 (d, J=2.0Hz, IH), 4.62 (dd,J=2.1, 1.4 Hz, IH), 4.60 - 4.52 (m, 2H), 4.19 (qd,J=7.1, 2.5 Hz, 2H), 2.73 (d,J=17.1 Hz, IH), 2.56 (td,J=10.9, 5.4 Hz, IH), 1.78 - 1.13 (m, 21H), 2.27 - 1.87 (m, 6H), 1.71 (s, 3H), 1.26 (t,J=6.8 Hz, 3H), 1.09 (s, 3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.88 (s, 3H); LC/MS (ESI) m/e 694.7 [(M+H) + , calcd for C45H64N3O3694.5], t R = 4.51 min (LCMS Method 14).

Step 4. Preparation of (R)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-((ls,4R)-l- hydroxy-4-

(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,lla-pen tamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate.

(R)-Ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (150 mg, 0.216 mmol) and 2-((ls,4s)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)acetaldehyde (76 mg, 0.346 mmol) were dissolved in MeOH (1.4 mL) and acetic acid (0.28 mL). Borane-2-picoline complex (37.0 mg, 0.346 mmol) was added and the mixture was stirred at room temperature for 14 h. The mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (3 mL) and sodium carbonate solution (2 mL). The aqueous layer was extracted with ethyl acetate (5 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate with 5% methanol/70% hexanes→ 100% ethyl acetate with 5% methanol; 24 g column, 25 min gradient) to afford (R)-ethyl l-(((3- cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)cyclohex-3-enecar boxylate (130 mg, 67% yield) as a white foam: ¾ NMR (500MHz, CHLOROFORM-d) δ 8.34 (dd, J=5.0, 2.0 Hz, 1H), 7.88 (dd, J=7.5, 2.0 Hz, 1H), 6.99 (dd, J=7.5, 5.0 Hz, 1H), 5.38 (br. s., 1H), 5.23 - 5.19 (m, 1H), 4.75 (d, J=1.7 Hz, 1H), 4.62 (s, 1H), 4.59 - 4.52 (m, 2H), 4.19 (dtt, J=10.8, 7.2, 3.8 Hz, 2H), 2.85 (s, 3H), 2.83 - 2.70 (m, 4H), 2.55 (td, J=10.9, 5.6 Hz, 1H), 2.28 - 0.89 (m, 37H), 1.70 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.87 (s, 3H); LC/MS (ESI) mle 898.7 [(M+H) + , calcd for C54H80N3O6S 898.6], tR = 4.43 min (LCMS Method 14).

Step 5. To a solution of (R)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((ls,4R)-l-hydroxy-4-

(methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylate (124 mg, 0.138 mmol) in dioxane (4 mL) and MeOH (2 mL) was added lithium hydroxide (2 mL, 2.00 mmol, 1 M aq). The mixture was heated at 60 °C for 10 h. Some starting material starting was detected by LC/MS (LCMS Method 16) along with formation of an amide by-product due to hydrolysis of the nitrile. The reaction was stopped at this point. The mixture was cooled to room temperature and was partially neutralized by the addition of 6 N HC1 (250 μί). The mixture was then filtered through a syringe filter, and was purified by reverse phase HPLC (5 injections) (Preparative HPLC Method 4). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford (R)-l-(((3- cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2- (( 1 s,4R)- 1 -hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8 , 11a- 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)cyclohex-3-enecar boxylic acid, TFA (48.1 mg, 34% yield) as a white amorphous solid: Ή NMR (500MHz, Acetic Acid-d4) δ 8.42 (dd, J=5.1, 1.9 Hz, IH), 8.05 (dd, J=7.6, 1.9 Hz, IH), 7.11 (dd, J=7.5, 5.2 Hz, IH), 5.43 (br. s., IH), 5.27 (d, J=4.6 Hz, IH), 4.83 (s, IH), 4.72 (s, IH), 4.68 - 4.59 (m, 2H), 3.46 - 3.33 (m, 2H), 3.09 - 2.99 (m, IH), 2.96 (s, 3H), 2.89 - 2.81 (m, IH), 2.74 (d, J=16.5 Hz, IH), 2.34 - 1.13 (m, 37H), 1.75 (s, 3H), 1.17 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H); LC/MS (ESI) m/e 870.7 [(M+H) + , calcd for C52H76N3O6S 870.5], t R = 1.24 min (LCMS Method 16); HPLC (Analytical HPLC Method 3): fe = 12.24 min; HPLC (Analytical HPLC Method 4): fa = 1 1.77 min.

Example A6. Preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylic acid.

Example A6 Step 1. Preparation of (R)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylate.

(R)-Ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR,13bR)-3a-amino-

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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (150 mg, 0.216 mmol) and 2-((lr,4r)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)acetaldehyde (76 mg, 0.346 mmol) were dissolved in MeOH (1.6 mL) and acetic acid (0.32 mL). Borane-2-picoline complex (37.0 mg, 0.346 mmol) was added and the mixture was stirred at room temperature for 14 h. The mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (5 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (30% ethyl acetate with 5% methanol/70% hexanes→ 100% ethyl acetate with 5% methanol; 24 g column) to afford (R)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylate (131 mg, 68% yield) as a white foam: ¾NMR (400MHz, CHLOROFORM-d) δ 8.33 (dd, J=5.1, 1.9 Hz, 1H), 7.87 (dd, J=7.4, 1.9 Hz, 1H), 6.98 (dd, J=7.4, 5.1 Hz, 1H), 5.37 (br. s., 1H), 5.22 - 5.17 (m, 1H), 4.71 (d, J=1.8 Hz, 1H), 4.61 - 4.51 (m, 3H), 4.23 - 4.14 (m, 2H), 2.99 - 2.90 (m, 1H), 2.87 (s, 3H), 2.82 - 2.61 (m, 3H), 2.54 (td, J=10.8, 5.5 Hz, 1H), 2.23 - 1.02 (m, 37H), 1.68 (s, 3H), 1.26 (q, J=7.3 Hz, 3H), 1.06 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H); LC/MS mle 898.7 [(M+H) + , calcd for C54H79N3O6S 898.6], t R = 4.43 min (LCMS Method 14). Step 2. To a solution of (R)-ethyl l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-((lr,4S)-l-hydroxy-4- (methylsulfonyl)cyclohexyl)ethyl)amino)-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)cyclohex-3-enecarboxylate (107 mg, 0.119 mmol) in dioxane (4 mL) and MeOH (2 mL) was added lithium hydroxide (2 mL, 2.00 mmol, 1 M aq). The mixture was heated at 60 °C for 10.5 h. Only a small amount of starting material was detected by LC/MS (LCMS Method 16). The reaction was stopped at this point. The mixture was cooled to room temperature and was partially neutralized by the addition of 6 N HC1 (250 μί). The mixture was then filtered through a syringe filter, and was purified by reverse phase HPLC (5 injections) (Preparative HPLC Method 4). The organic solvent was evaporated on the rotovapor and the aqueous mixture was lyophilized to afford (R)-l- (((3-cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- ((2-(( lr,4S)- l-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8, 8, 1 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)cyclohex-3-enecar boxylic acid, TFA (58 mg, 49% yield) as a white amorphous solid: ¾ NMR (400MHz, Acetic Acid-d4) δ 8.43 (dd, J=5.1, 1.9 Hz, 1H), 8.06 (dd, J=7.5, 1.8 Hz, 1H), 7.12 (dd, J=7.5, 5.0 Hz, 1H), 5.44 (br. s., 1H), 5.27 (d, J=4.8 Hz, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 4.69 - 4.60 (m, 2H), 3.43 - 3.29 (m, 2H), 3.20 - 3.09 (m, 1H), 2.99 (s, 3H), 2.91 - 2.81 (m, 1H), 2.75 (d, J=15.3 Hz, 1H), 2.32 - 1.33 (m, 37H), 1.76 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H); LC/MS (ESI) m/e 870.6 [(M+H) + , calcd for C52H75N3O6S 870.5], ta = 2.30 min (LCMS Method 15); HPLC (Analytical HPLC Method 3): fe = 14.96 min; HPLC (Analytical HPLC Method 4): fa = 14.64 min.

Example A7 and Example A8. Preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)- 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2,3-dih ydroxypropyl)amino)- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (Example A7) and (R)-l- (((3-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2,3-dihyd roxypropyl)amino)- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (Example A8).

Step 1. Preparation of ((R)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-amino- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(ethoxycarbonyl)cyclohex-3 -en- 1 -yl)methyl benzoate .

In a 150 mL medium pressure flask was combined

(lR,3aS,5aR,5bR,7aR, l laR, l lbR,13aR, 13bR)-3a-amino-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 trifluoromethanesulfonate (1.5 g, 2.69 mmol), (R)-(l- (ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)cyclohex-3-en-l- yl)methyl benzoate (1.259 g, 3.04 mmol) and Buchwald pre-catalyst (0.127 g, 0.161 mmol) in THF (25 mL). To the reaction mixture was added a solution of aqueous 0.5 M K3PO4 (13.45 mL, 6.72 mmol). The resulting brown solution was sparged with N 2 (g), stirred at 72 °C overnight. After 16h, the reaction was allowed to cool to rt, diluted with EtOAc (50 mL) and washed with 1.5M K3PO4 (50 mL). The aqueous layer was extracted with 2 x 50 mL EtOAc. The combined organic layer was washed with brine, dried over MgS04, filtered and concentrated to grey foam. Crude material was dissolved in DCM and loaded onto a silica gel column (S1O2, 80g Isco cartridge, eluted with 0%B to 50%B over 4 column volumes, and hold at 50%B until all product eluted, solvent A= DCM, solvent B = 90: 10 DCM:MeOH) and dried in vacuo to give ((R)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino-5a,5b,8,8, l 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate (1.8 g, 2.59 mmol, 96 % yield) as brown solid. LCMS: m/z 696.6 (M+H + ), retention time 1.589 min (LCMS Method 16). 'H NMR (400MHz, CHLOROFORM-d) δ 8.06 - 7.96 (m, 2H), 7.63 - 7.53 (m, 1H), 7.48 - 7.39 (m, 2H), 5.36 (br. s., 1H), 5.20 (dd, J=6.1, 1.7 Hz, 1H), 4.73 (d, J=2.0 Hz, 1H), 4.61 (s, 1H), 4.44 (q, J=10.8 Hz, 2H), 4.18 (qd, J=7.1, 1.0 Hz, 2H), 2.77 - 2.64 (m, 1H), 2.55 (td, J=10.9, 5.3 Hz, 1H), 2.26 - 2.13 (m, 3H), 2.08 (td, J=12.7, 5.7 Hz, 2H), 2.00 (dd, J=17.0, 6.5 Hz, 1H), 1.85 (dt, J=13.1, 6.4 Hz, 1H), 1.78 - 1.71 (m, 2H), 1.70 (s, 3H), 1.67 - 1.56 (m, 6H), 1.55 - 1.49 (m, 4H), 1.48 - 1.38 (m, 6H), 1.37 - 1.26 (m, 3H), 1.24 - 1.19 (m, 3H), 1.08 (s, 3H), 0.97 (s, 3H), 0.96 (br. s., 3H), 0.94 (s, 3H), 0.87 (s, 3H).

Step 2. Preparation of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR, 13bR)-3a- amino-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)- 1 -(hydroxymethyl)cyclohex-3 -enecarboxylate .

