C-3 and C-17 modified triterpenoids used as HIV-1 inhibitors

Abstract

The present invention relates to compounds having therapeutic and bioactive properties, their pharmaceutical compositions, and methods of use. In particular, the invention relates to derivatives of betulinic acid having unique antiviral activity, which are used as HIV maturation inhibitors, such as compounds of formula i: these compounds have proven useful in the treatment of HIV and AIDS.

Description

FIELD OF THE INVENTION

[0001] 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

[0002] 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®).

[0003] 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, non-compliance, 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.

[0004] HIV attachment inhibitors are a further subclass of antiviral compounds that bind to the HIV surface glycoprotein gp120, and interfere with the interaction between the surface protein gp120 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.

[0005] 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.

[0006] 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).

[0007] 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 WO2011 / 007230, WO2014 / 123889 and WO2015 / 157483

[0008] One HIV maturation compound that has been in development has been identified as Bevirimat or PA-457, with the chemical formula of C 36 H 56 O 6 and the IUPAC name of 3β-(3-carboxy-3-methyl-butanoyloxy) lup-20(29)-en-28-oic acid.

[0009] 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.

[0010] 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

[0011] 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.

[0012] One embodiment of the present invention is directed to a compound of Formula I, including pharmaceutically acceptable salts thereof: wherein R 1 is isopropenyl or isopropyl; A is -C 1-6 alkyl-ORo; wherein R 0 is heteroaryl-Q 0 ; Q 0 is selected from the group of -H, -CN, -C 1-6 alkyl, -COOH, -Ph, -OC 1-6 alkyl, -halo, -CF 3 , Y is selected from the group of -COOR 2 , -C(O)NR 2 SO 2 R 3 , -C(O)NHSO 2 NR 2 R 2 , -SO 2 NR 2 C(O)R 2 , -tetrazole, and -CONHOH; R 2 is -H, -C 1-6 alkyl, -alkylsubstituted C 1-6 alkyl or-arylsubstituted C 1-6 alkyl; W is absent, or is -CH 2 - or -CO-; R 3 is -H, -C 1-6 alkyl or -alkylsubstituted C 1-6 alkyl; R 4 is selected from the group of -H, -C 1-6 alkyl, -C 1-6 alkyl-C 3-6 cycloalkyl, -C 1-6 substituted -C 1-6 alkyl, -C 1-6 alkyl-Qi, -C 1-6 alkyl-C 3-6 cycloalkyl-Q 1 , aryl, heteroaryl, substituted heteroaryl, -COR 6 , -SO 2 R 7 , -SO 2 NR 2 R 2 , and wherein G is selected from the group of -O-, -SO 2 - and -NR 12 -; wherein Q 1 is selected from the group of -C 1-6 alkyl, - C 1-6 fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF 3 , -OR 2 , -COOR 2 , -NR 8 R 9 , -CONR 8 R 9 and -SO 2 R 7 ; R 5 is selected from the group of -H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkylsubstituted alkyl, -C 1-6 alkyl-NR 8 R 9 , -COR 3 , -SO 2 R 7 and -SO 2 NR 2 R 2 ; with the proviso that R 4 or R 5 is not -COR 6 when W is -CO-; with the further proviso that only one of R 4 or R 5 is selected from the group of -COR 6 , -COCOR 6 , -SO 2 R 7 and -SO 2 NR 2 R 2 ; R 6 is selected from the group of -H, -C 1-6 alkyl, -C 1-6 alkyl-substituted alkyl, -C 3-6 cycloalkyl, -C 3-6 substitutedcycloalkyl-Q 2 , -C 1-6 alkyl-Q 2 , -C 1-6 alkyl-substitutedalkyl-Q 2 , -C 3-6 cycloalkyl-Q 2 , aryl-Q 2 , -NR 13 R 14 , and -OR 15 ; wherein Q 2 is selected from the group of aryl, heteroaryl, substituted heteroaryl, -OR 2 , -COOR 2 , -NR 8 R 9 , SO 2 R 7 , -CONHSO 2 R 3 , and -CONHSO 2 NR 2 R 2 ; R 7 is selected from the group of -H, -C 1-6 alkyl, -C 1-6 substituted alkyl, -C 3-6 cycloalkyl, -CF 3 , aryl, and heteroaryl; R 8 and R 9 are independently selected from the group of -H, -C 1-6 alkyl, -C 1-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -C 1-6 alkyl-Q 2 , and -COOR 3 , or R 8 and R 9 are taken together with the adjacent N to form a cycle selected from the group of: M is selected from the group of -R 15 , -SO 2 R 2 , -SO 2 NR 2 R 2 , -OH and -NR 2 R 12 ; V is selected from the group of -CR 10 R 11 -, -SO 2 -, -O- and -NR 12 -; with the proviso that only one of R 8 or R 9 can be -COOR 3 ; Rio and R 11 are independently selected from the group of -H, -C 1-6 alkyl, -C 1-6 substituted alkyl and -C 3-6 cycloalkyl; R 12 is selected from the group of -H, -C 1-6 alkyl, -alkylsubstituted C 1-6 alkyl,-CONR 2 R 2 , -SO 2 R 3 , and -SO 2 NR 2 R 2 ; R 13 and R 14 are independently selected from the group of -H, -C 1-6 alkyl, -C 3-6 cycloalkyl,-C 1-6 substituted alkyl, -C 1-6 alkyl-Q 3 , -C 1-6 alkyl-C 3-6 cycloalkyl-Q 3 , and C 1-6 substituted alkyl-Q 3 ; Q 3 is selected from the group of heteroaryl, substituted heteroaryl, -NR 2 R 12 , -CONR 2 R 2 , -COOR 2 , -OR 2 , and -SO 2 R 3 ; R 15 is selected from the group of -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 substituted alkyl, -C 1-6 alkyl-Q 3 , -C 1-6 alkyl-C 3-6 cycloalkyl-Q 3 and -C 1-6 substituted alkyl-Q 3 ; R 16 is selected from the group of -H, -C 1-6 alkyl, -NR 2 R 2 , and -COOR 2 ; with the proviso that when V is -NR 12 -; R 16 is not -NR 2 R 2 ; and R 17 is selected from the group of -H, -C 1-6 alkyl, -COOR 3 , and aryl.

[0013] 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.

[0014] 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.

[0015] In another embodiment of the invention there is provided one or more methods for making the compounds of Formula I herein.

[0016] Also described herein are intermediate compounds useful in making the compounds of Formula I herein.

[0017] The present invention is directed to these, as well as other important ends, hereinafter described.DETAILED DESCRIPTION OF THE EMBODIMENTS

[0018] As used herein, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.

[0019] 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

[0020] 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.

[0021] The term "C 1-6 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.

[0022] "C 1 -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;

[0023] "Halogen" or "halo" refers to chlorine, bromine, iodine or fluorine.

[0024] 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.

[0025] 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.

[0026] 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-1-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.

[0027] 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.

[0028] 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, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, amidino, guanidino, ureido, phosphonyl, amino and -NR x< R y< with R x< and R y< as defined above.

[0029] 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.

[0030] 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.

[0031] A "hydroxy" group refers to an -OH group.

[0032] An "alkoxy" group refers to both an -O-alkyl and an -O-cycloalkyl group as defined herein.

[0033] An "aryloxy" group refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.

[0034] A "heteroaryloxy" group refers to a heteroaryl-O- group with heteroaryl as defined herein.

[0035] A "heteroalicycloxy" group refers to a heteroalicyclic-O- group with heteroalicyclic as defined herein.

[0036] A "thiohydroxy" group refers to an -SH group.

[0037] A "thioalkoxy" group refers to both an S-alkyl and an -S-cycloalkyl group, as defined herein.

[0038] A "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl group, as defined herein.

[0039] A "thioheteroaryloxy" group refers to a heteroaryl-S- group with heteroaryl as defined herein.

[0040] A "thioheteroalicycloxy" group refers to a heteroalicyclic-S- group with heteroalicyclic as defined herein.

[0041] A "carbonyl" group refers to a -C(=O)-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.

[0042] An "aldehyde" group refers to a carbonyl group where R" is hydrogen.

[0043] A "thiocarbonyl" group refers to a -C(=S)-R" group, with R" as defined herein.

[0044] A "keto" group refers to a -CC(=O)C- group wherein the carbon on either or both sides of the C=O may be alkyl, cycloalkyl, aryl or a carbon of a heteroaryl or heteroalicyclic group.

[0045] A "trihalomethanecarbonyl" group refers to a Z 3 CC(=O)- group with said Z being a halogen.

[0046] A "C-carboxy" group refers to a -C(=O)O-R" groups, with R" as defined herein.

[0047] An "O-carboxy" group refers to a R"C(-O)O-group, with R" as defined herein.

[0048] A "carboxylic acid" group refers to a C-carboxy group in which R" is hydrogen.

[0049] A "trihalomethyl" group refers to a -CZ 3 , group wherein Z is a halogen group as defined herein.

[0050] A "trihalomethanesulfonyl" group refers to a Z 3 CS(=O) 2 - groups with Z as defined above.

[0051] A "trihalomethanesulfonamido" group refers to a Z 3 CS(=O) 2 NR x< - group with Z as defined above and R x< being H or (C 1-6 )alkyl.

[0052] A "sulfinyl" group refers to a -S(=O)-R" group, with R" being (C 1-6 )alkyl.

[0053] A "sulfonyl" group refers to a -S(=O) 2 R" group with R" being (C 1-6 )alkyl.

[0054] A "S-sulfonamido" group refers to a -S(=O) 2 NR X< R Y< , with R X< and R Y< independently being H or (C 1-6 )alkyl.

[0055] A "N-sulfonamido" group refers to a R"S(=O) 2 NR X - group, with R x being H or (C 1-6 )alkyl.

[0056] A "O-carbamyl" group refers to a -OC(=O)NR x< R y< group, with R X< and R Y< independently being H or (C 1-6 )alkyl.

[0057] A "N-carbamyl" group refers to a R x< OC(=O)NR y< group, with R x< and R y< independently being H or (C 1-6 )alkyl.

[0058] A "O-thiocarbamyl" group refers to a -OC(=S)NR x< R y< group, with R x< and R y< independently being H or (C 1-6 )alkyl.

[0059] A "N-thiocarbamyl" group refers to a R x< OC(=S)NR y< - group, with R x< and R y< independently being H or (C 1-6 )alkyl.

[0060] An "amino" group refers to an -NH 2 group.

[0061] A "C-amido" group refers to a -C(=O)NR x< R y< group, with R x< and R y< independently being H or (C 1-6 )alkyl.

[0062] A "C-thioamido" group refers to a -C(=S)NR x< R y< group, with R x< and R y< independently being H or (C 1-6 )alkyl.

[0063] A "N-amido" group refers to a R x< C(=O)NR y< - group, with R x< and R y< independently being H or (C 1-6 )alkyl.

[0064] An "ureido" group refers to a -NR x< C(=O)NR y< R y2< group, with R x< , R y< , and R y2< independently being H or (C 1-6 )alkyl.

[0065] 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 (C 1-6 )alkyl.

[0066] A "amidino" group refers to a R x< R y< NC(=N)- group, with R x< and R y< independently being H or (C 1-6 )alkyl.

[0067] A "cyano" group refers to a -CN group.

[0068] A "silyl" group refers to a -Si(R") 3 , with R" being (C 1-6 )alkyl or phenyl.

[0069] A "phosphonyl" group refers to a P(=O)(OR x< ) 2 with R x< being (C 1-6 )alkyl.

[0070] 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 (C 1-6 )alkyl.

[0071] A "4, 5, or 6 membered ring cyclic N-lactam" group refers to

[0072] 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").

[0073] 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.

[0074] 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.

[0075] 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.

[0076] Pharmaceutically acceptable salts 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 morpholine.

