NITROGEN RING CONTAINING COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No. 61/470,606, filed April 1, 2011.

FIELD OF THE INVENTION

The present invention is in the area of methods and compositions for the treatment and prophylaxis of inflammatory disorders and, in particular, for the treatment or prophylaxis of respiratory inflammatory diseases such as asthma.

BACKGROUND OF THE INVENTION

A growing consensus among scientists is that common disorders such as asthma, atherosclerosis, colon cancer, diabetes and Alzheimer's disease are all caused in part by a chronic inflammatory syndrome. Generally, chronic inflammation is involved in diseases as diverse as allergy, anemia, aortic valve stenosis, arthritis, atherosclerosis, cancer, heart valve dysfunction, obesity, diabetes, congestive heart failure, digestive system diseases, and Alzheimer's disease (Brouqui et al. (1994) Am J Med. 97:451-8; Devaux et al. (1997) Eur Heart J. 18:470-9.; De Keyser et al. (1998) Rheum Dis Clin North Am. 24:785). Chronic inflammation inevitably causes tissue damage and is accompanied by simultaneous attempts at healing and repair. The exact nature, extent and time course of chronic inflammation is variable, and depends on a balance between the causative agent and the attempts of the body to remove it. Disorders associated with inflammation are debilitating to individuals suffering from them and cost billions in reduced productivity and increased medical expenses.

Asthma is one of the most common chronic health conditions and is on the rise due to irritants such as pollution and chronic exposure to indoor allergens such as cigarette smoke, cockroaches, dust mites, mold, animals, pollen, cold air, exercise, stress, and respiratory infections. Asthma and related respiratory disorders such as chronic obstructive pulmonary disease (COPD) are chronic or recurring inflammatory conditions in which the airway develops increased responsiveness to various stimuli, characterized by bronchial hyper- responsiveness, inflammation, increased mucus production, and intermittent airway obstruction.

Coronary heart disease (CHD) remains the leading cause of death in the industrialized countries. Cardiovascular disease has been linked to several causative factors, which include hypercholesterolemia, hyperlipidemia, and the expression of VCAM-1 on vascular endothelial cells. The primary cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids in the arterial vessel wall, resulting in a narrowing of the vessel passages and ultimately hardening the vascular system, which is likely mediated by the expression of certain inflammatory cytokines and VCAM-1. Atherosclerosis as manifested in its major clinical complication, ischemic heart disease, continues to be a major cause of death in industrialized countries. It is now well accepted that atherosclerosis can begin with local injury to the arterial endothelium followed by proliferation of arterial smooth muscle cells from the medial layer to the intimal layer along with the deposition of lipid and accumulation of foam cells in the lesion. As the atherosclerotic plaque develops it progressively occludes more and more of the affected blood vessel and can eventually lead to ischaemia or infarction.

Cells that are chronically exposed to higher than normal levels of polyunsaturated fatty acids (PUFAs) or their oxidized counterparts can initiate an immune response that is not normal and out of proportion to the threat presented, leading to a diseased state. The oversensitization of vascular endothelial cells to PUFAs and ox-PUFAs can accelerate the formation, for example, of atherosclerotic plaque.

Many inflammatory disorders are mediated by certain cytokines. These include the IL-6 and IL-8 families. Regulation of these and other related cytokines can be a strategy when overstimmulation of the immune responses leads to adverse events.

Cytokines produced predominantly by activated immune cells such as microglia and are involved in the amplification of inflammatory reactions. These include IL-1, IL-6, TNF-a, and TGF-B.

The IL-6 family all act through receptors sharing a common gpl30 subunit and includes interleukin-6, interleukin-11, ciliary neurotrophic factor, LIF, oncostatin M and cardiotrophin-1. IL-6 is a pleiotropic cytokine that plays an important role in host defense by regulating immune and inflammatory responses. Produced by activated T cells, monocytes, fibroblasts, endothelial cells and keratinocytes, IL-6 has diverse biological functions. IL-6 acts in synergy with IL-1 and TNF-alpha in many immune responses, including T-cell activation. In particular, IL-6 is the primary inducer of the acute-phase response in liver. IL-6 also enhances the differentiation of B-cells and their consequent production of immunoglobulin. It also synergizes with IL-3 in megakaryocyte development and platelet production, induces expression of hepatic acute-phase proteins, and regulates bone metabolism. Glucocorticoid synthesis is also enhanced by IL-6. Unlike IL-1, IL-2 and TNF-a, IL-6 does not induce cytokine expression; its main effects, therefore, are to augment the responses of immune cells to other cytokines.

In contrast to IL-6, IL-8 is a chemokine, an interleukin that belongs to an ever- expanding family of proteins that exert chemoattractant activity to leukocytes and fibroblasts. IL-8 is produced by monocytes, neutrophils, and NK cells and is chemoattractant for neutrophils, basophils and T-cells. In addition, IL-8 activates neutrophils to degranulate.

Probucol derivatives

Derivatives of probucol have been developed as therapeutics, for example, for the treatment of cardiovascular disease and as anti-inflammatory agents. Probucol contains two hydroxyl groups and can be modified to form mono-substituted or di-substituted derivatives. Mono-esters and ethers of probucol have been reported to be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and dermatitis. Methods for treating transplant rejection using mono-substituted derivatives of probucol also have been reported. See U.S. Patent Publication No. 2004/138147.

U.S. Patent No. 5,262,439 to Parthasarathy discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups that increase the water solubility of the compound. A series of French patents disclose that certain probucol derivatives are hypocholesterolemic and hypolipemic agents: Fr 2168137 (bis 4hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); Fr 2140769 (benzofuryloxyalkanoic acid derivatives of probucol); Fr 2134810 (bis-(3-alkyl-5-t-alkyl-4-thiazole-5-carboxy)phenylthio)alka nes; FR 2133024 (bis-(4 nicotinoyloxyphenylthio)-propanes; and Fr 2130975 (bis(4- phenoxyalkanoyloxy)phenylthio)alkanes).

European Patent Application No. 348 203 discloses phenolic thioethers which inhibit the denaturation of LDL and the incorporation of LDL by macrophages. Hydroxamic acid derivatives of these compounds are disclosed in European Patent Application No. 405 788 and are alleged as useful for the treatment of arteriosclerosis, ulcer, inflammation and allergy. Carbamoyl and cyano derivatives of the phenolic thioethers are disclosed in U.S. Patent No. 4,954,514 to Kita, et al. U.S. Patent No. 6,121,319 and corresponding WO 98/51662 and US Patent No.

6,147,250 filed by AtheroGenics, Inc. describe certain probucol derivatives and their use for the treatment of disorders mediated including inflammatory and cardiovascular disorders.

WO 01/70757 (also U.S. 6,852,878) filed by AtheroGenics, Inc. also describes the use of certain thioethers of the following formula, and pharmaceutically acceptable salts thereof:

wherein

R _a , ¾, R _c , and R^ are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) CMO alkyl or substituted CMO alkyl, terminated by sulfonic acid, (iv) Ci-i ₀ alkyl or substituted CMO alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted CMO alkyl-O-C(O)-Ci.i ₀ alkyl, (vi) straight chained polyhydroxylated C ₃ -i ₀ alkyl; (vii) -(CR ₂ )i-6- COOH, wherein R is independently hydrogen, halo, amino, or hydroxy, and wherein at least one of the R substituents is not hydrogen; or (viii) -(CR ₂ )i-6~X, wherein X is aryl, heteroaryl, or heterocycle, and R is independently hydrogen, halo, amino, or hydroxy.

Meng et al., discloses a series of phenolic inhibitors of TNF-inducible expression of VCAM-1 with concurrent antioxidant and lipid-modulating properties. The compounds disclosed have demonstrated efficacies in animal models of atherosclerosis and

hyperlipidemia. (Novel Phenolic Antioxidants As Multifunctional Inhibitors Of Inducible VCAM-1 Expression For Use In Atherosclerosis, Bioorganic & Medl Chem Ltrs. 12(18), 2545-2548, 2002).

WO 05/030721 to Nippon Chemiphar Co., Ltd. describes certain piperidine derivatives as antioxidants. These compound are of the formula:

wherein Ri represents an alkyl group having 1-8 carbon atoms or the like; R ₂ represents a hydrogen atom, an alkyl group having 1-8 carbon atoms, an alkylcarbonyl group having 2-8 carbon atoms or the like; and R ₃ and R4 may be the same or different and represent alkyl groups having 1-8 carbon atoms or the like.

WO 91/01124 and related U.S. 5,981,603 and U.S. 5,874,478 to Biodor U.S. Holding and Vyrex Corp. also describes certain compounds for use as antioxidants for treatment of viral infections. These compounds are of the general structure:

wherein n = 1, 2, 3, or 4, wherein m =

0 or 1, wherein X represents O, S or CH ₂ , wherein Rj represents hydrogen or tertiary butyl or lower alkyl of from one to six carbon atoms, inclusive, R ₂ represents tertiary butyl or lower alkyl of from one to six carbon atoms, and wherein R ₃ represents hydrogen or alkyl or aryl or mixed alkyl/aryl, containing a total of 5 to 25 carbon atoms. One of the compounds specifically identified in the application is of the following:

There remains a need for improved compounds and methods for the treatment of chronic inflammatory disorders, in particular for respiratory inflammatory disorders mediated by cytokines. In particular there is a need for improved treatments for chronic respiratory disorders such as asthma.

It is therefore an object of the present invention to provide new compounds, pharmaceutical compositions and methods for the treatment of inflammatory disorders.

It is a further object of the invention to provide compounds, compositions and methods of treating disorders and diseases mediated by inflammatory cytokines, including respiratory and cardiovascular inflammatory diseases.

It is yet another object of the invention to treat or prevent certain chronic disorders such as diabetes. SUMMARY OF THE INVENTION

It has been discovered that certain piperidine-containing compounds are useful in the treatment or prophylaxis of inflammatory conditions. In particular, compounds described below are useful for treating respiratory inflammation such as found in asthma as well as other inflammatory disorders such as atherosclerosis or arthritis, or for treatment or prevention of diabetes.

In one embodiment, compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including administration of a compound of Formula I, or its pharmaceutically acceptable salt, ester, derivative or prodrug, are provided:

(I)

wherein:

R ^! , R ² , R ³ , and R ⁴ are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, Ci-C ₆ branched alkyl, C1-C6 cyclic alkyl, hydroxyalkyi, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, and alkaryl;

X and Y can be the same or different and are independently a saturated Ci-C ₆ straight alkyl;

W is selected from the group consisting of R ⁵ , R ⁵ -OH, R ⁵ -C(0)OH, -C(0)-R ⁵ , -C(O)- N(H)-R ⁵ , -C(0)-NR ⁵ R ⁶ , -C(0)-N(H)-C(0)-R ⁵ , and -C(0)-N(H)-S(0) ₂ -R ⁵ ;

Z is selected from the group consisting of R ⁷ , R ⁷ -OH, R ⁷ -C(0)OH, -C(0)-R ⁷ , -C(O)- N(H)-R ⁷ , -C(0)-NR ⁷ R ⁸ , -C(0)-N(H)-C(0)-R ⁷ , and -C(0)-N(H)-S(0) ₂ -R ⁷ ;

Q is selected from the group consisting of R ⁹ , R ⁹ -OH, R ⁹ -C(0)OH, -OH, -OR ⁹ , -C(O)- R ⁹ , -C(0)-OR ⁹ , -C(0)-C(0)-OR ⁹ , -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ⁹ , - C(0)-NR R ¹⁰ , -C(0)-N(H)-C(0)-R ⁹ , -C(0)-N(H)-S(0) ₂ -R ⁹ , -S(0) ₂ -R ⁹ , and -C(0)-H;

R ⁵ , R ⁷ and R ⁹ are the same or different and are independently selected from the group consisting of hydrogen, Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyi, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl;

R ⁶ , R ⁸ and R ¹⁰ are the same or different and are independently selected from the group consisting of hydrogen, Ci-C ₆ straight alkyl, Ci-C ₆ branched alkyl, Ci-C ₆ cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl;

wherein each option for R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , X, Y, W, Z, Q, may be optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^U R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , -C(0)-NH ₂ , -C(0)-N(H)R ^u , -C(0)-NR ⁿ R ¹² , - S(0) _n -R ⁶ , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ⁿ and -S(0) ₂ -NR ^u R ¹²

R ⁵ and R ⁶ taken together or R ⁷ and R ⁸ taken together or R ⁹ and R ¹⁰ taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ¹¹ , - C(0)R ⁿ , -CCO^NH^ -C^-N^^^ -C^-NR ¹¹ ^ ² , -S(0) _n -R ⁿ , -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ⁿ and -S(0) ₂ -NR ⁿ R ¹² ;

R ¹¹ and R ¹ are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more

independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;

R ¹¹ andR ¹² taken together form a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

n is 0, 1 or 2;

with the proviso that when Q is hydrogen, Ci-g alkyl or C _2-8 alkyl carbonyl, and X and Y are substituted with Ci.g alkyl, then both W and Z are not hydrogen.

In a particular embodiment, R ¹ , R ² , R ³ , and R ⁴ are independently selected from C] -C6 straight alkyl or Ci-C ₆ branched alkyl. In a more particular embodiment, R ¹ , R ² , R ³ , and R ⁴ are tert-butyl.

In another particular embodiment, X and Y can be the same or different and are independently selected from -CH ₂ - or -CH ₂ -CH ₂ -. In a particular embodiment, one of W and Z is not hydrogen. In one embodiment, W is hydrogen. In a particular embodiment when W is hydrogen, Z and Q are not hydrogen. In a particular embodiment, W is hydrogen and Z is selected from the group consisting of ⁷ , -C(0)-R ⁷ , -C(0)-N(H)-R ⁷ , C(0)-NR ⁷ R ⁸ , -C(O)- N(H)-C(0)-R ⁷ , and -C(0)-N(H)-S(0) ₂ -R ⁷ .

In another principle embodiment, compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including administration of a compound of Formula II, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug, are provided:

(II)

wherein:

Zi is selected from the group consisting of Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,

alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, acyl, -C(0)-R ^7* , -C(0)-N(H)-R ^7* , -C(O)- NR ^7* R ^8* , -C(0)-N(H)-C(0)-R ^7* , and -C(0)-N(H)-S(0) ₂ -R ^7* ;

Qi is selected from the group consisting of Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,

alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, -OH, -OR ^9* , -C(0)-R ^9* , -C(0)-OR ^9* , -C(O)- C(0)-OR ^9* , -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ^9* , -C(0)-NR ^9* R ^10* , - C(0)-N(H)-C(0)-R ^9* , -C(0)-N(H)-S(0) ₂ -R ^9* , and -C(0)-H;

R ^7* and R ^9* are the same or different and are independently selected from the group consisting of hydrogen, Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Q-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl;

R ^6* , R ^8* and R ^10* are the same or different and are independently selected from the group consisting of hydrogen, Ci-C ₆ straight alkyl, Ci-C ₆ branched alkyl, C C6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl;

wherein each option for R ^6* , R ^7* , R ^8* , R ^9* , R ^10* , Z _ls Qi, may be optionally substituted by one or more substituents independently selected from the group wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^{U *} R ^12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ^6* , - C(0)R ^6* , -C(0)-NH _2, -C(0)-N(H)R ^11* _, -C(0)-NR ⁿ *R ¹²ⁱ , -S(0) _n -R ^6* , -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ^U* and -S(0) ₂ -NR ^{n *} R ^12* ;

R ^7* and R ^8* taken together or R ^9* and R ^10* taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^n* R ^12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ^{1 1*} , - C(0)R ^{n *} , -C(0)-NH _2, -C(0)-N(H)R ^{n *} _, -C(0)-NR ^{u *} R ^12* , -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ^{n *} and -S(0) ₂ -NR ^{n *} R ^12* ;

n is 0, 1 or 2;

R ^{11 *} and R ¹² * are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more

independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;

R ^{11 *} and R ¹² * taken together form a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring.

In one embodiment of Formula II, Zi is selected from the group consisting of Ci-C ₆ straight alkyl, C -C6 branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,

carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, heterocyclicalkyl, -C(0)-R ^7* , and -C(O)- NR ^7* R ^8* , wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, cyano, and carboxy.

In one embodiment, Qi is selected from the group consisting of Q-C6 straight alkyl, C\- Ce branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, carboxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocycle, -C(0)-R ⁹ *, -C(0)-OR ⁹ *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ⁹ *, -C(0)-NR ⁹ *R ¹⁰ *, and -S(0) ₂ -R ⁹ *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *.

In one embodiment, R ⁷ *and R ⁹ * are the same or different and are independently selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *.

In one embodiment, Zi is selected from the group consisting of C1-C6 straight alkyl, Q- C(, branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, cyano, and carboxy. In a further embodiment, Q can be selected from the group consisting of C1-C6 straight alkyl, Ci-C ₆ branched alkyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, heterocycle, -C(0)-R ⁹ *, -C(O)- OR ⁹ *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ⁹ *, and -S(0) ₂ -R ⁹ *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *. In a further embodiment, R ⁹ * can be selected from the group consisting of Ci-C ₆ straight alkyl, Ci-C ₆ branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *; and R ⁶ * can be independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, Q-C6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and alkoxycarbonyl.

In another embodiment, Z _\ is selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl and carboxy. In a further embodiment, Q is selected from the group consisting of -C6 straight alkyl, Ci-C ₆ branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, heterocycle, -C(0)-R ⁹ *, -C(0)-OR ⁹ *, -C(O)- C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ⁹ *, and -S(0) ₂ -R ⁹ *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *. In a further embodiment, R ⁹ * is selected from the group consisting of Ci-C ₆ straight alkyl, Ci-C ₆ branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ^6* and R ⁶ * is independently selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and alkoxycarbonyl.

In another embodiment, Zi is selected from the group consisting of C1-C4 straight alkyl, and C1 -C4 branched alkyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy. In a further embodiment, Qi can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, -C(0)-R ⁹ *, and -S(0) ₂ -R ⁹ *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl. In yet a further embodiment, R ⁹ * can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl,

hydroxyalkyl, carboxyalkyl, and heteroaryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl.

In a more specific embodiment, Z _\ is selected from the group consisting of methyl, ethyl, and propyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy. In one embodiment, Qi is selected from the group consisting of 2- hydroxyethyl, 3-hydroxypropyl, carboxymethyl, -C(0)-R ⁹ *, and -S(0) ₂ -R ⁹ *. In one embodiment, R ⁹ * is selected from pyrrolyl or imidazolyl, wherein all may be substituted by one or more independently selected from the group consisting of methyl, hydroxymethyl, and carboxy.

In one embodiment, the compounds are administered for the treatment or prophylaxis of an inflammatory disorder. In certain embodiments, the inflammatory disorder is a respiratory disorder. In particular embodiments, the inflammatory disorder is asthma or COPD. In other embodiments the inflammatory disorder is a cardiovascular disorder.

Cardiovascular inflammatory disorders include atherosclerosis, post-angioplasty, restenosis, coronary artery diseases, agina, and other cardiovascular diseases. In certain embodiments the disorder is a non-cardiovascular inflammatory disorder such as rheumatoid and osteoarthritis, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, eczematous dermatitis, Kaposi's sarcoma, or multiple sclerosis. In yet another embodiment, the compounds disclosed herein can be selected to treat antiinflammatory conditions that are mediated by mononuclear leucocytes. In an alternative embodiment, the compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.

In certain embodiments, the compounds reduce the levels of one or more

inflammatory cytokines. In certain embodiments, inflammatory disorders associated with those cytokines are treated or prevented. In one embodiment, the compounds reduce the levels of IL-6. In other embodiments, the compounds reduce levels of IL-8. In certain embodiments, therefore, the compounds can be administered in individuals at risk for or in need of treatment for an inflammatory disorder mediated by a cytokine, such as IL-6 or IL-8.

In one embodiment, a pharmaceutical composition comprising a compound of Formula I or II, a pharmaceutically acceptable carrier, is provided. In certain embodiments, the pharmaceutical composition is for the treatment or prophylaxis of an inflammatory disorder.

In one embodiment, a method for the treatment or prophylaxis of an inflammatory disorder comprising administering an effective amount of a compound of Formula I or II to a host in need thereof, is provided. In one embodiment, a use of a compound of Formula I or II in the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disorder, is provided.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that compounds of Formula (I) inhibit the expression of certain inflammatory cytokines and can be used to treat an inflammatory disease in a patient.

Inflammatory disorders include, but are not limited to asthma, atherosclerosis, post- angioplasty, restenosis, coronary artery diseases, angina, as well as other cardiovascular and noncardiovascular inflammatory diseases such as rheumatoid and osteoarthritis, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, eczematous dermatitis, Kaposi's sarcoma, multiple sclerosis, as well as proliferative disorders of smooth muscle cells.