To a solution of ((R)-4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-amino- 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)-l-(ethoxycarbonyl)cyclohex-3-en-l -yl)methyl benzoate (0.692 g, 0.994 mmol) in THF (10 mL) and Me OH (1 mL) was added sodium hydroxide (0.994 mL, 0.994 mmol) and the resulting mixture was stirred at rt. After 3h, the reaction was concentrated to dryness and the material was dissolved in DCM:MeOH and purified by flash column chromatography (Si0 2 , 40g Isco cartridge, eluted with 95:5 DCM:MeOH) and dried in vacuo to give (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a- amino-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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylate (427 mg, 0.721 mmol, 72.6 % yield) as light yellow solid. LCMS: m/z 592.5 (M+H + ), retention time 1.705 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCl3:METHANOL-d 4 ) δ 5.30 (br. s., 1H), 5.14 (d, J=4.6 Hz, 1H), 4.72 (br. s., 1H), 4.60 (br. s., 1H), 4.22 - 4.00 (m, 2H),

3.74 - 3.53 (m, 2H), 2.60 - 2.42 (m, 2H), 2.13 (br. s., 2H), 2.06 - 1.87 (m, 4H), 1.78 - 1.70

(m, 1H), 1.67 (br. s., 5H), 1.63 - 1.51 (m, 6H), 1.43 (br. s., 7H), 1.32 (br. s., 1H), 1.24 (t, J=7.0 Hz, 4H), 1.06 (br. s., 4H), 0.97 (br. s., 3H), 0.92 (br. s., 3H), 0.90 (br. s., 3H), 0.85 (br. s., 3H).

Step 3. Preparation of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR, 13bR)-3a- amino-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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate.

(R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-amino- 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)-l-(hydroxymethyl)cyclohex-3-eneca rboxylate (420 mg, 0.710 mmol) and 3-cyano-2-fluoropyridine (130 mg, 1.064 mmol) were combined in DMF (3 mL) and THF (3 mL) chilled to 0°C. To the yellow slurry was treated with a solution of potassium tert-butoxide (0.781 mL, 0.781 mmol) in THF. The reaction became almost totally homogeneous; the cold bath was removed and the reaction was stirred to rt. After 3.5h, there was still a small amount of starting material left; thus to the reaction was added more 3-cyano-2-fluoropyridine (43.3 mg, 0.355 mmol) and potassium tert-butoxide (0.142 mL, 0.142 mmol) and stirred at RTfor an additional lh. The reaction was diluted with EtO Ac and washed with 0.5N HC1 25 mL. The aqueous layer was extracted with 2 x 50 mL EtO Ac. The combined organic layer was washed with saturated NaHC03, brine, dried over MgS04, filtered and concentrated to brown paste. Crude material was purified by flash column chromatography (Si0 2 , 40 g Isco cartridge, eluted with 95:5 DCM:MeOH) and dried under vacuo to give (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)- 3a-amino-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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (426 mg, 0.614 mmol, 87 % yield) as light brown solid. LCMS: m/z 694.9 (M+H + ), retention time 1.517 min (LCMS Method 16).

Step 4. Preparation of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR, 13bR)-3a- (((R)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)amino )-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)-l-(((3-cyanopyri din-2- yl)oxy)methyl)cyclohex-3-enecarboxylate, TFA.

To a solution of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- amino-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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate (48.5 mg, 0.070 mmol) in acetonitrile (0.5 mL) and 1,4-dioxane (0.5 mL) was added tert-butyldimethylsilyl (R)-(-)-glycidyl ether (0.094 mL, 0.489 mmol) and the mixture was stirred at 100 °C overnight. After 19h, the reaction was allowed to cool to RT and was purified by reverse phase preparative HPLC using preparative HPLC method 8 and dried under vacuo to give (R)-ethyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-(((R)-3-((tert-butyldimethylsilyl)oxy)- 2-hydroxypropyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylate, TFA (22.8 mg, 0.023 mmol, 32.7 % yield, 53.5% yield based on recovered starting material) and recovered starting material (21.9 mg), both as clear glass solid. LCMS: m/z 882.4 (M+H + ), retention time 1.849 min (LCMS Method 16).

Step 5. To a solution of (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-

(((R)-3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)am ino)-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)- 1 -(((3-cyanopyridin-2- yl)oxy)methyl)cyclohex-3-enecarboxylate, TFA (22.8 mg, 0.023 mmol) in 2-Me-THF (1 mL) and H2O (0.3 mL) was added a solution of tetrabutylammonium hydroxide (0.105 mL, 0.160 mmol) and the mixture was stirred at RT for 4h but LC/MS showed no reaction. The reaction was then stirred at 50 °C. After 14 h, LC/MS showed approximately 60% of starting material remained; thus the mixture was stirred at 50°C for another night. After 40 h, the reaction mixture was purified by reverse phase preparative HPLC using preparative HPLC method 8 and product fractions were dried in vacuo to give two products, both as glass solids.

Example A8 was the first of the two isolated products to elute from the preparative HPLC column: (R)-l-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-(((R)-2,3-dihydroxypropyl)amino)- 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)cyclohex-3-enecarboxylic acid, TFA (4.0 mg, 4.36 μπιοΐ, 19.04 % yield). LCMS: m/z 758.7 (M+H + ), retention time 1.219 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh METHANOLS) δ 8.47 - 8.36 (m, 1H), 8.25 (d, J=3.2 Hz, 1H), 7.08 (dd, J=7.6, 4.9 Hz, 1H), 5.34 (br. s., 1H), 5.19 (d, J=4.9 Hz, 1H), 4.79 (s, 1H), 4.71 (br. s., 1H), 4.06 - 3.90 (m, 1H), 3.66 (d, J=4.2 Hz, 2H), 3.23 - 3.11 (m, 1H), 3.03 - 2.92 (m, 1H), 2.80 - 2.61 (m, 2H), 2.48 - 1.90 (m, 10H), 1.84 (d, J=6.6 Hz, 1H), 1.71 (s, 4H), 1.69 - 1.21 (m, 15H), 1.15 (d, J=12.7 Hz, 1H), 1.08 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H).

Example A7 was the second of the two isolated products to elute from the preparative

HPLC column: (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2,3-dihyd roxypropyl)amino)- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (6.5 mg, 7.46 μηιοΐ, 32.6 % yield). LCMS: m/z 740.6 (M+H + ), retention time 1.289 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh:METHANOL-d 4 ) δ 8.33 (dd,J=5.0, 1.8 Hz, 1H), 7.94 (dd, J=7.6, 1.7 Hz, 1H), 7.03 (dd,J=7.6, 5.1 Hz, 1H), 5.34 (br. s., 1H), 5.18 (d,J=4.9Hz, 1H), 4.79 (s, 1H), 4.71 (s, 1H), 3.99 (dd,J=8.6, 3.9 Hz, 1H), 3.66 (d,J=4.2Hz, 2H), 3.18 (dd, J=12.1, 3.5 Hz, 1H), 2.98 (dd, J=11.9, 8.9 Hz, 1H), 2.78 - 2.56 (m, 2H), 2.35 - 2.08 (m, 4H), 2.08 - 1.87 (m, 6H), 1.75 (br. s., 1H), 1.72 (s, 3H), 1.70 - 1.53 (m, 6H), 1.51 - 1.22 (m, 8H), 1.21 - 1.12 (m, 1H), 1.08 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H).

Example A9 and Example A 10. Preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)- 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2-hydro xy-3- methoxypropyl)amino)-5 a, 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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (Example A9) and (R)-l-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,lla S,llbR,13aR,13bR)-3a- (((R)-2-hydroxy-3-methoxypropyl)amino)-5a,5b,8,8,lla-pentame thyl-l-(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (Example A10).

The title compounds were prepared in 7.1% and 16.1% yield, respectively, from (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-5a,5b,8,8,l la- pentamethyl-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)- 1 -(((3-cyanopyridin-2- yl)oxy)methyl)cyclohex-3-enecarboxylate following the same procedure as described for the preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2,3-di hydroxypropyl)amino)- 5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2-yl)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA and (R)-l-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,lla S,llbR,13aR,13bR)-3a- (((R)-2,3-dihydroxypropyl)amino)-5a,5b,8,8,lla-pentamethyl-l -(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, except (R)-(-)-methyl glycidyl ether was used instead of tert-butyldimethylsilyl (R)-(-)-glycidyl ether in Step 4.

Example A10 was the first of the two isolated products to elute from the preparative HPLC column: (R)-l-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2-hydroxy -3- methoxypropyl)amino)-5 a, 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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (5.6 mg, 7.25 μπιοΐ, 16.13 % yield). LCMS: m/e 772.6 (M+H + ), 1.284 min (LCMS Method 16).

Example A9 was the second of the two isolated products to elute from the preparative HPLC column: (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2-hydroxy -3- methoxypropyl)amino)-5 a, 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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (2.9 mg, 3.17 μπιοΐ, 7.06 % yield). LCMS: m/z 754.6 (M+H + ), retention time 1.345 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh:METHANOL-d 4 ) δ 8.33 (dd, J=5.0, 1.8 Hz, 1H), 7.94 (dd,

J=7.5, 1.8 Hz, 1H), 7.03 (dd, J=7.5, 5.0 Hz, 1H), 5.34 (br. s., 1H), 5.18 (d, J=4.4 Hz, 1H),

4.79 (s, 1H), 4.71 (s, 1H), 4.07 (dd, J=9.9, 4.0 Hz, 1H), 3.54 - 3.44 (m, 2H), 3.39 (s, 3H),

3.15 (dd,J=11.9, 3.3 Hz, 1H), 2.93 (t,J=ll.l Hz, 1H), 2.75 - 2.59 (m, 2H), 2.31 - 2.08 (m, 4H), 2.07 - 1.89 (m, 6H), 1.79 - 1.73 (m, 1H), 1.71 (s, 3H), 1.67 (br. s., 1H), 1.65 - 1.57 (m, 3H), 1.56 - 1.39 (m, 6H), 1.37 - 1.22 (m, 4H), 1.21 - 1.13 (m, 1H), 1.08 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H). Example All and Example A 12. Preparation of (R)-l-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR, 1 laS,l lbR, 13aR, 13bR)-3a-(((S)-2-hydroxy-3- methoxypropyl)amino)-5 a, 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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (Example Al 1) and (R)- l-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((S)-2-hydr oxy-3- methoxypropyl)amino)-5 a, 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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (Example A12).

The title compounds were prepared in 26.9% and 6.1% yield, respectively, from (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-5a,5b,8,8,l la- pentamethyl-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)- 1 -(((3-cyanopyridin-2- yl)oxy)methyl)cyclohex-3-enecarboxylate following the same procedure as described for the preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2,3-di hydroxypropyl)amino)- 5a,5b,8,8,l 1 a-pentamethyl- 1 -(prop- l-en-2-y 1)-

2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octade cahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA and (R)-l-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- (((R)-2,3-dihydroxypropyl)amino)-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)cyclohex-3-enecarboxylic acid, except (S)-(+)-methyl glycidyl ether was used instead of tert-butyldimethylsilyl (R)-(-)-glycidyl ether in Step 4.