[0077] As set forth above, the invention is directed to a compound, including pharmaceutically acceptable salts thereof, which is selected from a compound of Formula I: wherein R 1 is isopropenyl or isopropyl; A is -C 1-6 alkyl-OR 0 ; wherein R 0 is heteroaryl-Q 0 ; Q 0 is selected from the group of -H, -CN, -C 1-6 alkyl, -COOH, -Ph, -OC 1-6 alkyl, -halo,-CF 3 , Y is selected from the group of -COOR 2 , -C(O)NR 2 SO 2 R 3 , -C(O)NHSO 2 NR 2 R 2 ,-SO 2 NR 2 C(O)R 2 , -tetrazole, and -CONHOH; R 2 is -H, -C 1-6 alkyl, -alkylsubstituted C 1-6 alkyl or-arylsubstituted C 1-6 alkyl; W is absent, or is -CH 2 - or -CO-; R 3 is -H, -C 1-6 alkyl or -alkylsubstituted C 1-6 alkyl; R 4 is selected from the group of -H, -C 1-6 alkyl, -C 1-6 alkyl-C 3-6 cycloalkyl, -C 1-6 substituted -C 1-6 alkyl, -C 1-6 alkyl-Q 1 , -C 1-6 alkyl-C 3-6 cycloalkyl-Q 1 , aryl, heteroaryl, substituted heteroaryl, -COR 6 , -SO 2 R 7 , -SO 2 NR 2 R 2 , and wherein G is selected from the group of -O-, -SO 2 - and -NR 12 -; wherein Q 1 is selected from the group of -C 1-6 alkyl, - C 1-6 fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF 3 , -OR 2 , -COOR 2 , -NR 8 R 9 , -CONR 8 R 9 and -SO 2 R 7 ; R 5 is selected from the group of -H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkylsubstituted alkyl, -C 1-6 alkyl-NR 8 R 9 , -COR 3 , -SO 2 R 7 and -SO 2 NR 2 R 2 ; with the proviso that R 4 or R 5 is not -COR 6 when W is -CO-; with the further proviso that only one of R 4 or R 5 is selected from the group of -COR 6 , -COCOR 6 , -SO 2 R 7 and -SO 2 NR 2 R 2 ; R 6 is selected from the group of -H, -C 1-6 alkyl, -C 1-6 alkyl-substitutedalkyl, -C 3-6 cycloalkyl, -C 3-6 substitutedcycloalkyl-Q 2 , -C 1-6 alkyl-Q 2 , -C 1-6 alkyl-substitutedalkyl-Q 2 , -C 3 - 6 cycloalkyl-Q 2 , aryl-Q 2 , -NR 13 R 14 , and -OR 15 ; wherein Q 2 is selected from the group of aryl, heteroaryl, substituted heteroaryl,-OR 2 , -COOR 2 , -NR 8 R 9 , SO 2 R 7 , -CONHSO 2 R 3 , and -CONHSO 2 NR 2 R 2 ; R 7 is selected from the group of -H, -C 1-6 alkyl, -C 1-6 substituted alkyl, -C 3-6 cycloalkyl, -CF 3 , aryl, and heteroaryl; R 8 and R 9 are independently selected from the group of -H, -C 1-6 alkyl, -C 1-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -C 1-6 alkyl-Q 2 , and -COOR 3 , or R 8 and R 9 are taken together with the adjacent N to form a cycle selected from the group of: M is selected from the group of -R 15 , -SO 2 R 2 , -SO 2 NR 2 R 2 , -OH and -NR 2 R 12 ; V is selected from the group of -CR 10 R 10 -, -SO 2 -, -O- and -NR 12 -; with the proviso that only one of R 8 or R 9 can be -COOR 3 ; R 10 and R 11 are independently selected from the group of -H, -C 1-6 alkyl, -C 1-6 substituted alkyl and -C 3-6 cycloalkyl; R 12 is selected from the group of -H, -C 1-6 alkyl, -alkylsubstituted C 1-6 alkyl, -CONR 2 R 2 , -SO 2 R 3 , and -SO 2 NR 2 R 2 ; R 13 and R 14 are independently selected from the group of -H, -C 1-6 alkyl, -C 3-6 cycloalkyl,-C 1-6 substituted alkyl, -C 1-6 alkyl-Q 3 , -C 1-6 alkyl-C 3-6 cycloalkyl-Q 3 , and C 1-6 substituted alkyl-Q 3 ; Q 3 is selected from the group of heteroaryl, substituted heteroaryl, -NR 2 R 12 , -CONR 2 R 2 , -COOR 2 , -OR 2 , and -SO 2 R 3 ; R 15 is selected from the group of -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 substituted alkyl, -C 1-6 alkyl-Q 3 , -C 1-6 alkyl-C 3-6 cycloalkyl-Q 3 and -C 1-6 substituted alkyl-Q 3 ; R 16 is selected from the group of -H, -C 1-6 alkyl, -NR 2 R 2 , and -COOR 2 ; with the proviso that when V is -NR 12 -; R 16 is not -NR 2 R 2 ; and R 17 is selected from the group of -H, -C 1-6 alkyl, -COOR 3 , and aryl.

[0078] In a preferred embodiment of the invention, R 1 is isopropenyl.

[0079] It is also preferred that Y is -COOR 2 . More preferably, R 2 in this embodiment is-H.

[0080] In another preferred embodiment of the invention, in the R 0 group the "heteroaryl" moiety is preferably selected from the group of:

[0081] It is also preferred that there is no intervening alkyl group or other substituent group between the -O moiety and the R 0 group in substituent A.

[0082] It is further preferred that R 4 is -C 1-6 alkyl-Q 1 .

[0083] Also preferred is the embodiment wherein Q 1 is -NR 8 R 9 .

[0084] Additionally, when R 8 and R 9 are taken together with the adjacent -N to form a cycle, the preferred cycle will be selected from the group of:

[0085] In some embodiments it is also preferred that Q 0 is -CN.

[0086] In another preferred embodiment, R 1 is isopropenyl, in the R 0 group the "heteroaryl" moiety is selected from the group of: Y is -COOH, R 4 is -C 1-6 alkyl-Q 1 , Q 1 is -NR 8 R 9 , and R 8 and R 9 are taken together with the adjacent -N to form a cycle which is selected from the group of:

[0087] In this embodiment, it is also preferred that R 7 and R 16 are each -H or -C 1-6 alkyl.

[0088] Preferred compounds, including pharmaceutically acceptable salts thereof, as part of the invention include the following:

[0089] In another embodiment, preferred compounds, including pharmaceutically acceptable salts thereof, will be the following:

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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

[0098] Drug NameManufacturerIndication097Hoechst / BayerHIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor)Amprenavir 141 W94 GW 141Glaxo WellcomeHIV infection, AIDS, ARC (protease inhibitor)Abacavir (1592U89) GW 1592Glaxo WellcomeHIV infection, AIDS, ARC (RT inhibitor)AcemannanCarrington Labs (Irving, TX)ARCAcyclovirBurroughs WellcomeHIV infection, AIDS, ARCAD-439Tanox BiosystemsHIV infection, AIDS, ARCAD-519Tanox BiosystemsHIV infection, AIDS, ARCAdefovir dipivoxil AL-721Gilead Sciences EthigenHIV infection ARC, PGL(Los Angeles, CA)HIV positive, AIDSAlpha InterferonGlaxo WellcomeKaposi's sarcoma, HIV in combination w / RetrovirAnsamycin LM 427Adria Laboratories (Dublin, OH) Erbamont (Stamford, CT)ARCAntibody which Neutralizes pH Labile alpha aberrant InterferonAdvanced Biotherapy Concepts (Rockville, MD)AIDS, ARCAR177Aronex PharmHIV infection, AIDS, ARCBeta-fluoro-ddANat'l Cancer InstituteAIDS-associated diseasesBMS-234475 (CGP-61755)Bristol-Myers Squibb / NovartisHIV infection, AIDS, ARC (protease inhibitor)CI-1012Warner-LambertHIV-1 infectionCidofovirGilead ScienceCMV retinitis, herpes, papillomavirusCurdlan sulfateAJI Pharma USAHIV infectionCytomegalovirusMedImmuneCMV retinitisImmune globinCytoveneSyntexSight threateningGanciclovirCMV peripheral CMV retinitisDarunavirTibotec- J & JHIV infection, AIDS, ARC (protease inhibitor)DelaviridinePharmacia-Upj ohnHIV infection, AIDS, ARC (RT inhibitor)Dextran SulfateUeno Fine Chem. Ind. Ltd. (Osaka, Japan)AIDS, ARC, HIV positive asymptomaticddC DideoxycytidineHoffman-La RocheHIV infection, AIDS, ARCddI DideoxyinosineBristol-Myers SquibbHIV infection, AIDS, ARC; combination with AZT / d4TDMP-450AVID (Camden, NJ)HIV infection, AIDS, ARC (protease inhibitor)Efavirenz (DMP 266, SUSTIVA®) (-)6-Chloro-4-(S)-cyclopropylethynyl-4(S)-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, STOCRINEBristol Myers SquibbHIV infection, AIDS, ARC (non-nucleoside RT inhibitor)EL10Elan Corp, PLC (Gainesville, GA)HIV infectionEtravirineTibotec / J & JHIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)FamciclovirSmith Klineherpes zoster, herpes simplexGS 840GileadHIV infection, AIDS, ARC (reverse transcriptase inhibitor)HBY097Hoechst Marion RousselHIV infection, AIDS, ARC (non-nucleoside reverse transcriptase inhibitor)HypericinVIMRx Pharm.HIV infection, AIDS, ARCRecombinant Human Interferon BetaTriton Biosciences (Almeda, CA)AIDS, Kaposi's sarcoma, ARCInterferon alfa-n3Interferon SciencesARC, AIDSIndinavirMerckHIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT / ddI / ddCISIS 2922ISIS PharmaceuticalsCMV retinitisKNI-272Nat'l Cancer InstituteHIV-assoc. diseasesLamivudine, 3TCGlaxo WellcomeHIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZTLobucavirBristol-Myers SquibbCMV infectionNelfinavirAgouron PharmaceuticalsHIV infection, AIDS, ARC (protease inhibitor)NevirapineBoeheringer IngleheimHIV infection, AIDS, ARC (RT inhibitor)NovaprenNovaferon Labs, Inc. (Akron, OH)HIV inhibitorPeptide T Octapeptide SequencePeninsula Labs (Belmont, CA)AIDSTrisodium PhosphonoformateAstra Pharm. Products, Inc.CMV retinitis, HIV infection, other CMV infectionsPNU-140690Pharmacia UpjohnHIV infection, AIDS, ARC (protease inhibitor)ProbucolVyrexHIV infection, AIDSRBC-CD4Sheffield Med. Tech (Houston, TX)HIV infection, AIDS, ARCRitonavirAbbottHIV infection, AIDS, ARC (protease inhibitor)SaquinavirHoffmann-LaRocheHIV infection, AIDS, ARC (protease inhibitor)Stavudine; d4T Didehydrodeoxy-ThymidineBristol-Myers SquibbHIV infection, AIDS, ARCTipranavirBoehringer IngelheimHIV infection, AIDS, ARC (protease inhibitor)ValaciclovirGlaxo WellcomeGenital HSV & CMV infectionsVirazole RibavirinViratek / ICN (Costa Mesa, CA)asymptomatic HIV positive, LAS, ARCVX-478VertexHIV infection, AIDS, ARCZalcitabineHoffmann-LaRocheHIV infection, AIDS, ARC, with AZTZidovudine; AZTGlaxo WellcomeHIV infection, AIDS, ARC, Kaposi's sarcoma, in combination with other therapiesTenofovir disoproxil, fumarate salt (VIREAD®)GileadHIV infection, AIDS, (reverse transcriptase inhibitor)EMTRIVA® (Emtricitabine) (FTC)GileadHIV infection, AIDS, (reverse transcriptase inhibitor)COMBIVIR®GSKHIV infection, AIDS, (reverse transcriptase inhibitor)Abacavir succinate (or ZIAGEN®)GSKHIV infection, AIDS, (reverse transcriptase inhibitor)REYATAZ® (or atazanavir)Bristol-Myers SquibbHIV infection AIDs, protease inhibitorFUZEON® (Enfuvirtide or T-20)Roche / TrimerisHIV infection AIDs, viral Fusion inhibitorLEXIVA® (or Fosamprenavir calcium)GSK / VertexHIV infection AIDs, viral protease inhibitorSelzentry Maraviroc; (UK 427857)PfizerHIV infection AIDs, (CCR5 antagonist, in development)Trizivir®GSKHIV infection AIDs, (three drug combination)Sch-417690 (vicriviroc)Schering-PloughHIV infection AIDs, (CCR5 antagonist, in development)TAK-652TakedaHIV infection AIDs, (CCR5 antagonist, in development)GSK 873140 (ONO-4128)GSK / ONOHIV infection AIDs, (CCR5 antagonist, in development)Integrase Inhibitor MK-0518 RaltegravirMerckHIV infection AIDsTRUVADA®GileadCombination of Tenofovir disoproxil fumarate salt (VIREAD®) and EMTRIVA® (Emtricitabine)Integrase Inhibitor GS917 / JTK-303 ElvitegravirGilead / Japan TobaccoHIV Infection AIDs in developmentTriple drug combination ATRIPLA®Gilead / Bristol-Myers SquibbCombination of Tenofovir disoproxil fumarate salt (VIREAD®), EMTRIVA® (Emtricitabine), and SUSTIVA® (Efavirenz)FESTINAVIR® 4'-ethynyl-d4TOncolys BioPharma BMSHIV infection AIDs in developmentCMX-157ChimerixHIV infectionLipid conjugate of nucleotide tenofovirAIDsGSK1349572 Integrase inhibitor dolutegravirGSKHIV infection AIDsS / GSK1265744 Integrase inhibitorGSKHIV infection AIDs IMMUNOMODULATORS