Compounds

In one embodiment, the compounds for treatment or propylaxis of inflammatory disorders are a compound of Formula I, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug:

(I)

wherein:

R ¹ , R ² , R ³ , and R ⁴ are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, Ci-C ₆ cyclic alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, and alkaryl, all of which may be optionally substituted by one or more substituent independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , -C(0)-NH ₂ , -C(0)-N(H)R ¹¹ , -C(0)-NR ¹¹ R ¹² , - S(0) _n -R ⁶ , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ⁿ and -S(0) ₂ -NR ⁿ R ¹² ;

X and Y can be the same or different and are independently a saturated C1-C6 straight alkyl optionally substituted by one or more substituent independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , -C(0)-NH ₂ , -C(0)-N(H)R ¹¹ _> -C(0)-NR ¹¹ R ¹² , - S(0) _n -R ⁶ , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ^u and -S(0) ₂ -NR ⁿ R ¹² ; W is selected from the group consisting of R ⁵ , R5-OH, R ⁵ -C(0)OH, -C(0)-R ⁵ , -C(O)- N(H)-R ⁵ , -C(0)-NR ⁵ R ⁶ , -C(0)-N(H)-C(0)-R ⁵ , and -C(0)-N(H)-S(0) ₂ -R ⁵ , wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , -C(0)-NH _2, -C(0)-N(H)R ¹¹ _i -C(0)-NR ^u R ¹² , -S(0) _n -R ⁶ , - S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ^{1 1} and -S(0) ₂ -NR ⁿ R ¹² ;

Z is selected from the group consisting of R ⁷ , R ⁷ -OH, R ⁷ -C(0)OH, -C(0)-R ⁷ , -C(O)- N(H)-R ⁷ , -C(0)-NR ⁷ R ⁸ , -C(0)-N(H)-C(0)-R ⁷ , and -C(0)-N(H)-S(0) ₂ -R ⁷ , wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , -C(0)-NH _2, -C(0)-N(H)R ⁿ _; -C(0)-NR ⁿ R ¹² , -S(0) _n -R ⁶ , - S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R" and -S(0) ₂ -NR ⁿ R ¹² ;

Q is selected from the group consisting of R ⁹ , R ⁹ -OH, R ⁹ -C(0)OH, -OH, -OR ⁹ , -C(O)- R ⁹ , -C(0)-OR ⁹ , -C(0)-C(0)-OR ⁹ , -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ⁹ , - C(0)-NR ⁹ R ¹⁰ , -C(0)-N(H)-C(0)-R ⁹ , -C(0)-N(H)-S(0) ₂ -R ⁹ , -S(0) ₂ -R ⁹ , and -C(0)-H, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^U R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , -C(0)-NH _2> -C(0)-N(H)R ^u , -C(0)-NR ^u R ¹² , -S(0) _n -R ⁶ , - S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ^u and -S(0) ₂ -NR ^u R ¹² ;

R ⁵ , R ⁷ and R ⁹ are the same or different and are independently selected from the group consisting of hydrogen, Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , -C(0)-NH ₂ , -C(0)-N(H)R ^u -C(O)- NR ^U R ¹² , -S(0) _n -R ⁶ , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ⁿ and -S(0) ₂ -NR ^u R ¹² ;

R ⁶ , R ⁸ and R ¹⁰ are the same or different and are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, Ci-C ₆ cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more

independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, - NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ¹¹ , -C(0)R ^H , -C(0)-NH _2j - C(0)-N(H)R ⁿ -C(0)-NR ⁿ R ¹² , -S(0) _n -R ⁿ , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ⁿ and -S(0) ₂ - NR ^U R ¹² ;

R ⁵ and R ⁶ taken together or R ⁷ and R ⁸ taken together or R ⁹ and R ¹⁰ taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^U R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ¹¹ , - C(0)R ⁿ , -C(0)-NH ₂ , -C(0)-N(H)R ⁿ , -C(0)-NR ⁿ R ¹² , -S(0) _n -R ⁿ , -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ⁿ and -S(0) ₂ -NR ⁿ R ¹² ;

R ¹¹ and R ¹² are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more

independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;

R ^{1 1} and R ¹² taken together form a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;

n is 0, 1 or 2;

with the proviso that when Q is hydrogen, C _1-8 alkyl or C _2- 8 alkyl carbonyl, and X and Y are substituted with Ci _-8 alkyl, then both W and Z are not hydrogen.

In a particular embodiment, R ¹ , R ² , R ³ , and R ⁴ are independently selected from Ci-C ₆ straight alkyl or Ci-C ₆ branched alkyl. In a more particular embodiment, R ¹ , R ² , R ³ , and R ⁴ are tert-butyl.

In another particular embodiment, X and Y can be the same or different and are independently selected from -CH ₂ - or -CH ₂ -CH ₂ -. In one embodiment, X and Y are the same. In another embodiment, X and Y are different.

In a particular embodiment, one of W and Z is not hydrogen. In one embodiment, W is hydrogen. In a particular embodiment when W is hydrogen, Z is not hydrogen. In another embodiment, Z and Q are not hydrogen. In one embodiment, Z and W are both not hydrogen. In a particular embodiment, W is hydrogen and Z is selected from the group consisting of R ⁷ , -C(0)-R ⁷ , -C(0)-N(H)-R ⁷ , C(0)-NR ⁷ R ⁸ , -C(0)-N(H)-C(0)-R ⁷ , and -C(O)- N(H)-S(0) ₂ -R ⁷ . In another principle embodiment, compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including administration of a compound of Formula II, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug, are provided:

(Π)

wherein:

Zi is selected from the group consisting of Ci-C ₈ straight alkyl, Q-Cg branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,

alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, acyl, -C(0)-R ^7* , -C(0)-N(H)-R ⁷ *, -C(O)- NR ^7* R ^8* , -C(0)-N(H)-C(0)-R ^7* , and -C(0)-N(H)-S(0) ₂ -R ^7* , wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR R , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR , - C(0)R ^6* , -C(0)-NH _2, -C(0)-N(H)R ⁿ VC(0)-NR ^n* R ^12* , -S(0) _n -R ⁶ *, -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ^n* and -S(0) ₂ -NR ^{n *} R ^12* ;

Qi is selected from the group consisting of Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,

alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, -OH, -OR ^9* , -C(0)-R ^9* , -C(0)-OR ^9* , -C(O)- C(0)-OR ^9* , -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ^9* , -C(0)-NR ⁹ *R ^10* , - C(0)-N(H)-C(0)-R ^9* , -C(0)-N(H)-S(0) ₂ -R ^9* , -S(0) ₂ -R ^9* , and -C(0)-H, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^n* R ^12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ^6* , - C(0)R ^6* , -C(0)-NH ₂ , -C(0)-N(H)R ^u *, -C(0)-NR ^n* R ^12* , -S(0) _n -R ^6* , -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ^n* and -S(0) ₂ -NR ^n* R ^12* ;

R ^7* and R ^9* are the same or different and are independently selected from the group consisting of hydrogen, Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR R , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ^6* , -C(0)R ^6* , -C(0)-NH ₂ , -C(0)-N(H)R ^n* , - C(0)-NR ^n* R ^12* , -S(0) _n -R ^6* , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ^n* and -S(0) ₂ -NR ^n* R ^12* ;

R , R and R are the same or different and are independently selected from the group consisting of hydrogen, Ci-Ce straight alkyl, C1-C6 branched alkyl, Ci-Ce cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, - NR ^U* R ^12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ^11* , -C(0)R ^n* , -C(0)- NHz. -C^-N^R ^11* , ^^)^ ^11* ^ ^2* , -S(0)n-R ^n* , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ^n* and - S(0) ₂ -NR ^n* R ^12* ;

R ^7* and R ^8* taken together or R ^9* and R ^10* taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^n* R ^12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ^11* , - C(0)R ^n* , -C(0)-NH ₂ , -C(0)-N(H)R ^u *, -C(0)-NR ^u* R ^12* , -S(0) _n -R ^n* , -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ^n* and -S(0) ₂ -NR ^{u *} R ^12* ;

n is 0, 1 or 2;

R andR ^l are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more

independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;

R ^11* andR ^12* taken together form a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring.

In one embodiment of Formula II, Zi is selected from the group consisting of C1-C6 straight alkyl, C1-C branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,

carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, heterocyclicalkyl, -C(0)-R ⁷ *, and -C(O)- NR ⁷ *R ⁸ *, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, cyano, and carboxy.

In one embodiment, Qi is selected from the group consisting of C1-C6 straight alkyl, C Ce branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, carboxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocycle, -C(0)-R ⁹ *, -C(0)-OR ⁹ *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ^9* , -C(0)-NR ^9* R ^10* , and -S(0) ₂ -R ^9* , wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *.

In one embodiment, R ⁷ *and R ^9* are the same or different and are independently selected from the group consisting of C1-C6 straight alkyl, Ci-C ₆ branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ^6* .

In another embodiment, R ⁶ * and R ⁸ * are the same or different and are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, Q-C6 branched alkyl, Ci-C ₆ cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and alkoxycarbonyl.

In a further embodiment, R and R taken together or R and R taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, oxo, carboxy, and carboxyalkyl.

In one embodiment, Zi is selected from the group consisting of Ci-Ce straight alkyl, Q- C ₆ branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, cyano, and carboxy. In a further embodiment, Q can be selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, heterocycle, -C(0)-R , -C(O)- OR ⁹ *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ^9* , and -S(0) ₂ -R ⁹ *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *. In yet a further embodiment, R ⁹ * can be selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *; and R ⁶ * can be independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, C1-C6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and alkoxycarbonyl.

In another embodiment, Zi is selected from the group consisting of C1-C6 straight alkyl, C1-C branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl and carboxy. In a further embodiment, Q is selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, heterocycle, -C(0)-R ⁹ *, -C(0)-OR ⁹ *, -C(O)- C(0)-OH, -C(0)-OH, -C(0)-NH ₂ , -C(0)-N(H)-R ⁹ *, and -S(0) ₂ -R ^9* , wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ *. In a further embodiment, R ⁹ * is selected from the group consisting of Ci-C ₆ straight alkyl, C1-C6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR ⁶ * and R ⁶ * is independently selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and alkoxycarbonyl.

In another embodiment, Zi is selected from the group consisting of C1-C4 straight alkyl, and C1 -C4 branched alkyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy. In a further embodiment, Qi can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, -C(0)-R ⁹ *, and -S(0)2-R ⁹ *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl. In yet a further embodiment, R can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl,

hydroxyalkyl, carboxyalkyl, and heteroaryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl.

In a more specific embodiment, Z _\ is selected from the group consisting of methyl, ethyl, and propyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy. In one embodiment, Qi is selected from the group consisting of 2- hydroxyethyl, 3-hydroxypropyl, carboxymethyl, -C(0)-R ⁹ *, and -S(0) ₂ -R ⁹ *. In one embodiment, R ⁹ * is selected from pyrrolyl or imidazolyl, wherein all may be substituted by one or more independently selected from the group consisting of methyl, hydroxymethyl, and carboxy.

In certain embodiments, Zi is hydroxyalkyl, optionally substituted or terminated with carboxy.

In one embodiment, Q or Qi is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl,

sulfonamidoalkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, -OR ⁹ *, -C(0)-R ⁹ *, -C(0)-OR ^9* , -C(0)-OH, -S(0) ₂ -R ^9* wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, - NR ⁿ *R ¹² *, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ *, -C(0)R ⁶ *, -C(0)-NH ₂ , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ^u * and -S(0) ₂ - NR" *R ¹² *.

In one embodiment, Q, is selected from -OR ⁹ *, -C(0)-R ^9* , and -C(0)-OR ⁹ *. In this embodiment, R ⁹ * can be substituted or unsubstituted Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl or alkoxyalkyl.

In another embodiment, Oj is -S(0) ₂ -R ⁹ *. In certain particular embodiments, R ⁹ * can be a heterocycle or heteroaromatic ring. In one embodiment, R ⁹ * is a nitrogen containing heterocycle or heteroaromatic. In one embodiment, R is a nitrogen containing heteroaromatic. In one embodiment, R ^9* is selected from pyrrolyl or imidazolyl. In a specific embodiment, R ^9* is further substituted. In a particular embodiment, R ^9* is substituted with for example with alkyl, carboxy or -C(0)R ^6* . In a specific embodiment, R ^9* is substituted with more than one substituent. In one embodiment, R ^9* is substituted with at least one carboxy. In one embodiment, R9* is substituted with at least one alkyl, optionally substituted with hydroxyl and/or carboxy. In another embodiment, R ^9* is substituted with at least one carboxy and at least one alkyl.

In certain embodiment, R ^9* is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, hydroxyalkyl, alkoxyalkyl, acyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR R , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR , - C(0)R ^6* , -C(0)-NH _2j -C(0)-N(H)R ^u* _; -C(0)-NR ^u* R ^12* , -S(0) _n -R ^6* , -S(0) ₂ -NH ₂ , -S(0) ₂ - N(H)R ^U* and -S(0) ₂ -NR ^n* R ^12* . In one embodiment, the substitutions are hydroxyl, hydroxyalkyl, -OR ^6* , or -C(0)R ^6* .

In a separate embodiment, Qi can be selected from Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, aryl, aralkyl, -OH, - C(0)-C(0)-OR ^9* , -C(0)-C(0)-OH, - C(0)-NH ₂ , -C(0)-N(H)-R ^9* , -C(0)-N(H)-C(0)-R ^9* , -C(0)-N(H)-S(0) ₂ -R ^9* and -C(0)-H, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ^n* R ^12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ^6* , -C(0)R ^6* , -C(0)-NH ₂ , -C(0)-N(H)R ^n* , -C(0)- NR ^n* R ^12* , -S(0) _n -R ^6* , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ^u* and -S(0) ₂ -NR ^u* R ^12* . In one embodiment, substitutions on Ci-C ₈ straight alkyl, Ci-C ₈ branched alkyl, Ci-C ₈ cyclic alkyl and aralkyl are hydroxyl or -OR ⁶ *.

In certain specific embodiment, Qi is selected from hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, -OR ^9* , -C(0)-R ^9* , -C(0)-OR ^9* , - C(0)-OH, -C(0)-NR ^9* R ^10* and -S(0) ₂ -R ^9* and Z, is selected from Ci-C ₆ straight alkyl, C C ₆ branched alkyl, and hydroxyalkyl, optionally substituted by one or more substituents independently selected from hydroxy or carboxy.

In some embodiments, compounds of the invention are as defined below in Table I:

r embodiments, the compounds are as disclosed in Table II:

Table II

yet other embodiments, the compound is as shown in Table III:

Table III

yet other embodiments, the compound is as shown in Table VI:

Table IV

Table V

other embodiments, the compounds are as disclosed in Table VI:

Table VI

other embodiments, the compounds are as disclosed in Table VII:

Table VII

Definitions

Whenever a term in the specification is identified as a range (i.e. C ₁ -4 alkyl), the range independently refers to each element of the range. As a non- limiting example, C _1-4 alkyl means, independently, Q, C ₂ , C3 or C ₄ alkyl. Similarly, when one or more substituents are referred to as being "independently selected from" a group, this means that each substituent can be any element of that group, and any combination of these groups can be separated from the group. For example, if R ¹ and R ² can be independently selected from X, Y and Z, this separately includes the groups R ¹ is X and R ² is X; R ¹ is X and R ² is Y; R ¹ is X and R ² is Z; R ¹ is Y and R ² is X; R ¹ is Y and R ² is Y; R ¹ is Y and R ² is Z; R ¹ is Z and R ² is X; R ¹ is Z and R ² is Y; and R ¹ is Z and R ² is Z.

The term "alkyl" is used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic (also identified as cycloalkyl), primary, secondary, or tertiary hydrocarbon, including but not limited to those of Ci to C ₆ . Illustrative examples of alkyl groups are methyl, ethyl, propyl, z ^' sopropyl, cyclopropyl, butyl, secbutyl, isobutyl, tertbutyl, cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl, isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl. Unless otherwise specified, the alkyl group can be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, thioether, oxime, carbamate, heterocyclic, heteroaryl, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. , Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

The term "lower alkyl,"unless otherwise specified, refers to a Ci to C5 saturated or unsaturated straight, branched carbon chain such as methyl, ethyl, isopropyl, n-butyl, tert- butyl, n-pentyl, sec-pentyl, 3-methylpentyl, and the like, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group.

The term "halo" or "halogen," refers to chloro, bromo, iodo, or fluoro.

The term "heteroaryl" or "heteroaromatic," refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring. The term "heterocyclic" refers to a non-aromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring. Nonlimiting examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines, thiazole, isothiazole, 1,2,3- oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl,

imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N ⁶ -alkylpurines, N ⁶ - benzylpurine, N ⁶ -halopurine, N ⁶ -vinypurine, N ⁶ -acetylenic purine, N ⁶ -acyl purine,N ⁶ - hydroxyalkyl purine, N ⁶ -thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2- mercaptopyrmidine, uracil, N ⁵ -alkylpyrimidines, N ⁵ -benzylpyrimidines, N ⁵ -halopyrimidines, N ⁵ -vinylpyrimidine, N ⁵ -acetylenic pyrimidine, N ⁵ -acyl pyrimidine, N ⁵ -hydroxyalkyl purine, and N ⁶ -thioalkyl purine, and isoxazolyl.

The heteroaromatic or heterocyclic group can be optionally substituted with one or more substituent independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR ⁿ R ¹² , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR ⁶ , -C(0)R ⁶ , - C(0)-NH ₂ , -C(0)-N(H)R ¹¹ , -C(0)-NR ¹¹ R ¹² , -S(0) _n -R ⁶ , -S(0) ₂ -NH ₂ , -S(0) ₂ -N(H)R ⁿ , -S(0) ₂ - NR ⁿ R ¹² , haloalkyl, alkoxy, carboxyl derivatives, amido, alkylamino, dialkylamino. The heteroaromatic can be partially or totally hydrogenated as desired. As a nonlimiting example, dihydropyridine can be used in place of pyridine. Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t- butyldimethylsilyl, and i-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl.

The term "aryl," unless otherwise specified, refers to a carbon based aromatic ring, including phenyl, biphenyl, or naphthyl. The aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, acyl, amino, halo, alkylamino, alkoxy, aryloxy, nitro, cyano, alkyl, hydroxyalkyl, carboxy, carboxyalkyl, or oxo, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991.

The term "aralkyl," unless otherwise specified, refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above. The term "alkaryl," unless otherwise specified, refers to an alkyl group as defmd above linked to the molecule through an aryl group as defined above. Other groups, such as acyloxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminoalkyl, alkylthioalkyl, amidoalkyl, aminoalkyl, carboxyalkyl, dialkylaminoalkyl, haloalkyl, heteroaralkyl, heterocyclicalkyl, hydroxyalkyl, sulfonamidoalkyl, sulfonylalkyl and thioalkyl are named in a similar manner.

The term "alkoxy," unless otherwise specified, refers to a moiety of the structure -O- alkyl, wherein alkyl is as defined above.

The term "acyl," refers to a group of the formula C(0)R' or "alkyl-oxy", wherein R' is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl.

The term "alkenyl" The term "alkenyl" means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Suitable alkenyl groups include, but are not limited to (C2-C8)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl,4- (2-methyl-3-butene)-pentenyl. An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.

The term "carbonyl" refers to a functional group composed of a carbon atom double- bonded to an oxygen atom : -C=0.

The term "amino" indicates presence of -N¾.

The term "thio" indicates the presence of a sulfur group. The prefix thio- denotes that there is at least one extra sulfur atom added to the chemical. The prefix 'thio-' can also be placed before the name of a ompoundto mean that an oxygen atom in the compound has been replaced by a sulfur atom. Although typically the term "thiol" is used to indicate the presence of -SH, in instances in which the sulfur atom would be have improper valance a radical if the hydrogen is improperly designated, the terms 'thio' and 'thiol' are used interchangeably, unless otherwise indicated.

The term "amido" indicates a group R-CO-NH-.

The term "carboxy" designates the terminal group -C(0)OH.

The term "sulfonyl" indicates an organic radical of the general formula R-S(=0)2-R', where there are two double bonds between the sulfur and oxygen. The term "pharmaceutically acceptable salt" refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects. Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid,

naphthalenedisulfonic acid, and polygalcturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed from ammonia, Ν,Ν-dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc tannate salt or the like. Also included in this definition are pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR ⁺ A ^" , wherein R is as defined above and A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.

It should be understood that the various possible stereoisomers of the groups mentioned above and herein are within the meaning of the individual terms and examples, unless otherwise specified. As an illustrative example, "1 -methyl-butyl" exists in both (R) and the (S) form, thus, both (R)-l -methyl-butyl and (S)-l -methyl-butyl is covered by the term "1 -methyl-butyl", unless otherwise specified.

Methods of use

The compounds of the invention can generally be administered to a host at risk of, or suffering from, an inflammatory condition. In one embodiment, the compounds are administered for the treatment or prophylaxis of an inflammatory disorder. In certain embodiments, the inflammatory disorder is a respiratory disorder. In particular embodiments, the inflammatory disorder is asthma or COPD. In other, separate embodiments the inflammatory disorder is a cardiovascular disorder. In certain embodiments, the

inflammatory condition is mediated by known cytokines such as IL-6 or IL-8. In other embodiments, the inflammatory condition is unrelated to levels of any particular cytokines, such as IL-6 or IL-8. Certain of the compounds of the invention are useful in the treatment of inflammatory respiratory conditions, such as asthma, independently of their effect on inflammatory cytokines related to chemotaxis or antibody-mediated immune responses.

Cytokines are small secreted proteins which mediate and regulate immunity, inflammation, and hematopoiesis. They must be produced de novo in response to an immune stimulus. They generally (although not always) act over short distances and short time spans and at very low concentration. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior (gene expression). Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation, and secretion of effector molecules.

It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. The largest group of cytokines stimulates immune cell proliferation and differentiation. This group includes Interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen- activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; Interferon gamma (IFND), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate

hematopoiesis. IL-6 is generally produced by monocytes, macrophages, Th2 cells and stromal cells. It acts on activated B cells to differente into plasma cells, plasma cells to induce antibody secretion, stem cells to induce differentiation, and on various other cells to induce acute inflammatory responses. IL-8, produced by macrophages and endothelial cells generally acts on neutrophils to induce chemotaxis.

Generally, inflammatory disorders include, but are not limited to, respiratory disorders (including asthma, COPD, chronic bronchitis and cystic fibrosis); cardiovascular related disorders (including atherosclerosis, post-angioplasty, restenosis, coronary artery diseases and angina); inflammatory diseases of the joints (including rheumatoid and osteoarthritis); skin disorders (including dermatitis, eczematous dermatitis and psoriasis); post transplantation late and chronic solid organ rejection; multiple sclerosis; autoimmune conditions (including systemic lupus erythematosus, dermatomyositis, polymyositis, inflammatory neuropathies (Guillain Barre, inflammatory polyneuropathies), vasculitis (Wegener's granulomatosus, polyarteritis nodosa), and rare disorders such as polymyalgia rheumatica, temporal arteritis, Sjogren's syndrome, Bechet's disease, Churg-Strauss syndrome, and Takayasu's arteritis); and proliferative disorders (including Kaposi's sarcoma and other proliferative disorders of smooth muscle cells).