Example A 12 was the first of the two isolated products to elute from the preparative HPLC column: (R)-l-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-(((S)-2-hydroxy-3- methoxypropyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-enecarboxylic acid, TFA (2.2 mg, 2.359 μιηοΐ, 6.11 % yield). LCMS: m/z 772.6 (M+H + ), retention time 1.279 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh METHANOLS) δ 8.41 (dd, J=7.6, 2.0 Hz, 1H), 8.25 (dd, J=4.8, 2.1 Hz, 1H), 7.08 (dd, J=7.6, 4.9 Hz, 1H), 5.35 (br. s., 1H), 5.19 (d, J=4.6 Hz, 1H), 4.80 (s, 1H), 4.73 (s, 1H), 4.11 (t, J=4.0 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.61 - 3.55 (m, 1H), 3.44 (s, 3H), 3.27 - 3.20 (m, 1H), 3.19 - 3.12 (m, 1H), 2.72 (d, J=15.9 Hz, 1H), 2.63 - 2.52 (m, 1H), 2.26 (br. s., 1H), 2.22 - 2.08 (m, 4H), 2.07 - 1.95 (m, 4H), 1.88 - 1.74 (m, 3H), 1.72 (s, 3H), 1.70 - 1.62 (m, 2H), 1.62 - 1.41 (m, 8H), 1.41 - 1.22 (m, 4H), 1.16 (br. s., 1H), 1.09 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H).

Example Al l was the second of the two isolated products to elute from the preparative HPLC column: (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-(((S)-2-hydroxy-3- methoxypropyl)amino)-5 a, 5b, 8 , 8 , 11 a-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-enecarboxylic acid, TFA (9.5 mg, 10.40 μιηοΐ, 26.9 % yield). LCMS: m/z 754.6 (M+H + ), retention time 1.347 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh METHANOLS) δ 8.33 (dd, J=5.1, 2.0 Hz, 1H), 7.94 (dd, J=7.6, 2.0 Hz, 1H), 7.03 (dd, J=7.6, 4.9 Hz, 1H), 5.34 (br. s., 1H), 5.18 (d, J=4.4 Hz, 1H), 4.80 (s, 1H), 4.73 (s, 1H), 4.11 (t, J=4.0 Hz, 1H), 3.70 - 3.54 (m, 2H), 3.44 (s, 3H), 3.27 - 3.20 (m, 1H), 3.19 - 3.12 (m, 1H), 2.64 (d, J=15.9 Hz, 1H), 2.60 - 2.51 (m, 1H), 2.20 (d, J=16.6 Hz, 3H), 2.11 - 1.89 (m, 7H), 1.82 - 1.74 (m, 2H), 1.72 (s, 3H), 1.70 - 1.63 (m, 2H), 1.63 - 1.22 (m, 12H), 1.20 - 1.11 (m, 1H), 1.09 (s, 3H), 1.05 (s, 2H), 0.96 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H). 13 C NMR (101MHz, 1:1 CDC13 METHANOLS) δ 178.3, 164.5, 152.27 - 152.01, 148.9, 147.7, 144.1, 139.7, 122.7, 121.9, 117.7, 112.5, 97.5, 78.5, 76.6, 72.6, 71.5, 65.1, 60.2, 53.8, 50.0, 46.8, 46.6, 45.3, 42.8, 41.4, 38.6, 38.3, 36.9, 34.2, 32.6, 31.1, 30.2, 30.1, 28.1, 27.4, 26.8, 25.9, 22.0, 21.7, 20.3, 19.2, 17.0, 16.0, 15.0.

Example A13 and Example A 14 Preparation of (R)-l-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-(((R)-2,3-dihydroxy- 2-methylpropyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-enecarboxylic acid, TFA (Example A13) and (R)-l- (((3-carbamoylpyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-(((R)-2,3-dihydroxy-2- methylpropyl)amino)-5a,5b,8,8, 1 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (Example A14).

The title compounds were prepared in 26.0% and 13.6% yield, respectively, from

(R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-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)- 1 -(((3-cyanopyridin-2- yl)oxy)methyl)cyclohex-3-enecarboxylate following the same procedure as described for the preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-(((R)-2,3-dihydroxypropyl)amino)- 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)cyclohex-3-enecarboxylic acid, TFA and (R)-l-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- (((R)-2,3-dihydroxypropyl)amino)-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)cyclohex-3-enecarboxylic acid, except (2R)-(-)-2- methylglycidyl 4-notrobenzoate was used instead of tert-butyldimethylsilyl (R)-(-)- glycidyl ether in Step 4.

Example A 14 was the first of the two isolated products to elute from the preparative HPLC column: (R)-l-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-(((R)-2,3-dihydroxy-2- methylpropyl)amino)-5a,5b,8,8, 1 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)cyclohex-3-enecarboxylic acid, TFA (4.8 mg, 5.91 μπιοΐ, 13.57 % yield). LCMS: m/z 772.6 (M+H + ), retention time 1.242 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh:METHANOL-d 4 ) δ 8.41 (dd, J=7.6, 2.0 Hz, 1H), 8.25 (dd, J=4.9, 2.0 Hz, 1H), 7.08 (dd, J=7.6, 4.9 Hz, 1H), 5.34 (br. s., 1H), 5.19 (d, J=4.6 Hz, 1H), 4.81 (s, 1H), 4.73 (s, 1H), 3.69 (s, 2H), 2.97 (d, J=12.2 Hz, 1H), 2.79 - 2.68 (m, 1H), 2.68 - 2.59 (m, 1H), 2.34 - 2.23 (m, 1H), 2.22 - 2.08 (m, 3H), 2.08 - 1.95 (m, 4H), 1.90 - 1.80 (m, 1H), 1.79 - 1.74 (m, 1H), 1.73 (s, 3H), 1.71 - 1.66 (m, 1H), 1.66 - 1.53 (m, 4H), 1.52 - 1.33 (m, 6H), 1.30 (br. s., 2H), 1.23 (s, 3H), 1.20 - 1.09 (m, 2H), 1.06 (s, 3H), 1.04 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H).

Example A13 was the second of the two isolated products to elute from the preparative HPLC column: (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-(((R)-2,3-dihydroxy-2- methylpropyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-enecarboxylic acid, TFA (8.7 mg, 0.011 mmol, 26.0 % yield). LCMS: m/z 754.6 (M+H + ), retention time 1.309 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh METHANOLS) δ 8.33 (dd, J=5.0, 1.8 Hz, 1H), 7.94 (dd, J=7.6, 2.0 Hz, 1H), 7.03 (dd, J=7.6, 5.1 Hz, 1H), 5.34 (br. s., 1H), 5.18 (d, J=4.4 Hz, 1H), 4.81 (s, IH), 4.73 (s, IH), 3.69 (s, 2H), 2.97 (d, J=12.0 Hz, IH), 2.72 - 2.59 (m, 2H), 2.30 -2.15 (m, 3H), 2.12 - 1.99 (m, 5H), 1.98 - 1.88 (m, 2H), 1.81-1.74 (m, IH), 1.73 (s, 3H), 1.71-1.66 (m, IH), 1.66 - 1.53 (m, 5H), 1.52 - 1.33 (m, 7H), 1.31-1.25 (m, IH), 1.23 (s, 3H), 1.19 - 1.09 (m, 2H), 1.06 (s, 3H), 1.04 (s, 2H), 0.96 (s, 3H), 0.91 (s, 3H), 0.86 (s, 3H). 13 C NMR (101MHz, 1:1 CDCl 3 METHANOLS) δ 178.3, 164.5, 152.2, 148.9, 147.8, 144.1, 139.7, 122.7, 121.9, 117.7, 112.4, 97.5, 78.6, 72.2, 71.6, 71.5, 69.6, 53.8, 50.0, 46.3, 45.3, 42.9, 42.6, 41.4, 38.6, 38.3, 36.9, 34.2, 32.1, 31.1, 30.2, 30.08 - 30.04, 28.5, 28.1, 27.7, 26.9, 26.0, 23.5, 22.0, 21.7, 20.3, 19.4, 17.0, 16.0, 15.0. Example A15 and Example A 16. Preparation of (R)-4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(((R)-2-carboxy-2- hydroxyethyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2 -yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(((3 -cyanopyridin-2-yl)oxy)methyl)cyclohex-3 - enecarboxylic acid, TFA (Example A15) and 2-(((R)-l-carboxy-4-

((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-(((R)-2-carboxy-2- hydroxyethyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2 -yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-en-l-yl)methoxy)nicotin ic acid, TFA (Example A16).

The title compounds were prepared in 19.5% and 17.9% yield, respectively, from (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-5a,5b,8,8,l la- pentamethyl-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)-l-(((3-cyanopyri din-2- yl)oxy)methyl)cyclohex-3-enecarboxylate following the same procedure as described for the preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-(((R)-2,3-dihydroxypropyl)amino)- 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)cyclohex-3-enecarboxylic acid, TFA and (R)-l-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- (((R)-2,3-dihydroxypropyl)amino)-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)cyclohex-3-enecarboxylic acid, except (R)-methylglycidate was used instead of tert-butyldimethylsilyl (R)-(-)-glycidyl ether in Step 4.

Example A16 was the first of the two isolated products to elute from the preparative HPLC column: 2-(((R)-l-carboxy-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- (((R)-2-carboxy-2-hydroxyethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)methoxy)nicotin ic acid (6.0 mg, 7.37 μπιοΐ, 17.94 % yield). LCMS: m/z 773.5 (M+H + ), retention time 1.224 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh METHANOLS) δ 8.41 (dd, J=7.6, 2.0 Hz, IH), 8.25 (dd, J=4.9, 2.0 Hz, IH), 7.08 (dd, J=7.6, 4.9 Hz, IH), 5.35 (br. s., IH), 5.19 (d, J=4.6 Hz, IH), 4.80 (s, IH), 4.71 (s, IH), 4.44 (dd, J=10.0, 4.2 Hz, IH), 3.40 - 3.34 (m, IH), 3.06 (t, J=11.0 Hz, IH), 2.77 - 2.62 (m, 2H), 2.26 (br. s., IH), 2.22 - 2.05 (m, 5H), 2.04 - 1.94 (m, 3H), 1.89 - 1.74 (m, 3H), 1.72 (s, 3H), 1.69 - 1.57 (m, 4H), 1.57 - 1.40 (m, 5H), 1.39 - 1.22 (m, 4H), 1.22 - 1.12 (m, IH), 1.10 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H).

Example A15 was the second of the two isolated products to elute from the preparative

HPLC column: (R)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-(((R)-2-carboxy-

2-hydroxyethyl)amino)-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)- 1 -(((3 -cyanopyridin-2-yl)oxy)methyl)cyclohex-3 - enecarboxylic acid (6.3 mg, 8.02 μιηοΐ, 19.52 % yield). LCMS: m/z 754.6 (M+H + ), retention time 1.289 min (LCMS Method 16). ¾ NMR (400MHz, 1:1

CDCh:METHANOL-d 4 ) δ 8.33 (dd, J=5.0, 1.8 Hz, IH), 7.94 (dd, J=7.6, 2.0 Hz, IH), 7.03 (dd, J=7.5, 5.0 Hz, IH), 5.34 (br. s., IH), 5.18 (d, J=4.4 Hz, IH), 4.80 (s, IH), 4.71 (s, IH), 4.41 (d,J=5.4 Hz, IH), 3.06 (t,J=10.8 Hz, IH), 2.65 (d,J=19.1 Hz, 2H), 2.20 (d, J=15.9Hz, 3H), 2.14 -2.05 (m, 2H), 2.05 - 1.87 (m, 5H), 1.82- 1.69 (m, 5H), 1.68 - 1.57 (m, 4H), 1.56 - 1.41 (m, 5H), 1.39 - 1.22 (m, 4H), 1.21 - 1.12 (m, IH), 1.10 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H).