[0099] Drug NameManufacturerIndicationAS-101Wyeth-AyerstAIDSBropiriminePharmacia UpjohnAdvanced AIDSAcemannanCarrington Labs, Inc. (Irving, TX)AIDS, ARCCL246,738Wyeth Lederle LabsAIDS, Kaposi's sarcomaFP-21399Fuki ImmunoPharmBlocks HIV fusion with CD4+ cellsGamma InterferonGenentechARC, in combination w / TNF (tumor necrosis factor)GranulocyteGenetics InstituteAIDSMacrophage Colony Stimulating FactorSandozGranulocyte Macrophage Colony Stimulating FactorHoechst-Roussel ImmunexAIDSGranulocyte Macrophage Colony Stimulating FactorSchering-PloughAIDS, combination w / AZTHIV Core Particle ImmunostimulantRorerSeropositive HIVIL-2 Interleukin-2 IL-2 Interleukin-2Cetus Hoffman-LaRoche ImmunexAIDS, in combination w / AZT AIDS, ARC, HIV, in combination w / AZTIL-2 Interleukin-2 (aldeslukin)ChironAIDS, increase in CD4 cell countsImmune Globulin Intravenous (human)Cutter Biological (Berkeley, CA)Pediatric AIDS, in combination w / AZTIMREG-1Imreg (New Orleans, LA)AIDS, Kaposi's sarcoma, ARC, PGLIMREG-2Imreg (New Orleans, LA)AIDS, Kaposi's sarcoma, ARC, PGLImuthiol DiethylMerieux InstituteAIDS, ARCDithio Carbamate Alpha-2 InterferonSchering PloughKaposi's sarcoma w / AZT, AIDSMethionine-EnkephalinTNI Pharmaceutical (Chicago, IL)AIDS, ARCMTP-PE Muramyl- TripeptideCiba-Geigy Corp.Kaposi's sarcomaGranulocyte Colony Stimulating FactorAmgenAIDS, in combination w / AZTRemuneImmune Response Corp.ImmunotherapeuticrCD4 Recombinant Soluble Human CD4GenentechAIDS, ARCrCD4-IgG hybridsAIDS, ARCRecombinant Soluble Human CD4BiogenAIDS, ARCInterferon Alfa 2aHoffman-La RocheKaposi's sarcoma AIDS, ARC, in combination w / AZTSK&F106528 Soluble T4Smith KlineHIV infectionThymopentinImmunobiology Research Institute (Annandale, NJ)HIV infectionTumor Necrosis Factor; TNFGenentechARC, in combination w / gamma Interferon ANTI-INFECTIVES

[0100] Drug NameManufacturerIndicationClindamycin with PrimaquinePharmacia UpjohnPCPFluconazolePfizerCryptococcal meningitis, candidiasisPastille Nystatin PastilleSquibb Corp.Prevention of oral candidiasisOrnidyl EflornithineMerrell DowPCPPentamidine Isethionate (IM & IV)LyphoMed (Rosemont, IL)PCP treatmentTrimethoprimAntibacterialTrimethoprim / sulfaAntibacterialPiritreximBurroughs WellcomePCP treatmentPentamidine Isethionate for InhalationFisons CorporationPCP prophylaxisSpiramycinRhone- PoulencCryptosporidial diarrheaIntraconazole-R51211Janssen-Pharm.Histoplasmosis; cryptococcal meningitisTrimetrexateWarner-LambertPCPDaunorubicinNeXstar, SequusKaposi's sarcomaRecombinant Human ErythropoietinOrtho Pharm. Corp.Severe anemia assoc. with AZT therapyRecombinant Human Growth HormoneSeronoAIDS-related wasting, cachexiaMegestrol AcetateBristol-Myers SquibbTreatment of anorexia assoc. W / AIDSTestosteroneAlza, Smith KlineAIDS-related wastingTotal Enteral NutritionNorwich Eaton PharmaceuticalsDiarrhea and malabsorption related to AIDS

[0101] 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.

[0102] 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.

[0103] 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 ddI. 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-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)-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 ddI and / or ddC; (2) indinavir, and any of AZT and / or ddI 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.

[0104] 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)

[0105] 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

[0106] 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 chromatography mass spectroscopy Prep =preparative HPLC =high performance liquid chromatography DAST =(diethylamino)sulfur trifluoride TEA =triethylamine DIPEA =N,N-diisopropylethylamine HATU =[O-(7-azabenzotriazol-1-yl)-1,1,3,3-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 =O-(benzotriazol-1-yl)-N,N,N';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 Tf 2 NPh =(trifluoromethylsulfonyl)methanesulfonamide dioxane =1,4-dioxane PG =protective group atm =atmosphere(s) mol =mole(s) mmol=milimole(s) mg =milligram(s) µg =microgram(s) µl =microliter(s) µm=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 TMSCl =trimethylsilyl chloride TBSCl =tert-Butyldimethylsilyl chloride TBSOTf =trimethylsilyl trifluoromethanesulfonate PhMe =toluene PhNTf 2 =N-Phenyl-bis(trifluoromethanesulfonimide) S-Phos =2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TFDO =methyl(trifluoromethyl)dioxirane TEMPO =2,2,6,6-tetramethylpiperidinyloxy DI =deionized water

[0107] 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 an illustrative triterpene: betulin):

[0108] The same numbering is maintained when referring to the compound series in schemes and general descriptions of methods. EXAMPLES

[0109] 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.ChemistryTypical Procedures and Characterization of Selected Examples:

[0110] 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). 1< H 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 δTMS = 0. The following internal references were used for the residual protons in the following solvents: CDCl 3 (δ H 7.26), CD 3 OD (δ H 3.30), acetic-d4 (Acetic Acid d 4 ) (δ H 11.6, 2.07), DMSO mix or DMSO-D6-CDCl 3 (δ H 2.50 and 8.25) (ratio 75%:25%), and DMSO-D6 (δ H 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

[0111] LCMS Method 1: Start % B = 0 Final % B = 100 Gradient Time = 2 min Flow Rate = 1 mL / min Wavelength = 220 nm Solvent A = 10% MeOH - 90% H 2 O - 0.1% TFA Solvent B = 90% MeOH - 10% H 2 O - 0.1% TFA Column = Phenomenex C18 2.0 x 30mm 3µm 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% H 2 O - 0.1% TFA Solvent B = 90% MeOH - 10% H 2 O - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 µm 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 O - 0.1% TFA Solvent B = 90% MeOH - 10% H 2 O - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 µm 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% H 2 O - 0.1% TFA Solvent B = 90% MeOH - 10% H 2 O - 0.1% TFA Column = Phenomenex C18 2.0 x 50mm 3 µm 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% H 2 O - 0.1% TFA Solvent B = 90% MeOH - 10% H 2 O - 0.1% TFA Column = Phenomenex C18 2.0 x 50mm 3 µm LCMS Method 6: Start % B = 20 Final % B = 100 Gradient Time = 2 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 C18 2.0 X 50 mm 3 µm 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% H2O - 0.1% TFA Solvent B = 90% MeOH - 10% H2O - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 µm 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% H2O - 0.1% TFA Solvent B = 90% MeOH - 10% H2O - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 µm 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% H2O - 10 mM Ammonium Acetate Solvent B = 95% MeCN - 5% H2O - 10 mM Ammonium Acetate Column = PHENOMENEX-LUNA C18 2.0 X 30mm 3 µm 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% MeOH - 90% H2O - 0.1% TFA Solvent B = 90% MeOH - 10% H2O - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 µm LCMS Method 11: 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 C18 2.0 X 50 mm 3 µm 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% MeOH - 90% H2O - 0.1% TFA Solvent B = 90% MeOH - 10% H2O - 0.1% TFA Column = Xbridge Phenyl 2.1 X 50 mm 2.5 µm 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% H2O - 0.1% TFA Solvent B = 90% MeOH - 10% H2O - 0.1% TFA Column = Phenomenex C18 2.0 X 50 mm 3 µm 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 C18, 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 µm 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 C18, 2.1 x 50 mm, 1.7 µm 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 C18, 50 x 2 mm, 3 µm 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 C18, 2.1 x 50 mm, 1.7 µm 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 C18, 2.1 x 50 mm, 1.7 µm 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 C18, 50 x 2 mm, 3 µm Oven temp = 40 °C Preparative HPLC Methods

[0112] 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 µm 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 C18, 5 µm, 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 150 mm, 5 µm 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 150 mm, 5 µm 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 150 mm, 5 µm 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

[0113] 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 150 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 150 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

[0114] Intermediate 1. Preparation of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0115]

[0116] A mixture of ethyl 4-oxocyclohexanecarboxylate (12.7 g, 75 mmol), ethylene glycol (21 ml, 373 mmol), (1S)-(+)-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 Na 2 SO 4 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 %). 1< H 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-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0117]

[0118] To a solution of ethyl 1,4-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 NH 4 Cl in 0.5 N HCl (250 mL) dropwise. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with saturated solution of NH 4 Cl in 0.5 N HCl (200 mL), brine (200 mL), dried over Na 2 SO 4 , 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 %). 1< H 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0119]

[0120] To a solution of the ethyl 8-formyl-1,4-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 NH 4 Cl (10 mL) and was then diluted with H 2 O until dissolved. The mixture was extracted with EtOAc (3 x 50 mL), washed with brine (50 mL), dried over Na 2 SO 4 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 %). 1< H 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0121]

[0122] To a solution of ethyl 8-(hydroxymethyl)-1,4-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 Na 2 SO 4 , 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 %). 1< H 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 (1-(ethoxycarbonyl)-4-oxocyclohexyl)methyl benzoate.

[0123]

[0124] A solution of ethyl 8-((benzoyloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate (4.3 g, 12.4 mmol) in acetone (120 mL) and 0.5N HCl (24.8 mL, 12.4 mmol) was stirred at 50 °C overnight. The reaction mixture was neutralized with saturated aqueous Na 2 CO 3 and partially concentrated in vacuo to remove acetone. The residue was diluted with H 2 O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed brine (50 mL), dried over Na 2 SO 4 , 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 %). 1< H 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 (1-(ethoxycarbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)methyl benzoate.

[0125]

[0126] A solution of (1-(ethoxycarbonyl)-4-oxocyclohexyl)methyl benzoate (3.8 g, 12.4 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (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 NH 4 Cl (50 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , 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. 1< H 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.

[0127]

[0128] A mixture of (1-(ethoxycarbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-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 PdCl 2 (dppf)-CH 2 Cl 2 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 Na 2 SO 4 , 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. 1< H 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)-(1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methyl benzoate and (R)-(1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methyl benzoate.

[0129]

[0130] 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)-(1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methyl benzoate.SFC Experimental Details:

[0131] Column:ChiralCel OJ-H, 30 x 250mm, 5µmMobile Phase:5% MeOH / 95% CO2Pressure:100 barTemperature:40°CFlow Rate:70 mL / minUV:225 nmInjection: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.

[0132]

[0133] To vacuum dried ethyl 8-(hydroxymethyl)-1,4-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 %). 1< H 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 α-substituted cyclohexenecarboxylic acid derivatives.

[0134] Step 1: Preparation of ether.

[0135] Step 1-A: To a solution of ethyl 8-(hydroxymethyl)-1,4-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-1,2-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 NH 4 Cl, extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , 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)-1,4-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.

[0136]

[0137] 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. Na 2 CO 3 and partially concentrated in vacuo to remove acetone. The residue was diluted with H 2 O, extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , 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.

[0138]

[0139] 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 NH 4 Cl. The mixture was extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , 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.

[0140]

[0141] In a pressure vessel, a mixture of triflate from step 3 (1 eq), bis(pinacolato)diboron (1.1 eq), KOAc (2.5 eq) and PdCl 2 (dppf)-CH 2 Cl 2 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 Na 2 SO 4 , 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 α-substituted cyclohexenecarboxylic ester.

[0142]

[0143] A mixture of C3-triflate (1 eq), boronate from step 4 (1eq), Na 2 CO 3 H 2 O (3 eq) and Pd(Ph 3 P) 4 (0.06 eq) in dioxane and H 2 O (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 H 2 O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by silica gel column eluted with ethyl acetate / hexanes to give the desired C-3 α-substituted cyclohexenecarboxylic ester.Step 6: Preparation of carboxylic acid.

[0144]

[0145] 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

[0146] Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid. Step 1. Preparation of ethyl 8-((pyridin-2-yloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0147]

[0148] 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. 1< H NMR (500MHz, CHLOROFORM-d) δ 8.14 (ddd, J=5.0, 2.0, 0.8 Hz, 1H), 7.59 - 7.53 (m, 1H), 6.87 (ddd, J=7.1, 5.1, 0.9 Hz, 1H), 6.73 (dt, J=8.4, 0.8 Hz, 1H), 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-1-((pyridin-2-yloxy)methyl)cyclohexane-1-carboxylate.

[0149]

[0150] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.14 (ddd, J=5.1, 1.9, 0.8 Hz, 1H), 7.61 - 7.55 (m, 1H), 6.90 (ddd, J=7.1, 5.1, 0.9 Hz, 1H), 6.74 (dt, J=8.3, 0.8 Hz, 1H), 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 1-((pyridin-2-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0151]

[0152] 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-1-((pyridin-2-yloxy)methyl)cyclohexane-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.14 (ddd, J=5.0, 2.0, 0.8 Hz, 1H), 7.62 - 7.55 (m, 1H), 6.90 (ddd, J=7.1, 5.1, 0.9 Hz, 1H), 6.73 (dt, J=8.3, 0.8 Hz, 1H), 5.80 - 5.76 (m 1H), 4.45 (d, J=10.3 Hz, 1H), 4.39 (d, J=10.3 Hz, 1H), 4.18 (qd, J=7.1, 1.3 Hz, 2H), 2.88 -2.80 (m, 1H), 2.56 - 2.25 (m, 4H), 2.02 - 1.93 (m, 1H), 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 1-((pyridin-2-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0153]

[0154] The title compound was prepared in 75 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 1-((pyridin-2-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0155]

[0156] The title compound was prepared in 71 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-((pyridin-2-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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).

[0157] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 32 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,1 1a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< 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 2Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0158] Step 1. Preparation of ethyl 8-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0159]

[0160] The title compound was prepared in 99 % yield as an oil, following the procedure described in general procedure A step 1-A, using 1-methyl-3-phenyl-1H-pyrazol-5-ol as reactant. 1< 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 1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0161]

[0162] The title compound was prepared in 81 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< 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 1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0163]

[0164] The title compound was prepared in 68 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate as reactant. 1< H 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 1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0165]

[0166] The title compound was prepared in 68 % yield as a wax, following the procedure described in general procedure A step 4, using ethyl 1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate as reactant. 1< 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate.