Respiratory Disorders

In one embodiment, compounds, compositions and methods of treatment of respiratory disorders comprising administering a compound are provided wherein the compound is as described herein. Respiratory disorders that may be prevented or treated include a disease or disorder of the respiratory system that can affect any part of the respiratory tract. These conditions range from life threatening to mild. Certain diseases cause respiratory symptoms although the diseases are initially caused by an infection, such as a cold virus, bronchitis, pneumonia and tuberculosis. Other disorders are caused by irritation of the lung tissue, such as, for example, by an allergen. These disorders include hay fever and other respiratory allergies and asthma. In certain embodiments, the host is at risk of or suffering from a disorder of the lower airway. These include bronchitis, simple and mucopurulent chronic bronchitis, unspecified chronic bronchitis (including chronic bronchitis NOS, chronic tracheitis and chronic tracheobronchitis), emphysema, other chronic obstructive pulmonary disease, asthma, status asthmaticus and bronchiectasis.

In asthma, the bronchi and bronchioles are typically temporarily constricted and inflamed. Other disorders typically involving lung irritants include emphysema, which can result from multiple factors including: smog, cigarette smoke, infection, and a genetic predisposition to the condition, laryngitis, lung cancer, respiratory distress syndrome (RDS), which refers to a group of symptoms that indicate severe malfunctioning of the lungs affecting adults and infants and specifically Adult respiratory distress syndrome (ARDS). Chronic respiratory insufficiency (or chronic obstructive pulmonary disease; COPD) is a prolonged or persistent condition characterized by breathing or respiratory dysfunction resulting in reduced rates of oxygenation or the ability to eliminate carbon dioxide.

The term "asthma" as used herein includes any asthmatic condition marked by recurrent attacks of paroxysmal dyspnea (i.e., "reversible obstructive airway passage disease") with wheezing due to spasmodic contraction of the bronchi (so called "bronchospasm"). Asthmatic conditions which may be treated or even prevented in accordance with this invention include allergic asthma and bronchial allergy characterized by manifestations in sensitized persons provoked by a variety of factors including exercise, especially vigorous exercise ("exercise-induced bronchospasm"), irritant particles (pollen, dust, cotton, cat dander) as well as mild to moderate asthma, chronic asthma, severe chronic asthma, severe and unstable asthma, nocturnal asthma, and psychologic stresses.

Other respiratory disorders include allergic and non-allergic rhinitis as well as non- malignant proliferative and/or inflammatory disease of the airway passages and lungs.

Allergic rhinitis means generally any allergic reaction of the nasal mucosa and includes hay fever (seasonal allergic rhinitis) and perennial rhinitis (non-seasonal allergic rhinitis) which are characterized by seasonal or perennial sneezing, rhinorrhea, nasal congestion, pruritis and eye itching, redness and tearing. Non-allergic rhinitis means eosinophilic nonallergic rhinitis which is found in patients with negative skin tests and those who have numerous eosinophils in their nasal secretions.

Non-malignant prolifertive and/or inflammatory diseases of the airway passages or lungs means one or more of (1) alveolitis, such as extrinsic allergic alveolitis, and drug toxicity such as caused by, e.g. cytotoxic and/or alkylating agents; (2) vasculitis such as Wegener's granulomatosis, allergic granulomatosis, pulmonary hemangiomatosis and idiopathic pulmonary fibrosis, chronic eosinophilic pneumonia, eosinophilic granuloma and sarcoidoses.

In one embodiment, the use of the compounds of the invention reduces symptoms of these disorders, including cough, shortness of breath, chest pain, wheezing, cyanosis, finger clubbing, stridor (a crowing sound when breathing), hemoptysis (coughing up of blood), and respiratory failure. The use of these compounds may reduce respiratory acidosis , due to a failure by the lungs to remove carbon dioxide.

In another embodiment, the use of the compounds improve lung function.

Cardiovascular related disorders

In one embodiment, the compounds of the invention are administered to a patient suffering from a cardiovascular disorder related to inflammation. These include, but are not limited to, atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina.

Generally, cardiovascular disorders are a class of diseases that involve the heart and/or blood vessels (arteries and veins). While the term technically refers to any disease that affects the cardiovascular system, it is usually used to refer to those related to atherosclerosis (arterial disease).

Cardiovascular inflammatory disorders include atherosclerosis, post-angioplasty, restenosis, coronary artery diseases, agina, and other cardiovascular diseases. In certain embodiments the disorder is a non-cardiovascular inflammatory disorder such as rheumatoid and osteoarthritis, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, eczematous dermatitis, Kaposi's sarcoma, or multiple sclerosis. In yet another embodiment, the compounds disclosed herein can be selected to treat antiinflammatory conditions that are mediated by mononuclear leucocytes. In an alternative embodiment, the compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.

Generally, unstable atherosclerotic plaque is a result of multiple factors but is commonly characterized by an infiltrate of inflammatory cells. Medical research strongly supports a role for inflammation in the pathogenesis, progression, and disruption of atherosclerotic plaque. Clinical studies have demonstrated systemic markers of inflammation to be strong predictors of clinical events, and specific treatments of atherosclerosis and its risk factors have been associated with reductions in inflammatory markers. The majority of cardiovascular events occur at sites of "nonsignificant" stenosis, as inflammation can lead to instability and rupture of these smaller atherosclerotic plaques, which are more numerous than the "significant," flow-limiting plaques. In fact, direct visualization of inflammatory cells within plaques is a predictor of unstable coronary disease. The source of inflammation is uncertain; various infectious agents have been proposed as a stimulator of this inflammatory process, and are discussed in detail in a companion article. Smooth muscle cell proliferation is also implicated both in chronic cardiovascular pathologies such as atherosclerosis, and more directly in, for example, post-angioplasty restenosis .

Diseases of arteries, arterioles and capillaries generally include atherosclerosis, peripheral vascular diseases including Raynaud's syndrome, thromboangiitis obliterans (Buerger) and other specified peripheral vascular diseases such as intermittent claudication.

Proliferative disorders

Chronic inflammation is a risk factor for many proliferative disorders. For example, in a variety of diseases, airway smooth muscle mass increases due to the coordinated increase in size (hypertrophy) and number (hyperplasia) of airway smooth muscle cells. Myocyte migration may also serve to regulate airway smooth muscle mass. For example, chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma. In addition, vascular smooth muscle, and immune cells are stimulated in cardiovascular disorders.

In particular, inflammation is a risk factor in development of cancers, including colon cancer, and data from experimental and observational studies suggest that inflammation acts early in the carcinogenic pathway of colorectal cancer, possibly promoting the progression of colorectal adenomas to adenocarcinoma (Tangrea et al. Non-steroidal anti-inflammatory drug use is associated with reduction in the recurrence of advanced and non-advanced colorectal adenomas. Cancer Causes Control 2003;14:403-11; Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 2004;4: 11-22; O'Byrne et al. Chronic immune activation and inflammation as the cause of malignancy. Br J Cancer 2001;85:473- 783; Balkwill et al. Inflammation and cancer: back to Virchow Lancet 2001;357:539-45; Coussens et al. Inflammation and cancer. Nature 2002;420:860-7). The inflammatory response to cellular stresses, injury and infection, results from increased mucosal production of proinflammatory cytokines. Proinflammatory cytokines, such as tumor necrosis factor n and the interleukins (IL-1B, IL-6, and IL-8),play a key role in angiogenesis, inhibition of apoptosis, and cell proliferation. These cytokines induce expression of cyclooxygenase 2 (COX-2), one of the key enzymes in the production of prostaglandins. COX-2 mRNA and protein are present in both colorectal adenomas and adenocarcinomas, and thus support a role of inflammation early in the carcinogenic pathway of colorectal cancer.

Other inflammatory disorders

In another embodiment, the compounds of the invention may be administered for the treatment or prophylaxis of an inflammatory disorder or the joints or connective tissue.

These disorders include rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, scleroderma (systemic sclerosis), dermatomyositis, polychondritis, polymyositis, polymyalgia rheumatica, osteoarthritis, septic arthritis, fibromyalgia, gout, pseudogout,

spondyloarthropathies, such as ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthropathy, enteropathic spondylitis and reactive arthropathy, vasculitis, such as polyarteritis nodosa, Henoch-Schonlein purpura, serum sickness, Wegener's granulomatosis, giant cell arteritis, temporal arteritis, Takayasu's arteritis, Behcet's syndrome, Kawasaki's disease (mucocutaneous lymph node syndrome) and Buerger's disease (thromboangiitis obliterans). In addition, autoimmune conditions such as acute disseminated

encephalomyelitis, Addison's disease, ankylosing spondylitisis, antiphospholipid antibody syndrome, autoimmune hepatitis, Coeliac disease, Crohn's disease, diabetes mellitus, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's Disease, lupus erythematosus, multiple sclerosis, Mmyasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, primary biliary cirrhosis, Reiter's syndrome, Sjogren's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia and Wegener's

granulomatosis.

In other embodiments, certain inflammtory skin disorders are treated or prevented, such as dermatitis, eczematous dermatitis and psoriasis. In general inflammatory skin disease is a broad category that includes many conditions, ranging in severity from mild itching to serious medical health complications. Other conditions that are inflammatory skin disorders include eczema generally, acne and rosacea.

Other disorders may also be treated or prophylactically prevented or reduced by administration of compounds of the invention. In certain embodiments, the disorder to be treated is selected from post transplantation late and chronic solid organ rejection; multiple sclerosis; autoimmune conditions (including systemic lupus erythematosus, dermatomyositis, polymyositis, inflammatory neuropathies (Guillain Barre, inflammatory polyneuropathies), vasculitis (Wegener's granulomatosus, polyarteritis nodosa), and rare disorders such as polymyalgia rheumatica, temporal arteritis, Sjogren's syndrome, Bechet's disease, Churg- Strauss syndrome, and Takayasu's arteritis).

Diabetes

Methods and pharmaceutical compositions are provided for the treatment or prophylaxis or delay of onset of diabetes, pre-diabetes and related disorders. Related disorders of diabetes includes, but is not limited to, hyperglycemia, abnormal glucose homeostasis, insulin resistance, Syndrome X, metabolic disorders, diabetic dyslipidemia.

In one embodiment, the disease to be treated or prevented is type 2 diabetes. The chronic overabundance of glucose associated with diabetes damages the body's blood vessels and can lead to many related disorders. Generally, high glucose levels in the blood plasma (hyperglycemia) can lead higher than normal amounts of particular hemoglobin, HbAlc. Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated with obesity, hypertension, and alterations of the lipid, lipoprotein and

apolipoprotein metabolism, as well as other metabolic and hemodynamic disease. Patients with type 2 diabetes mellitus have a significantly increased risk of macro vascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, microangiopathy, kidney disorders or failure, kidney and nerve damage, cardiac disease, diabetic retinopathy and other ocular disorders, including blindness. In extreme cases, diabetes can result in the amputation of limbs and death.

Other conditions related to diabetes reported by the CDC include: nervous system diseases, which often includes impaired sensation or pain in the feet or hands, slowed digestion of food in the stomach, carpal tunnel syndrome, and other nerve problems, periodontal disease, which is a type of gum disease that can lead to tooth loss, complications of pregnancy, including congenital malformations and death of the fetus, and other complications such as diabetic ketoacidosis and hyperosmolar nonketotic coma.

Many patients who have insulin resistance or type 2 diabetes often have several symptoms that together are referred to as syndrome X, or the metabolic syndrome. A patient having this syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic. Each of these symptoms is defined in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and

Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670.

In one embodiment, the compound is provided to a host to promote depletion of bile salts. Bile salts are steroids with detergent properties which are used to emulsify lipids in foodstuff passing through the intestine to enable fat digestion and absorption through the intestinal wall. They are secreted from the liver stored in the gall bladder and passed through the bile duct into the intestine when food is passing through. The most abundant of the bile salts in humans are cholate and deoxycholate, and they are normally conjugated with either glycine or taurine to give glycocholate or taurocholate respectively. Depletion of bile salts, including cholate and deoxycholate, force the liver to reabsorb cholesterol to make new bile. In one embodiment, patients at risk for developing diabetes are prophylactically treated to prevent onset. Patients with diabetes or at risk for developing diabetes can be identified through several risk factors. One of the key risk factors is age and obesity.

Generally patients who are 45 years or older and overweight (with a body mass index of 25 or greater) is at risk of developing diabetes.

Additional risk factors for type 2 diabetes include a family history, ethnicity (Alaska Native, American Indian, African American, Hispanic/Latino, Asian American, or Pacific Islander is at higher risk), having had gestational diabetes or giving birth to a baby weighing more than 9 pounds, previous history of high blood pressure or blood pressure of 140/90 mm Hg or higher, cholesterol levels not normal (including HDL below 35 mg/dL, or triglyceride level above 250 mg/dL), being fairly inactive (less than three times per week exercise), diagnosis of polycystic ovary syndrome, any test showing impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), clinical conditions associated with insulin resistance, such as acanthosis nigricans, or a history of cardiovascular disease. Tests to be conducted can include a fasting blood glucose test or an oral glucose tolerance test.

Glucose levels of approximately 100-126 mg/dl in a fasting plasma glucose test (FPG) or approximately 140-200 mg/dl in the oral glucose tolerance test (OGTT) indicate prediabetes. Levels of greater than or equal to 126 mg/dl in the FPG or greater than or equal to 200 mg/dl in the OGTT indicate diabetes. Symptoms of diabetes include increased thirst, increased hunger, fatigue, increased urination, especially at night, weight loss, blurred vision, sores that do not heal.

Pharmaceutical Compositions

Mammals, and specifically humans, suffering from an inflammatory disorder, including any of the above-described conditions, and in particular suffering from respiratory disorders, can be treated by either targeted or systemic administration, via oral, inhalation, topical, trans- or sub-mucosal, subcutaneous, parenteral, intramuscular, intravenous or transdermal administration of a composition comprising an effective amount of the compounds described herein or a pharmaceutically acceptable salt, ester or prodrug thereof, optionally in a pharmaceutically acceptable carrier.

The compounds or composition is typically administered by oral administration. Alternatively, compounds can be administered by inhalation. In another embodiment, the compound is administered transdermally (for example via a slow release patch), or topically. In yet another embodiment, the compound is administered subcutaneously, intravenously, intraperitoneally, intramuscularly, parenterally, or submucosally. In any of these

embodiments, the compound is administered in an effective dosage range to treat the target condition.

In one embodiment, compounds of the present invention are administered orally. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

When the compound is administered orally in the form of a dosage unit such as a tablets, pills, capsules, troches and the like, these can contain any of the following ingredients, or compounds of a similar nature: a binder (such as microcrystalline cellulose, gum tragacanth or gelatin); an excipient (such as starch or lactose), a disintegrating agent (such as alginic acid, Primogel, or corn starch); a lubricant (such as magnesium stearate or Sterotes); a glidant (such as colloidal silicon dioxide); a sweetening agent (such as sucrose or saccharin); and/or a flavoring agent (such as peppermint, methyl salicylate, or orange flavoring). When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier (such as a fatty oil). In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.

The compound or its salts can also be administered orally as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, a sweetening agent (such as sucrose, saccharine, etc.) and preservatives, dyes and colorings and flavors.

The compounds of the invention may be also administered in specific, measured amounts in the form of an aqueous suspension by use of a pump spray bottle. The aqueous suspension compositions of the present invention may be prepared by admixing the compounds with water and other pharmaceutically acceptable excipients. The aqueous suspension compositions according to the present invention may contain, inter alia, water, auxiliaries and or one or more of the excipients, such as: suspending agents, e.g.,

microcrystalline cellulose, sodium carboxymethylcellulose, hydroxpropyl-methyl cellulose; humectants, e.g. glycerin and propylene glycol; acids, bases or buffer substances for adjusting the pH, e.g., citric acid, sodium citrate, phosphoric acid, sodium phospate as well as mixtures of citrate and phosphate buffers; surfactants, e.g. Polysorbate 80; and antimicrobial preservatives, e.g., benzalkonium chloride, phenylethyl alcohol and potassium sorbate.

In a separate embodiment, the compounds of the invention are in the form of an inhaled dosage. In this embodiment, the compounds may be in the form of an aerosol suspension, a dry powder or liquid particle form. The compounds may be prepared for delivery as a nasal spray or in an inhaler, such as a metered dose inhaler. Pressurized metered-dose inhalers ("MDI") generally deliver aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11, CFC-12, or the non-chlorofiuorocarbons or alternate propellants such as the fluorocarbons, HFC-134A or HFC-227 with or without surfactants and suitable bridging agents. Dry -powder inhalers can also be used, either breath activated or delivered by air or gas pressure such as the dry-powder inhaler disclosed in the Schering Corporation International Patent Application No. PCT7US92/05225, published 7 Jan. 1993 as well as the Turbuhaler™ (available from Astra Pharmaceutical Products, Inc.) or the Rotahaler™ (available from Allen & Hanburys) which may be used to deliver the aerosolized particles as a finely milled powder in large aggregates either alone or in combination with some pharmaceutically acceptable carrier e.g. lactose; and nebulizers.

Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include at least some of the following components: a sterile diluent (such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents); antibacterial agents (such as benzyl alcohol or methyl parabens); antioxidants (such as ascorbic acid or sodium bisulfite); chelating agents (such as ethylenediaminetetraacetic acid); buffers (such as acetates, citrates or phosphates); and/or agents for the adjustment of tonicity (such as sodium chloride or dextrose). The pH of the solution or suspension can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

A parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa. In addition to the other materials listed above for systemic administration, thickening agents, emollients, and stabilizers can be used to prepare topical compositions. Examples of thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.

If administered intravenously, carriers can be physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.

Dosing

The compound is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated. In one embodiment, the compounds are administered less than three times daily. In one

embodiment, the compounds are administered in one or two doses daily. In one embodiment, the compounds are administered once daily. In some embodiments, the compounds are administered in a single oral dosage once a day.

The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects. An effective dose can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered including, but not limited to: the species of patient; its size, age, and general health; the specific disease involved; the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication.

Typical systemic dosages for the herein described conditions are those ranging from 0.01 mg/kg to 1500 mg/kg of body weight per day as a single daily dose or divided daily doses. Preferred dosages for the described conditions range from 0.5-1500 mg per day. A more particularly preferred dosage for the desired conditions ranges from 5-750 mg per day. Typical dosages can also range from 0.01 to 1500, 0.02 to 1000, 0.2 to 500, 0.02 to 200, 0.05 to 100, 0.05 to 50, 0.075 to 50, 0.1 to 50, 0.5 to 50, 1 to 50, 2 to 50, 5 to 50, 10 to 50, 25 to 50, 25 to 75, 25 to 100, 100 to 150, or 150 or more mg/kg/day, as a single daily dose or divided daily doses. In one embodiment, the daily dose is between 10 and 500 mg/day. In another embodiment, the dose is between about 10 and 400 mg/day, or between about 10 and 300 mg/day, or between about 20 and 300 mg/day, or between about 30 and 300 mg/day, or between about 40 and 300 mg/day, or between about 50 and 300 mg/day, or between about 60 and 300 mg/day, or between about 70 and 300 mg/day, or between about 80 and 300 mg/day, or between about 90 and 300 mg/day, or between about 100 and 300 mg/day, or about 200 mg/day. In one embodiment, the compounds are given in doses of between about 1 to about 5, about 5 to about 10, about 10 to about 25 or about 25 to about 50 mg/kg.

Typical dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.

The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time. Combination Treatment

The compound can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action. The active compounds can be administered in conjunction, i.e. combination or alternation, with other medications used in the treatment of respiratory disorders. In another embodiment, the compounds can be administered in conjunction (combination or alternation) with other medications used in treatment or prophylaxis of inflammatory conditions. In certain embodiments, the combination can be synergistic.

In one embodiment, the compounds can be administered in combination or alternation with drugs typically useful for treatment or prevention of respiratory conditions such as asthma, such as certain anti-inflammatory drugs and bronchodilators. Corticosteroids (inhaled and oral), mast cell stabilizers, and the leukotriene modifier drugs are typically a useful anti-inflammatory medication for people suffering from asthma. These drugs reduce swelling and mucus production in the airways. Bronchodilators typically relieve the symptoms of asthma by relaxing the muscle bands that tighten around the airways. This action rapidly opens the airways, letting more air come in and out of the lungs.

Bronchodilators also help clear mucus from the lungs.

Typically used compounds include inhaled corticosteroids, which prevent rather than relieve symptoms. Inhaled corticosteroids include: Advair (a combination medication that includes a corticosteroid (fluticasone) plus a long acting bronchodilator drug (in this case a β- 2 adrenergic receptor agonist, salmeterol)), aerobid (flunisolide), azmacort (triamcinolone), flovent (fluticasone), methylprednisolone, prednisone, pulmicort or serevent diskus

(salmeterol powder), theophylline, qvar, and xopenex (levalbuterol), Inhaled corticosteroids come in three forms: the metered dose inhaler (MDI), dry powder inhaler (DPI) and nebulizer solutions. Systemic steroids include: methylprednisolone (Medrol, Methylpred, Solu- Medrol), prednisone (Deltasone) and prednisolone (Prelone, Pediapred, Orapred). Mast Cell Stabilizers include Intal and Tilade, which work by preventing the release of irritating and inflammatory substances from mast cells. Leukotriene modifiers include accolate and singular and accolate (zafirlukast), singulair (montelukast) and zyflo (zileuton).

The compounds can be administered in combination with nonsteroidal

antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound can also be administered with corticosteriods.Any of the compounds described herein for combination or alternation therapy can be administered as any prodrug that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound. Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts"), and a compound which has been alkylated or acylated at an appropriate position. The modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound.