Example A17 and Example A18. Preparation of (R)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((S)-2-carboxy -2- hydroxyethyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en-2 -yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(((3 -cyanopyridin-2-yl)oxy)methyl)cyclohex-3 - enecarboxylic acid, TFA (Example A 17) and (R)-3-

(((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-9-((S)-4-(((3- carbamoylpyridin-2- yl)oxy)methyl)-4-(ethoxycarbonyl)cyclohex- 1 -en- 1 -yl)-5a,5b,8, 8, 11 a-pentamethyl- 1 - (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-

The title compounds were prepared in 19.5% and 16.0% yield, respectively, from (R)-ethyl 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-5a,5b,8,8,l la- pentamethyl-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)- 1 -(((3-cyanopyridin-2- yl)oxy)methyl)cyclohex-3-enecarboxylate following the same procedure as described for the preparation of (R)-l-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-(((R)-2,3-dihyd roxypropyl)amino)- 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)cyclohex-3-enecarboxylic acid, TFA and (R)-l-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a- (((R)-2,3-dihydroxypropyl)amino)-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)cyclohex-3-enecarboxylic acid, except (S)-methylglycidate was used instead of tert-butyldimethylsilyl (R)-(-)-glycidyl ether in Step 4.

Example A18 was the first of the two isolated products to elute from the preparative HPLC column: (R)-3-(((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-9-((S)-4-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-(ethoxycarbonyl)cyclohex - 1 -en- 1 -yl)- 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-3a-yl)amino)-2-hydroxypropanoic acid, TFA (5.7 mg, 6.11 μιηοΐ, 15.98 % yield). LCMS: m/z 772.7 (M+H + ), retention time 1.222 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh METHANOLS) δ 8.41 (dd, J=7.6, 2.0 Hz, IH), 8.25 (dd, J=4.9, 2.0 Hz, IH), 7.08 (dd, J=7.6, 4.9 Hz, IH), 5.35 (br. s., IH), 5.19 (d, J=4.6 Hz, IH), 4.79 (s, IH), 4.71 (s, IH), 4.41 (t, J=6.6 Hz, IH), 3.20 (d, J=6.4 Hz, 2H), 2.71 (d, J=13.4 Hz, 2H), 2.36 - 2.23 (m, IH), 2.16 (d, J=14.9 Hz, 2H), 2.13 - 2.06 (m, 2H), 2.05 - 1.95 (m, 4H), 1.89 - 1.80 (m, IH), 1.79 - 1.74 (m, IH), 1.72 (s, 3H), 1.68 (br. s., 2H), 1.65 - 1.57 (m, 2H), 1.57 - 1.50 (m, 2H), 1.49 - 1.39 (m, 4H), 1.39 - 1.22 (m, 4H), 1.12 (s, 3H), 1.08 (d, J=9.5 Hz, IH), 1.04 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H).

Example A17 was the second of the two isolated products to elute from the preparative HPLC column: (R)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-(((S)-2-carboxy- 2-hydroxyethyl)amino)-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)- 1 -(((3 -cyanopyridin-2-yl)oxy)methyl)cyclohex-3 - enecarboxylic acid, TFA (6.8 mg, 7.44 μιηοΐ, 19.46 % yield). LCMS: m/z 754.6(M+H + ), retention time 1.284 min (LCMS Method 16). ¾ NMR (400MHz, 1:1

CDCh:METHANOL-d 4 ) δ 8.33 (dd, J=5.0, 1.8 Hz, IH), 7.94 (dd, J=7.6, 2.0 Hz, IH), 7.03 (dd, J=7.6, 5.1 Hz, IH), 5.34 (br. s., IH), 5.18 (d, J=4.6 Hz, IH), 4.79 (br. s., IH), 4.71 (br. s., IH), 4.41 (br. s., IH), 3.20 (d, J=5.1 Hz, 2H), 2.70 (br. s., IH), 2.64 (d, J=18.8 Hz, IH), 2.20 (d, J=16.1 Hz, 3H), 2.12 - 1.89 (m, 7H), 1.75 (br. s., 2H), 1.72 (s, 3H), 1.70 - 1.51 (m, 6H), 1.51 - 1.39 (m, 4H), 1.38 - 1.22 (m, 4H), 1.12 (s, 3H), 1.08 (d,J=9.0Hz, 1H), 1.04 (s, 3H), 0.96 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H).

Example A19

Preparation of (lR)-4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-((2-carboxy-2- hydroxypropyl)amino)-5a,5b,8,8,lla-pentamethyl-l-(prop-l-en- 2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-l-(((3-cyanopyridin-2-yl)oxy)meth yl)cyclohex-3- enecarboxylic acid.

The title compound was prepared in 19.4% yield from (R)-ethyl 4- ((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a-amino-5a,5b,8,8,l la-pentamethyl-1- (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)- 1 -(((3 -cyanopyridin-2-yl)oxy)methyl)cyclohex-3 - enecarboxylate following the same procedure as described for the preparation of (R)-l- (((3-cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,ll aS,llbR,13aR,13bR)-3a- (((R)-2,3-dihydroxypropyl)amino)-5a,5b,8,8,lla-pentamethyl-l -(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA and (R)-l-(((3- carbamoylpyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,lla S,llbR,13aR,13bR)-3a- (((R)-2,3-dihydroxypropyl)amino)-5a,5b,8,8,lla-pentamethyl-l -(prop-l-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid; except methyl 2- methylglycidate was used instead of tert-butyldimethylsilyl (R)-(-)-glycidyl ether in Step 4. LCMS: m/z 768.5 (M+H + ), retention time 1.295 min (LCMS Method 16). ¾ NMR (400MHz, 1:1 CDCh METHANOLS) δ 8.33 (dd, J=5.0, 1.8 Hz, 1H), 7.94 (dd, J=7.6, 2.0 Hz, 1H), 7.03 (dd, J=7.5, 5.0 Hz, 1H), 5.34 (br. s., 1H), 5.18 (d, J=4.6 Hz, 1H), 4.79 (br. s., 1H), 4.71 (br. s., 1H), 3.08 - 2.89 (m, 1H), 2.80 - 2.57 (m, 2H), 2.33 - 2.09 (m, 4H), 2.08 - 1.87 (m, 6H), 1.82 - 1.74 (m, 1H), 1.72 (s, 3H), 1.70 - 1.57 (m, 4H), 1.56 - 1.41 (m, 8H), 1.40 - 1.22 (m, 4H), 1.12 (s, 1H), 1.09 (br. s., 1.5H), 1.07 (br. s., 1.5H), 1.05 (s, 3H), 1.01 (s, 1H), 0.96 (s, 3H), 0.92 (s, 3H), 0.86 (br. s., 3H). Preparation of 8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-oxaspiro[4 .5]dec-7-en-l- one.

Step 1 Step 2

Step 1 : Preparation of 8-((trimethylsilyl)oxy)-2-oxaspiro[4.5]dec-7-en-l-one.

To a 350 mL Chemglass pressure vessel with threaded stopper was added 3- methylenedihydrofuran-2(3H)-one (4.31 g, 43.9 mmol) and (buta-l,3-dien-2- yloxy)trimethylsilane (7.50 g, 52.7 mmol) and benzene (100 mL). Hydroquinone (0.726 g, 6.59 mmol) was added, then the solution was flushed with nitrogen, sealed and heated to 123 °C for 20 h. An additional 2.4 equivalents of (buta-l,3-dien-2- yloxy)trimethylsilane (15.0 g, 105.4 mmol) was then added to the vessel, and the mixture was heated to 123 °C for an additional 60 h. The mixture was concentrated in vacuo to give approximately 19 g of yellow oil. The crude mixture was loaded with minimum DCM and hexanes onto a hexanes preequilibrated Isco 330 g silica cartridge. Elution gradient 100% hexanes to 11 : 1 hexanes:EtOAc over 2 column volumes, then hold 11 : 1 hex:EtOAc for 3 column volumes, then gradient to 5: 1 hex:EtAc over 2 column volumes, then hold 5: 1 hex:EtOAc for 6 column volumes. Concentration of combined fractions containing the desired material provided the product as a white solid: 7.50 g (71.0 % yield). ¾ NMR (400MHz, CHLOROFORM-d) δ 4.85 (d, J=5.6 Hz, 1H), 4.40 - 4.23 (m, 2H), 2.47 (dd, J=16.6, 2.2 Hz, 1H), 2.19 - 2.10 (m, 4H), 2.06 (d, J=3.4 Hz, 1H), 2.04 - 1.99 (m, 1H), 1.75 - 1.65 (m, 1H), 0.22 (s, 9H).

Step 2. Preparation of 2-oxaspiro[4.5]decane-l,8-dione.

8-((trimethylsilyl)oxy)-2-oxaspiro[4.5]dec-7-en-l-one (7.50 g, 31.2 mmol) was combined with THF (100 mL) and hydrochloric acid, 0.05M aqueous (3.12 mL, 0.156 mmol). The mixture was stirred for 18 h at RT. The reaction mixture was then concentrated in vacuo to a residue. The residue was taken up in EtOAc (200 mL) and washed with saturated NaHCC (50 mL) and with brine (50 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was loaded in minimum DCM onto a hexanes preequilibrated Isco 330 g silica cartridge. Elution gradient 100% hexanes to 1 : 1 hexanes:EtOAc over 10 column volumes, hold 1 : 1 hexanes:EtOAc for 6 column volumes. Partial separation of the two materials was achieved. Like fractions were combined and set aside, and mixed fractions were rechromatographed in a similar manner. The desired material was the major product from the reaction and was the second of the two materials to elute from the silica column. The desired material was recovered as a white solid: 4.14 g (79.0 % yield). 'H NMR (400MHz, CHLOROFORM-d) δ 4.40 (t, J=7.1 Hz, 2H), 2.87 - 2.70 (m, 2H), 2.44 - 2.29 (m, 4H), 2.24 (ddd, J=13.6, 8.3, 5.5 Hz, 2H), 1.96 (dt, J=13.6, 6.5 Hz, 2H).

Step 3. Preparation of l-oxo-2-oxaspiro[4.5]dec-7-en-8-yl trifluoromethane sulfonate.

In a 250 mL round bottom flask fitted with magnetic stirrer and rubber septum were combined 2-oxaspiro[4.5]decane-l,8-dione (4.13 g, 24.6 mmol) and N,N- bis(trifluoromethylsulfonyl)aniline (10.1 g, 28.2 mmol) in anhydrous tetrahydrofuran (100 mL). The solution was cooled to -78 °C in a dry ice/acetone bath. To the cold solution was added dropwise potassium hexamethyldisilazide, 0.5M in toluene (56.5 mL, 28.2 mmol) over 15 min. The mixture was stirred at -78 °C for a total of 4 h when it was treated slowly with 100 mL of saturated aqueous ammonium chloride. The mixture was stirred at RT for 15 min and was concentrated in vacuo to remove most of the THF, then to the residue was added ethyl acetate (300 mL). The resulting mixture was shaken and phases were separated. The organic was washed with water (2 x 100 mL) and with brine (50mL). The organic was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude yellow oil. The crude residue was loaded as an oil onto a hexanes preequilibrated Isco 220 g silica cartridge and the flask was rinsed with minimum DCM and this was added to the column as well. Elution gradient 100% hexanes to 3: 1 hexanes:EtOAc over 3 column volumes, then hold 3: 1 hex:EtOAc for 3 column volumes, then 2: 1 hex:EtOAc for 3 column volumes. Like product fractions were combined and concentrated in vacuo to give the desired material as a slightly yellow oil: 6.44 g (87.0 % yield). ¾ NMR (400MHz, CHLOROFORM-d) δ 5.86 - 5.76 (m, 1H), 4.44 . 4.29 (m, 2H), 2.63 (dd, J=17.7, 2.8 Hz, 1H), 2.59 - 2.38 (m, 2H), 2.30 - 2.16 (m, 3H), 2.16 - 2.04 (m, 1H), 1.86 (dt, J=13.7, 2.9 Hz, 1H).