[0167]

[0168] The title compound was prepared in 59 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.74 - 7.70 (m, 2H), 7.40 - 7.33 (m, 2H), 7.31 - 7.25 (m, 1H), 5.83 (s, 1H), 5.36 (br. s., 1H), 5.19 (d, J=4.8 Hz, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.59 (s, 1H), 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).

[0169] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 81 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-3-phenyl-1H-pyrazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, METHANOL-d 4 ) 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 3Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0170] Step 1. Preparation of ethyl 8-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0171]

[0172] The title compound was prepared in 86 % yield as an oil, following the procedure described in general procedure A step 1-A, using 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ol as reactant. 1< 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 1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0173]

[0174] The title compound was prepared in 98 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< 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 1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0175]

[0176] The title compound was prepared in 70 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate as reactant. 1< 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 1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0177]

[0178] The title compound was prepared in 79 % yield as a wax, following the procedure described in general procedure A step 4, using ethyl 1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate.

[0179]

[0180] The title compound was prepared in 88 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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).

[0181] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 56 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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 4Preparation of 2-((1-carboxy-4-((1R,3aS,5aR,5bR,7aR, 11aS,11bR, 13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-en-1-yl)methoxy)thiazole-4-carboxylic acid.

[0182] Step 1. Preparation of ethyl 2-((8-(ethoxycarbonyl)-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)thiazole-4-carboxylate.

[0183]

[0184] 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-((1-(ethoxycarbonyl)-4-oxocyclohexyl)methoxy)thiazole-4-carboxylate.

[0185]

[0186] 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)-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)thiazole-4-carboxylate as reactant. 1< 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-((1-(ethoxycarbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)methoxy)thiazole-4-carboxylate.

[0187]

[0188] The title compound was prepared in 40 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 2-((1-(ethoxycarbonyl)-4-oxocyclohexyl)methoxy)thiazole-4-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.60 (s, 1H), 5.80 - 5.76 (m, 1H), 4.66 (d, J=10.0 Hz, 1H), 4.60 (d, J=10.3 Hz, 1H), 4.38 (q, J=7.0 Hz, 2H), 4.19 (qd, J=7.1, 0.8 Hz, 2H), 2.87 -2.79 (m, 1H), 2.56 - 2.23 (m, 4H), 1.99 - 1.90 (m, 1H), 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-((1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methoxy)thiazole-4-carboxylate.

[0189]

[0190] The title compound was prepared in 57 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 2-((1-(ethoxycarbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)methoxy)thiazole-4-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.58 (s, 1H), 6.54 - 6.49 (m, 1H), 4.64 (d, J=10.0 Hz, 1H), 4.56 (d, J=10.0 Hz, 1H), 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, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methoxy)thiazole-4-carboxylate.

[0191]

[0192] The title compound was prepared in 79 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 2-((1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methoxy)thiazole-4-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.58 (s, 1H), 5.33 (br. s., 1H), 5.18 (d, J=6.0 Hz, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.67 - 4.60 (m, 2H), 4.59 (s, 1H), 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).

[0193] Step 6. 2-((1-carboxy-4-((1R,3aS,5aR,5bR7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-en-1-yl)methoxy)thiazole-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methoxy)thiazole-4-carboxylate as reactant. 1< H 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 5Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0194] Step 1. Preparation of ethyl 8-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)-1,4-dioxaspiro [4.5] decane-8 -carboxylate.

[0195]

[0196] 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-1,2,5-thiadiazol-3-ol as reactant. 1< H 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 1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0197]

[0198] 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-1,2,5-thiadiazol-3-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0199]

[0200] The title compound was prepared in 60 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 5.82 - 5.78 (m, 1H), 4.52 (d, J=10.3 Hz, 1H), 4.47 (d, J=10.3 Hz, 1H), 4.26 - 4.12 (m, 2H), 2.90 - 2.82 (m, 1H), 2.59 - 2.27 (m, 4H), 2.36 (s, 3H), 2.00 - 1.93 (m, 1H), 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 1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0201]

[0202] The title compound was prepared in 74 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 6.56 - 6.52 (m, 1H), 4.51 (d, J=10.0 Hz, 1H), 4.44 (d, J=10.0 Hz, 1H), 4.16 (qd, J=7.1, 1.1 Hz, 2H), 2.71 (dq, J=19.1, 3.3 Hz, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate.

[0203]

[0204] The title compound was prepared in 73 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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).

[0205] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 53 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((4-methyl-1,2,5-thiadiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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 6Preparation of 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0206] Step 1. Preparation of ethyl 8-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0207]

[0208] The title compound was prepared in 92 % yield as an oil, following the procedure described in general procedure A step 1-A, using 1,2,5-thiadiazol-3-ol as reactant. 1< H 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 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0209]

[0210] The title compound was prepared in 80 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0211]

[0212] The title compound was prepared in 34 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.99 (s, 1H), 5.81 - 5.78 (m, 1H), 4.55 (d, J=10.3 Hz, 1H), 4.50 (d, J=10.3 Hz, 1H), 4.20 (qd, J=7.1, 0.8 Hz, 2H), 2.90 - 2.81 (m, 1H), 2.57 - 2.25 (m, 4H), 2.04 - 1.95 (m, 1H), 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 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0213]

[0214] The title compound was prepared in 69 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1 -carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.96 (s, 1H), 6.56 - 6.52 (m, 1H), 4.54 (d, J=10.0 Hz, 1H), 4.45 (d, J=10.0 Hz, 1H), 4.16 (q, J=7.0 Hz, 2H), 2.71 (dq, J=18.9, 3.4 Hz, 1H), 2.30-2.17 (m, 3H), 2.03 - 1.94 (m, 1H), 1.92 - 1.83 (m, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0215]

[0216] The title compound was prepared in 76 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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).

[0217] Step 6. 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid was prepared in 56 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 1-(((1,2,5-thiadiazol-3-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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 7Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0218] Step 1. Preparation of ethyl 8-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-1,4-dioxaspiro [4.5] decane-8 -carboxylate.

[0219]

[0220] 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-1H-1,2,3-triazol-5-ol as reactant. 1< H 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 1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0221]

[0222] The title compound was prepared in 86 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0223]

[0224] The title compound was prepared in 35 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate as reactant. 1< H 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 1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0225]

[0226] The title compound was prepared in 57 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate.

[0227]

[0228] The title compound was prepared in 90 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.07 (s, 1H), 5.35 (br. s., 1H), 5.18 (d, J=6.0 Hz, 1H), 4.70 (s, 1H), 4.59 (s, 1H), 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).

[0229] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-ethyl-1H-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-ethyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.10 (s, 1H), 5.36 (br. s., 1H), 5.18 (br. s., 1H), 4.69 (s, 1H), 4.59 (s, 1H), 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 min (LCMS Method 3).Example 8Preparation of 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0230] Step 1. Preparation of ethyl 8-((benzo[d]isothiazol-3-yloxy)methyl)-1,4-dioxaspiro [4.5] decane-8 -carboxylate.

[0231]

[0232] 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. 1< H NMR (500MHz, CHLOROFORM-d) δ 7.88 (dd, J=8.1, 0.9 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.53 (ddd, J=8.2, 7.1, 1.1 Hz, 1H), 7.39 (td, J=7.5, 0.8 Hz, 1H), 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 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0233]

[0234] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.87 (dt, J=8.0, 1.0 Hz, 1H), 7.79 (dt, J=8.2, 0.8 Hz, 1H), 7.54 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.40 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 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 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0235]

[0236] The title compound was prepared in 64 % yield as an oil, following the procedure described in general procedure A step 3, using ethyl 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-oxocyclohexane-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.86 (dt, J=8.0, 1.0 Hz, 1H), 7.79 (dt, J=8.1, 0.8 Hz, 1H), 7.54 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.43 - 7.39 (m, 1H), 5.83 - 5.79 (m, 1H), 4.68 (d, J=10.0 Hz, 1H), 4.63 (d, J=10.3 Hz, 1H), 4.20 (qd, J=7.2, 2.1 Hz, 2H), 2.97 - 2.88 (m, 1H), 2.59 - 2.32 (m, 4H), 2.07 - 1.98 (m, 1H), 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 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0237]

[0238] The title compound was prepared in 61 % yield as an oil, following the procedure described in general procedure A step 4, using ethyl 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.85 (dt, J=7.9, 0.9 Hz, 1H), 7.76 (dt, J=8.2, 0.8 Hz, 1H), 7.52 (ddd, J=8.2, 7.0, 1.1 Hz, 1H), 7.42 - 7.37 (m, 1H), 6.58 - 6.54 (m. 1H), 4.66 (d, J=10.0 Hz, 1H), 4.58 (d, J=10.0 Hz, 1H), 4.16 (qd, J=7.1, 1.0 Hz, 2H), 2.76 (dq, J=18.9, 2.7 Hz, 1H), 2.37 - 2.28 (m, 1H), 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 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0239]

[0240] The title compound was prepared in 47 % yield as a solid, following the procedure described in general procedure A step 5, using ethyl 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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).

[0241] Step 6. 1-((benzo[d]isothiazol-3-yloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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 9Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-4-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0242] Step 1. Preparation of ethyl 8-((pyridm-4-yloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0243]

[0244] The title compound was prepared in 77 % yield, following the procedure described in general procedure A step 1-A, using 4-hydroxypyridine as reactant. 1< H 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-1-((pyridin-4-yloxy)methyl)cyclohexane-1-carboxylate.

[0245]

[0246] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-((pyridin-4-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0247]

[0248] The title compound was prepared in 66 % yield, following the procedure described in general procedure A step 3, using ethyl 4-oxo-1-((pyridin-4-yloxy)methyl)cyclohexanecarboxylate as reactant. 1< H 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 1-((pyridin-4-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0249]

[0250] The title compound was prepared in 59 % yield, following the procedure described in general procedure A step 4, using ethyl 1-((pyridin-4-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-4-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0251]

[0252] The title compound was prepared in 34 % yield, following the procedure described in general procedure A step 5, using ethyl 1-((pyridin-4-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. LC / MS: m / e 831.45 (M+H) +< , 2.54 min (LCMS Method 3). 1< H 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).

[0253] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-4-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 47 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-4-yloxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, METHANOL-d 4 )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 10Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-enecarboxylic acid.

[0254] Step 1. Preparation of ethyl 8-((pyridin-3-yloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0255]

[0256] The title compound was prepared in 84 % yield, following the procedure described in general procedure A step 1-A, using 3-hydroxypyridine as reactant 1< H 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-1-((pyridin-3-yloxy)methyl)cyclohexane-1-carboxylate.

[0257]

[0258] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. LCMS: m / e 279.00 (M+H) +< , 2.079 min (LCMS Method 8). 1< H NMR (400MHz, CHLOROFORM-d) δ 8.22 (dd, J=2.6, 0.9 Hz, 1H), 8.16 (dd, J=4.3, 1.8 Hz, 1H), 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 1-((pyridin-3-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0259]

[0260] The title compound was prepared in 51.9 % yield, following the procedure described in general procedure A step 3, using ethyl 4-oxo-1-((pyridin-3-yloxy)methyl)cyclohexanecarboxylate as reactant. LCMS: m / e 410.00 (M+H) +< , 1.983 min (LCMS Method 8). 1< 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 1-((pyridin-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0261]

[0262] The title compound was prepared in 88 % yield, following the procedure described in general procedure A step 4, using ethyl 1-((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). 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-ene-1-carboxylate and ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-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,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-enecarboxylate.

[0263]

[0264] 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 1-((pyridin-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. For ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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). 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-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,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-enecarboxylate: LCMS: m / e 858.55 (M+H) +< , 2.454 min (LCMS Method 8). 1< H 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).

[0265] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-enecarboxylic acid was prepared in 68.1 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H NMR (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 11Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-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,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-enecarboxylic acid.

[0266]

[0267] The title compound was prepared in 4.02 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(propl-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-3-yloxy)methyl)cyclohex-3-enecarboxylate as reactant. LCMS: m / e 830.50 (M+H) +< , 2.367 min (LCMS Method 8). 1< H 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 12Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-methylisothiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0268] Step 1. Preparation of ethyl 8-((isothiazol-3-yloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0269]

[0270] 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. 1< H 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 1-(((5-methylisothiazol-3-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0271]

[0272] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-(((5-methylisothiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0273]

[0274] The title compound was prepared in 87 % yield, following the procedure described in general procedure A step 3, using ethyl 1-(((5-methylisothiazol-3-yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. 1< H 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 1-(((5-methylisothiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0275]

[0276] The title compound was prepared in 32 % yield, following the procedure described in general procedure A step 4, using ethyl 1-(((5-methylisothiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-methylisothiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate.

[0277]

[0278] 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-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. 1< H 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).

[0279] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-methylisothiazol-3-yl)oxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H 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 13Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0280] Step 1. Preparation of ethyl 8-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-1,4-dioxaspiro [4.5] decane-8 -carboxylate.

[0281]

[0282] The title compound was prepared in 82 % yield, following the procedure described in general procedure A step 1-A, using 1-methyl-1H-tetrazol-5-ol as reactant. 1< 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 1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0283]

[0284] The title compound was prepared in 91 % yield, following the procedure described in general procedure A step 2, using ethyl 8-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0285]

[0286] The title compound was prepared in 29 % yield, following the procedure described in general procedure A step 3, using ethyl 1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. 1< H 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 1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[0287]

[0288] The title compound was prepared in 90 % yield, following the procedure described in general procedure A step 4, using ethyl 1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate

[0289]

[0290] The title compound was prepared in 56 % yield, following the procedure described in general procedure A step 5, using ethyl 1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. 1< H 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).