In another embodiment, the active compounds can be administered in conjunction with medications used in the treatment or prophylaxis of conditions associated with cardiovascular disease. These compounds include lipid lowering agents, such as statins, probucol and nicotinic acid; platelet aggregation inhibitors such as aspirin; antithrombotic agents such as Coumadin; calcium channel blockers such as varapamil, diltiazem, and nifedipine; angiotensin converting enzyme (ACE) inhibitors such as captopril and enalopril, and β-blockers such as propanalol, terbutalol, and labetalol. The compounds can also be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound can also be administered, for example, with corticosteriods.

In some embodiments, the compounds are administered in combination or alternation with ACE (angiotensin-converting enzyme) inhibitors. Nonlimiting examples are captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), quinapril (Accupril), ramipril (Altace), benazepril (Lotensin) and fosinopril (Monopril). In another embodiment, the compounds are administered in combination or alternation with beta blockers. Nonlimiting examples are atenolol (Tenormin), carvedilol (Coreg), labetolol (Normodyne), metoprolol (Lopressor, Toprol) and propanolol (Inderal). In another embodiment, the compounds are administered in combination or alternation with blood thinners such as aspirin or warfarin (Coumadin) or calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor), nifedipine (Adalat, Procardia), nicardipine (Cardene) or verapamil (Calan). In another embodiment, the compounds are administered in combination or alternation with a statin. Nonlimiting examples of currently used statins are lovastatin (Mevacor, Altocor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor).

The compounds can also be administered in combination or alternation with compounds that are generally used for treatment of skin inflammatory conditions, such as Acitretin , Alclometasone dipropionate , Allantoin / Coal tar extract / Hydrocortisone , Alphaderm , Alphosyl HC , Asmanex , Benzalkonium chloride / Dimeticone 350 /

Hydrocortisone / Nystatin , Betacap , Betamethasone dipropionate , Betamethasone dipropionate / Calcipotriol hydrate , Betamethasone dipropionate / Salicylic acid ,

Betamethasone Valerate , Betamethasone Valerate / Clioquinol , Betamethasone Valerate / Fusidic Acid , Betamethasone valerate / Neomycin sulphate , Betnovate , Betnovate-C , Betnovate-N , Bettamousse , Calcipotriol , Calcipotriol hydrate , Calcitriol , Calmurid HC , Canesten HC , Chlorquinaldol / Hydrocortisone Butyrate , Ciclosporin , Clarelux , Clioquinol / Hydrocortisone , Clobetasol propionate , Clobetasol propionate / Neomycin sulphate / Nystatin , Clobetasone butyrate , Clobetasone butyrate / Nystatin / Oxytetracycline calcium , Clotrimazole / Hydrocortisone , Crotamiton / Hydrocortisone , Cutivate, Daktacort ,

Dandrazol , Dermovate , Dermovate-NN , Dioderm , Diprosalic , Diprosone , Dithranol , Dithrocream , Dovobet , Dovonex , Dovonex cream , Econacort , Econazole nitrate / Hydrocortisone , Efalizumab , Efcortelan , Elidel , Enbrel , Etanercept , Eumovate , Eurax Hydrocortisone , Fluticasone propionate , Fucibet , Fucidin H , Fucidin H ointment , Fusidic acid / Hydrocortisone acetate , Gramicidin / Neomycin sulphate / Nystatin / Triamcinolone acetonide , Hydrocortisone , Hydrocortisone acetate / Sodium fusidate , Hydrocortisone butyrate , Hydrocortisone / Lactic Acid / Urea , Hydrocortisone / Miconazole nitrate , Hydrocortisone / Urea , Infliximab , enalog, Ketoconazole , Locoid , Locoid C , Maxtrex , Methotrexate , Methotrexate sodium , Modrasone , Mometasone , Nasofan , Neoral , Neotigason , Nizoral , Pimecrolimus , Protopic , Raptiva , Remicade , Silkis , Tacrolimus monohydrate , Tazarotene , Timodine , Tri-Adcortyl , Triamcinolone acetonide , Trimovate , Vioform-Hydrocortisone and Zorac.

Any of the compounds described herein for combination or alternation therapy can be administered as any prodrug that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound. Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts"), and a compound which has been alkylated or acylated at an appropriate position. The modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its ability to inhibit the expression of VCAM-1 according to known methods.

General Synthesis

Scheme A

Step 1: Approximately two equivalents of a 2,6-dialkyl-4-mercaptophenol, for example 2,6-di-tert-butyl-4-mercaptophenol, and about one equivalent of a 4-oxo-piperidine- 1-carboxylalkyl or a 4-oxo-piperidine-l-carboxylic acid alkyl ester, for example, 4-oxo- piperidine-l-carboxylic acid ethyl ester, are combined with an organic solvent or a polar solvent or a protic solvent, for example methanol. The concentration of the 2,6-di-alkyl-4- mercaptophenol and 4-oxo-piperidine-l-carboxylic acid alkyl ester in the solvent is approximately 0.1 to 10 M, for example, about 1 M. The solution is heated, for example, to about 45°C, and stirred, for example, for 20 hours. An acid is added during or at the start of the reaction. For example, HC1 gas, which can be generated by the addition of concentrated sulfuric acid to NaCl, can be bubbled through the solution for about 2 h. Stirring is then continued for example, for 18 h or until after a solid has formed. The slurry is cooled, for example, to 0°C and stirred, for example, for an additional 1 h. The solid is isolated, for example by filtration, and can be washed, for example with a small amount of cold methanol, and dried, for example in vacuo. The product is a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylalkyl compound or a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine- 1 -carboxylic acid alkyl ester compound, for example, 4,4- bis-(3,5-di-ier?-butyl-4-hydroxyphenylsulfanyl)piperidine-l- carboxylic acid ethyl ester.

Step 2: The 4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine-l-ca rboxylic acid alkyl ester is hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in an alcohol such as 2-methoxyethanol. The mixture may be heated and stirred under an inert atmosphere, for example to 120°C for 18 h under N ₂ gas. The reaction mixture is subsequently cooled, for example to ambient temperature and the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield a 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound, for example 4,4-bis-(3,5-di-ter/-butyl-4- hydroxylphenylsulfanyl)piperidine.

Step 3: The 4,4-bis-(3,5-dialkyl-4-hydroxylphenylsulfanyl)piperidine compound, for example 4,4-bis-(3,5-di-feri-butyl-4-hydroxylphenylsulfanyl)piperidi ne, is reacted with one or more equivalents of a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as N,N-diisopropylethylamine, in an anhydrous organic solvent, for example tetrahydrofuran. The [4,4-bis-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)piperidi n- l-yl]acetic acid alkyl ester product may be isolated by extraction. For example, the reaction mixture is concentrated in vacuo, the residue is taken up in an organic solvent such as ethyl acetate, washed, for example with water and brine, dried with a drying agent such as sodium sulfate, filtered and reduced to dryness.

Step 4: The ester of Step 3 can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran. The mixture may be heated and stirred, for example to 60°C for 6 h. The pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HC1. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid, for example [4,4-Bis-(3,5-di-te -butyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid. The product can be further purified by chromatography or recrystallization.

In an alternative to Steps 3 and 4, the 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound, for example 4,4-bis-(3,5-di-/er/-butyl-4- hydroxylphenylsulfanyl)piperidine, is reacted with one or more equivalents of an alkali metal carbonate, for example potassium carbonate, and an organic anhydride, for example succinic anhydride, in an anhydrous organic solvent, for example dimethylformamide. The mixture is stirred at, for example, ambient temperature for two hours, and quenched with water and acidified to a pH of about 5 or less with an acid, for example, HC1. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4,4-Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l- yl]carboxyalkyl-l-one compound, for example [4,4-Bis-(3,5-di-teri-butyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]-4-oxo-butyric acid. The product can be further purified by chromatography or recrystallization.

The [4,4-Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl ]carboxyalkyl-l-one compound product can optionally be converted to a [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]hydroxyalkyl-l-one compound by reacting the [4,4- Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]carb oxyalkyl-l-one compound, for example [4,4-Bis-(3 ,5-di-/ert-butyl-4-hydroxyphenylsulfanyl)piperidin- 1 -yl]-4-oxo-butyric acid, with an excess of borane, for example 1.0 M borane/tetrahydrofuran solution, in an organic solvent such as tetrahydrofuran. The mixture is stirred at, for example, ambient temperature for two hours, and quenched with water. The product can be isolated for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4,4-Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l- yl]hydroxyalkyl-l-one compound, for example, [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]-4-hydroxy-butan-l-one. The product can be further purified by chromatography or recrystallization.

In another alternative to Steps 3 and 4, the 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound, for example 4,4-bis-(3,5-di-fer/'-butyl-4- hydroxylphenylsulfanyl)piperidine, is reacted with an amine base, for example N,N- diisopropylethylamine, in an anhydrous organic solvent, for example tetrahydrofuran, a trialkylacetyl chloride, for example trimethylacetyl chloride, is added to the reaction mixture. The solution is stirred, for example at ambient temperature for 1 hour, and quenched, for example with water. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo. The residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo. The product is a [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]alkyl-l-one compound, for example [4,4-Bis-(3,5-di- ½ri-butyl-4-hydroxyphenylsulfanyl)piperidin- 1 -yl] -2,2-dimethyl-propan- 1 -one.

In another alternative to Steps 3 and 4, the 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound, for example 4,4-bis-(3,5-di-ier/-butyl-4- hydroxylphenylsulfanyl)piperidine, is reacted with one or more equivalents of an amine base, for example N^V-diisopropylethylamine, in an organic solvent, for example tetrahydrofuran, and a halosulfonylalkyl or halosulfonylaryl compound, for example methyl (5- chlorosulfonyl)-l -methyl- lH-pyrrole-2-carboxy late or ethyl 4-(chlorosulfonyl)-3,5-dimethyl- lH-pyrrole-2-carboxylate or methyl-5-(chlorosulfonyl)-2-furoate, is added to the reaction mixture. The solution is stirred, for example at ambient temperature for 2 hours, and quenched, for example with an acid such as HC1, and optionally, diluted with water. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo. The residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo. The product is a [4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl ]-(alkyl or aryl)- sulfonyl compound. The product may be further purified by chromatography or

recrystallization.

Scheme B

(A = R ⁹ or OR ⁹ ) Alkylation or

acylation

Step 1: A 4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine-l-ca rboxylic acid alkyl ester compound, for example, 4,4-bis-(3,5-di-½rt-butyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester, is combined with one or more equivalents of an alkali metal carbonate, for example potassium carbonate, and a haloalkyl or haloalcohol, for example 2-bromoethanol or 2-bromopropanol, in an anhydrous organic solvent, for example dimethylformamide. The mixture is heated, for example to 80 °C for 100 hours, and quenched, for example with water. The product can be isolated for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to isolate the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester, for example 4-[3,5-Di-½r - butyl-4-(2-hydroxyethoxy)phenylsulfanyl]-4-(3,5-di-teri-buty l-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester or 4-(3,5-di-fert-butyl-4- hydroxyphenylsulfanyl)-4-[3,5-di-terf-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester or 4-{4-(3,5-di-/eri-butyl-4- hydroxyphenylsulfanyl)-4-[3,5-di-teri-butyl-4-(3-hydroxy-pro poxy)phenylsulfanyl]piperidin- l-yl}-4-oxo-butyric acid methyl ester. The product can be further purified by

chromatography or recrystallization. Optionally, 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester, for example 4-{4-(3,5-di- ½rr-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-ieri-butyl-4-( 3-hydroxy- propoxy)phenylsulfanyl]piperidin-l-yl}-4-oxo-butyric acid methyl ester, can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran. The mixture may be heated and stirred, for example to 60 °C for 6 h. The pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HC1. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo. The product can be further purified by chromatography or recrystallization.

Scheme C

Alkylation or acylation

Step 1: Approximately two equivalents of a 2,6-dialkyl-4-mercaptophenol, for example 2,6-di-½r/-butyl-4-mercaptophenol, and about one equivalent of a 4-oxo-piperidine- 1-carboxylalkyl or a 4-oxo-piperidine-l-carboxylic acid alkyl ester, for example, 4-oxo- piperidine-l-carboxylic acid ethyl ester, are combined with an organic solvent or a polar solvent or a protic solvent, for example methanol. The concentration of the 2,6-di-alkyl-4- mercaptophenol and 4-oxo-piperidine-l-carboxylic acid alkyl ester in the solvent is approximately 0.1 to 10 M, for example, about 1 M. The solution is heated, for example, to about 45 °C, and stirred, for example, for 20 hours. An acid is added during or at the start of the reaction. For example, HC1 gas, which can be generated by the addition of concentrated sulfuric acid to NaCl, can be bubbled through the solution for about 2 h. Stirring is then continued for example, for 18 h or until after a solid has formed. The slurry is cooled, for example, to 0 °C and stirred, for example, for an additional 1 h. The solid is isolated, for example by filtration, and can be washed, for example with a small amount of cold methanol, and dried, for example in vacuo. The compound is a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylalkyl compound or a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester compound, for example, 4,4- bis-(3,5-di-ierf-butyl-4-hydroxyphenylsulfanyl)piperidine-l- carboxylic acid ethyl ester.

Step 2: A 4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine-l-ca rboxylic acid alkyl ester compound, for example, 4,4-bis-(3,5-di-tert-butyl-4- hydroxyphenylsulfanyl)piperidine- 1 -carboxylic acid ethyl ester, is combined with one or more equivalents of an alkali metal carbonate, for example potassium carbonate, and a haloalkyl or haloalcohol, for example 2-bromoethanol or 2-bromopropanol, in an anhydrous organic solvent, for example dimethylformamide. The mixture is heated, for example to 80 °C for 100 hours, and quenched, for example with water. The product can be isolated for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to produce the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l -carboxylic acid alkyl ester, for example 4-[3,5-Di-/er - butyl-4-(2-hydroxyethoxy)phenylsulfanyl]-4-(3,5-di-½r^-buty l-4- hydroxyphenylsulfanyI)piperidine-l -carboxylic acid ethyl ester or 4-(3,5-di-½r/-butyl-4- hydroxyphenylsulfanyl)-4-[3,5-di-tert-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidine-l -carboxylic acid ethyl ester or 4-{4-(3,5-di-feri-butyl-4- hydroxyphenylsulfanyl)-4- [3 ,5 -di-ter/-butyl-4-(3 -hydroxy-propoxy)phenylsulfanyl]piperidin- l-yl}-4-oxo-butyric acid methyl ester. The product can be further purified by

chromatography or recrystallization.

Optionally, 4- [3 , 5 -dialkyl-4-(alkoxy)pheny lsulfany 1] -4-(3 , 5 -dialkyl-4- hydroxyphenylsulfanyl)piperidine-l -carboxylic acid alkyl ester, for example 4-{4-(3,5-di- feri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-ier/-butyl-4-( 3-hydroxy- propoxy)phenylsulfanyl]piperidin-l-yl}-4-oxo-butyric acid methyl ester, can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran. The mixture may be heated and stirred, for example to 60 °C for 6 h. The pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HC1. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo. The product can be further purified by chromatography or recrystallization.

Optionally, a 4- [3 , 5 -dialky l-4-(hydroxyalkoxy)pheny lsulfanyl]-4-(3 , 5 -dialky 1-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester, for example the 4-(3,5-di- ½ri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di- er?-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester, can be used in the preparation of a 4- {3, 5 -dialky 1 -4-[(pyrazol-l-yl)alkoxy]-phenylsulfanyl}-4-(3,5-dialkyl -4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester, for example 4-{3,5-di-½ri- butyl-4-[3-(3-hydroxymethyl-5-methylpyrazol-l-yl)propoxy]-ph enylsulfanyl}-4-(3,5-di-teri- butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester. The 4-[3,5-dialkyl- 4-(hydroxyalkoxy)phenylsulfany 1] -4-(3 , 5 -dialky 1-4-hydroxyphenylsulfany l)piperidine- 1 - carboxylic acid alkyl ester is reacted with an alkylsulfonyl chloride, for example

methanesulfonylchloride, in the presence of a base, for example an amine base such as N,N- diisopropylethylamine, in an organic solvent, for example methylene chloride. The product is isolated by, for example, extraction, then combined with an anhydrous organic solvent, such as dimethylformamide, and a pyrazole compound, such as (5-methyl-2H-pyrazol-3-yl)- methanol. One or more equivalents of an alkyl metal hydride, such as sodium hydride, or other hydride reagent or alkyl lithium reagent, is added to the reaction mixture. The reaction is quenched, if necessary, and the product is isolated, for example by extraction.

Scheme D Alkylation or

acylation or

(A = R ⁹ or OR ⁹ ) sulfonylation or urea formation

Step 1: The 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester is hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in an alcohol such as 2-methoxyethanol. The mixture may be heated and stirred under an inert atmosphere, for example to 120 °C for 18 h under N ₂ gas. The reaction mixture is subsequently cooled, for example to ambient temperature and the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield a 4-[3,5- dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyph enylsulfanyl)piperidine compound.

Step 2: The 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine compound is reacted with one or more equivalents of a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as N^V-diisopropylethylamine, in an anhydrous organic solvent, for example tefrahydrofuran. The [4,4-bis-(3,5-di-/ert-butyl-4-hydroxyphenylsulfanyl)piperidi n-l-yl]acetic acid alkyl ester product may be isolated by extraction. For example, the reaction mixture is concentrated in vacuo, the residue is taken up in an organic solvent such as ethyl acetate, washed, for example with water and brine, dried with a drying agent such as sodium sulfate, filtered and reduced to dryness.

Step 3: The ester of Step 3 can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran. The mixture may be heated and stirred, for example to 60 °C for 6 h. The pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HCl. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4-[3,5-dialkyl-4- (alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyphenylsulfan yl)piperidin-l-yl]acetic acid compound. The product can be further purified by chromatography or recrystallization.

In an alternative to Steps 2 and 3, the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5- dialkyl-4-hydroxyphenylsulfanyl)piperidine compound is reacted with one or more equivalents of an alkali metal carbonate, for example potassium carbonate, and an organic anhydride, for example succinic anhydride, in an anhydrous organic solvent, for example dimethylformamide. The mixture is stirred at, for example, ambient temperature for two hours, and quenched with water and acidified to a pH of about 5 or less with an acid, for example, HCl. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4-[3,5-dialkyl-4- (alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyphenylsulfan yl)piperidin-l- yl]carboxyalkyl-l-one compound. The product can be further purified by chromatography or recrystallization.

The [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]carboxyalkyl-l-one compound product can optionally be converted to a [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]hydroxyalkyl-l-one compound by reacting the [4-[3,5- dialky l-4-(alkoxy)pheny lsulfany 1] -4-(3 , 5 -dialkyl-4-hydroxypheny lsulfany l)piperidin- 1 - yl]carboxyalkyl-l-one compound with an excess of borane, for example 1.0 M

borane/tetrahydrofuran solution, in an organic solvent such as tetrahydrofuran. The mixture is stirred at, for example, ambient temperature for two hours, and quenched with water. The product can be isolated for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate. The volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4-[3,5-dialkyl-4- (alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyphenylsulfan yl)piperidin-l- yl]hydroxyalkyl-l-one compound. The product can be further purified by chromatography or recrystallization.

In another alternative to Steps 2 and 3, the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]- 4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine compound is reacted with an amine base, for example N _^ N-diisopropylethylamine, in an anhydrous organic solvent, for example tetrahydrofuran, a trialkylacetyl chloride, for example trimethylacetyl chloride, is added to the reaction mixture. The solution is stirred, for example at ambient temperature for 1 hour, and quenched, for example with water. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo. The residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo. The product is a [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]- 4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]alkyl- l-one compound.

In another alternative to Steps 2 and 3, the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]- 4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine compound is reacted with one or more equivalents of an amine base, for example N,N-diisopropylethylamine, in an organic solvent, for example tetrahydrofuran, and a halosulfonylalkyl or halosulfonylaryl compound, for example methyl (5-chlorosulfonyl)-l -methyl- lH-pyrrole-2-carboxylate or ethyl 4- (chlorosulfonyl)-3,5-dimethyl-lH-pyrrole-2-carboxylate or methyl-5-(chlorosulfonyl)-2- furoate, is added to the reaction mixture. The solution is stirred, for example at ambient temperature for 2 hours, and quenched, for example with an acid such as HC1, and optionally, diluted with water. The product is isolated, for example by extraction with an organic solvent, for example ethyl acetate. The extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo. The residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo. The product is a [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5- dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]-(alkyl or aryl)-sulfonyl compound. The product may be further purified by chromatography or recrystallization. Scheme E

Alkylation or acylation or

(A = R ⁹ or OR ⁹ ) sulfonylation or urea formation

EXAMPLES

Example 1 : [4,4-Bis-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)piperidi n-l-yl] acetic acid

Ex. la: A 500 mL flask was charged with 2,6-di-tert-butyl-4-mercaptophenol (9.1 g, 38 mmol), 4-oxo-piperidine-l-carboxylic acid ethyl ester (3.3 g, 19 mmol) and 50 mL of methanol. The solution was heated to 45 °C. HCl gas (generated by the addition of concentrated sulfuric acid to salt) was bubbled through the solution for 2 h. Stirring was continued for another 18 h at 45 °C during which a solid formed. The slurry was cooled to 0 °C and stirred for an additional 1 h. The solid was collected by filtration, washed with a small amount of cold methanol, and dried in vacuo to yield 4,4-bis-(3,5-di-½r/-butyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester as a white solid (9.2 g, 80%), mp 170-171 °C. ^J H-NMR (CDC1 ₃ ): δ 7.50 (s, 4H), 5.39 (s, 2H), 4.08 (q, 2H, J= 6.9 Hz), 3.60 (t, 4H, J = 4.8 Hz), 1.69 (t, 4H, J = 4.8 Hz), 1.44 (s, 36H), 1.22 (t, 3H, J = 7.2 Hz). HRMS (ESI) calcd for C36H55NO4S2: 652.3459 (M+Na) ⁺ . Found: 652.3470. Anal. Calcd for C ₃ 6H55NO ₄ S2: C, 68.64; H, 8.80; N, 2.22; S, 10.18. Found: C, 68.85; H, 9.07; N, 2.19; S, 9.85.