Step 4. In a 250 mL round bottom flask fitted with a reflux condenser were combined 1- oxo-2 -oxaspiro[4.5]dec-7-en-8-yl trifluoromethane sulfonate (6.43 g, 21.4 mmol), potassium acetate (5.25 g, 53.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (5.71 g, 22.5 mmol) and PdCk dppQ.CHiCk (0.529 g, 0.642 mmol) in dry 1,4-dioxane (100 mL). The mixture was flushed with nitrogen and heated to 70 °C for 5 h. The reaction mixture was concentrated in vacuo to approx. 25 mL total volume and was diluted with ethyl acetate (300 mL) and water (150 mL). The mixture was shaken and phases were separated. The organic was again washed with water (100 mL) and then with brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a deep red residue. The crude mixture was dissolved in minimum DCM and loaded onto a hexanes preequilibrated Isco 220 g silica cartridge. Elution gradient 100% hexanes to 20% ethyl acetate in hexanes over 10 column volumes, then hold 20% ethyl acetate in hexanes for 6 column volumes, then gradient to 15% ethyl acetate in hexanes over 2 column volumes, then hold 25% ethyl acetate in hexanes for 6 column volumes. Product fractions were combined and concentrated in vacuo to give the desired material as a white foam solid = 4.94 g (83.0% yield). ¾ NMR (400MHz, CHLOROFORM-d) δ 6.60 - 6.49 (m, 1H), 4.39 - 4.22 (m, 2H), 2.50 (d, J=17.6 Hz, 1H), 2.40 (dd, J=18.1, 3.9 Hz, 1H), 2.21 - 2.01 (m, 4H), 1.85 (td, J=12.3, 5.5 Hz, 1H), 1.73 - 1.62 (m, 1H), 1.29 (s, 12H).

Example A20. Preparation of 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR, 13bR)-3a-((2- (l,l-dioxidomiomoφholino)ethyl)amino)-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)- 1 -(2-(pyridin-2-yloxy)ethyl)cyclohex-3-ene- 1 -carboxylic acid.

Step 1. Preparation of 8-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8, 11, 1 la, 1 lb, 12, 13, 13a, 13b-octadecahydro-lH- cyclopenta[a]chryse

In a 150 mL Chemglass pressure vessel with magnetic stir bar were combined (lR,3aS,5aR,5bR,7aR,l laR,l lbR,13aR,13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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 trifluoromethanesulfonate (2.00 g, 2.78 mmol) with 8-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2-oxaspiro[4.5]dec-7-en -l-one (0.851 g, 3.06 mmol) and Buchwald precatalyst 13 (0.131 g, 0.167 mmol). The vessel was sealed with a rubber septum. A needle was inserted into the septum and the vessel was iteratively evacuated and then purged with nitrogen in a vacuum oven at RT four times over a 15 min period. To the nitrogen purged reaction flask was added anhydrous THF (40 mL) and freshly prepared, nitrogen sparged aqueous 0.5 M K3PO4 (13.9 mL, 6.95 mmol) was added. The vessel was sealed and the resulting yellow solution was stirred at 80 °C for 20.5 h. The mixture darkened to a very deep green color after 30 min of heating, and after 20.5 h of heating a nearly colorless biphasic mixture was present. The mixture was diluted with EtOAc (150 mL) and washed with saturated aqueous sodium bicarbonate (50 mL x 2) and then with brine (50 mL). The combined aqueous layer was extracted with 2 x 100 mL of chloroform and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to a slightly yellow foam solid. The crude yellow material was loaded in minimum DCM onto a hexanes preequilibrated Isco 80 g silica cartridge. Elution gradient 100% hexanes to 1 : 1 hexanes:EtOAc over 2 column volumes, hold 1 : 1 hexanes:EtOAc for 3 column volumes, then gradient 1 : 1 hexanes:EtOAc to 1 :4 hex:EtOAc over 8 column volumes, then hold 1 :4 hexanes:EtOAc for 10 column volumes. Product fractions were combined and concentrated in vacuo to give an off-white glassy solid: 1.63 g (81.0% yield). LCMS m/z = 721.6 (M+H + ), retention time 2.404 min (LCMS Method 17). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 5.41 - 5.30 (m, 1H), 5.22 (d, J=5.6 Hz, 1H), 4.70 (br. s., 1H), 4.42 - 4.27 (m, 2H), 3.19 - 2.97 (m, 8H), 2.78 - 2.53 (m, 4H), 2.52 - 2.32 (m, 2H), 2.29 - 2.10 (m, 4H), 2.04 - 1.75 (m, 6H), 1.69 (s, 4H), 1.66 - 1.54 (m, 4H), 1.53 (br. s., 1H), 1.45 (br. s., 4H), 1.40 - 1.32 (m, 2H), 1.32 - 1.13 (m, 5H), 1.10 (s, 6H), 1.04 (br. s., 1H), 0.99 (br. s., 5H), 0.95 (d, J=7.3 Hz, 3H), 0.88 (s, 3H).

Step 2. Preparation of potassium 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-

((2-(l, l-dioxidothiomo holino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- l-en-2- yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octad ecahydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(2-hydroxyethyl)cyclohex-3 -ene- 1 -carboxylate .

In a 250 mL round bottom flask fitted with a reflux condenser were combined 8- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-2-oxaspiro[4.5]dec-7-en-l-one (1.61 g, 2.23 mmol) with potassium carbonate (1.54 g, 11.2 mmol) in a mixture of MeOH (20 mL) and THF (20 mL). The result was heated to 70°C in an oil bath for 2.5 h. Solvent was removed in vacuo to leave a solid brown residue which was carried into the next step without further manipulation. LCMS m/z = 739.5 (M+H + ), retention time 1.852 min (LCMS Method 18).

Step 3. Preparation of isopropyl 4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(2-hydroxyethyl)cyclohex-3 -ene- 1 -carboxylate .

In a 250 mL round bottom flask fitted with a reflux condenser were combined the crude reaction mixture from Step 2 containing potassium 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-hydroxyethyl)cyclohex-3-enec arboxylate (1.73 g, 2.23 mmol) with potassium carbonate (1.543 g, 11.17 mmol) in a mixture of acetonitrile (20 mL) and DMF (20 mL). To the mixture was added 2-iodopropane (4.46 mL, 44.7 mmol). The resulting suspension was stirred at 80 °C for 2.5 h. The mixture was concentrated in vacuo to a residue. Ethyl acetate (120 mL) and water (100 mL) were added and the mixture was shaken and phases were separated. The organic phase was washed twice more with water (2 x 50 mL) and then with brine (20 mL). The slightly yellow organic was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a residue. The material was loaded in DCM onto an Isco 120 g silica gel cartridge which was preequilibrated with DCM. Elution gradient 100% DCM to 19: 1 DCM:MeOH over 6 column volumes, hold 19: 1 DCM:MeOH for 8 column volumes. The combined product fractions were concentrated in vacuo to a beige foam: 1.55 g (89% yield over 2 steps). LCMS m/z = 781.5 (M+H + ), retention time 2.873 min (LCMS Method 19). ¾ NMR (400MHz, CHLOROFORM-d) δ 5.34 (br. s., 1H), 5.18 (d, J=5.6 Hz, 1H), 5.04 (dt, J=12.4, 6.1 Hz, 1H), 4.73 (s, 1H), 4.61 (s, 1H), 3.73 (d, J=4.9 Hz, 1H), 3.16 - 2.97 (m, 7H), 2.75 - 2.54 (m, 4H), 2.54 - 2.42 (m, 1H), 2.28 - 2.16 (m, 1H), 2.13 (dd, J=12.1, 6.5 Hz, 1H), 2.07 - 1.91 (m, 4H), 1.89 - 1.75 (m, 4H), 1.71 (s, 3H), 1.70 - 1.62 (m, 2H), 1.62 - 1.49 (m, 5H), 1.49 - 1.39 (m, 4H), 1.39 - 1.29 (m, 3H), 1.29 - 1.22 (m, 7H), 1.22 - 1.11 (m, 2H), 1.08 (s, 6H), 1.01 - 0.95 (m, 6H), 0.94 - 0.90 (m, 3H), 0.88 (s, 3H). Step 4. Preparation of isopropyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-((methylsulfonyl)oxy)ethyl)c yclohex-3-ene-l- carboxylate.

Isopropyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-hydroxyethyl)cyclohex-3-enec arboxylate (0.800 g, 1.02 mmol) was dissolved in a mixture of triethylamine (5 mL) and DCM (5 mL). The clear mixture was chilled in an ice bath and to it was slowly added a solution of

methanesulfonic anhydride (0.446 g, 2.56 mmol) in DCM (3 mL). The colorless solution took on a slightly yellow color turning to deep orange and finally to brown over the course of the reaction. The brown mixture was stirred at 0 °C for 4 h and was then concentrated in vacuo to a residue without warming. The crude residue was diluted with EtOAc (100 mL) and washed with 5% aqueous NaHCC (2 x 20 mL), water (20 mL) and brine (20 mL). The organic was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a reddish/brown foam. The crude material was loaded in minimum DCM onto an 80 g Isco silica cartridge which was preequilibrated with hexanes. Elution gradient 100% hexanes to 3:2 hexanes:acetone over 3 column volumes, hold 3:2 hexanes: acetone for 10 column volumes. Desired product fractions were combined and concentrated in vacuo to give a yellow foam: 667 mg (76.0% yield). LCMS m/z = 859.6 (M+H + ), retention time 3.160 min (LCMS Method 19). Ή NMR (400MHz,

CHLOROFORM-d) δ 5.33 (br. s., 1H), 5.18 (d, J=5.4 Hz, 1H), 5.04 (dt, J=12.2, 6.3 Hz, 1H), 4.75 (br. s., 1H), 4.63 (br. s., 1H), 4.29 (t, J=7.0 Hz, 1H), 3.72 (t, J=6.5 Hz, 1H), 3.25 (s, 1H), 3.16 (s, 1H), 3.08 (br. s., 6H), 3.01 (s, 2H), 2.83 (s, 1H), 2.77 - 2.54 (m, 4H), 2.49 (br. s., 1H), 2.30 - 2.09 (m, 3H), 2.09 - 1.95 (m, 4H), 1.95 - 1.76 (m, 4H), 1.72 (br. s., 3H), 1.66 (dd, J=14.3, 7.2 Hz, 3H), 1.61 - 1.50 (m, 5H), 1.50 - 1.38 (m, 5H), 1.33 (t, J=13.1 Hz, 3H), 1.29 - 1.21 (m, 7H), 1.18 - 1.03 (m, 6H), 1.00 (br. s., 3H), 0.97 (d, J=7.3 Hz, 3H), 0.93 (d, J=5.4 Hz, 3H), 0.88 (s, 3H). Step 5. Preparation of isopropyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-(pyridin-2-yloxy)ethyl)cyclo hex-3-ene-l-carboxylate.