[0291] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-1H-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-methyl-1H-tetrazol-5-yl)oxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H 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 14Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0292] Step 1. Preparation of ethyl 8-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-1,4-dioxaspiro [4.5] decane-8 -carboxylate.

[0293]

[0294] The title compound was prepared in 90 % yield, following the procedure described in general procedure A step 1-A, using 5-(methylthio)-1,2,4-thiadiazol-3-ol as reactant. 1< H 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 1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-4-oxocyclohexanecarboxylate.

[0295]

[0296] The title compound was prepared in 100 % yield, following the procedure described in general procedure A step 2, using ethyl 8-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0297]

[0298] The title compound was prepared in 55 % yield, following the procedure described in general procedure A step 3, using ethyl 1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 5.74 (td, J=3.1, 1.8 Hz, 1H), 4.50 (d, J=10.3 Hz, 1H), 4.45 (d, J=10.3 Hz, 1H),4.15 (q, J=7.0 Hz, 2H), 2.84 - 2.75 (m, 1H), 2.65 (s, 3H), 2.51 - 2.19 (m, 4H), 2.02 - 1.94 (m, 1H), 1.21 (t, J=7.2 Hz, 3H).Step 4. Preparation of ethyl 1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate.

[0299]

[0300] The title compound was prepared in 39 % yield, following the procedure described in general procedure A step 4 for 7 h, using ethyl 1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 6.50 (dt, J=3.5, 1.8 Hz, 1H), 4.49 (d, J=10.0 Hz, 1H), 4.40 (d, J=10.0 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.72 - 2.64 (m, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)cyclohex-3-enecarboxylate.

[0301]

[0302] The title compound was prepared, following the procedure described in general procedure A step 5 at 90 °C for 4 h, using ethyl 1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. LC / MS: m / e 883.55 (M+H) +< , 3.11 min (LCMS Method 3).

[0303] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 10 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-(methylthio)-1,2,4-thiadiazol-3-yl)oxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H 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 15Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((thiazol-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0304] Step 1: Preparation of ethyl 8-((thiazol-2-yloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0305]

[0306] 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. 1< H NMR (400MHz, CHLOROFORM-d) δ 6.39 (d, J=5.5 Hz, 1H), 6.03 (d, J=5.3 Hz, 1H), 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-1-((thiazol-2-yloxy)methyl)cyclohexane-1-carboxylate.

[0307]

[0308] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) □ 6.47 (d, J=5.5 Hz, 1H), 6.13 (d, J=5.5 Hz, 1H), 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 1-((thiazol-2-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0309]

[0310] 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-1-((thiazol-2-yloxy)methyl)cyclohexane-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 6.43 (d, J=5.5 Hz, 1H), 6.11 (d, J=5.3 Hz, 1H), 5.73 (td, J=3.4, 1.5 Hz, 1H), 4.16 (qd, J=7.2, 2.6 Hz, 2H), 3.90 (s, 2H), 2.74 - 2.64 (m, 1H), 2.45 - 2.39 (m, 2H), 2.33 - 2.20 (m, 2H), 1.85 - 1.76 (m, 1H), 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-1,3,2-dioxaborolan-2-yl)-1-((thiazol-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0311]

[0312] The title compound was prepared in 71 % yield, following the procedure described in general procedure A step 4, using ethyl 1-((thiazol-2-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((thiazol-2-yloxy)methyl)cyclohex-3-enecarboxylate.

[0313]

[0314] The title compound was prepared in 30 % yield as a solid, following the procedure described in general procedure A step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((thiazol-2-yloxy)methyl)cyclohex-3-enecarboxylate as reactants. 1< 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).

[0315] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((thiazol-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 68 % yield as a solid, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((thiazol-2-yloxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< 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 16Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0316] Step 1. Preparation of ethyl 8-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-1,4-dioxaspiro [4.5] decane-8 -carboxylate.

[0317]

[0318] The title compound was prepared following the procedure described in general procedure A step 1-A, using 1-phenyl-1H-1,2,3-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-1-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohexanecarboxylate.

[0319]

[0320] The title compound was prepared in 9 % yield, following the procedure described in general procedure A step 2, using ethyl 8-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.66 - 7.59 (m, 2H), 7.53 - 7.45 (m, 1H), 7.45 - 7.36 (m, 2H), 7.20 (s, 1H), 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 1-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate.

[0321]

[0322] 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-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohexanecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.69 - 7.63 (m, 2H), 7.54 - 7.48 (m, 2H), 7.46 -7.40 (m, 1H), 7.22 (s, 1H), 5.80 - 5.75 (m, 1H), 4.29 (d, J=9.0 Hz, 1H), 4.22 (d, J=8.8 Hz, 1H), 4.17 - 4.11 (m, 2H), 2.87 - 2.79 (m, 1H), 2.56 - 2.44 (m, 1H), 2.42 - 2.22 (m, 3H), 1.97 - 1.89 (m, 1H), 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 1-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3 -enecarboxylate.

[0323]

[0324] 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-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.68 - 7.63 (m, 2H), 7.50 - 7.43 (m, 2H), 7.41 - 7.35 (m, 1H), 7.19 (s, 1H), 6.49 (dt, J=3.5, 1.8 Hz, 1H), 4.25 (d, J=8.8 Hz, 1H), 4.19 (d, J=8.8 Hz, 1H), 4.08 (qd, J=7.1, 1.0 Hz, 2H), 2.69 - 2.60 (m, 1H), 2.28 - 2.05 (m, 3H), 1.98 - 1.90 (m, 1H), 1.88 - 1.81 (m, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-enecarboxylate.

[0325]

[0326] 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-ene-1-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-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.71 - 7.65 (m, 2H), 7.51 - 7.44 (m, 2H), 7.41 - 7.35 (m, 1H), 7.19 (s, 1H), 5.32 (br. s., 1H), 5.15 (d, J=4.8 Hz, 1H), 4.68 (d, J=2.0 Hz, 1H), 4.57 (s, 1H), 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).

[0327] 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-phenyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.79 - 7.70 (m, 2H), 7.53 - 7.46 (m, 2H), 7.43 - 7.37 (m, 1H), 7.26 - 7.22 (m, 1H), 5.36 (br. s., 1H), 5.18 (t, J=5.5 Hz, 1H), 4.70 (s, 1H), 4.61 (s, 1H), 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, 1H), 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, 1H), 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 17Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0328] Step 1. Preparation of ethyl 8-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-1,4-dioxaspiro [4.5] decane-8 -carboxylate.

[0329]

[0330] 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 1-isopropyl-1H-1,2,3-triazol-5-ol as reactant. 1< H 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 1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-oxocyclohexane-1-carboxylate.

[0331]

[0332] The title compound was prepared in 91 % yield as an oil, following the procedure described in general procedure A step 2, using ethyl 8-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.02 (s, 1H), 4.50 (spt, J=6.8 Hz, 1H), 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 1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate.

[0333]

[0334] 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-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 7.04 (s, 1H), 5.79 - 5.73 (m, 1H), 4.53 (spt, J=6.8 Hz, 1H), 4.19 - 4.04 (m, 4H), 2.88 - 2.76 (m, 1H), 2.55 - 2.21 (m, 4H), 1.92 (ddd, J=13.7, 7.9, 6.3 Hz, 1H), 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 1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate.

[0335]

[0336] The title compound was prepared in 100 % yield, following the procedure described in general procedure A step 4, using ethyl 1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-enecarboxylate.

[0337]

[0338] The title compound was prepared in 100 % yield, following the procedure described in general procedure A step 5, using ethyl 1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. 1< H 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).

[0339] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 45 % yield, following the procedure described in general procedure A step 6, using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((1-isopropyl-1H-1,2,3-triazol-5-yl)oxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H 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=65 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 18Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-(prop-1-en-2-yl)isothiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0340] Step 1. Preparation of ethyl 8-((isothiazol-3-yloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0341]

[0342] 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. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.42 (d, J=4.8 Hz, 1H), 6.57 (d, J=4.8 Hz, 1H), 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.

[0343]

[0344] To a solution of ethyl 8-((isothiazol-3-yloxy)methyl)-1,4-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 HCl, 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 %). 1< H 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 1-(((5-(2-hydroxypropan-2-yl)isothiazol-3-yl)oxy)methyl)-4-oxocyclohexanecarboxylate.

[0345]

[0346] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H 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 1-(((5-(prop-1-en-2-yl)isothiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[0347]

[0348] The title compound was prepared in 22 % yield, following the procedure described in general procedure A step 3 using ethyl 1-(((5-(2-hydroxypropan-2-yl)isothiazol-3-yl)oxy)methyl)-4-oxocyclohexanecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 6.50 (s, 1H), 5.76 (td, J=3.3, 1.8 Hz, 1H), 5.45 (s, 1H), 5.18 (s, 1H), 4.47 (d, J=10.0 Hz, 1H), 4.41 (d, J=10.0 Hz, 1H), 4.19 (qd, J=7.1, 0.8 Hz, 2H), 2.85 - 2.77 (m, 1H), 2.53 - 2.22 (m, 4H), 2.09 (s, 3H), 1.98 - 1.90 (m, 1H), 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 1-(((5-(prop-1-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.

[0349]

[0350] The title compound was prepared in 78 % yield, following the procedure described in general procedure A step 4 using ethyl 1-(((5-(prop-1-en-2-yl)isothiazol-3-yl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 6.55 - 6.50 (m, 1H), 6.49 (s, 1H), 5.43 (s, 1H), 5.14 (s, 1H), 4.46 (d, J=10.0 Hz, 1H), 4.37 (d, J=10.0 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 2.74 - 2.64 (m, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-(prop-1-en-2-yl)isothiazol-3-yl)oxy)methyl)cyclohex-3-enecarboxylate.

[0351]

[0352] The title compound was prepared in 42 % yield, following the procedure described in general procedure A step 5 using ethyl 1-(((5-(prop-1-en-2-yl)isothiazol-3-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 6.51 (s, 1H), 5.44 (s, 1H), 5.35 (br. s., 1H), 5.19 (br. s., 1H), 5.17 (s, 1H), 4.76 (s, 1H), 4.71 (s, 1H), 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).

[0353] Step 7. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-(prop-1-en-2-yl)isothiazol-3-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid was prepared in 56 % yield, following the procedure described in general procedure A step 6 using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,1la-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((5-(prop-1-en-2-yl)isothiazol-3-yl)oxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H 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 19Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridazin-3-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0354] Step 1. Preparation of ethyl 8-((pyridazin-3-yloxy)methyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate.

[0355]

[0356] To the solution of ethyl 8-(hydroxymethyl)-1,4-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-1-((pyridazin-3-yloxy)methyl)cyclohexanecarboxylate.

[0357]

[0358] 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)-1,4-dioxaspiro[4.5]decane-8-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.82 (dd, J=4.5, 1.3 Hz, 1H), 7.37 (dd, J=9.0, 4.5 Hz, 1H), 6.96 (dd, J=8.9, 1.4 Hz, 1H), 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 1-((pyridazin-3-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate.

[0359]

[0360] The title compound was prepared in 39 % yield, following the procedure described in general procedure A step 3 using ethyl 4-oxo-1-((pyridazin-3-yloxy)methyl)cyclohexanecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.82 (dd, J=4.5, 1.3 Hz, 1H), 7.36 (dd, J=9.0, 4.5 Hz, 1H), 6.94 (dd, J=9.0, 1.3 Hz, 1H), 5.75 (td, J=3.1, 1.8 Hz, 1H), 4.62 (d, J=10.5 Hz, 1H), 4.59 (d, J=10.5 Hz, 1H), 4.18 - 4.11 (m, 2H), 2.88 - 2.79 (m, 1H), 2.53 - 2.23 (m, 4H), 1.97 - 1.90 (m, 1H), 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 1-((pyridazin-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate.

[0361]

[0362] The title compound was prepared in 43 % yield, following the procedure described in general procedure A step 4 using ethyl 1-((pyridazin-3-yloxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.78 (dd, J=4.5, 1.3 Hz, 1H), 7.32 (dd, J=8.9, 4.4 Hz, 1H), 6.91 (dd, J=8.9, 1.4 Hz, 1H), 6.49 (dt, J=3.7, 1.8 Hz, 1H), 4.62 (d, J=10.3 Hz, 1H), 4.53 (d, J=10.5 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 2.72 - 2.64 (m, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridazin-3-yloxy)methyl)cyclohex-3-enecarboxylate.

[0363]

[0364] The title compound was prepared following the procedure described in general procedure A step 5 using ethyl 1-((pyridazin-3-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactant. The crude material was taken directly into the next step without purification.

[0365] Step 6. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridazin-3-yloxy)methyl)cyclohex-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1 -(prop-1 -en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridazin-3-yloxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< H 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) α-substituted cyclohexenecarboxylic acid derivatives.

[0366] Step 1. Preparation of ((R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate.

[0367]

[0368] A mixture of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yltrifluoromethanesulfonate (1 eq), (R)-(1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methylbenzoate (1.2 eq), Na 2 CO 3 (3 eq) and Pd(Ph 3 P) 4 (0.06 eq) in 1,4-dioxane and H 2 O (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 Na 2 SO 4 , 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. 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-carboxylate.