Ex. lb: 4,4-Bis-(3,5-di-½rr-butyl-4-hydroxyphenylsulfanyl)piperidin e-l-carboxylic acid ethyl ester (Ex. la, 0.25 g, 0.40 mmol) was charged to a 25 mL round bottom flask containing 5 mL of 2-methoxyethanol and 5 mL of IN NaOH. The resulting mixture was heated to 120 °C and stirred under nitrogen for 18 h. The reaction mixture was cooled to ambient temperature and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure to dryness, and then dried in vacuo to yield 4,4-bis-(3,5-di-tert-butyl-4- hydroxylphenylsulfanyl)piperidine as a pale pink solid (0.22 g, 95%), mp 69-72 °C. 'H-NMR (CDC1 ₃ ): δ: 7.45 (s, 4H), 5.36 (brs, 2H), 3.00 (t, 4H, J = 5.1 Hz), 1.72 (t, 4H, J = 6.3 Hz), 1.44 (s, 36H). HRMS (ESI) calcd for C33H ₅₂ N0 ₂ S ₂ : 558.3434 (M+H) ⁺ . Found: 558.3439. Anal. Calcd for C ₃ 3H5 ₂ N0 ₂ S2: C, 71.04; H, 9.21; N, 2.51; S, 11.50. Found: C, 70.92; H, 9.29; N, 2.51; S, 11.24.

Ex. lc: A 100 mL round bottom flask was charged with 4,4-bis-(3,5-di-½rt-butyl-4- hydroxylphenylsulfanyl)piperidine (Ex. lb, 0.50 g, 0.90 mmol), 20 mL of anhydrous THF, N,N-diisopropylethylamine (0.35 g, 2.7 mmol) and ethyl bromoacetate (0.17 g, 1.0 mmol). After the resultant mixture was stirred at ambient temperature for 2 h the starting material was consumed. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water and brine, and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was dried in vacuo (0.55 g, 95%) to give [4,4-bis-(3,5-di- eri-butyl-4-hydroxyphenylsulfanyl)piperidin-l- yl]acetic acid ethyl ester as a solid, mp 172-174 °C. ^X H- MR (CDC1 ₃ ) 5 7.47 (s, 4H), 5.36 (s, 2H), 4.17 (q, 2H, J = 1.1 Hz), 3.21 (s, 2H), 2.73 (t, 4H, J = 5.5 Hz), 1.87 (brm, 4H), 1.44 (s, 36H), 1.26 (t, 3H, J = 7.9 Hz). HRMS (ESI) calcd for C ₃₇ H ₅ 7N0 ₄ S ₂ : 644.3807 (M+H) ⁺ . Found: 644.3802. Anal. Calcd for C ₃₇ H ₅₇ 0 ₄ S2: C, 69.01; H, 8.92; N, 2.18; S, 9.96. Found: C, 69.33; H, 9.19; N, 2.19; S, 9.58.

4,4-Bis-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)piperi din-l-yl]acetic acid ethyl ester (Ex. lc, 0.55 g) was charged to a 50 mL round bottom flask containing 10 mL of THF and 5 mL of IN NaOH. The resulting solution was warmed to 60 °C and stirred for 6 h. The solution was adjusted to pH < 5 using IN HC1 and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (MeOH/CH ₂ Cl ₂ , 5-20% gradient) to yield the title compound as a light tan solid (0.40 g, 73%), mp 158-160 °C. Ή-NMR (CDCI ₃ ) δ 7.51 (brs, 4H), 5.41 (brs, 2H), 3.87 (s, 2H), 3.58 (brs, 4H), 2.48 (brs, 2H), 1.80 (brm, 2H), 1.44 (s, 36H). HRMS (ESI) calcd for C ₃ 5H5 ₄ N0 ₄ S ₂ : 616.3494 (M+H) ⁺ . Found: 616.3515. Example 2: 4-[4,4-Bis-(3,5-di-ieri-butyl-4-hydroxyphenylsulfanyl)piperi din-l-yl]-4-oxo- butyric acid

A 100 mL round bottom flask was charged with 4,4-bis-(3,5-di-tert-butyl-4- hydroxylphenylsulfanyl)piperidine (Ex. lb, 0.50 g, 0.90 mmol), 10 mL of anhydrous DMF, potassium carbonate (0.50 g, 3.6 mmol) and succinic anhydride (0.10 g, 1.0 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with 20 mL of water and the pH adjusted to <5 using IN HC1. The resultant mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel chromatography (EtOAc/hexanes, 0 to 50% gradient) to give a solid (0.40 g, 68%), mp 196-198 °C; ^-NMR (CDC1 ₃ ) δ 7.50 (s, 4H), 5.41 (s, 2H), 3.76 (t, 2H, J = 5.1 Hz), 3.61 (t, 2H, J= 4.8 Hz), 2.64 (brm, 4H), 1.78 (t, 2H, J= 5.4 Hz), 1.69 (t, 2H, J= 6.0 Hz), 1.45 (s, 36H). HRMS (ESI) calcd for C ₃₇ H ₅₆ N0 ₅ S2: 658.3582 (M+H) ⁺ . Found: 658.3600. Anal. Calcd for C^HseNC^: C, 67.54; H, 8.43; N, 2.13; S, 9.75. Found: C, 67.49; H, 8.66; N, 2.18; S, 9.68.

Example 3: 4-[3,5-Di-teri-butyl-4-(2-hydroxyethoxy)phenylsulfanyl]-4-(3 ,5-di-teri-butyl- 4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester

4,4-Bis-(3,5-di-/e^bu1yl-4-hydroxyphenylsulfanyl)piperidine- l-carboxylic acid ethyl ester (Ex. la, 5.0 g, 7.94 mmol) was charged to a 200 mL round bottom flask containing 50 mL of anhydrous DMF, potassium carbonate (4.4 g, 31.8 mmol) and 2-bromoethanol (2.0 g, 15.9 mmol). The mixture was heated to 85 °C for 100 h, at which time HPLC analysis indicated the presence of 27% product and 67% unreacted starting material. The reaction was quenched with 50 mL of water and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with IN HC1, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 0 to 50% gradient) gave the title compound as a solid (2.5 g, 45%), mp 192-195 °C. 'H-NMR (CDCb) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.39 (s, 1H), 4.09 (q, 2H, J = 8.0 Hz), 4.04 (t. 2H, J = 5.4 Hz), 3.93 (t, 2H, J= 4 Hz), 3.60 (dd, 4H, J= 6.9, 5.6 Hz), 1.89 (t, 1H, J = 5.2 Hz), 1.72 (t, 4H, J = 4 Hz), 1.44 (s, 36H), 1.21 (t, 3H, J = 8.0 Hz). HRMS (ESI) Calcd for C ₃ 8H ₅₉ N0 ₅ S ₂ : 696.3737 (M+Na) ⁺ . Found: 696.3732. Anal. Calcd for C ₃₈ H ₅₉ N0 ₅ S ₂ : C, 67.72; H, 8.82; N, 2.08; S, 9.51. Found: C, 67.74; H, 8.93; N, 2.13; S, 9.41.

Example 4 : 4-(3,5-Di-fe *i-butyl-4-hydroxyphenylsuIfanyl)-4- [3,5-di-fert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester

4,4-Bis-(3,5-di-/ert-butyl-4-hydroxyphenylsulfanyl)piperi dine-l-carboxylic acid ethyl ester (Ex. la, 5.0 g, 7.94 mmol) was charged to a 200 mL round bottom flask containing 50 mL of anhydrous DMF, potassium carbonate (4.4 g, 31.8 mmol) and 3-bromopropanol (2.21 g, 15.9 mmol). The mixture was heated to 85 °C for 6 h, at which time HPLC analysis indicated the presence of 20% bis substituted, 44% expected product and 27% unreacted starting material. The reaction was quenched with 50 mL of water and extracted with ethyl acetate (3 x lOOmL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 0 to 50% gradient) gave the title compound as a solid (2.5 g, 45%), mp 80- 83 °C. 1H- MR (DMSO-i/ ₆ ): δ 7.53 (s, 2H), 7.38 (s, 2H), 4.55 (m, 1H), 3.96 (q, 2H, J = 7.0 Hz), 3.75 (t, 2H, J = 7.2 Hz), 3.54 (q, 2H, J = 5.2 Hz), 3.47 (m, 2H), 1.96 (m, 2H), 1.60 (m, 4H), 1.38 (s, 36H), 1.09 (t, 3H, J = 7.2 Hz). HRMS (ESI) calcd for C39H61NO5S2: 710.3871 (M+Na) ⁺ . Found: 710.3889. Anal. Calcd for C39H61NO5S2: C, 68.08; H, 8.94; N, 2.04; S, 9.32. Found: C, 67.88; H, 9.15; N, 2.09; S, 9.40.

Example 5: 2,6-Di-tert-butyl-4-{4-[3,5-di-tert-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol

4-(3 , 5 -Di-tert-butyl-4-hydroxyphenylsulf ny l)-4- [3 , 5 -di-teri-buty l-4-(3 -hy droxy- propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester (Ex. 4, 2.5 g, 3.6 mmol) was charged to a 100 mL round bottom flask containing 20 mL of 2-methoxyethanol and 25 mL of IN NaOH. The mixture was heated to 120 °C for 18 h. The reaction was cooled to ambient temperature, quenched with 50 mL of water, and extracted with ethyl acetate (3 x lOOmL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography [MeOH (1% NH ₄ 0H)/CH ₂ C1 ₂ , 0 to 20% gradient] gave the title compound as a solid (350 mg, 16%), mp

158-160 °C. ^J H-NMR (DMSO-d ₆ ): δ 7.56 (s, 2H), 7.38 (s, 2H), 5.76 (s, 1H), 4.58 (t, 1H, J = 4.2 Hz), 3.77 (t, 2H, J = 6.8 Hz), 3.55 (m, 2H, J = 5.8, 4.9 Hz), 3.17 (brm, 4H), 1.97 (m, 2H, J = 6.5 Hz), 1.83 (m, 4H, J = 5.5 Hz), 1.40 (s, 18H), 1.39 (s, 18H). HRMS (ESI) calcd for C36H58NO3S2: 616.3852 (M+H) ⁺ , Found: 616.3858. Example 6: l-[4,4-Bis-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)piperi din-l-yl]-2,2- dimethyl-propan-l-one

A 50 mL flask was charged with 4,4-bis-(3,5-di-½ri-butyl-4-hydroxylphenylsulfanyl)- piperidine (Ex. lb, 1.82 g, 3.3 mmol), 20 mL of anhydrous THF and N,N- diisopropylethylamine (0.84 g, 6.5 mmol). Trimethylacetyl chloride (0.41 g, 3.43 mmol) was added dropwise to the reaction mixture and the resulting solution was stirred at ambient temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with IN HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with hexanes. The precipitate was collected by filtration, washed with a small portion of hexanes, and dried in vacuo to yield the title compound as an off-white solid (2.0 g, 95%), mp 114-117 °C. ^! H-NMR (CDC1 ₃ ) δ 7.48 (s, 4H), 5.39 (s, 2H), 3.74 (t, 4H, J= 5.3 Hz), 1.72 (t, 4H, J = 5.2 Hz), 1.44 (s, 36H), 1.20 (s, 9H). HRMS (ESI) calcd for C38H60NO3S2: 642.3995 (M+H) ⁺ . Found: 642.4014. Anal. Calcd for C38H59NO3S2: C, 71.09; H, 9.26; N, 2.18; S, 9.99. Found: C, 71.25; H, 9.46; N, 2.17; S, 9.41.

Example 7: l-{4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-t ert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidin-l-yl}-2,2-dimethylp ropan-l-one

A 50 mL flask was charged with l-[4,4-Bis-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)- piperidin-l-yl]-2,2-dimethyl-propan-l-one (Ex. 6, 1.6 g, 2.5 mmol), 20 mL of anhydrous DMF and potassium carbonate (1.38 g, 10 mmol). 3-Bromopropanol (0.69 g, 5.0 mmol) was added and the reaction stirred for 3.5 h at 85 °C. The reaction was cooled to ambient temperature, quenched with water, and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with IN HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 0-50% gradient) yielded the title compound as an off-white solid (0.30 g,

17%), mp 102-104 °C. ^X H-NMR (DMSO-ifc) δ 7.51 (s, 2H), 7.34 (s, 2H), 4.56 (brs, 1H), 3.75 (t, 2H, J = 6.9 Hz), 3.60 (m, 4H), 3.54 (m, 2H), 1.96 (m, 2H), 1.59 (m, 4H), 1.38 (s, 18H), 1.37 (s, 18H), 1.05 (s, 9H). HRMS (ESI) calcd for 700.4440 (M+H) ⁺ . Found:

700.4433.

Example 8: l-[4,4-Bis-(3,5-di-tert-butyl-4-hydroxyphenylsuIfanyl)piperi din-l-yl]-4- hydroxy-butan-l-one

A 200 mL round bottom flask was charged with 4-[4,4-bis-(3,5-di-ter/-butyl-4-hydroxy- phenylsulfanyl)piperidin-l-yl]-4-oxo-butyric acid (Ex. 2, 1.0 g, 1.5 mmol), 10 mL of anhydrous THF and 10 mL of 1.0 M borane/THF solution. The reaction mixture was stirred at ambient temperature for 1 h, quenched with water, and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 5-50% gradient) gave the title compound as a solid (0.68 g, 70%), mp 104- 106 °C. ^-NMR (CDC1 ₃ ) δ 7.50 (s, 2H), 7.48 (s, 2H), 5.42 (s, 1H), 5.40 (s, 1H), 3.61 (m, 2H), 3.05 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H), 1.84 (m, 6H), 1.44 (s, 36H). Example 9: 4-{4-(3,5-Di-tert-butyI-4-hydroxyphenylsulfanyl)-4-[3,5-di-t ert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidin-l-yl}-4-oxo-butyric acid

Ex. 9a: A 500 mL round bottom flask was charged with 4,4-bis-(3,5-di-?erf-butyl-4- hydroxylphenylsulfanyl)piperidine (Ex. lb, 12.6 g, 22.6 mmol), 150 mL of anhydrous THF and N,N-diisopropylethylamine (5.8 g, 45.2 mmol). Methyl-4-chloro-4-oxobutyrate (3.6 g, 23.7 mmol) was slowly added and the resulting solution was stirred at ambient temperature for 2 h. The reaction was quenched with water and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (3 x 100 mL) and the combined organic extracts were washed with IN HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 0-40% gradient) yielded 4-[4,4-bis-(3,5-di-fer^butyl-4-hydroxy-phenylsulfanyl)piperi din-l-yl]-4- oxo-butyric acid methyl ester as an off-white solid (13.0 g, 86%), mp 96-98 °C. ^-NMR (CDC1 ₃ ) δ 7.50 (s, 4H), 5.40 (s, 2H), 3.73 (t, 2H, J= 4.2 Hz), 3.67 (s, 3H), 3.61 (t, 2H, J= 5.1 Hz), 2.60 (m, 4H), 1.79 (t, 2H, J = 4.2 Hz), 1.67 (t, 2H, J = 4.7 Hz), 1.45 (s, 36H). HRMS (ESI) calcd for C38H57NO5S2: 672.3756 (M+H) ⁺ . Found: 672.3741. Anal. Calcd for C38H57NO5S2: C, 67.92; H, 8.55; N, 2.08; S, 9.54. Found: C, 68.33; H, 8.79; N, 1.99; S, 9.14.

Ex. 9b: A 200 mL round bottom flask was charged with 4-[4,4-bis-(3,5-di-ter?-butyl-4- hydroxylphenylsulfanyl)piperidin-l-yl]-4-oxobutyric acid methyl ester (Ex. 9a, 9.9 g, 14.7 mmol), 50 mL of anhydrous DMF and potassium carbonate (8.1 g, 58.8 mmol). 1- Bromopropanol was added and the mixture was stirred at 85 °C for 3 h. After cooling to ambient temperature, the reaction was quenched with water and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with 20% sodium bisulfite (100 mL), water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 5-80% gradient) yielded 4-{4-(3,5-di-terf-butyl- 4-hydroxyphenylsulfanyl)-4-[3,5-di-/eri-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidin-l-yl}-4-oxo-butyric acid methyl ester as an off-white solid (3.1 g, 30%), mp 96-98 °C; ^! H-NMR (CDC1 ₃ ) δ 7.59 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 3.89 (q, 4H, J= 5.9 Hz), 3.75 (m, 2H), 3.67 (s, 3H), 3.62 (m, 2H), 2.60 (m, 4H), 2.14 (pentet, 2H, J= 6.4 Hz), 1.79 (m, 2H), 1.67 (m, 2H), 1.45 (s, 18H), 1.43 (s, 18H).

A 200 mL round bottom flask was charged with 4-{4-(3,5-di-½ri-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di- er/-butyl-4-(3-hydroxypropoxy)phenylsulfanyl]-piperidin-l-yl }-4- oxo-butyric acid methyl ester (Ex. 9b, 2.4 g, 3.3 mmol), 25 mL of THF and 10 mL of IN NaOH. The reaction mixture was stirred at ambient temperature for 18 h. The mixture was adjusted to pH<5 using IN HC1 and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine and concentrated under reduced pressure. Silica gel chromatography (MeOH/CH ₂ Cl ₂ , 0-20% gradient) gave a residue which was slurried in hexanes. The precipitate was collected by filtration, rinsed with a small amount of hexanes and dried in vacuo to yield the title compound as an off-white solid (2.1 g, 90%), mp 150-152 °C. Ή-NMR (CDC1 ₃ ) δ 7.55 (s, 2H), 7.49 (s, 2H), 5.43 (s, 1H), 3.89 (m, 4H), 3.75 (m, 2H), 3.60 (t, 2H, J = 5.1 Hz), 2.61 (m, 4H), 2.13 (pentet, 2H, J = 6.5 Hz), 1.78 (m, 2H), 1.67 (m, 2H), 1.45 (s, 18H), 1.42 (s, 18H). HRMS ESI) calcd for C ₄ oH ₆₂ N0 ₆ S ₂ : 716.4014 (M+H) ⁺ . Found: 716.4018. Anal. Calcd for C ₄ oH ₆ iN0 ₆ S ₂ : C, 67.09; H, 8.59; N, 1.96; S, 8.96. Found: C, 66.85; H, 8.85; N, 1.86; S, 8.29.

Examples 10: 4-{3,5-Di-tert-butyl-4-[3-(3-hydroxymethyl-5-methylpyrazol-l - yl)propoxy]-phenylsulfanyl}-4-(3,5-di-tert-butyl-4-hydroxyph enylsulfanyl)piperidine-l- carboxylic acid ethyl ester

Ex. 10a: 4-(3,5-Di-ier^-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-teri -butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester (Ex. 4, 18.0 g, 25.3 mmol) was charged to a 500 mL round bottom flask containing 300 mL of anhydrous CH2CI2 and N,N-diisopropylethylamine (3.9 g, 30.4 mmol). Methanesulfonyl chloride (3.0 g, 26.7 mmol) was slowly added to the solution. The solution was stirred at ambient temperature for 18 h and then quenched with 50 mL of IN HC1. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 150mL). The combined organic extracts were washed with IN HC1, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. After drying in vacuo, the crude solid of 4-(3,5-di-½ri-butyl-4- hydroxyphenylsulfanyl)-4-[3,5-di-½ri-butyl-4-(3-methane- sulfonyloxypropoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester was used without further purification (19.5 g, 95%), mp 75-77 °C. Ή-NMR (CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 4.44 (t, 2H, J = 5.7 Hz), 4.09 (q, 2H, J = 7.5 Hz), 3.87 (t, 2H, J = 7.2 Hz), 3.61 (m, 4H), 3.03 (s, 3H), 2.33 (p, 2H, J= 6.6 Hz), 1.72 (t, 4H, J= 5.4 Hz), 1.44 (s, 18H), 1.42 (s, 18H), 1.22 (t, 3H, J= 7.5 Hz).

A 500 mL round bottom flask was charged with 4-(3,5-di-fert-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di-½ri-butyl-4-(3-methanesulfonyloxy propoxy)phenylsulfanyl]- piperidine-l-carboxylic acid ethyl ester (Ex. 10a, 19.5 g, 25.5 mmol), 150 mL of anhydrous DMF and (5-methyl-2H-pyrazol-3-yl)-methanol (4.2 g, 38.3 mmol). Sodium hydride (4.1 g, 100 mmol) was added and the reaction mixture stirred at ambient temperature for 1.5 h. HPLC analysis indicated the consumption of starting material. The reaction was quenched with water and extracted with ethyl acetate (3 x 150 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 10-100% gradient) gave two regioisomers as solids. Major isomer (5.1 g, 26%), mp 82-85 °C. Ή-NMR (CDC1 ₃ ) δ 7.57 (s, 2H), 7.48 (s, 2H), 6.01 (s, 1H), 5.39 (s, 1H), 4.61 (s, 2H), 4.17 (t, 2H, J = 6.7 Hz), 4.09 (q, 2H, J = 6.1 Hz), 3.77 (t, 2H, J = 7.4 Hz), 3.59 (m, 4H), 2.39 (m, 2H), 2.28 (s, 3H), 1.71 (m, 4H), 1.44 (s, 18H), 1.38 (s, 18H), 1.21 (t, 3H, J= 6.4 Hz). See Ex. 11 for minor isomer. Examples 11: 4-{3,5-Di-tert-butyl-4-[3-(5-hydroxymethyl-3-methylpyrazoL-l - yl)propoxy]-phenylsulfanyl}-4-(3,5-di-tert-butyl-4-hydroxyph enylsulfanyl)piperidine-l- carboxylic acid ethyl ester

Minor isomer in Ex 10 (1.1 g, 6%), mp 82-85°C. ^! H-NM (CDC13) δ 7.57 (s, 2H), 7.54 (s, 2H), 5.96 (s, 1H), 5.39 (s, 1H), 4.62 (s, 2H), 4.24 (t, 2H, J= 7.0 Hz), 4.07 (q, 2H, J= 6.1 Hz), 3.74 (t, 2H, J = 8.3 Hz), 3.58 (m, 4H), 2.44 (m, 2H), 2.23 (s, 3H), 1.71 (m, 4H), 1.44 (s, 18H), 1.37 (s, 18H), 1.21 (t, 3H, J = 6.4 Hz). HRMS (ESI) Calcd. for C ₄ 4H ₆₈ N ₃ 0 ₅ S2: 782.4618 (M+H) ⁺ . Found: 782.4600. Anal. Calcd for C ₄ 4H ₆ 7N ₃ 0 ₅ S ₂ : C, 67.57; H, 8.63; N, 5.37; S, 8.20. Found: C, 67.50; H, 8.88; N, 5.24; S, 7.92.