In a 1 dram vial with PTFE screwcap were combined pyridin-2-ol (0.0190 g, 0.204 mmol) and isopropyl 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-((methylsulfonyl)oxy)ethyl)c yclohex-3-enecarboxylate (0.0250 g, 0.0290 mmol) in anhydrous DMF (0.5 mL). To the mixture was added

NaHMDS, 1.0M in THF (0.175 mL, 0.175 mmol) with stirring. The resulting slightly yellow mixture was heated to 50 °C and stirred for 3 d. The crude mixture was purified by reverse phase preparative HPLC (Preparative HPLC Method 6). Thus was isolated the desired material (0.00940 g, 29.7 % yield) as a white solid TFA salt. LCMS m/z = 858.6 (M+H + ), retention time 1.627 min (LCMS Method 16).

Step 6. In a 1 dram vial with PTFE screwcap were combined isopropyl 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-(pyridin-2-yloxy)ethyl)cyclo hex-3-enecarboxylate, TFA salt (0.00940 g, 8.65 μιηοΐ) with lithium hydroxide, 1.0M aqueous (0.087 mL, 0.087 mmol) and a mixture of THF (0.3 mL) and MeOH (0.3 mL). The resulting mixture was stirred at 75 °C for 48 h. The crude mixture was purified by reverse phase preparative HPLC (Preparative HPLC Method 6). The fraction containing the desired material was concentrated in vacuo to give the title compound as a white glassy solid (0.0035 g 33% yield). LCMS m/z = 816.5 (M+H + ), retention time 2.182 min (LCMS Method 17). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 8.07 (d, J=5.1 Hz, 1H), 7.65 - 7.59 (m, 1H), 6.90 (t, J=6.1 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 5.33 (br. s., 1H), 5.18 (d, J=5.6 Hz, 1H), 4.80 (s, 1H), 4.72 (s, 1H), 4.34 (t, J=6.6 Hz, 2H), 3.24 (br. s., 3H), 3.21 - 3.13 (m, 3H), 3.12 - 2.96 (m, 4H), 2.84 - 2.72 (m, 1H), 2.60 (d, J=15.4 Hz, 1H), 2.26 - 1.96 (m, 10H), 1.87 - 1.70 (m, 6H), 1.69 - 1.59 (m, 3H), 1.57 (br. s., 2H), 1.53 - 1.43 (m, 5H), 1.40 (br. s., 1H), 1.39 - 1.22 (m, 2H), 1.15 (s, 3H), 1.11 (br. s., 1H), 1.08 (s, 3H), 1.04 - 0.99 (m, 1H), 0.97 (br. s., 3H), 0.93 (s, 3H), 0.90 (s, 3H).

Example A21. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-((5-methylisothiazol-3-yl)ox y)ethyl)cyclohex-3-ene-l- carboxylic acid.

The title compound was obtained by the same procedures used in the preparation 0f 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR, 13aR, 13bR)-3a-((2-(l, l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(2-(pyridin-2-yloxy)ethyl)cyclohex-3-ene- 1 -carboxylic acid, except 5-methylisothiazol-3-ol (0.023 g, 0.204 mmol) was used in place of pyridin-2-ol in Step 5. Thus was obtained the title compound as a white glassy solid (0.0027 g, 8.3 % combined yield for Steps 5 and 6). LCMS m/z = 836.5 (M+H + ), retention time 2.394 min (LCMS Method 17). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 5.32 (br. s., 1H), 5.18 (d, J=5.4 Hz, 1H), 4.80 (s, 1H), 4.73 (s, 1H), 4.36 (t, J=6.6 Hz, 2H), 3.75 (t, J=6.0 Hz, 2H), 3.27 - 3.12 (m, 8H), 3.12 - 2.94 (m, 5H), 2.78 (td, J=10.8, 4.4 Hz, 1H), 2.58 (d, J=16.1 Hz, 1H), 2.25 - 1.95 (m, 11H), 1.92 - 1.70 (m, 8H), 1.70 - 1.59 (m, 3H), 1.59 - 1.39 (m, 9H), 1.39 - 1.24 (m, 3H), 1.22 (s, 1H), 1.18 - 1.04 (m, 7H), 0.97 (d, J=2.7 Hz, 3H), 0.92 (br. s., 3H), 0.90 (s, 3H).

Example A22. Preparation of l-(2-((3-cyanopyridin-2-yl)oxy)ethyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-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)cyclohex-3-ene-l-carboxylic acid.

Step 1. Preparation of potassium 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- ((2-(l, l-dioxidothiomo holino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl-l-(prop-l-en-2- yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octad ecahydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(2-hydroxyethyl)cyclohex-3 -ene- 1 -carboxylate .

In a 50 mL round bottom flask fitted with a reflux condenser were combined 8- ((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)-2-oxaspiro[4.5]dec-7-en-l-one (0.700 g, 0.971 mmol) with potassium carbonate (1.34 g, 9.71 mmol) in a mixture of MeOH (10 mL) and THF (15 mL). The result was heated to reflux in an 85 °C oil bath for 24 h. The mixture was allowed to cool to RT, then DCM was added and the result was filtered to remove white solids. Solvent was removed in vacuo and the residue was dried in a vacuum oven at 50 °C overnight to afford the desired material as a white powder (0.940 g, 125% yield). Mass recovery indicated that the material was approximately 80% pure with the remainder as excess potassium salts. This material was used directly in the next step without further purification. LCMS m/z = 739.5 (M+H + ), retention time 1.852 min (LCMS Method 17). Step 2. To the crude powder product from Step 1 containing approx. 80% by weight potassium 4-((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l, 1- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-hydroxyethyl)cyclohex-3-enec arboxylate (0.025 g, 0.026 mmol) was added 2-fluoronicotinonitrile (0.016 g, 0.129 mmol), anhydrous DMF (0.4 mL) and anhydrous THF (0.3 mL) to give a slightly cloudy yellow mixture. To the mixture was added potassium tert-butoxide, l .OM in THF (0.103 mL, 0.103 mmol). The mixture was stirred at RT for 2 h, and then additional 6-fluoropicolinonitrile (0.032 g, 0.258 mmol) and potassium tert-butoxide, l .OM in THF (0.206 mL, 0.206 mmol) and more DMF (0.2 mL) were added and the mixture was stirred for another 1 h. The crude mixture was purified by reverse phase preparative HPLC (Preparative HPLC Method 7). The title compound was thus obtained as a slightly yellow powder (0.0086 g, 25% yield) as a TFA salt. LCMS m/z = 841.6 (M+H + ), retention time 2.289 min (LCMS Method 17). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 8.34 (dd, J=4.2, 1.0 Hz, 1H), 7.94 (dd, J=8.1, 1.7 Hz, 1H), 7.03 (dd, J=7.1, 5.1 Hz, 1H), 5.40 - 5.28 (m,

1H), 5.17 (d, J=4.6 Hz, 1H), 4.80 (br. s., 1H), 4.71 (br. s., 1H), 4.39 - 4.31 (m, 1H), 3.28 - 3.12 (m, 7H), 3.09 (br. s., 2H), 3.01 (br. s., 2H), 2.82 (br. s., 1H), 2.61 (d, J=17.4 Hz, 1H), 2.25 - 1.96 (m, 10H), 1.86 (d, J=10.5 Hz, 1H), 1.78 - 1.68 (m, 5H), 1.67 - 1.53 (m, 5H), 1.53 - 1.38 (m, 6H), 1.38 - 1.24 (m, 3H), 1.19 - 1.03 (m, 8H), 1.03 - 0.82 (m, 9H).

Example A23. Preparation of 2-(2-( 1 -carboxy-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-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-octadecah ydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid.

Step 1. Preparation of potassium 4-((lR,3aS,5aR,5bR,7aR,l laS,l lbR,13aR,13bR)-3a- ((2-(l, l-dioxidothiomo holino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -en-: yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,ll,lla,llb,12,13,13a,13b-octad ecahydro-lH- cyclopenta[a]chrysen-9-yl)- 1 -(2-hydroxyethyl)cyclohex-3 -ene- 1 -carboxylate .

In a 50 mL round bottom flask fitted with a reflux condenser were combined 8-

((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-2-oxaspiro[4.5]dec-7-en-l-one (0.700 g, 0.971 mmol) with potassium carbonate (1.34 g, 9.71 mmol) in a mixture of MeOH (10 mL) and THF (15 mL). The result was heated to reflux in an 85 °C oil bath for 24 h. The mixture was allowed to cool to RT, then DCM was added and the result was filtered to remove white solids. Solvent was removed in vacuo and the residue was dried in a vacuum oven at 50 °C overnight to afford the desired material as a white powder (0.940 g, 125% yield). 0.9155 g of this material was dissolved with stirring in 10 mL of 9: 1 DCM:MeOH and this suspension (salts did not dissolve) was loaded onto a short 40 mL silica gel plug in a 60 mL glass frit suction funnel. The material was eluted with 400 mL of 9: 1 DCM:MeOH. Much of the orange color associated with the impure product was left behind on the silica. Concentration in vacuo afforded a pinkish/white solid which was placed in a vacuum oven at 45 °C for several hours. The desired material was thus obtained as a white powder (0.5082 g, 69.4% yield). LCMS m/z = 739.6 (M+H + ), retention time 1.978 min (LCMS Method 21).

Step 2. To the purified Step 1 product potassium 4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-hydroxyethyl)cyclohex-3-enec arboxylate (0.025 g, 0.032 mmol) was added 2-chloroisonicotinic acid (0.025 g, 0.161 mmol) followed by anhydrous DMF (0.35 mL). To the mixture was added potassium tert-butoxide, l .OM in THF (0.322 mL, 0.322 mmol). The mixture became slightly yellow and cloudy with suspended solid upon addition of the base. The mixture was stirred at RT for 70 h. The reaction mixture was quenched by addition of 3 drops of acetic acid. 0.5 mL MeOH was then added and the mixture was filtered. The crude mixture was purified by reverse phase preparative HPLC in a single injection (Preparative HPLC Method 8). Thus was obtained the title compound as a white solid (0.0069 g, 18% yield) TFA salt. LCMS m/z = 860.6 (M+H + ), retention time 1.559 min (LCMS Method 20).