[0369]

[0370] A suspension of ((R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-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 HCl and the solvent was removed in vacuo. The residue was taken into CH 2 Cl 2 , washed with H 2 O followed by brine, dried over Na 2 SO 4 , 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. 1< H 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) α-methyl ether.

[0371]

[0372] To a solution of ethyl (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-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 Na 2 SO 4 , and concentrated in vacuo to give crude product which was used in the next step without further purification.Step 4: Preparation of (R) α-substituted cyclohexenecarboxylic acid.

[0373]

[0374] A solution of (R) α-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 20Preparation of (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0375] Step 1 - 2: General procedure B.Step 3. Preparation of ethyl (R)-4-((1R,3aS,5aR,5bR,7aR,11aS, 1bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0376]

[0377] 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).

[0378] Step 4. (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (500MHz, CHLOROFORM-d) δ 8.21 (dd, J=5.3, 1.4 Hz, 1H), 7.70 (ddd, J=8.6, 7.0, 2.0 Hz, 1H), 6.98 (ddd, J=1.1, 5.3, 0.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 5.37 (br. s., 1H), 5.20 (dd, J=6.1, 1.7 Hz, 1H), 4.78 (s, 1H), 4.71 (s, 1H), 4.49 (d, J=9.9 Hz, 1H), 4.45 (d, J=9.9 Hz, 1H), 3.38 - 3.31 (m, 1H), 3.25 - 3.00 (m, 9H), 2.98 - 2.85 (m, 2H), 2.79 (dt, J=10.9, 5.6 Hz, 1H), 2.70 - 2.62 (m, 1H), 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 21Preparation of (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrimidin-4-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0379] Step 1 - 2: General procedure B.Step 3. Preparation of ethyl (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrimidin-4-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0380]

[0381] 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).

[0382] Step 4. (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrimidin-4-yloxy)methyl)cyclohex-3-ene-1-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrimidin-4-yloxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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 22Preparation of (R)-1-(((3-chloropyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0383] Step 1 - 2: General procedure B.Step 3. Preparation of ethyl (R)-1-(((3-chloropyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0384]

[0385] 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).

[0386] Step 4. (R)-1-(((3-chloropyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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)-1-(((3-chloropyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H 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 23Preparation of (R)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0387] Step 1 - 2: General procedure B.Step 3. Preparation of ethyl (R)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0388]

[0389] 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. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.33 (dd, J=5.0, 2.0 Hz, 1H), 7.87 (dd, J=7.4, 1.9 Hz, 1H), 7.00 - 6.95 (m, 1H), 5.37 (br. s., 1H), 5.19 (d, J=4.8 Hz, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.60 (s, 1H), 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).

[0390] Step 4. (R)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, METHANOL-d 4 ) δ 8.37 (dd, J=5.0, 2.0 Hz, 1H), 8.06 (dd, J=7.5, 1.8 Hz, 1H), 7.10 (dd, J=7.5, 5.0 Hz, 1H), 5.37 (br. s., 1H), 5.22 (dd, J=6.0, 1.5 Hz, 1H), 4.85 (s, 1H), 4.76 (t, J=1.5 Hz, 1H), 4.63 - 4.55 (m, 2H), 3.27 - 3.07 (m, 11 H), 2.91 (ddd, J=14.4, 10.0, 4.6 Hz, 1H), 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 24Preparation of (R)-1-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0391]

[0392] 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate. The material was isolated in 14 % yield as a solid. 1< H NMR (400MHz, METHANOL-d 4 ) δ 8.40 (dd, J=7.8, 2.0 Hz, 1H), 8.29 (dd, J=5.0, 2.0 Hz, 1H), 7.13 (dd, J=7.7, 4.9 Hz, 1H), 5.37 (br. s., 1H), 5.21 (d, J=4.5 Hz, 1H), 4.83 (s, 1H), 4.72 (s, 1H), 4.64 (d, J=10.3 Hz, 1H), 4.53 (d, J=10.5 Hz, 1H), 3.28 - 3.03 (m, 11H), 3.01 - 2.90 (m, 1H), 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) α-substituted cyclohexenecarboxylic acid derivatives.

[0393] Step 1. Preparation of ((S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate.

[0394]

[0395] The title compound was prepared in 86% of yield as a solid, following the procedure described in General procedure B step 1, using (S)-(1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methyl 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). 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-carboxylate.

[0396]

[0397] 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate instead of ((R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate as the reactant. LC / MS m / z 753.55 (M+H) +< , 2.754 min (LCMS Method 3). 1< H NMR (400MHz, CHLOROFORM-d) δ 5.30 (s, 1H), 5.16 (d, J=5.0 Hz, 1H), 4.72 (s, 1H), 4.61 (s, 1H), 4.23 - 4.12 (m, 2H), 3.67 (s, 2H), 3.28 - 2.65 (m, 13H), 2.54 (d, J=16.1 Hz, 1H), 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)-1-((aryloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0398]

[0399] To a solution of ethyl (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-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 Na 2 SO 4 , 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)-1-((aryloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0400]

[0401] A solution of ethyl (S)-1-((aryloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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 25Preparation of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0402] Step 1 - 2: General procedure C step 1-2.Step 3. Preparation of ethyl (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0403]

[0404] 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).

[0405] Step 4. (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a, 11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 827.50 (M+H) +< , 3.393 min (LCMS Method 7). 1< H NMR (400MHz, METHANOL-d 4 ) δ 8.40 (dd, J=5.1, 1.9 Hz, 1H), 8.08 (dd, J=7.5, 2.0 Hz, 1H), 7.12 (dd, J=7.5, 5.0 Hz, 1H), 5.39 (br. s., 1H), 5.25 - 5.21 (m, 1H), 4.85 (s, 1H), 4.76 (s, 1H), 4.62 (d, J=10.3 Hz, 1H), 4.58 (d, J=10.3 Hz, 1H), 3.31 - 3.18 (m, 8H), 3.16 - 3.12 (m, 2H), 3.12 - 3.07 (m, 1H), 3.02 - 2.87 (m, 1H), 2.80 (td, J=11.0, 5.5 Hz, 1H), 2.73 - 2.63 (m, 2H), 2.37 - 2.27 (m, 1H), 2.26 - 2.01 (m, 8H), 1.97 - 1.91 (m, 1H), 1.88 - 1.75 (m, 2H), 1.78 (s, 3H), 1.72 - 1.44 (m, 10H), 1.42 - 1.31 (m, 1H), 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylic acid, HCl. To a flask containing a suspension of (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(fluoromethyl)cyclohex-3-enecarboxylic acid (4.08 g, 5.61 mmol) prepared as described in WO 2015157483 in 1,4-dioxane (50.0 mL) 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 HCl. 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylic acid, HCl (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 HCl (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 C18 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)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 26Preparation of (S)-1-(((3-carbamoylpyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0406]

[0407] 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)-1-3-canopyridin-2-yl)oxy)methyl-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 845.55 (M+H-H 2 O) +< , 3.349 min (LCMS Method 7). 1< H NMR (400MHz, METHANOL-d 4 ) δ 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 27Preparation of (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0408]

[0409] 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR, 3bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 860.65 (M+H) +< , 2.93 min (LCMS Method 7). 1< H NMR (400MHz, METHANOL-d 4 ) δ 8.30 (dd, J=5.0, 2.0 Hz, 1H), 8.17 (dd, J=7.5, 2.0 Hz, 1H), 7.06 (dd, J=7.5, 5.0 Hz, 1H), 5.39 (br. s., 1H), 5.25 - 5.21 (m, 1H), 4.85 (s, 1H), 4.75 (s, 1H), 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, 1H), 2.81 (td, J=11.0, 5.4 Hz, 1H), 2.73 - 2.63 (m, 1H), 2.36 - 2.00 (m, 9H), 2.00 - 1.90 (m, 1H), 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 28Preparation of (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((6-methoxypyridin-2-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0410] Step 1 - 2: General procedure C step 1-2.Step 3. Preparation of ethyl (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((6-fluoropyridin-2-yl)oxy)methyl)cyclohex-3-ene-1-carboxylate.

[0411]

[0412] 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).

[0413] Step 4. (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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). 1< H NMR (500MHz, METHANOL-d 4 ) δ 7.54 (t, J=7.9 Hz, 1H), 6.32 (d, J=2.9 Hz, 1H), 6.30 (d, J=2.9 Hz, 1H), 5.38 (br. s., 1H), 5.29 - 5.15 (m, 1H), 4.85 (s, 1H), 4.76 (s, 1H), 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, 1H), 2.78 (td, J=11.0, 5.4 Hz, 1H), 2.67 - 2.60 (m, 1H), 2.30 (d, J=18.2 Hz, 1H), 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, 1H), 1.19 (s, 3H), 1.13 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).Example 29Preparation of (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((6-fluoropyridin-2-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0414]

[0415] 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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). 1< H NMR (500MHz, ACETONE-d 6 ) δ 7.85 (q, J=8.1 Hz, 1H), 6.71 (dd, J=8.0, 1.3 Hz, 1H), 6.61 (dd, J=7.8, 2.3 Hz, 1H), 5.42 - 5.35 (m, 1H), 5.23 (dd, J=6.2, 1.8 Hz, 1H), 4.79 (d, J=1.2 Hz, 1H), 4.68 (d, J=1.4 Hz, 1H), 4.46 (d, J=10.2 Hz, 1H), 4.41 (d, J=10.2 Hz, 1H), 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, 1H), 2.70 - 2.61 (m, 1H), 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, 1H), 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 30Preparation of (S)-1-(((4-carbamoylpyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0416] Step 1 - 2: General procedure C step 1-2.Step 3. Preparation of ethyl (S)-1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0417]

[0418] 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).

[0419] Step 4. (S)-1-(((4-carbamoylpyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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)-1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 845.55 (M+H) +< , 3.048 min (LCMS Method 7). 1< 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 31Preparation of (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0420] Step 1 - 2: General procedure C step 1-2.Step 3. Preparation of ethyl (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0421]

[0422] 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+1=830.55. 2.822 min (LCMS Method 3).

[0423] Step 4. (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 802.45 (M+H) +< , 2.824 min (LCMS Method 3). 1< H NMR (400MHz, CHLOROFORM-d) δ 8.21 (dd, J=5.1, 1.4 Hz, 1H), 7.69 (ddd, J=8.6, 7.0, 1.8 Hz, 1H), 6.97 (td, J=6.2, 0.9 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 5.38 (br. s., 1H), 5.21 (d, J=4.5 Hz, 1H), 4.80 (s, 1H), 4.72 (s, 1H), 4.51 (d, J=10.0 Hz 1H), 4.46 (d, J=10.0 Hz 1H), 3.37 - 3.34 (m, 1H), 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, 1H), 2.73 (d, J=15.3 Hz, 1H), 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, 1H), 1.06 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H).Example 32Preparation of (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrazin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0424] Step 1 - 2: General procedure C step 1-2.Step 3. Preparation of ethyl (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrazin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0425]

[0426] 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+1=831.55. 2.922 min (LCMS Method 3).

[0427] Step 4. (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrazin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 803.42 (M+H) +< , 2.38 min (LCMS Method 1). 1< H NMR (400MHz, CHLOROFORM-d) δ 8.27 (br. s., 2H), 8.17 (br. s., 1H), 5.39 (br. s., 1H), 5.22 (d, J=4.8 Hz, 1H), 4.79 (s, 1H), 4.73 (s, 1H), 4.62 - 4.48 (dd, J=10.5, 17.3 Hz, 2H), 3.44 - 3.32 (m, 1H), 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 α-pyridin-2-yloxy cyclohexenecarboxylic acid derivatives.

[0428] Step 1. Preparation of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13aR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0429]

[0430] A mixture of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (1 eq), ethyl 1-((pyridin-2-yloxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1eq), Na 2 CO 3 (3 eq) and Pd(Ph 3 P) 4 (0.06 eq) in 1,4-dioxane and H 2 O (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 Na 2 SO 4 , 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. 1< H 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.

[0431]

[0432] To a solution of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-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 Na 2 CO 3 . The resulting slurry was extracted with dichloromethane, washed with brine, dried over Na 2 SO 4 , 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.

[0433]

[0434] 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 33Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0435] Step 1: General procedure D step 1.Step 2. Preparation of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0436]

[0437] 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-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)acetaldehyde as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 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).

[0438] Step 3. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate as reactant. 1< H NMR (400MHz, CHLOROFORM-d) δ 8.29 (br. s., 1H), 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=53 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 α-substituted cyclohexenecarboxylic acid derivatives via alkylation of α-methyl alcohol.

[0439] Step 1. Preparation of (4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,12b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate.

[0440]

[0441] A mixture of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (1 eq), (1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methyl benzoate (1.05 eq), Na 2 CO 3 H 2 O (3 eq) and Pd(Ph 3 P) 4 (0.06 eq) in 1,4-dioxane and H 2 O (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 H 2 O. The separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine dried over Na 2 SO 4 , 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). 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-carboxylate.

[0442]

[0443] A suspension of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-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 Na 2 SO 4 , 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 α-substituted cyclohexenecarboxylic ester.

[0444]

[0445] To a solution of ethyl -4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-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 Na 2 SO 4 , and concentrated in vacuo to give crude product which was used in next step without further purification.Step 4. Preparation of α-substituted cyclohexenecarboxylic acid.

[0446]

[0447] A solution of α-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 34Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrimidin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0448] Step 1-2: General procedure E.Step 3. Preparation of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrimidin-2-yloxy)methyl)cyclohex-3-ene-1-carboxylate.