Example 12: Ethyl 2-(4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-4-((4-(3- hydroxypropoxy)-3,5-di-tert-butylphenyl)sulfanyl)piperidin-l -yl)acetate

A 50 mL round bottom flask was charged with 2,6-di-¾r/-butyl-4-{4-[3,5-di-iert-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-4-ylsulfanyl}-phe nol (Ex. 5, 0.8 g, 1.30 mmol), 10 mL of anhydrous THF and N,N-diisopropylethylamine (0.67 g, 5.2 mmol). Ethyl bromoacetate (0.24 g, 1.43 mmol) was slowly added and the resulting solution was warmed to 60 °C. After 2 h, the reaction mixture was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel chromatography (1% NH ₄ OH in MeOH/CH ₂ Cl ₂ , 0-10% gradient) gave {4-(3,5-di-ter/-butyl-4-hydroxy- phenylsulfany l)-4- [3 ,5 -di-feri-butyl-4-(3 -hydroxy-propoxy)-phenylsulfanyl]-piperidin- 1 -yl } - acetic acid ethyl ester as a solid (0.91 g, 95%), mp 80-82 °C (dec). 'H-NMR (CDCI ₃ ) δ 7.59 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 4.17 (q, 2H, J = 7.8 Hz), 3.90 (m, 4H), 3.21 (s, 2H), 2.73 (t, 4H, J= 5.1 Hz), 2.13 (m, 2H), 1.89 (m, 4H), 1.43 (s, 36H).

Example 13:{4-(3,5-Di-tert-butyl-4-hydroxy-phenyIsulfanyl)-4-[3,5-di -tert-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-acetic acid

A 50 mL round bottom flask was charged with {4-(3,5-di-feri-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di- eri-butyl-4-(3-hydroxy-propoxy)-phenylsulfanyl]-piperidin-l- yl}- acetic acid ethyl ester (Ex. 12, 0.91 g, 1.30 mmol), 12 mL of THF/water/MeOH (4: 1:1) and lithium hydroxide monohydrate (0.27 g, 6.5 mmol). The mixture was stirred at ambient temperature for 72 h, at which time TLC indicated the consumption of starting material. It was adjusted to pH<6 using IN HCl and was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with hexanes. The precipitate was collected by vacuum filtration, washed with a small portion of hexanes, and dried in vacuo to give the title compound as a solid (0.50 g, 57%), mp 140-144 °C (dec). ^-NMR

(CDCI ₃ ): δ 7.56 (s, 2H), 7.50 (s, 2H), 5.4 (br s, 1H), 3.90 (m, 4H), 3.53 (s, 2H), 3.34 (m, 4H), 2.10 (m, 2H), 2.03 (m, 4H), 1.44 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₃ 8H ₆ oN0 ₅ S ₂ : 674.3900 (M+H) ⁺ . Found: 674.3913. Anal. Calcd for C ₃ 8H ₅₉ N0 ₅ S ₂ : C, 67.72; H, 8.82; N, 2.08; S, 9.51. Found: C, 65.02; H, 8.74; N, 1.92; S, 8.68. Example 14: l-{4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di- ieri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-2-pyrrolidi n-l-yl-ethanone

Ex. 14a: A 200 mL round bottom flask was charged with 2,6-di-/ert-butyl-4-{4-[3,5-di-teri- butyl-4-(3-hydroxy-propoxy)-phenylsulfanyl]-piperidin-4-ylsu lfanyl} -phenol (Ex. 5, 2.0 g, 3.3 mmol), 25 mL of anhydrous THF and N,N-diisopropylethylamine (2.1 g, 16.3 mmol). Chloroacetyl chloride (0.39 g, 3.4 mmol) was slowly added and the reaction mixture stirred at ambient temperature for 1.5 h. The reaction was quenched with water and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with IN HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure to dryness. Silica gel chromatography (EtOAc/hexanes, 0-50% gradient) yielded 2-chloro-l-{4-(3,5-di-ier/-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di-terr-butyl-4-(3-hydroxy-propoxy)-p henylsulfanyl]-piperidin-l-yl}- ethanone (1.1 g, 50%). Ή-NMR (CDC1 ₃ ): δ 7.58 (s, 2H), 7.47 (s, 2H), 5.42 (s, 1H), 4.00 (s, 2H), 3.89 (m, 4H), 3.74 (m, 2H), 3.63 (t, 2H, J= 5.0 Hz), 2.14 (p, 2H, J = 6.7 Hz), 1.88 (m, 2H), 1.69 (m, 2H), 1.44 (s, 18H), 1.43 (s, 18H).

A 50 mL round bottom flask was charged with 2-chloro-l-{4-(3,5-di-½ri-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di-½r?-butyl-4-(3-hydroxy-propoxy)-p henylsulfanyl]-piperidin-l-yl}- ethanone (Ex. 14a, 0.51 g, 0.74 mmol), 10 mL of anhydrous THF and pyrrolidine (0.21 g, 3.0 mmol). The reaction mixture was warmed to 55 °C and stirred for 2 h. After cooling to ambient temperature, the reaction was quenched with water and partitioned using ethyl acetate. The aqueous layer was extracted with additional ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to dryness. Silica gel chromatography (1% NH ₄ OH in MeOH/CH ₂ Cl ₂ , 0-10% gradient) yielded the title compound as a solid (0.31 g, 58%), mp 90- 93°C. Ή-NMR (CDCI ₃ ) δ 7.59 (s, 2H), 7.47 (s, 2H), 5.40 (s, 1H), 3.89 (m, 4H), 3.82 (m, 1H), 3.68 (m, 3H), 3.23 (m, 2H), 2.46 (m, 2H), 2.14 (p, 2H, J= 6.4 Hz), 1.71 (brm, 9H), 1.69 (m, 2H), 1.44 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C42H67N2O4S2: 727.4542 (M+H) ⁺ . Found: 727.4542. Anal. Calcd for C ₄ 2H ₆ 6N ₂ 04S ₂ : C, 69.38; H, 9.15; N, 3.85; S, 8.82. Found: C, 69.98; H, 9.35; N, 3.63; S, 8.24.

Example 15: l-{4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di- tert-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-2-imidazol- l-yl-ethanone

A 50 mL round bottom flask was charged with 2-chloro-l-{4-(3,5-di-/eri-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di-½ri-butyl-4-(3-hydroxy-propoxy)-p henylsulfanyl]-piperidin-l-yl}- ethanone (Ex. 14a, 0.51 g, 0.74 mmol), 10 mL of anhydrous THF and pyrrolidine (0.21 g, 3.0 mmol). The reaction mixture was warmed to 55 °C and stirred for 2 h. After cooling to ambient temperature, the reaction was quenched with water and partitioned using ethyl acetate. The aqueous layer was extracted with additional ethyl acetate (3 x 50 mL) and the combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to dryness. The residue was absorbed onto silica gel and purified by silica gel chromatography (1% N^OH/MeOH/CP^Cb, 0-10% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.20 g, 34%), mp 126-129 °C. 'H- MR (CDCI3) δ 7.56 (s, 2H), 7.49 (s, 2H), 7.37 (s, 1H), 7.04 (s, 1H), 6.89 (s, 1H), 5.49 (s, 1H), 4.69 (m, 2H), 3.87 (m, 4H), 3.77 (m, 2H), 3.58 (m, 2H), 2.14 (p, 2H, J = 6.4 Hz), 1.74 (brm, 5H), 1.45 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C ₄ iH ₆ 2N ₃ 0 ₄ S ₂ : 724.4175 (M+H) ⁺ . Found: 724.4182. Anal. Calcd for C ₄ iH ₆ iN ₃ 0 ₄ S ₂ : C, 68.01; H, 8.49; N, 5.80; S, 8.86. Found: C, 68.02; H, 8.65; N, 5.52; S, 8.27. Example 16: 4-(3,5-Di-tert-butyI-4-hydroxy-phenylsulfanyl)-4-(3,5-di-ter t-butyl-4- methoxy-phenylsulfanyl)-piperidine-l-carboxylic acid ethyl ester

A 1000 mL round bottom flask was charged with 4,4-bis-(3,5-di-terf-butyl-4- hydroxylphenylsulfanyl)-piperidine-l-carboxylic acid ethyl ester (Ex. la, 50.7 g, 80.5 mmol), 500 mL of anhydrous THF and 88.5 mL of 1.0 M solution of potassium terr-butoxide (88.5 mmol). Dimethylsulfate (11.1 g, 88.5 mmol) was added and the resulting solution refluxed under nitrogen for 5 h. After cooling to ambient temperature, water was slowly added to quench the reaction and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 150 mL) and the combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/hexanes, 0-5% gradient). The fractions containing the product were concentrated under reduced pressure to dryness and dried in vacuo (15.3 g, 30%). ^] H-NMR (CDC1 ₃ ) δ 7.59 (s, 2H), 7.48 (s, 2H), 5.39 (s, 1H), 4.09 (q, 2H, J = 6.7 Hz), 3.71 (s, 3H), 3.60 (m, 4H), 1.72 (m, 4H), 1.44 (s, 18H), 1.43 (s, 18H), 1.22 (t, 3H, J = 6.7 Hz).

Example 17: 2,6-Di-teri-butyl-4-[4-(3,5-di-teri-butyl-4-methoxy-phenylsu lfanyl)- pip eridin-4-ylsulf anyl] -phenol

A 500 mL round bottom flask was charged with 4-(3,5-di-iert-butyl-4-hydroxy- phenylsulfanyl)-4-(3,5-di-½^butyl-4-methoxy-phenylsulfanyl) -piperidine-l-carboxylic acid ethyl ester (Ex. 16, 15.3 g, 23.4 mmol), 300 mL of isopropanol and potassium hydroxide (26.7 g, 475 mmol). The resulting reaction mixture was heated to reflux and stirred under nitrogen for 18 h. HPLC analysis indicated the presence of <3.5% starting material present. After cooling to ambient temperature, the reaction was diluted with water and the pH adjusted to approx. 6 using IN HC1. The aqueous layer was extracted with ethyl acetate (4 x 200 mL). The combined organics were washed with water, saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate and concentrated under reduced pressure to dryness and used without further purification (15.3 g, 30%). ^-NMR (CDC1 ₃ ) δ 7.59 (s, 2H), 7.48 (s, 2H), 5.39 (s, 1H), 4.09 (q, 2H, J= 6.7 Hz), 3.71 (s, 3H), 3.60 (m, 4H), 1.72 (m, 4H), 1.44 (s, 18H), 1.43 (s, 18H), 1.22 (t, 3H, J= 6.7 Hz).

Example 18: [4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-te ri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-(6-trifluoromethyl-p yridin-3-yl)-methanone

A 50 mL round bottom flask was charged with 2,6-di-teri-butyl-4-[4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 750 mg, 1.31 mmol), 15 mL of anhydrous THF and diisopropylethylamine (0.68 g, 5.24 mmol). 6- (Trifluoromethyl)nicotinoyl chloride (0.30 g, 1.44 mmol) was added and the reaction mixture was stirred for 1 h at ambient temperature. The reaction was partitioned using water/ethyl acetate and the aqueous layer was extracted with additional ethyl acetate (3 x 50 mL). The combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 0-20% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.54 g,

41%), mp 100-102 °C (dec). Ή-NM (CDC1 ₃ ) δ 8.66 (d, 1H, J = 2.4 Hz), 7.83 (dd, 1H, J = 8.1, 2.4 Hz), 7.20 (d, 2H, J= 8.1 Hz), 7.60 (s, 2H), 7.49 (s, 2H), 3.93 (brm, 2H), 3.71 (s, 3H), 3.52 (m, 2H), 1.83 (m, 2H), 1.76 (m, 2H), 1.45 (s, 18H), 1.44 (s, 18H). HRMS Calcd. for C ₄ iH55N ₂ F ₃ 0 ₃ S ₂ : 745.3684 (M+H) ⁺ . Found: 745.3692. Anal. Calcd for C ₄ iH ₅₅ N2F ₃ 0 ₃ S ₂ : C, 66.10; H, 7.44; N, 3.76; S, 8.61. Found: C, 66.10; H, 7.29; N, 3.77; S, 8.40.

Example 19

A 50 mL round bottom flask was charged with 2,6-di-ter?-butyl-4-[4-(3,5-di-/ert-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.75 g, 1.31 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.68 g, 5.24 mmol). 6-chloronicotinoyl chloride (0.25 g, 1.44 mmol) was added and the reaction mixture was stirred for 0.5 h. at ambient temperature. The reaction was partitioned using water/ethyl acetate and the aqueous layer was extracted with additional ethyl acetate (3 x 50 mL). The combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 0-20% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.50 g, 54%), mp 109-11 1 °C (dec).

'H-NMR (CDCI ₃ ) δ 8.35 (d, 1H, J = 2.2 Hz), 7.62 (dd, 1H, J = 8.4, 2.2 Hz), 7.60 (s, 2H), 7.49 (s, 2H), 7.37 (d, 2H, J = 8.4 Hz), 3.90 (brm, 2H), 3.71 (s, 3H), 3.55 (m, 3H), 1.77 (m, 4H), 1.45 (s, 18H), 1.44 (s, 18H). HRMS Calcd. for QoHssClI^C^: 711.3421. Found: 711.3403 (M+H) ⁺ . Anal. Calcd for C ₄ oH ₅₅ Cl ₂ 0 ₃ S ₂ : C, 67.53; H, 7.79; N, 3.94; S, 9.01. Found: C, 68.17; H, 8.11 ; N, 3.79; S, 8.49. Example 20 : [4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-te rt-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-pyridin-3-yl-methano ne

A 50 mL round bottom flask was charged with 2,6-di-ieri-butyl-4-[4-(3,5-di-/'eri-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 750 mg, 1.31 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.68 g, 5.24 mmol). Nicotinoyl chloride (0.26 g, 1.44 mmol) was added and the reaction mixture was stirred for 3 h. at ambient temperature. The reaction was partitioned using water/ethyl acetate and the aqueous layer was extracted with additional ethyl acetate (3 x 50 mL). The combined organics were washed with saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (MeOH/CH ₂ Cl ₂ , 0-10% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.50 g,

56%), mp 92-95 °C (dec). ^-NMR (CDC1 ₃ ) δ 8.65 (dd, 1H, J= 4.8, 1.2 Hz), 8.57 (d, 1H, J = 1.8 Hz), 7.64 (dt, 1H, J = 8.1, 2.1 Hz), 7.60 (s, 2H), 7.49 (s, 2H), 7.32 (m,lH), 5.42 (s, 1H), 3.90 (brm, 2H), 3.71 (s, 3H), 3.55 (m, 2H), 1.79 (m, 4H), 1.45 (s, 18H), 1.44 (s, 18H). HRMS Calcd. for C ₄ oH56N ₂ 03S ₂ : 677.3810 (M+H) ⁺ . Found: 677.3822. Anal. Calcd for C ₄ oH56N ₂ 0 ₃ S ₂ : C, 70.96; H, 8.34; N, 4.14; S, 9.47. Found: C, 71.05; H, 8.35; N, 4.07; S, 8.94.

Example 21 : 3-[4-(3,5-Di-½/-i-butyI-4-hydroxy-phenyIsulfanyl)-4-(3,5-di -te i-butyl-4- methoxy-phenylsulfanyl)-piperidine-l-carbonyl]-benzoic acid methyl ester

A 50 mL round bottom flask was charged with mono-methyl isophthalate (0.30 g, 1.66 mmol), 20 mL of anhydrous methylene chloride and 2 drops of anhydrous DMF. Thionyl chloride (0.24 g, 2.0 mmol) was added and the resulting mixture was stirred at ambient temperature for 18 h. The pale yellow solution was concentrated under to an oil, which was diluted with 5 mL of anhydrous THF and charged to 100 mL round bottom flask containing 2,6-di-½ri-butyl-4-[4-(3,5-di-½r/-butyl-4-methoxy-phenylsu lfanyl)-piperidin-4-ylsulfanyl]- phenol (Ex. 17, 0.86 g, 1.51 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.78 g, 6.0 mmol). The resulting dark red solution was stirred at ambient temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with IN HCl, water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by chromatography (EtOAc/hexanes, 0-25% gradient). The fractions containing the product were concentrated to dryness and then dried in vacuo (0.70 g, 63%), mp 112-115 °C (dec).

'H-NMR (CDCI3) δ 8.07 (dt, 1H, J = 6.8, 1.8 Hz), 8.00 (s, 1H), 7.60 (s, 2H), 7.49 (s, 2H), 7.44 (m, 2H), 5.41 (s, 1H), 3.92 (s, 3H), 3.92 (m, 2H), 3.71 (s, 3H), 3.52 (m, 2H), 1.78 (m, 4H), 1.45 (s, 18H), 1.44 (s, 18H); HRMS (ESI) Calcd. for C43H59NO5S2: 734.3913 (M+H) ⁺ . Found: 734.3907. Anal. Calcd for C ₄ 3H ₅₉ 0 ₅ S2: C, 70.36; H, 8.10; N, 1.91; S, 8.74. Found: C, 70.46; H, 8.30; N, 1.86; S, 8.42. Example 22 : 3-[4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- fer/-butyl-4- methoxy-phenylsulfanyl)-piperidine-l-carbonyl]-benzoic acid

A 100 mL round bottom flask was charged with 3-[4-(3,5-di-½ri-butyl-4-hydroxy- phenylsulfanyl)-4-(3 ,5-di-½r -butyl-4-methoxy-phenylsulfanyl)-piperidine- 1 -carbonyl]- benzoic acid methyl ester (Ex. 21, 0.70 g, 0.95 mmol), 10 mL of THF, 2.5 mL of water and lithium hydroxide monohydrate (0.20 g, 4.8 mmol). The reaction was stirred at ambient temperature for 18 h, during which the time HPLC analysis indicated the complete consumption of starting material. The pH was lowered to <5 using IN HCl and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by chromatography and purified by chromatography (MeOH/CEkCk, 0-20% gradient). The fractions containing the product were concentrated to dryness and then dried in vacuo (0.50 g, 73%), mp 102-104 °C. ^! H-NMR (CDC1 ₃ ) δ 8.13 (dt, 1H, J = 7.2, 2.3 Hz), 8.05 (s, 1H), 7.61 (s, 2H), 7.55 (m, 2H), 7.50 (s, 2H), 5.42 (s, 1H), 3.92 (m, 4H), 3.71 (s, 3H), 3.54 (m, 2H), 1.79 (m, 4H), 1.45 (s, 18H), 1.44 (s, 18H). HRMS (ESI) Calcd. for C42H57NO5S2: 720.3756 (M+H) ⁺ . Found: 720.3743. Anal. Calcd for C ₄₂ H ₅₇ N0 ₅ S ₂ : C, 70.06; H, 7.98; N, 1.95; S, 8.91. Found: C, 70.61; H, 8.35; N, 1.82; S, 8.30.

Example 23 : [4-(3,5-Di-teri-butyI-4-hydroxy-phenyIsulfanyI)-4-(3,5-di-fe ri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-pyrazin-2-yl-methano ne

A 50 mL round bottom flask was charged with 2-pyrazine carboxylic acid (0.30 g, 2.11 mmol), 10 mL of anhydrous methylene chloride and 2 drops of anhydrous DMF. Thionyl chloride (0.30 g, 2.54 mmol) was added and the resulting mixture was stirred at ambient temperature for 18 h. A solution containing 2,6-di- eri-butyl-4-[4-(3,5-di-/eri-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl] -phenol (Ex. 17, 1.0 g, 1.75 mmol), 20 mL of anhydrous THF and diisopropylethylamine (1.37 g, 10.6 mmol) was added to the previous mixture and the resulting mixture was stirred at ambient temperature for 6 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with IN HC1, water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by chromatography (EtOAc/hexanes, 0-40% gradient). The fractions containing the product were concentrated to dryness and then dried in vacuo (350 mg, 24%), mp 109-1 12 °C (dec).