Example A24. Preparation of l-(2-((4-cyanopyridin-2-yl)oxy)ethyl)-4-

((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-fluoroisonicotinonitrile (0.020 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a slightly yellow solid (0.0133 g, 36.0 % yield) TFA salt. LCMS m/z = 841.6 (M+H + ), retention time 1.689 min (LCMS Method 20). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 8.28 (d, J=5.4 Hz, 1H), 7.11 (dd, J=5.1, 1.2 Hz, 1H), 7.00 (s, 1H), 5.33 (br. s., 1H), 5.17 (d, J=4.4 Hz, 1H), 4.79 (s, lH), 4.71 (s, 1H), 4.47 - 4.39 (m, 2H), 3.28 - 3.04 (m, 9H), 3.04 - 2.96 (m, 2H), 2.86 - 2.74 (m, 1H), 2.59 (d, J=16.4 Hz, 1H), 2.24 - 1.95 (m, 11H), 1.89 - 1.74 (m, 3H), 1.73 (s, 4H), 1.68 - 1.42 (m, 10H), 1.42 - 1.29 (m, 3H), 1.15 (s, 3H), 1.11 (br. s., 2H), 1.08 (s, 4H), 0.96 (d, J=2.4 Hz, 3H), 0.92 (d, J=2.9 Hz, 3H), 0.90 (s, 3H). Example A25. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-(pyrimidin-2-yloxy)ethyl)cyc lohex-3-ene-l-carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-(l-carboxy-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-bromopyrimidine (0.026 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, 1.0M in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a white solid (0.0056 g, 14.2 % yield) TFA salt. LCMS m/z = 817.6 (M+H + ), retention time 1.547 min (LCMS Method 20). Ή NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 8.50 (d, J=4.9 Hz, IH), 7.02 (t, J=4.8 Hz, IH), 5.35 (dd, J=14.7, 2.9 Hz, IH), 5.25 - 5.14 (m, IH), 4.80 (s, IH), 4.72 (s, IH), 4.50 - 4.44 (m, IH), 4.38 - 4.31 (m, IH), 3.27 - 2.98 (m, 10H), 2.84 - 2.75 (m, IH), 2.64 - 2.58 (m, IH), 2.25 - 1.96 (m, 10H), 1.89 - 1.75 (m, 3H), 1.73 (s, 3H), 1.69 - 1.53 (m, 5H), 1.53 - 1.25 (m, 8H), 1.15 (d, J=2.9 Hz, 3H), 1.11 (br. s., 2H), 1.08 (s, 3H), 1.03 - 0.84 (m, 9H). Example A26. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(2-((4-methylpyrimidin-2-yl)oxy)ethyl)cyclohex-3-ene- 1 - carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-(l-carboxy-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-chloro-4-methylpyrimidine (0.021 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, 1.0M in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a white solid (0.0056 g, 14.2 % yield) TFA salt. LCMS m/z = 831.7 (M+H + ), retention time 1.550 min (LCMS Method 20). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 8.21 (d, J=6.1 Hz, 1H), 6.52 (d, J=5.9 Hz, 1H), 5.40 - 5.34 (m, 1H), 5.23 (d, J=4.6 Hz, 1H), 4.79 (s, 1H), 4.71 (s, 1H), 4.41 - 4.27 (m, 2H), 3.30 - 3.05 (m, 10H), 3.01 (d, J=3.4 Hz, 2H), 2.81 (td, J=11.2, 4.9 Hz, 1H), 2.49 - 2.33 (m, 2H), 2.27 - 1.98 (m, 10H), 1.93 - 1.81 (m, 2H), 1.81 - 1.74 (m, 2H), 1.72 (s, 4H), 1.69 - 1.40 (m, 12H), 1.38 - 1.34 (m, 1H), 1.21 - 1.03 (m, 9H), 1.02 - 0.86 (m, 8H). Example A27. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- (1,1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-((4-methoxypyrimidin-2-yl)ox y)ethyl)cyclohex-3-ene-l- carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-(l-carboxy-4-((lR,3aS,5aR,5bR,7aR, l laS,l lbR,13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-chloro-4-methoxypyrimidine (0.023 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, 1.0M in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a white solid (0.0116 g, 28.8 % yield) TFA salt. LCMS m/z = 847.7 (M+H + ), retention time 1.525 min (LCMS Method 20). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 7.28 (d, J=7.6 Hz, 1H), 5.62 (d, J=7.6 Hz, 1H), 5.40 - 5.33 (m, 1H), 5.23 (d, J=4.9 Hz, 1H), 4.79 (s, 1H), 4.71 (s, 1H), 4.41 - 4.29 (m, 2H), 3.27 - 2.97 (m, 12H), 2.81 (td, J=11.2, 4.9 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.28 - 1.98 (m, 10H), 1.92 - 1.81 (m, 2H), 1.80 - 1.73 (m, 2H), 1.73 (s, 3H), 1.70 - 1.40 (m, 12H), 1.38 - 1.34 (m, 1H), 1.16 (s, 3H), 1.15 - 1.09 (m, 2H), 1.08 (s, 3H), 1.00 (d, J=3.2 Hz, 3H), 0.96 (d, J=7.6 Hz, 3H), 0.91 (s, 3H). Example A28. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-((3-methylpyridin-2-yl)oxy)e thyl)cyclohex-3-ene-l- carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-fluoro-3-methylpyridine (0.018 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a white solid (0.0262 g, 74.7 % yield) TFA salt. LCMS m/z = 830.7 (M+H + ), retention time 1.707 min (LCMS Method 20). Ή NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 7.89 (dd, J=5.1, 1.2 Hz, 0.35H), 7.44 (dd, J=7.1, 1.0 Hz, 0.35H), 7.42 - 7.37 (m, 0.65H), 7.22 (dd, J=6.5, 1.3 Hz, 0.65H), 6.81 (dd, J=7.0, 5.3 Hz, 0.35H), 6.29 (t, J=6.7 Hz, 0.65H), 5.39 - 5.30 (m, 1H), 5.23 (d, J=4.9 Hz, 0.65H), 5.18 (d, J=4.6 Hz, 0.35H), 4.79 (s, 1H), 4.71 (s, 1H), 4.41 - 4.29 (m, 2H), 3.27 - 2.98 (m, 12H), 2.81 (td, J=l l . l, 4.6 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.30 - 2.07 (m, 10H), 2.07 - 1.94 (m, 4H), 1.92 - 1.73 (m, 4H), 1.72 (s, 3H), 1.69 - 1.40 (m, 12H), 1.38 - 1.34 (m, 1H), 1.20 - 1.05 (m, 9H), 1.02 - 0.86 (m, 9H).

Example A29. Preparation of l-(2-((3-chloropyridin-2-yl)oxy)ethyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-ene-l-carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 3-chloro-2-fluoropyridine (0.021 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a white solid (0.0156 g, 42.7 % yield) TFA salt. LCMS m/z = 850.6 (M+H + ), retention time 1.770 min (LCMS Method 20). Ή NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 7.99 (dd, J=4.9, 1.7 Hz, 1H), 7.65 (dd, J=7.7, 1.6 Hz, 1H), 6.86 (dd, J=7.6, 4.9 Hz, 1H), 5.33 (br. s., 1H), 5.17 (d, J=4.6 Hz, 1H), 4.79 (s, 1H), 4.72 (s, 1H), 4.45 (t, J=6.6 Hz, 2H), 3.27 - 2.98 (m, 12H), 2.80 (td, J=l l . l, 4.8 Hz, 1H), 2.60 (d, J=15.7 Hz, 1H), 2.25 - 1.95 (m, 10H), 1.90 - 1.74 (m, 3H), 1.73 (s, 3H), 1.68 - 1.42 (m, 10H), 1.40 (br. s., 1H), 1.38 - 1.29 (m, 2H), 1.29 - 1.23 (m, 1H), 1.15 (s, 3H), 1.12 (d, J=5.4 Hz, 1H), 1.08 (s, 3H), 0.99 - 0.84 (m, 9H).

Example A30. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- (l,l-dioxidomiomoφholino)ethyl)amino)-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)-l-(2-((3-(trifluoromethyl)pyridin -2-yl)oxy)ethyl)cyclohex-3- ene-l-carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- (1,1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-chloro-3-(trifluoromethyl)pyridine (0.029 g, 0.161 mmol) was used instead of 2-chloroisonicotinic acid, and there was also less potassium tert-butoxide, 1.0M in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a white solid (0.0020 g, 4.9 % yield) TFA salt. LCMS m/z = 884.6 (M+H + ), retention time 1.810 min (LCMS Method 20).

Example A31. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)- 1 -(2-(pyrazin-2-yloxy)ethyl)cyclohex-3-ene- 1 -carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-chloropyrazine (0.018 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was isolated as a white solid (0.0102 g, 28.2 % yield) TFA salt. LCMS m/z = 817.6 (M+H + ), retention time 1.592 min (LCMS Method 20). Ή NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D,

CD30D lock) δ 8.16 - 8.08 (m, 2H), 8.05 (d, J=2.4 Hz, 1H), 5.33 (br. s., 1H), 5.18 (d, J=5.4 Hz, 1H), 4.79 (s, 1H), 4.71 (br. s., 1H), 4.44 (t, J=6.2 Hz, 2H), 3.27 - 3.13 (m, 7H), 3.13 - 3.05 (m, 3H), 3.05 - 2.95 (m, 2H), 2.86 - 2.74 (m, 1H), 2.60 (d, J=17.4 Hz, 1H), 2.25 - 1.96 (m, 10H), 1.89 - 1.81 (m, 1H), 1.81 - 1.74 (m, 2H), 1.73 (s, 4H), 1.65 - 1.42 (m, 10H), 1.40 (br. s., 1H), 1.38 - 1.24 (m, 3H), 1.15 (s, 3H), 1.11 (br. s., 2H), 1.08 (s, 3H), 1.01 - 0.86 (m, 9H).

Example A32. Preparation of 4-((lR,3aS,5aR,5bR,7aR,l laS, l lbR,13aR,13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)-l-(2-((4-methoxypyridin-2-yl)oxy) ethyl)cyclohi

carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-bromo-4-methoxypyridine (0.030 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was one of two compounds isolated from this reaction. The material was obtained as a white solid (0.0068 g, 18.3 % yield) TFA salt. LCMS m/z = 846.7 (M+H + ), retention time 1.335 min (LCMS Method 20). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 7.97 (d, J=6.6 Hz, IH), 6.76 (dd, J=6.6, 2.2 Hz, IH), 6.59 (d, J=2.0 Hz, IH), 5.34 (br. s., IH), 5.18 (d, J=4.6 Hz, IH), 4.79 (s, IH), 4.71 (s, IH), 4.42 (t, J=6.7 Hz, 2H), 3.98 (s, 3H), 3.27 - 3.04 (m, 10H), 3.01 (d, J=3.4 Hz, 2H), 2.86 - 2.76 (m, IH), 2.67 - 2.57 (m, IH), 2.27 - 2.15 (m, 3H), 2.15 - 1.96 (m, 8H), 1.85 (td, J=12.2, 3.3 Hz, IH), 1.81 - 1.73 (m, 2H), 1.72 (s, 4H), 1.66 - 1.38 (m, 10H), 1.38 - 1.28 (m, 2H), 1.15 (s, 3H), 1.12 (br. s., 2H), 1.07 (s, 3H), 1.01 - 0.85 (m, 9H).