[0449]

[0450] 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).

[0451] Step 4. 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyrimidin-2-yloxy)methyl)cyclohex-3-enecarboxylate as reactant. 1< 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 35Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((7-methoxyisoquinolin-1-yl)oxy)methyl)cyclohex-3-ene-1-carboxylic acid.

[0452] Step 1-2: General procedure E.Step 3. Preparation of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((7-methoxyisoquinolin-1-yl)oxy)methyl)cyclohex-3-enecarboxylate.

[0453]

[0454] The title compound was prepared as crude product, following the procedure described in general procedure E step 3, using 1-chloro-7-methoxyisoquinoline as reactant. LC / MS: m / e 910.65 (M+H) +< , 2.98 min (LCMS Method 3).

[0455] Step 4: 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 36Preparation of 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0456] Step 1-2: General procedure E.Step 3. Preparation of ethyl 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate.

[0457]

[0458] The title compound was prepared in 41 % yield, following the procedure described in general procedure E step 3, using 2-chloronicotinonitrile as reactant. 1< H 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).

[0459] Step 4. 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid was prepared in 33 % yield, following the procedure described in general procedure E step 3 at RT, using ethyl 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate as reactant. 1< H 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=11.0, 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 α-substituted cyclohexenecarboxylic acid derivatives via silyl carboxylate.

[0460] Step 1. Preparation of (1-((benzyloxy)carbonyl)-4-oxocyclohexyl)methyl benzoate.

[0461]

[0462] To a solution of benzyl 1-(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 Na 2 SO 4 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 %). 1< H NMR (400MHz, CHLOROFORM-d) δ 7.92 (d, J=7.8 Hz, 2H), 7.65 - 7.54 (m, 1H), 7.44 - 7.37 (m, 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 (1-((benzyloxy)carbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)methyl benzoate.

[0463]

[0464] To a solution of (1-((benzyloxy)carbonyl)-4-oxocyclohexyl)methyl benzoate (4.2 g, 11.5 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)-methanesulfonamide (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 NH 4 Cl. The mixture was extracted with EtOAc, washed with brine, dried over Na 2 SO 4 , 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 %). 1< H 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 (1-((benzyloxy)carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methyl benzoate.

[0465]

[0466] A mixture of (1-((benzyloxy)carbonyl)-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-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 PdCh(dppf)-CH 2 Cl 2 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 Na 2 SO 4 , 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 %). 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-1-(buta-2,3-dien-2-yl)-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((benzyloxy)carbonyl)cyclohex-3-en-1-yl)methyl benzoate.

[0467]

[0468] A mixture of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (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 CO 3 H 2 O (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 H 2 O (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 Na 2 SO 4 , 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 α-substituted cyclohexenecarboxylic ester (1.8 g, 55 %). 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-en-1-yl)methyl benzoate.

[0469]

[0470] A suspension of (4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 K 3 PO 4 (2.24 g, 10.55 mmol) in acetonitrile (20 mL) was flushed with N 2 , 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 Na 2 SO 4 , 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). 1< H 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-carboxylate.

[0471]

[0472] To a solution of (1-((benzyloxy)carbonyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-en-1-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 Na 2 SO 4 , 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 1-((aryloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0473]

[0474] To a solution of benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-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 Na 2 SO 4 , 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 1-((aryloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0475]

[0476] 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 N 2 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 1-((aryloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-l-carboxylic acid.

[0477]

[0478] 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 1-((aryloxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.Example 37Preparation of 1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,1lbR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0479] Step 1-6: General procedure F steps 1-6Step 7. Preparation of benzyl 1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0480]

[0481] 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+1=917.65, 4.765 min (LCMS Method 7).Step 8. Preparation of tert-butyldimethylsilyl 1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0482]

[0483] The title compound was prepared as a solid, following the procedure described in general procedure F, step 8, using benzyl 1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS m / z M+1=941.75, 3.467 min (LCMS Method 7).

[0484] Step 9. 1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino )ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid was prepared in 10.7% yield as a solid, following the procedure described in general procedure F, step 9, using tert-butyldimethylsilyl 1-(((4-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,1lbR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 827.60 (M+H) +< , 3.00 min (LCMS Method 7). 1< HNMR (400MHz, CHLOROFORM-d) δ 8.31 (d, J=5.0 Hz, 1H), 7.21 (dd, J=5.1, 1.1 Hz, 1H), 7.14 (s, 1H), 5.36 (br. s., 1H), 5.21 (d, J=4.8 Hz, 1H), 4.84 (s, 1H), 4.75 (s, 1H), 4.52 (dd, J=4.3, 10.3 Hz, 1H), 4.45 (dd, J=1.8, 10.3 Hz, 1H), 3.28 - 3.15 (m, 8H),3.14 - 3.06 (m, 4H), 2.98 - 2.87 (m, 1H), 2.76 (td, J=11.1, 5.4 Hz, 1H), 2.45 - 2.58 (m, 1H), 2.35 - 2.21 (d, J=8.5 Hz, 1H), 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 38Preparation of 1-(((5-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0485] Step 1-6: General procedure F steps 1-6Step 7. Preparation of benzyl 1-(((5-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0486]

[0487] 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+1=917.65, 3.136 min (LCMS Method 7).Step 8: Preparation of tert-butyldimethylsilyl 1-(((5-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0488]

[0489] The title compound was prepared as a solid, following the procedure described in general procedure F, step 8, using benzyl 1-(((5-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS m / z M+1=941.70, 3.311 min (LCMS Method 7).

[0490] Step 9. 1-(((5-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 1-(((5-cyanopyridin-2-yl)oxy)methyl)-4-(1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 827.55 (M+H) +< , 3.049 min (LCMS Method 7). 1< H NMR (400MHz, METHANOL-d 4 ) δ 8.52 (d, J=2.3 Hz, 1H), 7.96 (dd, J=8.8, 2.3 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.35 (br. s., 1H), 5.21 (d, J=4.5 Hz, 1H), 4.84 (s, 1H), 4.75 (s, 1H), 4.56 (dd, J= 2.8, 10.5 Hz, 1H), 4.49 (d, J=10.5 Hz, 1H), 3.28 - 3.15 (m, 8H), 3.14 - 3.06 (m, 3H), 2.93 (dt, J=14.2, 5.2 Hz, 1H), 2.81 - 2.71 (m, 1H), 2.67 - 2.57 (m, 1H), 2.35 - 2.21 (m, 1H), 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, 1H), 1.20 - 1.07 (m, 1H), 1.18 (s, 3H), 1.11 (s, 3H), 1.02 - 0.98 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H).Example 39Preparation of 1-(((6-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,1lbR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0491] Step 1-6: General procedure F steps 1-6Step 7. Preparation of benzyl 1-(((6-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0492]

[0493] 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+1=917.65, 3.083 min (LCMS Method 7).Step 8. Preparation of tert-butyldimethylsilyl 1-(((6-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0494]

[0495] The title compound was prepared as a solid, following the procedure described in general procedure F, step 8, using benzyl 1-(((6-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS m / z M+1=941.70, 3.516 min (LCMS Method 7).

[0496] Step 9. 1-(((6-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11as,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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 1-(((6-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,1 1a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 827.55 (M+H) +< , 3.003 min (LCMS Method 7). 1< H NMR (400MHz, METHANOL-d 4 ) 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 40Preparation of 1-(((6-carbamoylpyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR, 11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid.

[0497] Step 1. Preparation of methyl 1-(((6-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate.

[0498]

[0499] The title compound was prepared as a solid, following the procedure described in general procedure F, step 7, using 6-chloropicolinonitrile and methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-carboxylate instead of benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-ene-1-carboxylateas the reactants. LC / MS m / z M+1=841.60, 3.164 min (LCMS Method 7).

[0500] Step 2. 1-(((6-carbamoylpyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylate as the reactant. LC / MS: m / e 845.60 (M+H) +< , 2.931 min (LCMS Method 7). 1< H NMR (400MHz, METHANOL-d 4 ) 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.

[0501]

[0502] To a solution of (methylsulfonyl)ethene (10.0 g, 94 mmol) in benzene (50 mL) was added (buta-1,3-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 CDCl 3 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 (prc-chillcd 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 µL aliquot was removed, flash dried into a film, and was analyzed by NMR in CDCl 3 . 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: 1< H 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-(cis-1-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde and 2-(trans-1-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde.

[0503] Step 1. Preparation of (cis)-1-allyl-4-(methylsulfonyl)cyclohexanol and (trans)-1-allyl-4-(methylsulfonyl)cyclohexanol.

[0504]

[0505] 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 NHaCl 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 MgSO 4 , 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 (cis)-1-allyl-4-(methylsulfonyl)cyclohexanol (374 mg, 1.713 mmol, 29% yield) as a white solid and (trans)-1-allyl-4-(methylsu l fonyl)cyclohexanol (551 mg, 2.52 mmol, 43% yield) as a colorless oil.(cis)-1-allyl-4-(methylsulfonyl)cyclohexanol:

[0506] 1< H NMR (400MHz, CDCl 3 ) 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, CDCl 3 ) δ 132.50, 120.02, 69.06, 62.26, 47.86, 36.85, 35.67, 21.13. The structure of (cis)-1-allyl-4-(methylsulfonyl)cyclohexanol was confirmed by X-ray crystallography.(trans)-1-allyl-4-(methylsulfonyl)cyclohexanol:

[0507] 1< HNMR (400MHz, CDCl 3 ) 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, CDCl 3 ) δ 132.62, 120.19, 69.20, 62.41, 48.00, 36.98, 35.83, 21.29.Step 2a. Preparation of 2-((cis)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde.

[0508]

[0509] (trans)-1-Allyl-4-(methylsulfonyl)cyclohexanol (3.4 g, 15.57 mmol) was dissolved in CH 2 Cl 2 (160 mL) and MeOH (32.0 mL) in a 500 mL round bottom flask. N-Methylmorpholine-N-oxide (NMO) (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-((1s,4s)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde (3.31 g, 15.03 mmol, 96% yield) as a white solid: 1< H NMR (400MHz, CHLOROFORM-d) δ 9.87 (t, J=1.1 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-((trans)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde.

[0510]

[0511] (1r,4r)-1-Allyl-4-(methylsulfonyl)cyclohexanol (2 g, 9.16 mmol) was dissolved in CH 2 Cl 2 (80 mL) and MeOH (16.00 mL) in a 500 mL round bottom flask. N-Methylmorpholine-N-oxide (NMO) (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-((1r,4r)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)acetaldehyde (1.58 g, 7.17 mmol, 78% yield) as a white solid: 1< H 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 A1. Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylic acid.

[0512] Step 1. Preparation of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylate.

[0513]

[0514] A mixture of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylate (65 mg, 0.097 mmol), 2-((1s,4s)-1-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 MgSO 4 , 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylate (69 mg, 81% yield) as a colorless solid: 1< H NMR (500MHz, CHLOROFORM-d) δ 8.15 (dd, J=5.0, 1.8 Hz, 1H), 7.56 (ddd, J=8.5, 6.9, 2.0 Hz, 1H), 6.87 (td, J=6.1, 0.7 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.37 (br. s., 1H), 5.20 (d, J=6.1 Hz, 1H), 4.75 (d, J=1.5 Hz, 1H), 4.62 (s, 1H), 4.50 - 4.44 (m, 1H), 4.43 - 4.37 (m, 1H), 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, 1H), 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 C 53 H 81 N 2 O 6 S 873.6], t R = 4.67 min (LCMS Method 14).

[0515] Step 2. A solution of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)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 HCl (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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylic acid, TFA (48.4 mg, 67% yield) as a white amorphous solid: 1< H NMR (500MHz, Acetic Acid-d 4 ) δ 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=16.0 Hz, 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 C 51 H 77 N 2 O 6 S 845.6], t R = 4.36 min (LCMS Method 14); HPLC (Analytical HPLC Method 1): t R = 18.86 min; HPLC (Analytical HPLC Method 2): t R = 20.24 min.Example A2. Preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylic acid.

[0516] Step 1. Preparation of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylate.

[0517]

[0518] A mixture of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylate (65 mg, 0.097 mmol), 2-((1r,4r)-1-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-((1r,4r)-1-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 MgSO 4 , 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylate (42.4 mg, 50% yield) as a colorless foam: 1< H 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 C 53 H 81 N 2 O 6 S 873.6], t R = 4.62 min (LCMS Method 14).

[0519] Step 2. A solution of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)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 HCl (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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-((pyridin-2-yloxy)methyl)cyclohex-3-enecarboxylic acid, TFA (31.3 mg, 67% yield) as a white amorphous solid. 1< H 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 C 51 H 77 N 2 O 6 S 845.6], t R = 4.33 min (LCMS Method 14); HPLC (Analytical HPLC Method 1): t R = 18.86 min; HPLC (Analytical HPLC Method 2): t R = 20.48 min.Example A3. Preparation of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid.

[0520] Step 1. Preparation of ((S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate.

[0521]

[0522] To a flask containing (1R,3aS,5aR,5bR,7aR1aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 N 2 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate (1.15 g, 92% yield) as an off-white solid: 1< H 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 C 46 H 65 NO 4 696.5], t R = 2.60 min (LCMS Method 15).Step 2. Preparation of (S)-ethyl 4-((1R,3aS,5aR,5bR,7aR11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylate.