Ή-NM (CDC1 ₃ ) 6 8.85 (d, 1H, J= 1.7 Hz), 8.61 (d, 1H, J = 2.9 Hz), (8.49 (dd, 1H, J = 2.9, 1.7 Hz), 7.60 (s, 2H), 7.50 (s, 2H), 5.41 (s, 1H), 3.92 (m, 2H), 3.70 (s, 3H), 3.68 (m, 2H), 1.89 (m, 2H), 1.81 (t, 2H, J = 5.5 Hz), 1.45 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C39H55N3O3S2 700.3583 (M+Na) ⁺ . Found: 700.3596. Anal. Calcd for C39H55N3O3S2: C, 69.09; H, 8.18; N, 6.20; S, 9.46. Found: C, 69.49; H, 8.47; N, 5.84; S, 9.05. Example 24: 3-(2,6-Di-tei-i-butyl-4-{4-[3,5-di-tert-butyl-4-(3-hydroxy-p ropoxy)- phenylsulfanyl]-piperidin-4-ylsulfanyl}-phenoxy)-propan-l-ol

A 200 mL round bottom flask was charged with the 4,4-bis-[3,5-di-tert-butyl-4-(3-hydroxy- propoxy)-phenylsulfanyl]-piperidine-l-carboxylic acid ethyl ester (crude as a side product from Ex. 4, 3.7 g, 5.0 mmol), 50 mL of iPrOH and potassium hydroxide (5.6 g, 100 mmol). The resulting mixture was heated to reflux and stirred under nitrogen for 18 h. HPLC analysis indicated complete consumption of the starting material. The reaction mixture was neutralized using IN HC1 and extracted ethyl acetate (3 x 50 mL). The combined organics were washed with saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by chromatography (MeOH/CH ₂ Cl). The residue was absorbed onto silica gel and purified by chromatography (MeOH/CH ₂ Cl ₂ , 0-20% gradient). The fractions containing the product were concentrated under reduced pressure to dryness and dried in vacuo (1.3 g,

39%), mp 143-45 °C (dec). ^-NMR (CDC1 ₃ ) δ 7.60 (s, 4H), 3.88 (m, 8H), 3.11 (m, 4H), 2.13 (p, 4H, J = 6.3 Hz), 1.83 (m, 4H)1.43 (s, 36H). HRMS Calcd for Cs^NC^: 674.4277 (M+H) ⁺ . Found: 674.4263. Anal. Calcd for C ₃ 9¾ ₃ N0 ₄ S2: C, 69.49; H, 9.42; N, 2.08; S, 9.51. Found: C, 66.96; H, 9.20; N, 1.92; S, 8.93.

Example 25

Ex. 25a: A 50 mL round bottom flask was charged with 3-(2,6-di-fert-butyl-4-{4-[3,5-di-teri- butyl-4-(3-hydroxy-propoxy)-phenylsulfanyl]-piperidin-4-ylsu lfanyl}-phenoxy)-propan-l-ol (Ex. 24, 0.75 g, 1.1 1 mmol), 15 mL of anhydrous THF and diisopropylethylamine (0.57 g, 4.44mmol). Ethyl bromoacetate (0.20 g, 1.22 mmol) was slowly added and the resulting solution stirred at 60 °C for 2 h. TLC analysis indicated complete consumption of the starting material. The reaction mixture was partitioned using water/ethyl acetate and the aqueous layer was extracted with additional ethyl acetate (3 x 50 mL). The combined organics were washed with IN HCl, water, brine, dried over sodium sulfate and concentrated under reduced pressure to yield {4,4-bis-[3,5-di-½ri-butyl-4-(3-hydroxy-propoxy)-phenylsulf anyl]- piperidin-l-yl} -acetic acid ethyl ester as an off-white solid (0.90 g, >95%), mp 98-100 °C (dec). Ή-NMR (CDC1 ₃ ) δ 7.70 (s, 2H), 7.50 (s, 2H), 4.25 (m, 2H), 3.91 (m, 8H), 3.73 (m, 2H), 3.18 (m, 2H), 2.13 (m, 4H), 1.81 (m, 4H), 1.43 (s, 36H). HRMS Calcd. for C ₄ 3H ₆ 9N0 ₆ S ₂ : 760.4644 (M+H) ⁺ . Found: 760.4632.

A 100 mL round bottom flask was charged with {4,4-bis-[3,5-di-/er/-butyl-4-(3-hydroxy- propoxy)-phenylsulfanyl]-piperidin-l-yl}-acetic acid ethyl ester (Ex. 25a, 0.90 g, 1.18 mmol), 30 mL of THF/water/MeOH (4: 1 : 1) and lithium hydroxide monohydrate (0.25 g, 5.9 mmol). The reaction was stirred at ambient temperature for 2.5 h, during which the time HPLC analysis indicated the complete consumption of starting material. The pH was lowered to <5 using IN HCl and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was slurried with hexanes, filtered to collect the solid and dried in vacuo (0.70 g, 81%), mp 110 °C (dec). ^! H-NMR (CDC1 ₃ ) δ 7.56 (s, 4H), 4.10 (s, 2H), 3.86 (m, 12H), 3.47 (m, 4H), 2.12 (m, 4H), 1.42 (s, 36H). HRMS Calcd. for C ₄ iH ₆ 5N0 ₆ S ₂ : 732.4331 (M+H) ⁺ . Found: 732.4333. Anal. Calcd for C ₄ iH ₆₅ N0 ₆ S ₂ : C, 67.25; H, 8.95; N, 1.91; S, 8.76. Found: C, 63.69; H, 8.98; N, 1.70; S, 7.43.

Example 26: [4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-ie rt-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-(lH-imidazol-4-yl)-m ethanone

A 50 mL round bottom flask was charged with 2,6-di-/er/-butyl-4-[4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.85 g, 1.5 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.78 g, 6.0 mmol). lH-imidazole-4-carbonyl chloride hydrochloride was added and the reaction mixture stirred for 18 h at ambient temperature. The reaction was quenched with water and partitioned using ethyl acetate. The aqueous layer was extracted with additional ethyl acetate (3 x 50 mL) and the combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (MeOH/CH ₂ Cl2, 0-10% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.20 g, 20%), mp

117-120 °C. ^! H-NMR (CDC1 ₃ ) δ 7.64 (s, 1H), 7.61 (s, 2H), 7.50 (s, 2H). 7.43 (s, 1H), 5.40 (s, 1H), 4.0 (brm, 4H), 3.70 (s, 3H), 1.84 (brm, 4H), 1.69 (m, 2H), 1.44 (s, 18H), 1.43 (s, 18H). HRMS Calcd. for C38H55N3O3S2: 666.3763 (M+H) ⁺ . Found: 666.3768. Anal. Calcd for C ₃₈ H55N ₃ 0 ₃ S2: C, 68.53; H, 8.32; N, 6.31; S, 9.63. Found: C, 68.66; H, 8.33; N, 5.98; S, 9.01.

Example 27: [4-(3,5-Di-te/*i-butyl-4-hydroxy-phenylsu]fanyl)-4-(3,5-di-i ert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-[l-(4-trifluoromethy l-pyrimidin-2-yl)- piperidin-4-yl] -methanone

A 50 mL flask was charged with 2,6-di-/eri-butyl-4-[4-(3,5-di-½ri-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.75 g, 1.31 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.68 g, 5.2 mmol). l-[4- (Trifluoromethyl)pyrimidin-2-yl]piperidine-4-carbonyl chloride (0.42 g, 1.43 mmol) was slowly added and the resulting solution was stirred at ambient temperature for 18 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with IN HC1, water, brine and dried over sodium sulfate. After concentrating under reduced pressure, the residue was absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 10%-50% gradient). The fractions containing the product were concentrated to dryness under reduced pressure and dried in vacuo (0.55 g, 51%), mp 107-1 10 °C. 'H-NMR (CDCI ₃ ) 6 8.47 (d, 1H, J = 5.5 Hz), 7.59 (s, 2H), 7.48 (s, 2H), 6.72 (d, 1H, J = 5.5 Hz), 5.41 (s, 1H), 4.78 (m, 2H), 3.71 (s, 3H), 3.67 (m, 4H), 2.97 (m, 2H), 2.73 (m, 1H), 1.84 (m, 2H), 1.72 (m, 6H), 1.45 (s, 18H), 1.44 (s, 18H). HRMS (ESI) Calcd. for C45H63F3N4O3S2: 829.4372 (M+H) ⁺ Found: 829.4372. Anal. Calcd for C ₄₅ H ₆₃ F ₃ N ₄ 0 ₃ S ₂ : C, 65.19; H, 7.66; N, 6.76; S, 7.73. Found: C, 65.44; H, 7.81 ; N, 6.63;

S, 7.55. Example 28: [4-(3,5-Di-feri-butyl-4-hydroxy-phenyIsuIfanyI)-4-(3,5-di-fe ri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-(6-morpholin-4-yl-py ridin-3-yl)-methanone

A 50 mL flask was charged with 2,6-di-/er/-butyl-4-[4-(3,5-di-½rr-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.75 g, 1.31 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.68 g, 5.2 mmol). 6-Morpholin-4-yl-nicotinoyl chloride (0.35 g, 1.5 mmol) was dissolved in 5 mL of THF and added dropwise to the reaction mixture. The resulting solution was stirred at ambient temperature for 18 h. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with IN HC1, water, brine and dried over sodium sulfate. The filtrate was concentrated under reduced pressure. The residue absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 10%-50% gradient). The fractions containing the product were concentrated to dryness under reduced pressure and dried in vacuo (0.54g, 54%), mp 116-120 °C. ^! H-NMR (CDC1 ₃ ) 5 8.18 (d, 1H, J = 1.6 Hz), 7.60 (s, 2H), 7.53 (dd, 1H, J = 8.7, 3.0 Hz), 7.49 (s, 2H), 6.58 (d, 1H, J = 8.8 Hz), 5.41 (s, 1H), 3.80 (t, 4H, J= 5.1 Hz), 3.76 (m, 4H), 3.71 (s, 3H), 3.56 (t , 4H, J= 5.1 Hz), 1.78 (t, 4H, J = 5.1 Hz), 1.45 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C ₄₄ H@N ₃ 0 ₄ S2: 762.4338 (M+H) ⁺ . Found: 762.4330. Anal. Calcd for C ₄₄ H ₆₃ N ₃ 0 ₄ S ₂ -2.5 H ₂ 0: C, 65.47; H, 8.49; N, 5.21; S, 7.95. Found: C, 65.59; H, 8.59; N, 5.16; S, 7.95. Example 29: [4-(3,5-Di-te/-i-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-t eri-butyl-4- methoxy-phenyIsulfanyl)-piperidin-l-yl]-acetic acid

Ex. 29a: To 2,6-di-½ri-butyl-4-[4-(3,5-di-/er/-butyl-4-methoxy-phenylsu lfanyl)-piperidin-4- ylsulfanyl] -phenol (Ex. 17, 0.75 g, 1.31 mmol) in alOO mL round bottom flask was added anhydrous THF (33 mL) and DIPEA (0.69 mL, 3.94 mmol) and the resulting mixture was treated with bromo acetic acid ethyl ester (0.16 mL, 1.44 mmol). HPLC indicated that the reaction was complete after 18 h. The reaction mixture was diluted with water (15 mL) and ethyl acetate (30 mL). The organic portion was washed with IN HC1, saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by silica gel chromatography (10% EtOAc in hexanes) to provide 0.62 g (72%) of [4-(3,5-di-rer/-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-fe r?-butyl-4-methoxy- phenylsulfanyl)-piperidin-l-yl]-acetic acid as a white solid, mp 93 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 4.18 (q, 2H, J = 6.9 Hz), 3.70 (s, 3H), 3.21 (brs, 2H), 2.74-2.71 (m, 4H), 1.83-1.88 (m, 4H), 1.43 (brs, 36H), 1.26 (t, 3H, J = 7.5 Hz). HRMS (ESI) Calcd. for C38H59NO4S2: 658.3964 (M+H) ⁺ . Found: 658.3971. Anal. Calcd. C38H59NO4S2 -H ₂ 0: C, 69.36; H, 9.04; N, 2.13; S, 9.75. Found: C, 69.88; H, 9.17; N, 2.16; S, 9.58.

In a 100 mL round bottom flask, [4-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- /er/-butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl]-acetic acid (Ex. 29a, 0.62 g, 0.94 mmol) was combined with THF (10 mL) and a solution of IN NaOH (5.6 mL, 5.6 mmol) and the resulting mixture was stirred rapidly at rt. HPLC indicated that the reaction was complete after 18 h. The reaction mixture was concentrated to dryness and diluted with water (10 mL) and EtOAc (20 mL). This mix was acidified to a pH = 2 with 3N HC1. The organic portion was collected, washed with 1 :1 watenbrine solution, dried over sodium sulfate, and concentrated to a brown oil. The crude material was purified by silica gel chromatography (5% MeOH in dichloromethane) to provide 0.34 g (52%) of the title compound as an off white solid, mp 178 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.41 (brs, 1H), 3.68 (s, 3H), 3.42 (brs, 2H), 3.17 (brs, 4H), 2.00 (brs, 4H), 1.42-1.41 (m, 36H). HRMS (ESI) Calcd. for C36H ₅₅ N0 ₄ S ₂ : 630.3651 (M+H) ⁺ . Found: 630.3651. Anal. Calcd. C ₃ 6H55N0 ₄ S2-H ₂ 0: C, 66.73; H, 8.87; N, 2.16; S, 9.90. Found: C, 66.92; H, 8.54; N, 2.07; S, 9.60.

Example 30: l-[4-(3,5-di-ieri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-hydroxy-ethanone

Ex. 30a: In a 100 mL round bottom flask, 2,6-di-tert-butyl-4-[4-(3,5-di-ter?-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl] -phenol (Ex. 17, 0.76 g, 1.34 mmol) was combined with anhydrous THF (34 mL) and DIPEA (0.70 mL, 0.57 mmol) and the resulting mixture was treated with acetoxy acetyl chloride (0.16 mL, 4.01 mmol). HPLC indicated that the reaction was over in 10 min. The reaction mixture was diluted with water (15 mL) and ethyl acetate (30 mL). The organic portion was washed with IN HCl, saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by silica gel chromatography (40% EtOAc in hexanes) to provide 0.67 g (72%) of acetic acid 2-[4-(3,5-di-ier/-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- eri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl ester as a white solid, mp 118 °C. ^l R- NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.47 (s, 2H), 5.42 (s, 1H), 4.66 (s, 2H), 3.82-3.64 (m, 5H), 3.52-3.48 (m, 2H), 2.15 (s, 3H), 1.82-1.78 (m, 2H), 1.72-1.69 (m, 2H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for 694.3576 (M+Na) ⁺ . Found: 694.3570.

In a 100 mL round bottom flask a solution of acetic acid 2-[4-(3,5-di-feri-butyl-4-hydroxy- phenylsulfanyl)-4-(3 ,5 -di-/eri-butyl-4-methoxy-phenylsulfanyl)-piperidin- 1 -yl] -2-oxo-ethyl ester (Ex. 30a, 0.67 g, 1.0 mmol) in THF (19 mL) was chilled to 0 °C and treated with lithium hydroxide monohydrate (63.1 mg, 1.0 mmol). The resulting mixture stirred at rt and HPLC indicated that the reaction was complete after 6 h. The reaction was quenched with IN HCl and extracted with EtOAc (20 mL). The organic portion was dried over sodium sulfate and concentrated to an off white foam. The crude material was purified by silica gel chromatography (25% EtOAc in hexanes) to provide 0.32 g ( 1%) of the title compound as a white solid, mp 101 °C. 1H-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.47 (s, 2H), 5.42 (s, 1H), 4.09 (s, 2H), 3.86-3.74 (m, 2H), 3.71 (s, 3H), 3.40-3.36(m, 2H), 1.79-1.64 (m, 4H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C36H55NO4S2: 630.3651 (M+H) ⁺ . Found: 630.3637. Anal. Calcd. C ₃ 6H ₅ 5N0 ₄ S ₂ : C, 68.69; H, 8.80; N, 2.22; S, 10.18. Found: C, 68.69; H, 8.87; N, 2.10; S, 9.91.

Example 31 : l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-pyrrolidin-l-yl-et hanone

Ex. 31a: In a 100 mL round bottom flask, 2,6-di-ter?-butyl-4-[4-(3,5-di-fert-butyl-4- methoxy-phenyIsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 1.44 g, 2.52 mmol) was combined with anhydrous THF (63 mL) and DIPEA (1.32 mL, 7.56 mmol) and the resulting mixture was treated with chloroacetyl chloride (0.22 mL, 2.77 mmol). HPLC indicated that the reaction was over in 10 min. The reaction mixture was diluted with water (15 mL) and ethyl acetate (30 mL). The organic portion was washed with IN HCl, saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by silica gel chromatography (30% EtOAc in hexanes) to provide 1.32 g (81%) of 2-chloro-l-[4-(3,5-di-½r -butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-½r/-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-ethanone as an off white solid, mp 87 °C. 1H-NMR (300 MHz, CDCI3) δ 7.58 (s, 2H), 7.47 (s, 2H), 5.41 (s, 1H), 4.00 (s, 2H), 3.81-3.79 (m, 2H), 3.70 (s, 3H), 3.65-3.61 (m, 2H), 1.90-1.86 (m, 2H), 1.71-1.68 (m, 2H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₃₆ H ₅ 4C1N0 ₃ S ₂ : 670.3131 (M+Na) ⁺ . Found: 670.3106. Anal. Calcd. C ₃₆ H ₅₄ C1N0 ₃ S2: C, 66.68; H, 8.39; N, 2.16; S, 9.89. Found: C, 66.92; H, 8.54; N, 2.07; S, 9.60.

In a 100 mL round bottom flask, 2-chloro-l-[4-(3,5-di-½rr-butyl-4-hydroxy-phenylsulfanyl)- 4-(3,5-di-½r -butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl]-ethanone (Ex. 31a, 0.59 g, 0.94 mmol) was combined with THF (15 mL) and pyrrolidine (0.24 mL, 2.93 mmol) and the resulting mixture was stirred rapidly and heated to 50 °C. HPLC indicated that the reaction was complete after 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 15 mL). The organic portion was dried over sodium sulfate and concentrated to a beige oil. The crude material was purified by silica gel chromatography (3% MeOH in dichloromethane) to provide 0.36 g (58%) of the title compound as an off white solid, mp 93 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.47 (s, 2H), 5.40 (s, 1H), 3.84-3.63 (m, 7H), 3.21 (d, 1H, J= 19 Hz), 3.25 (d, 1H, J= 19 Hz), 2.46 (brs, 4H), 1.76-1.68 (m, 8H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₄ oH62N ₂ 0 ₃ S2: 683.4280 (M+H) ⁺ . Found: 683.4276. Anal. Calcd. C ₄ oH62N ₂ 0 ₃ S ₂ : C, 70.33; H, 9.15; N, 4.10; S, 9.39. Found: C, 70.36; H, 9.10; N, 4.00; S, 9.06.

Example 32: l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- teri-butyI-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-imidazol-l-yI-etha none

In a 50 mL round bottom flask, 2-chloro-l-[4-(3,5-di-ier^-butyl-4-hydroxy-phenylsulfanyl)-4 - (3,5-di-½ri-butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl] -ethanone (Ex. 31a, 0.59 g, 0.90 mmol) was combined with DMF (15 mL), potassium carbonate (0.30 g, 2.17 mmol), and imidazole (74 mg, 1.08 mmol) and the resulting mixture was stirred rapidly and heated to 65 °C. HPLC indicated that the reaction was complete after 18 h. The reaction mixture was diluted with an aqueous solution of saturated ammonium chloride (20 mL) and extracted with ethyl acetate (2 15 mL). The organic was washed with 1:1 water:brine solution, dried over Na ₂ S0 ₄ , filtered, concentrated to a brown oil. The crude material was purified by silica gel chromatography (3% MeOH in dichloromethane) to provide 0.31 g (51%) of the title compound as an off white solid, mp 116 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.64 (s, 2H), 7.52 (s, 2H), 7.49 (brs, 1H), 7.10 (brs, 1H), 6.93 (brs, 1H), 5.50 (brs, 1H), 4.75 (s,2H), 3.91-3.70 (m, 5H), 3.64-3.60 (m, 2H), 1.84-1.74 (m, 4H), 1.48-1.47 (m, 36H). HRMS (ESI) Calcd. for C ₃₉ H57N ₃ 0 ₃ S ₂ : 680.3919 (M+H) ⁺ . Found: 680.3900. Anal. Calcd. C ₃₉ H57N ₃ 0 ₃ S ₂ : C, 68.88; H, 8.45; N, 6.18; S, 9.43. Found: C, 68.59; H, 8.55; N, 5.81; S, 9.03.

Example 33 : 1- [4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-te *i-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-morpholin-4-yl-eth anone

In a 50 mL round bottom flask, 2-chloro-l-[4-(3,5-di- er -butyl-4-hydroxy-phenylsulfanyl)-4- (3,5-di-½rr-butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl] -ethanone (Ex. 31a, 0.45 g, 0.69 mmol) was combined with DMF (20 mL), potassium carbonate (0.20 g, 1.46 mmol), and moropholine (64 mg, 0.73 mmol) and the resulting mixture was stirred rapidly and heated to 60 °C. HPLC indicated the reaction was complete after 18 h. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 : 1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (2% MeOH in dichloromethane) to provide 0.33 g (68%) of the title compound as an off white solid, mp 110

°C. Ή-NMR (300 MHz, CDC1 ₃ ) 5 7.64 (s, 2H), 7.51 (s, 2H), 5.45 (s, 1H), 3.92-3.51 (m, 11H), 3.15 (d, 1H, J= 17 Hz), 3.14 (d, 1H, J = 17 Hz), 2.48-2.44 (m, 4H), 1.82-1.74 (m, 4H), 1.48 (m, 36H). HRMS (ESI) Calcd. for C ₄ oH6 ₂ N ₂ 0 ₄ S2: 699.4229 (M+H) ⁺ . Found: 699.4224. Anal. Calcd. C ₄₀ H ₆₂ N ₂ O ₄ S ₂ : C, 68.72; H, 8.94; N, 4.01; S, 9.17. Found: C, 69.00; H, 9.08; N, 3.88; S, 8.79. Example 34: 2,6-Di-teri-butyl-4-[4-(3,5-di-fe?-i-butyl-4-methoxy-phenyls ulfanyl)-l- pyrimidin-2-yl-piperidin-4-ylsulfanyl]-phenol

In a 50 mL round bottom flask, 2,6-di-½rf-butyl-4-[4-(3,5-di-tert-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.50 g, 0.87 mmol) was combined with DMF (20 mL), potassium carbonate (0.25 g, 1.84 mmol), and 2-chloropyrimidine (0.10 g, 0.73 mmol) and the resulting mixture was stirred rapidly and heated to 60 °C. HPLC indicated the reaction was complete after 18 h. The reaction mixture was quenched with 0.5N HC1 and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 :1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (3%-6% EtOAc in hexanes) to provide 0.35 g (61%) of the title compound as an off white solid, mp 93 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 8.62 (d, 2H, J= 4.8 Hz), 7.60 (s, 2H), 7.50 (s, 2H), 6.43 (t, 1H, J= 4.5 Hz), 5.37 (s, 1H), 4.09-3.89 (m, 4H), 3.68 (s, 3H), 1.82-1.78 (m, 4H), 1.43-1.42 (m, 36H). HRMS (ESI) Calcd. for C ₃₈ H ₅₅ N ₃ 0 ₂ S ₂ : 650.3814 (M+H) ⁺ . Found: 650.3802. Anal. Calcd. C ₃₈ H ₅₅ N ₃ 0 ₂ S ₂ : C, 70.22; H, 8.53; N, 6.46; S, 9.87. Found: C, 70.20; H, 8.44; N, 6.40; S, 9.72.