Example A33. Preparation of l-(2-((4-bromopyridin-2-yl)oxy)ethyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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]chrys -9-yl)cyclohex-3-ene-l-carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- ( 1 , 1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8, 8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2-bromo-4-methoxypyridine (0.030 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was one of two compounds isolated from this reaction. The material was obtained as a white solid (0.0045 g, 12.2 % yield) TFA salt. LCMS m/z = 894.5 (M+H + ), retention time 1.672 min (LCMS Method 20). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) 5 8.09 (d, J=5.9 Hz, IH), 7.06 (d, J=2.2 Hz, IH), 6.86 (dd, J=5.9, 2.2 Hz, IH), 5.33 (br. s., IH), 5.21 - 5.15 (m, IH), 4.80 (s, IH), 4.72 (s, IH), 4.16 (t, J=6.6 Hz, 2H), 3.27 - 2.98 (m, 12H), 2.84 - 2.74 (m, IH), 2.60 (dd, J=18.7, 2.8 Hz, IH), 2.24 - 1.96 (m, 11H), 1.87 - 1.74 (m, 3H), 1.73 (s, 4H), 1.68 - 1.55 (m, 4H), 1.55 - 1.38 (m, 7H), 1.38 - 1.25 (m, 2H), 1.15 (s, 3H), 1.14 - 1.10 (m, IH), 1.08 (s, 3H), 1.01 - 0.96 (m, 3H), 0.96 - 0.91 (m, 3H), 0.90 (s, 3H). Example A34. Preparation of l-(2-((4-chloropyridin-2-yl)oxy)ethyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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]chrys -9-yl)cyclohex-3-ene-l-carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- (1,1 -dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 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-octadecahydro-lH- cyclopenta[a]chrysen-9-yl)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2,4-dichloropyridine (0.024 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was one of two compounds isolated from this reaction. The material was obtained as a slightly yellow solid (0.0143 g, 38.7 % yield) TFA salt. LCMS m/z = 850.6 (M+H + ), retention time 1.637 min (LCMS Method 20). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 8.11 (d, J=5.9 Hz, IH), 6.91 (d, J=2.2 Hz, IH), 6.83 (dd, J=5.9, 2.2 Hz, IH), 5.33 (br. s., IH), 5.18 (d, J=4.6 Hz, IH), 4.79 (s, IH), 4.71 (s, IH), 4.17 (t, J=6.6 Hz, 2H), 3.27 - 2.98 (m, 12H), 2.80 (td, J=11.2, 4.8 Hz, IH), 2.60 (d, J=16.6 Hz, IH), 2.26 - 1.97 (m, 11H), 1.89 - 1.74 (m, 3H), 1.72 (s, 4H), 1.67 - 1.38 (m, 11H), 1.38 - 1.27 (m, 2H), 1.15 (s, 3H), 1.10 (d, J=11.0 Hz, IH), 1.07 (s, 3H), 0.99 - 0.86 (m, 9H). Example A35. Preparation of l-(2-((2-chloropyridin-4-yl)oxy)ethyl)-4- ((lR,3aS,5aR,5bR,7aR, l laS, l lbR,13aR,13bR)-3a-((2-(l,l- dioxidothiomoφholino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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]chrys -9-yl)cyclohex-3-ene-l-carboxylic acid.

The title compound was prepared following the procedure described for the preparation of 2-(2-( 1 -carboxy-4-(( lR,3aS,5aR,5bR,7aR, 1 laS, 1 IbR, 13aR, 13bR)-3a-((2- (1,1 -dioxidothiomo holino)ethyl)amino)-5a,5b,8,8, 1 la-pentamethyl- 1 -(prop- 1 -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)cyclohex-3-en-l-yl)ethoxy)isonicot inic acid, except in the present case 2,4-dichloropyridine (0.024 g, 0.161 mmol) was used instead of 2- chloroisonicotinic acid, and there was also less potassium tert-butoxide, l .OM in THF used in the present case (0.129 mL, 0.129 mmol). The title compound was one of two compounds isolated from this reaction. The material was obtained as a slightly yellow solid (0.0168 g, 41.2 % yield) TFA salt. LCMS m/z = 850.6 (M+H + ), retention time 1.809 min (LCMS Method 20). ¾ NMR (400MHz, 1 : 1 mixture of CDC13 and CD30D, CD30D lock) δ 8.00 (d, J=5.6 Hz, IH), 6.90 (dd, J=5.6, 1.7 Hz, IH), 6.76 (d, J=1.7 Hz, IH), 5.32 (br. s., IH), 5.17 (d, J=4.9 Hz, IH), 4.79 (s, IH), 4.71 (s, IH), 4.41 - 4.33 (m, 2H), 3.28 - 2.98 (m, 12H), 2.80 (td, J=11.0, 4.6 Hz, IH), 2.58 (d, J=15.4 Hz, IH), 2.26 - 1.96 (m, 11H), 1.89 - 1.73 (m, 2H), 1.72 (s, 4H), 1.67 - 1.38 (m, 11H), 1.38 - 1.26 (m, 2H), 1.18 - 1.04 (m, 8H), 1.01 - 0.86 (m, 9H). HIV CELL CULTURE ASSAY

Cells. MT-2 cells and 293T cells were obtained from the NIH AIDS Research and Reference Reagent Program. Cell lines were sub-cultured twice a week in either RPMI 1640 (MT-2) or DMEM (293T, HeLa) media supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 units/mL of penicillin G and 100 μg/mL of streptomycin. The DMEM medium was additionally supplemented with 10 mM HEPES buffer, pH 7.55, 2 mM L-glutamine and 0.25 μg/mL of amphotericin B.

Viruses. NLRepRluc virus contains the Renilla luciferase marker in place of the viral nef gene. The proviral plasmid pNLRepRluc was constructed at Bristol-Myers Squibb, starting from a proviral NL4-3 clone (B subtype) that was obtained from the NIH AIDS

Research and Reference Reagent Program. The parental recombinant wild type (WT) virus (NLRepRlucP373S) was derived from NLRepRluc and contains the additional substitution of P373 for serine in Gag (within the SP1 spacer), the most common 373 variation in subtype B. Other recombinant viruses (A364V, V370A/AT371 and the "T332S triple" (T332S/V362I + HIV-1 protease R41G)) were generated by site-directed mutagenesis of plasmid pNLRepRlucP373S to introduce those amino acid substitutions in Gag and protease. Recombinant virus DNA was then used to generate virus stocks by transfection of 293T cells (Lipofectamine PLUS kit, Invitrogen). Titers of virus stocks were determined using a luciferase assay (Dual-Luciferase® Reporter Assay System, Promega, Milwaukee, WI, USA) endpoint.

Multiple cycle drug susceptibility assay. Pellets of MT-2 cells were infected with

NLRepRlucP373S Gag site-directed viruses, where initial inocula of the reporter strains were normalized using equivalent endpoint luciferase activity signals. Such cell-virus mixtures were resuspended in medium, incubated for 1-hour at 37°C/C0 2 , and added to compound containing 96-well plates at a final cell density of 10,000 cells per well. The test compounds were 3-fold serially diluted in 100% DMSO, and assayed at a final DMSO concentration of 1%. After 4 - 5 day incubation at 37°C/C0 2 , virus yields were determined by Renilla luciferase activity (Dual-Luciferase® Reporter Assay System, Promega). The endpoint luminescence was detected on a Wallac Trilux (PerkinElmer).

The 50% inhibitory concentrations (ECsos) were calculated by using the exponential form of the median effect equation where Percent Inhibition = 1/[1+ (EC 5 o/drug conc.) m ], where m is a parameter that reflects the slope of the concentration-response curve. Background was taken as the residual signal observed upon inhibition at the highest concentration of a control protease inhibitor, NFV (3 μΜ).

The 90% inhibitory concentrations (ECs>os) were calculated by using the exponential form of the median effect equation where ECF = [(F/(100-F)] 1 H -EC5o, where H is a parameter that reflects the slope of the concentration-response curve. Background was taken as the residual signal observed upon inhibition at the highest concentration of a control protease inhibitor, NFV (3 μΜ).

HIV cell culture assay

HIV-1 NL4-3 expressing Renilla luciferase gene was converted to the gag V370A/AT371 virus by site directed mutagenesis. A364V is a site directed mutant.

T332s/V362I/Pr R41G (N14.3, B Clade) virus' was obtained as follows: Selection for

HIV maturation inhibitor (MI) compound

started at the EC50 for this virus (2 nM), with a two-fold increase in the maturation inhibitor compound concentration applied at each passage. At passage 8 virus was harvested and sequenced. The selected virus population contained Gag amino acid substitutions T332S and V362I and the R41G substitution in protease. These substitutions were subsequently introduced into

NLRepRlucP373, a derivative of HIV-1 clone NL4-3 modified to contain P373S, the most common polymorphic substitution in subtype B at position 373, and the Renilla luciferase gene inserted into the «e locus.

The emergence of selected substitutions in the wt genotypic background is discussed herein:

Starting from wt virus, the HIV protease R41G substitution was detected in one of three in vitro selections for resistance to the MI compound above along with Gag V362I and Gag T332S. R41G is not a primary PI resistance substitution 1 and is not present in the LANL database (2010). There is a single report of R41G associated with in vitro selection for resistance to an investigational PI". However, in that case, R41G did not itself convey PI resistance. A related change, R41K, is a common subtype B polymorph (27% of LANL database), and R41K may be involved in the emergence of protease resistance to an investigational protease inhibitor. 111 R41 is located in a loop proximal to the HIV-1 protease substrate binding site, and this change might act allosterically to facilitate closing the protease active site pocket over the substrate, thereby allowing catalysis. It might be that R41G alters the dynamics of the loop motion and the final positioning of the loop, which could cause the active site to better recognize the primary MI compound (above)- selected changes (V362I/T332S). An analysis of the V362I/T332S/Pr R41G substitutions, and their effects on MI compound susceptibility and viral growth, are described in the Table 1 below:

Table 1 : Anti- Viral Sensitivity of Site Directed Mutants Group Genotype Virus titer, TCID 50 (xl0 5 /mL) Fold wt

CPE luc RT MI BVM

Compound (Bevirimat)

Key substitutions

Crosswise effects of T332S and Pr R41G on V362I

6 V362I 2.6 1.6 2.6 2.2 0.6

T332S 2.6 6.6 0.4 1.9 23

HIV protease R41G 2.6 2.6 1.0 1.5 1.9

T332S/V362I/ 4.1 6.6 4.1 5.7 3.1

T332S/prR41G 0.6 1.0 0.4 6.1 4.2

V362I/prR41G 0.6 1.6 0.6 9.3 3.9

T332S/V362I Pr41G 0.3 1.6 0.1 217 10 Viruses were constructed that contain T332S and HIV protease R41G combinations, with and without V362I.). Viruses with only a single change are only ~2-fold less sensitive to the MI compound, while double combinations of these 3 substitutions are 5.7- to 9.3-fold less sensitive. The virus with the triple change is much less sensitive to the MI compound, suggesting that the R41G change in protease may 'crosstalk' with Gag changes to further reduce sensitivity to the MI compound, an unexpected finding. Thus, the T332S/V362I Site directed mutant (SDM) virus exhibits a fold change of only 5.7, but addition of the R41G protease change substantially increases the FC to 217. 1 Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, Schapiro JM,

Richman DD. Update of the drug resistance mutations in HIV-1: December 2009. Top HIV

Med. 2009 Dec; 17(5): 138-45.

" Dierynck, I, Van Markck, H, Van Ginderen, M, Jonckers, TH, Nalam, MN, Schiffer, CA,

Raoof, A, Kraus, G, Picchio, G. TMC310911, a novel human immunodeficiency virus type 1

protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to

resistance compared

Ui Stray KM, Callebaut C, Glass B, Tsai L, Xu L, Miiller B, Krausslich HG, Cihlar T. Mutations in multiple domains of Gag drive the emergence of in vitro resistance to the phosphonate-containing HIV-1 protease inhibitor GS-8374. J Virol. 2013 87:454-63

All three recombinant viruses were used as described above in the HIV cell culture assay for the NL4-3 virus. The EC50 WT, EC50 V370A/AT371, EC50 A364V and EC50

T332s/V362I/Pr R41G data for the compounds is shown in Table 2.

Biological Data Key for EC50S

Table 2.

-295-

-296-

-302-

-303-

In Table 3 below, two compounds corresponding to two embodiments of the invention (Examples 25 and A3) were tested and compared with two other (comparative) compounds outside the scope thereof. Each compound was assessed for EC50 (WT) or EC90 values (see identified strains below, including the T332S/V362I/pr R41G triple mutant):

Table 3

As can be deduced from Table 3, the two identified compounds according to the invention had better EC90 values versus the comparative compounds, when tested against the specified mutant strains identified above.

The foregoing description is merely illustrative and should not be understood to limit the scope or underlying principles of the invention in any way. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the following examples and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.