[0523]

[0524] To a solution of ((S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-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 NaHCO 3 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 MgSO 4 , filtered, and concentrated to afford (S)-ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bF,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylate (0.535 g, 59% yield) as a white solid. The crude product was used directly in the next step. 1< H NMR (400MHz, CHLOROFORM-d) δ 5.34 (t, J=3.8 Hz, 1H), 5.20 (dd, J=6.1, 1.9 Hz, 1H), 4.75 (d, J=2.0 Hz, 1H), 4.63 (d, J=1.3 Hz, 1H), 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) m / e 614.6 [(M+H) +< , calcd for C 39 H 6 NO 3 Na 614.5], t R = 4.28 min (LCMS Method 14).Step 3. Preparation of (S)-ethyl 4-((1R,3aS,5aR5bR7aR11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-cyanopyridin-2-yl)oxy)methyl)cyclohex-3-enecarboxylate.

[0525]

[0526] To a solution of (S)-ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylate (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 tert-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 NaHCO 3 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 MgSO 4 , filtered, and concentrated.

[0527] 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b, 8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-cyanopyridin-2-yl)oxy)methyl)cyclohex-3-enecarboxylate (344 mg, 59% yield) as an off-white solid: 1< H 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, 5.0 Hz, 1H), 5.38 (br. s., 1H), 5.21 (dd, J=6.1, 1.6 Hz, 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) m / e 694.7 [(M+H) +< , calcd for C 45 H 64 N 3 O 3 694.5], t R = 4.52 min (LCMS Method 14).Step 4. Preparation of (S)-ethyl 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4 ((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate.

[0528]

[0529] (S)-Ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-cyanopyridin-2-yl)oxy)methyl)cyclohex-3-enecarboxylate (150 mg, 0.216 mmol) and 2-((1s,4s)-1-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 MgSO 4 , 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 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((lR,3aS,5aR,5bR,7aR,llaS,llbR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (134.6 mg, 69% yield) as a white foam: 1< H 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) m / e 898.7 [(M+H) +< , calcd for C 54 H 80 N 3 O 6 S 898.6], t R = 4.44 min (LCMS Method 14).

[0530] Step 5. To a solution of (S)-ethyl 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 µL). 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)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (51.6 mg, 38% yield) as a white amorphous solid: 1< H NMR (500MHz, Acetic Acid-d 4 ) 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 (s, 1H), 5.27 (d, J=4.7 Hz, 1H), 4.83 (s, 1H), 4.72 (s, 1H), 4.68 - 4.61 (m, 2H), 3.47 - 3.33 (m, 2H), 3.08 - 2.99 (m, 1H), 2.96 (s, 3H), 2.90 - 2.81 (m, 1H), 2.74 (d, J=15.6 Hz, 1H), 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 C 52 H 76 N 3 O 6 S 870.5], t R = 1.31 min (LCMS Method 16); HPLC (Analytical HPLC Method 3): t R = 12.19 min; HPLC (Analytical HPLC Method 4): t R = 11.64 min.Alternate route for the preparation of Example A3Preparation of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid.

[0531] Step 1. Preparation of ((S)-1-(ethoxycarbonyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,lla-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-en-1-yl)methyl benzoate.

[0532]

[0533] ((S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate (7.63 g, 10.96 mmol), and 2-((1s,4s)-1-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 MgSO 4 , 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)-1-(ethoxycarbonyl)-4-((1R,3aS,5aR,5bR,7aR,11aS, 11bR, 13aR, 13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-en-1-yl)methyl benzoate (8.81 g, 89% yield) as a white solid: 1< H 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 C 55 H 82 NO 7 S 900.6], t R = 4.55 min (LCMS Method 14).Step 2. Preparation of (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylic acid.

[0534]

[0535] To a solution of ((S)-1-(ethoxycarbonyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-en-1-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 HCl (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 C18 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylic 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. 1< H 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 C 46 H 74 NO 6 S 768.5], tR = 3.85 min. (LCMS Method 14).

[0536] Step 3. To a solution of (S)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(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 CH 2 Cl 2 to elute the high R f material and then 12% methanol in CH 2 Cl 2 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)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,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 / H 2 O (60 / 40) and was slowly passed through an AG 1-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)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, HCl (4.26 g, 66% yield) as a white amorphous solid: 1< H NMR (500MHz, Acetic Acid-d 4 ) 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 C 52 H 76 N 3 O 6 S 870.5], t R = 4.56 min (LCMS Method 14); HPLC (HPLC Method 3): t R = 13.13 min; HPLC (HPLC Method 4): tR = 12.46 min.Example A4. Preparation of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid.

[0537] Step 1. Preparation of (S)-ethyl 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate.

[0538]

[0539] (S)-Ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-cyanopyridin-2-yl)oxy)methyl)cyclohex-3-enecarboxylate (150 mg, 0.216 mmol) and 2-((1r,4r)-1-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 MgSO 4 , 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 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (131 mg, 68% yield) as a white foam: 1< H NMR (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 m / e 898.7 [(M+H) +< , calcd for C 54 H 79 N 3 O 6 S 898.6], t R = 4.44 min (LCMS Method 14).

[0540] Step 2. To a solution of (S)-ethyl 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 HCl (250 µL). 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)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1r,4S)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid, TFA (69 mg, 48% yield) as a white amorphous solid: 1< H 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 C 52 H 75 N 3 O 6 S 870.5], t R = 2.37 min (LCMS Method 15); HPLC (Analytical HPLC Method 3): t R = 16.00 min; HPLC (Analytical HPLC Method 4): t R = 13.90 min.Example A5. Preparation of (R)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid.

[0541] Step 1. Preparation of ((R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate.

[0542]

[0543] To a flask containing (1R,3aS,5aR,5bR,7aR11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (2.2 g, 3.94 mmol) was added (S)-(1-(ethoxycarbonyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-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 N 2 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(ethoxycarbonyl)cyclohex-3-en-1-yl)methyl benzoate (2.47 g, 90% yield) as an off-white solid: 1< H 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 C 46 H 65 NO 4 696.5], t R = 2.55 min (LCMS Method 15).Step 2. Preparation of (R)-ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8.11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13, 13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylate.

[0544]

[0545] To a solution of ((R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-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 NaHCO 3 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 MgSO 4 , filtered, and concentrated to afford (R)-ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylate (450 mg, 44% yield) as a white solid. The crude product was used directly in the next step. 1< H NMR (400MHz, CHLOROFORM-d) δ 5.34 (br. s., 1H), 5.20 (dd, J=6.0, 1.8 Hz, 1H), 4.75 (d, J=2.0 Hz, 1H), 4.62 (s, 1H), 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 C 39 H 61 NO 3 Na 614.5], t R = 4.27 min (LCMS Method 14).Step 3. Preparation of (R)-ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-cyanopyridin-2-yl)oxy)methyl)cyclohex-3-enecarboxylate.

[0546]

[0547] To a solution of (R)-ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-arnino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(hydroxymethyl)cyclohex-3-enecarboxylate (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 tert-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 NaHCO 3 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 MgSO 4 , 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-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-cyanopyridin-2-yl)oxy)methyl)cyclohex-3-enecarboxylate (365 mg, 0.526 mmol, 76% yield) as an off-white solid: 1< H NMR (400MHz, CHLOROFORM-d) δ 8.34 (dd, J=5.0, 2.0 Hz, 1H), 7.88 (dd, J=7.4, 1.9 Hz, 1H), 6.99 (dd, J=7.5, 5.0 Hz, 1H), 5.38 (br. s., 1H), 5.21 (dd, J=6.3, 1.8 Hz, 1H), 4.74 (d, J=2.0 Hz, 1H), 4.62 (dd, J=2.1, 1.4 Hz, 1H), 4.60 - 4.52 (m, 2H), 4.19 (qd, J=7.1, 2.5 Hz, 2H), 2.73 (d, J=17.1 Hz, 1H), 2.56 (td, J=10.9, 5.4 Hz, 1H), 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 C 45 H 64 N 3 O 3 694.5], t R = 4.51 min (LCMS Method 14).Step 4. Preparation of (R)-ethyl 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1s,4R)-1-hydroxy-4-(methylsulfonyl)cyclohexyl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate.

[0548]

[0549] (R)-Ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-1-(((3-cyanopyridin-2-yl)oxy)methyl)cyclohex-3-enecarboxylate (150 mg, 0.216 mmol) and 2-((1s,4s)-1-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 MgSO 4 , filtered, and concentrated....

Claims

1. A compound of Formula I, including pharmaceutically acceptable salts thereof: wherein R1 is isopropenyl or isopropyl; A is -C1-6 alkyl-ORo; wherein R0 is heteroaryl-Q0; Q0 is selected from the group of -H, -CN, -C1-6 alkyl, -COOH, -Ph, -OC1-6 alkyl, -halo, - CF3, Y is selected from the group of -COOR2, -C(O)NR2SO2R3, -C(O)NHSO2NR2R2, - SO2NR2C(O)R2, -tetrazole, and -CONHOH, wherein n = 1-6; R2 is -H, -C1-6 alkyl, -alkylsubstituted C1-6 alkyl or-arylsubstituted C1-6 alkyl; W is absent, or is -CH2- or -CO-; R3 is -H, -C1-6 alkyl or -alkylsubstituted C1-6 alkyl; R4 is selected from the group of -H, -C1-6 alkyl, -C1-6 alkyl-C3-6 cycloalkyl, -C1-6 substituted -C1-6 alkyl, -C1-6 alkyl-Q1, -C1-6 alkyl-C3-6 cycloalkyl-Q1, aryl, heteroaryl, substituted heteroaryl, -COR6, -SO2R7, -SO2NR2R2, and wherein G is selected from the group of -O-, -SO2- and -NR12-; wherein Q1 is selected from the group of -C1-6 alkyl, - C1-6 fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, -CF3, -OR2, -COOR2, -NR8R9, -CONR8R9 and -SO2R7; R5 is selected from the group of -H, -C1-6 alkyl, -C3-6 cycloalkyl, -C1-6 alkylsubstituted alkyl, -C1-6 alkyl-NR8R9, -COR3, -SO2R7 and -SO2NR2R2; with the proviso that R4 or R5 is not -COR6 when W is -CO-; with the further proviso that only one of R4 or R5 is selected from the group of -COR6, -COCOR6, -SO2R7 and -SO2NR2R2; R6 is selected from the group of -H, -C1-6 alkyl, -C1-6 alkyl-substitutedalkyl, -C3-6 cycloalkyl, -C3-6 substitutedcycloalkyl-Q2, -C1-6 alkyl-Q2, -C1-6 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, -C1-6 alkyl, -C1-6 substituted alkyl, -C3-6 cycloalkyl, -CF3, aryl, and heteroaryl; Rs and R9 are independently selected from the group of -H, -C1-6 alkyl, -C1-6 substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -C1-6 alkyl-Q2, and -COOR3, or R8 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 R8 or R9 can be -COOR3; R10 and R11 are independently selected from the group of -H, -C1-6 alkyl, -C1-6 substituted alkyl and -C3-6 cycloalkyl; R12 is selected from the group of -H, -C1-6 alkyl, -alkylsubstituted C1-6 alkyl, - CONR2R2, -SO2R3, and -SO2NR2R2; R13 and R14 are independently selected from the group of -H, -C1-6 alkyl, -C3-6 cycloalkyl, - C1-6 substituted alkyl, -C1-6 alkyl-Q3, -C1-6 alkyl-C3-6 cycloalkyl-Q3, and C1-6 substituted alkyl-Q3; Q3 is selected from the group of heteroaryl, substituted heteroaryl, -NR2R12, - CONR2R2, -COOR2, -OR2, and -SO2R3; R15 is selected from the group of -C1-6 alkyl, -C3-6 cycloalkyl, -C1-6 substituted alkyl, -C1-6 alkyl-Q3, -C1-6 alkyl-C3-6 cycloalkyl-Q3 and -C1-6 substituted alkyl-Q3; R16 is selected from the group of -H, -C1-6 alkyl, -NR2R2, and -COOR2; with the proviso that when V is -NR12-; R16 is not -NR2R2; and R17 is selected from the group of -H, -C1-6 alkyl, -COOR3, and aryl.

2. The compound of claim 1, wherein in the R0 group the heteroaryl moiety is selected from the group of 3. The compound of claim 2, wherein R1 is isopropenyl.

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

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

6. The compound of claim 1, wherein R4 is -C1-6 alkyl-Q1.

7. The compound of claim 6, wherein Q1 is -NR8R9.

8. The compound of claim 7, wherein when R8 and R9 are taken together with the adjacent -N to form a cycle, the cycle is selected from the group of:

9. The compound of claim 8, wherein R7 and R16 are each selected from the group of -H and -C1-6 alkyl.

10. The compound of claim 1, wherein Q0 is -CN.

11. The compound of claim 1, wherein R1 is isopropenyl, in the R0 group the "heteroaryl" moiety is selected from the group of: Y is -COOH, R4 is -C1-6 alkyl-Q1, Q1 is -NR8R9, and R8 and R9 are taken together with the adjacent -N to form a cycle which is selected from the group of:

12. A compound according to claim 1, including pharmaceutically acceptable salts thereof, which is selected from the group of:

13. A compound according to claim 1, including pharmaceutically acceptable salts thereof, which is and 14. A compound, including pharmaceutically acceptable salts thereof according to claim 13, which is :

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

16. A compound or pharmaceutically acceptable salt thereof as claimed in claims 1-14 for use in therapy.

17. A compound or pharmaceutically acceptable salt thereof as claimed in claims 1-14 for use in treating a mammal infected with the HIV virus.