Example 35 : 2,6-Di-teri-butyl-4-[4-(3,5-di-teri-butyl-4-methoxy-phenylsu lfanyl)-l-(4- trifluoromethyl-pyrimidin-2-yl)-piperidin-4-yIsuIfanyl]-phen ol

In a 50 mL round bottom flask, 2,6-di-½ri-butyl-4-[4-(3,5-di-teri-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.50 g, 0.87 mmol) was combined with DMF (20 mL), potassium carbonate (0.25 g, 1.84 mmol), and 2-chloro-4-trifluoromethyl pyrimidine (0.11 g, 0.92 mmol) and the resulting mixture was stirred rapidly and heated to 60 °C. HPLC indicated the reaction was complete after 18 h. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 : 1 watenbrine solution, dried over Na ₂ S04, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (3% EtOAc in hexanes) to provide 0.51 g (82%) of the title compound as an off white solid, mp 173 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 8.43 (d, 1H, J = 5.7 Hz), 7.60 (s, 2H), 7.50 (s, 2H), 6.69 (d, 1H, J = 5.4 Hz), 5.38 (s, 1H), 4.14-3.88 (m, 4H), 3.66 (s, 3H), 1.82-1.76 (m, 4H), 1.44-1.42 (m, 36H). Anal. Calcd. C39H54F3N3O2S2: C, 65.24; H, 7.58; N, 5.85; S, 8.93. Found: C, 65.69; H, 7.81; N, 5.86; S, 8.66.

Example 36: l-{2-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5- di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl}-piperid ine-4-carboxylic acid

Ex. 36a: In a 50 mL round bottom flask, 2-chloro-l-[4-(3,5-di-ieri-butyl-4-hydroxy- phenylsulfanyl)-4-(3,5-di-½rr-butyl-4-methoxy-phenylsulfany l)-piperidin-l-yl]-ethanone (Ex. 31a, 0.45 g, 0.69 mmol) was combined with DMF (20 mL), potassium carbonate (0.20 g, 1.46 mmol), and piperidine-4-carboxylic acid ethyl ester (0.11 g, 0.73 mmol) and the resulting mixture was stirred rapidly and heated to 60 °C. HPLC indicated the reaction was complete after 18 h. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 :1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (2% MeOH in dichloromethane) to provide 0.47 g (88%) of l-{2-[4- (3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-½ri- butyl-4-methoxy-phenylsulfanyl)- piperidin-l-yl]-2-oxo-ethyl}-piperidine-4-carboxylic acid ethyl ester as an off white solid, mp 93 °C. ^! H-NMR (300 MHz, CDCI ₃ ) δ 7.64 (s, 2H), 7.52 (s, 2H), 5.44 (s, 1H), 4.16 (q, 2H, J = 6.3 Hz), 3.87-3.69 (m, 7H), 3.13 (s, 2H), 2.83-2.79 (m, 2H), 2.31-2.08 (m, 3H), 1.92-1.65 (m, 8H), 1.48-1.47 (m, 36H), 1.29 (t, 3H, J = 7.5 Hz). HRMS (ESI) Calcd. for C ₄₄ H ₆ 8N ₂ 0 ₅ S ₂ : 769.4648 (M+H) ⁺ . Found: 769.4641.

In a 50 mL round bottom flask a solution of l-{2-[4-(3,5-di-ter -butyl-4-hydroxy- phenylsulfanyl)-4-(3,5-di-½ri-butyl-4-methoxy-phenylsulfany l)-piperidin-l-yl]-2-oxo-ethyl}- piperidine-4-carboxylic acid ethyl ester (Ex. 36a, 0.45 g, 0.59 mmol) in a solution of THF:EtOH:H ₂ 0 (20 mL, 4:2: 1) was chilled to 0 °C and treated with lithium hydroxide monohydrate (62 mg, 1.48 mmol). The resulting mixture was stirred at rt and HPLC indicated that the reaction was complete after 18 h. The reaction was acidified to a pH of 3 with 0.5N HCl and extracted with EtOAc (20 mL). The organic portion was washed with water, dried over sodium sulfate and concentrated to an off white foam. The crude material was purified by silica gel chromatography (5% MeOH in dichloromethane). NMR analysis indicated that the material was the salt form; therefore, the isolated product was dissolved in EtOAc and diluted with water. The pH of the mixture was adjusted to 6 with IN HCl. The organic portion was washed with water, 1 : 1 watenbrine solution solution, dried over sodium sulfate, and concentrated to provide 0.34 g (78%) of the title compound as an off white solid, mp 135 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.49 (s, 2H), 5.40 (s, 1H), 3.84-3.61 (m, 7H), 3.22 (brs, 2H), 2.83-2.80 (m, 2H), 2.36-2.11 (m, 4H), 1.92-1.64 (m, 8H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₄₂ H64N ₂ 0 ₅ S ₂ : 741.4335 (M+H) ⁺ . Found: 741.4323. Anal. Calcd. C ₄₂ H ₆₄ N ₂ 0 ₅ S ₂ : C, 68.07; H, 8.70; N, 3.78; S, 8.65. Found: C, 68.35; H, 8.88; N, 3.66; S, 8.19.

Example 37: 4-[4-(3,5-Di-fe/-i-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di -ie *i-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo-butyric acid

In a 50 mL round bottom flask, 2,6-di-/err-butyl-4-[4-(3,5-di-½ri-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.50 g, 0.87 mmol) was combined with DMF (20 mL), potassium carbonate (0.48 g, 3.5 mmol), and succinic anhydride (96.2 mg, 0.96 mmol). HPLC indicated the reaction was complete after 18 h. The reaction mixture was acidified with IN HC1 and extracted with EtOAc. The organic was washed with 1:1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (5% MeOH in dichloromethane) to provide 0.41 g (70%) of the title compound as an off white solid, mp 204 °C. 'H-NMR (300 MHz, CDC1 ₃ ) 5 7.60 (s, 2H), 7.49 (s, 2H), 5.42 (s, 1H), 3.86-3.59 (m, 7H), 2.65 (brs, 4H), 1.81-1.78 (m, 2H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₃₈ H ₅₇ NO ₅ S ₂ : 694.3576 (M+Na) ⁺ . Found: 694.3574. Anal. Calcd. C _SS H _JT NO^: C, 67.92; H, 8.55; N, 2.08; S, 9.54. Found: C, 67.80; H, 8.56; N, 2.14; S, 9.49.

Example 38: l-[4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- teri'-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-(4-hydroxy-piperid in-l-yl)-ethanone

In a 50 mL round bottom flask, 2-chloro-l-[4-(3,5-di-/eri-butyl-4-hydroxy-phenylsulfanyl)-4 - (3,5-di-/e^butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl]-e thanone (Ex. 31a, 0.44 g, 0.68 mmol) was combined with DMF (25 mL), potassium carbonate (0.20 g, 1.42 mmol), and piperidin-4-ol (72 mg, 0.71 mmol) and the resulting mixture was stirred rapidly and heated to 60 °C. HPLC indicated the reaction was complete after 5 h. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 : 1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (1% -3% MeOH in dichloromethane) to provide 0.31 g (65%) of as the title compound as an off white solid, mp

109 °C. 1H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.49 (s, 2H), 5.40 (s, 1H), 3.84-3.61 (m, 7H), 3.10 (brs, 2H), 2.71-2.67 (m, 2H), 2.23-2.16 (m, 2H), 1.88-1.64 (m, 6H), 1.59-1.44 (m, 40H). HRMS (ESI) Calcd. for C4 ₁ H64N2O4S2: 713.4386 (M+H) ⁺ . Found: 713.43912. Anal. Calcd. C ₄ iH64N ₂ 0 ₄ S ₂ : C, 69.06; H, 9.05; N, 3.93; S, 8.99. Found: C, 69.94; H, 9.29; N, 3.84;

S, 8.53.

Example 39: l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- fe/'i-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-(4-hydroxymethyl-p iperidin-l-yl)-ethanone

In a 50 niL roimd bottom flask, 2-chloro-l-[4-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-4 - (3,5-di-ter -butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl]-ethanone (Ex. 31a, 434 mg, 0.67 mmol) was combined with DMF (25 mL), potassium carbonate (0.19 g, 1.41 mmol), and piperidin-4-yl methanol (81 mg, 0.70 mmol) and the resulting mixture was stirred rapidly and heated to 60 °C. HPLC indicated the reaction was complete after 5 h. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 :1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (5% MeOH in dichloromethane) to provide 0.41 g (84%) of the title compound as a white solid, mp 110 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 3.79-3.68 (m, 7H), 3.48-3.46 (m, 2H), 3.10 (s, 2H), 2.84-2.82 (m, 2H), 2.01 (t , 2H, J = 5.4 Hz), 1.76 (t , 2H, J = 2.4 Hz), 1.70-1.66 (m, 4H), 1.57 (brs, 4H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₄₂ H ₆₆ N ₂ 0 ₄ S ₂ : 727.4542 (M+H) ⁺ . Found: 727.4539. Anal. Calcd. C^^O&xV^O: C, 68.45; H, 9.15; N, 3.82; S, 8.75. Found: C, 68.83; H, 9.21; N, 3.81; S, 8.42.

Example 40: 4,4-Bis-(3,5-di-ter/-butyl-4-methoxy-phenylsulfanyl)-piperid ine-l- carboxylic acid ethyl ester

In a 1L round bottom flask, 4,4-bis-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)piperidin e-l- carboxylic acid ethyl ester (Ex. la., 25 g, 39.7 mmol) was treated with a 1M solution of t- BuO in THF (44 mL, 43.6 mmol) and stirred for 5 min. The resulting mixture was treated with dimethyl sulfate (4.1 mL, 43.1 mmol), stirred rapidly and heated to 60 °C. HPLC indicated the reaction was complete after 18 h. The mixture was diluted with EtOAc, washed with water, 1 : 1 water:brine solution, dried over Na ₂ SC>4, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (3 -5% MeOH in dichloromethane) to provide 4.75 g (18%) of the title compound as a white solid, mp 102 -103 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 4H), 4.09 (q, 2H, J = 7.5 Hz), 3.71 (s, 6H), 3.62-3.58 (m, 4H), 1.73 (brs, 4H), 1.43 (s, 36H), 1.21 (t, 3H, J= 12 Hz). HRMS (ESI) Calcd. for CssHsgNC^: 680.3783 (M+Na) ⁺ . Found: 680.3779. Anal. Calcd. CsgH^NC^: C, 69.36; H, 9.04; N, 2.13; S, 9.75. Found: C, 69.37; H, 9.11; N, 2.06; S, 9.54.

Example 41 : [4,4-Bis-(3,5-di-/eri-butyl-4-methoxy-phenylsulfanyl)-piperi din-l-yl]-acetic acid

Ex. 41a: In a 200 mL round-bottom flask 4,4-bis-(3,5-di-terf-butyl-4-methoxy- phenylsulfanyl)-piperidine- 1 -carboxylic acid ethyl ester (Ex. 40, 3.5 g, 5.32 mmol) was combined with IPA (66 mL) and KOH (5.76 g, 102.92 mmol) and the resulting mixture was stirred rapidly and heated to 82 °C. HPLC indicated the reaction was complete after 18 h. The reaction mixture was concentrated to dryness and combined with water. This mix was acidified to a pH of 4 with 3N HC1 and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 : 1 water-brine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (10% MeOH in dichloromethane) to provide 2.62 g (84%) of 4,4-Bis-(3,5-di-½rt-butyl-4-methoxy- phenylsulfanyl)-piperidine as an off white solid, mp 66 °C. 'H-NMR (300 MHz, CDC1 ₃ ) 5 7.59 (s, 4H), 3.71 (s, 6H), 3.27-3.23 (m, 4H), 2.02-1.88 (m, 4H), 1.40 (s, 36H). HRMS (ESI) Calcd. for C ₃ 5H ₅₅ N0 ₂ S ₂ : 586.3752 (M+H) ⁺ . Found: 586.3755.

Ex. 41b: In a 100 mL round bottom flask 4,4-bis-(3,5-di-ter/-butyl-4-methoxy- phenylsulfanyl)-piperidine (Ex. 41a, 1.0 g, 1.71 mmol) was combined with anhydrous THF (43 mL) and DIPEA (0.89 mL, 5.12 mmol) and the resulting mixture was treated with bromoacetic acid ethyl ester (0.21 mL, 1.89 mmol). HPLC indicated that the reaction was complete after 18 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (30 mL). The organic portion was washed with 1 : 1 water:brine solution, dried over sodium sulfate, concentrated, and dried. The crude material was purified by silica gel chromatography (20% EtOAc in hexanes) to provide 0.96 g (89%) of [4,4-bis-(3,5-di-½rr- butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl] -acetic acid ethyl ester as an off white solid, mp 78 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.56 (s, 4H), 4.17 (q, 2H, J = 6.9 Hz), 3.71 (s, 6H), 3.21 (brs, 2H), 2.73 (t, 4H, J= 5.4 Hz), 1.90 (brs, 4H), 1.43 (s, 36H), 1.24 (t, 3H, J= 7.5 Hz). HRMS (ESI) Calcd. for C39H61NO4S2: 672.4120 (M+H) ⁺ . Found: 672.4114.

In a 100 mL round bottom flask, [4,4-bis-(3,5-di-ier/-butyl-4-methoxy-phenylsulfanyl)- piperidin-l-yl] -acetic acid ethyl ester (Ex. 41b, 0.95 g, 1.4 mmol) was combined with THF (16 mL) and a solution of IN NaOH (8.5 mL, 8.5 mmol) and the resulting mixture was stirred rapidly at rt. HPLC indicated that the reaction was complete after 18 h. The reaction mixture was concentrated to dryness and diluted with water (10 mL) and EtOAc (20 mL). This mix was acidified to a pH of 6 with 3N HC1. The organic portion was collected, washed with water, 1 :1 watenbrine solution, dried over sodium sulfate, concentrated, and dried. The crude material was purified by silica gel chromatography (5% MeOH in dichloromethane) to provide 0.62 g (73%) of the title compound as a white solid, mp 210 °C. ^X H-NMR (300 MHz, CDCI ₃ ) δ 7.58 (s, 4H), 3.70 (s, 6H), 3.37 (brs, 2H), 3.21 (brs, 4H), 2.00 (brs, 4H), 1.42 (s, 36H). HRMS (ESI) Calcd. for C ₃ 7H ₅₇ N0 ₄ S2: 644.3807 (M+H) ⁺ . Found: 644.3801. Anal. Calcd. C37H57NO4S2: C, 69.01; H, 8.92; N, 2.18; S, 9.96. Found: C, 69.04; H, 8.91; N, 2.12; S, 9.63.

Example 42 : l-[4-(3,5-Di-iert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- tert-butyl-4- methoxy-phenylsulfanyl)-piperidm-l-yl]-2-(2-hydroxymethyl-py rrolidin-l-yl)-ethanone

In a 20 mL vial, 2-chloro-l-[4-(3,5-di-ter/-butyl-4-hydroxy-phenylsulfanyl)-4 -(3,5-di-½r/- butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl]-ethanone (Ex. 31a, 0.50 g, 0.77 mmol) was combined with DMF (15 mL), potassium carbonate (0.37 g, 2.7 mmol), and pyrrolidin-2-yl- methanol (83 mg, 0.85 mmol) and the resulting mixture was stirred and heated to 120 °C via microwave. The reaction mixture continued to stir overnight at room temp. HPLC indicated that the reaction was complete after 18 h. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 : 1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (2% MeOH in dichloromethane) to provide 0.27 g (48%) of the title compound as an off white solid, mp 114 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (d, 2H, J = 2.45 Hz), 7.47 (d, 2H, J = 4.8 Hz), 5.41 (s, 1H), 3.85-3.60 (m, 7H), 3.54- 3.46 (m, 2H), 3.39-3.23 (m, 2H), 3.04-3.02 (m, 1H), 2.65-2.48 (m, 2H), 1.86-1.58 (m, 9H), 1.44 (s, 36H). HRMS (ESI) Calcd. for C ₄ iH64N ₂ 0 ₄ S2: 713.4386 (M+H) ⁺ . Found: 713.4377. Anal. Calcd. C ₄ iH ₆₄ N ₂ 0 ₄ S ₂ : C, 69.06; H, 9.05; N, 3.93; S, 8.99. Found: C, 69.07; H, 9.05; N, 3.92; S, 8.78.

Example 43 : l-{2-[4-(3,5-Di-½ri'-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5 -di-tert-butyI-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl}-pyrroli dine-2-carboxylic acid

Ex. 43a: In a 50 mL round bottom flask, 2-chloro-l-[4-(3,5-di-/'eri-butyl-4-hydroxy- phenylsulfanyl)-4-(3,5-di-teri-butyl-4-methoxy-phenylsulfany l)-piperidin-l-yl]-ethanone (Ex. 31a, 0.50 g, 0.77 mmol) was combined with ACN (19 mL), potassium carbonate (0.43 g, 3.09 mmol), and L-proline methyl ester hydrochloride (0.14 g, 0.85 mmol) and the resulting mixture was stirred rapidly and heated to 65 °C. HPLC indicated the reaction was complete after 18 h. The reaction mixture was quenched with IN HCl and extracted with EtOAc. The organic was washed with saturated sodium bicarbonate, 1 :1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (25% EtOAc in hexanes) to provide 0.39 g (68%) of l-{2-[4-(3,5-di-ier/- butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-ier -butyl-4-methoxy-phenylsulfanyl)-piperidin-l- yl]-2-oxo-ethyl}-pyrrolidine-2-carboxylic acid methyl ester as an off white solid, mp 113 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (d, 2H, J = 15.3 Hz), 7.49 (d, 2H, J = 7.5 Hz), 5.39 (d, 1H, J = 4.2 Hz), 3.96-3.51 (m, 10H), 2.99-2.88 (m, 1H), 2.59-2.47 (m, 1H), 2.16-2.04 (m, 1H), 1.95-1.70 (m, 8H), 1.45-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₄₂ H ₆₄ N ₂ 0 ₅ S ₂ : 741.7335 (M+H) ⁺ . Found: 741.4341.

In a 100 mL round bottom flask, l-{2-[4-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5- di-ieri-butyl-4-methoxy-phenylsulfanyl)-piperidin- 1 -yl] -2-oxo-ethyl } -pyrrolidine-2- carboxylic acid methyl ester (Ex. 43a, 0.38 g, 0.52 mmol) was combined with THF (20 mL) and a solution of IN NaOH (3.1 mL, 3.10 mmol) and the resulting mixture was stirred rapidly at rt. HPLC indicated that the reaction was complete after 3 h. The reaction mixture was concentrated to dryness and diluted with water (10 mL) and EtOAc (25 mL). This mix was acidified to a pH of 2 with IN HCl. The organic portion was collected, washed with 1 :1 water:brine solution, dried over sodium sulfate, concentrated, and dried. The crude material was purified by silica gel chromatography (10%-30% MeOH in dichloromethane) to provide 0.30 g (80%) of the title compound as an off white solid, mp 232 °C. ^-NMR (300 MHz, CDCI3) δ 7.61 (d, 2H, J = 6.0 Hz), 7.50 (d, 2H, J = 6.0 Hz), 5.41 (br , 1H), 4.82 (brs, 1H), 4.68-4.66 (m, 1H), 4.42-4.39 (m, 1H), 3.90-3.81 (m, 2H), 3.77-3.68 (m, 4H), 3.61-3.45 (m, 3H), 2.64-2.60 (m, 1H), 2.29-2.18 (m, 2H), 2.09-2.06 (m, 2H), 1.82 (brs, 2H), 1.73-1.67 (m, 2H), 1.44-1.42 (m, 36H). HRMS (ESI) Calcd. for C ₄ iH ₆₂ N ₂ 0 ₅ S2: 727.4178 (M+H) ⁺ . Found: 727.4182.

Example 44: 5-[4-(3,5-Di-tert-butyI-4-hydroxy-phenyIsulfanyI)-4-(3,5-di- ie/-i-butyI-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-5-oxo-pentanoic acid

In a 50 mL round bottom flask, 2,6-di-ier/-butyl-4-[4-(3,5-di-ieri-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.75 g, 1.31 mmol) was combined with DMF (30 mL), potassium carbonate (0.72 g, 5.24 mmol), and glutaric anhydride (0.16 g, 1.44 mmol). TLC indicated the reaction was complete after 5 min. The reaction mixture was acidified with 3N HCl and extracted with EtOAc. The organic was washed 1 : 1 water :brine solution, dried over Na ₂ S04, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (10% MeOH in dichloromethane) to provide 0.58 g (76%) of the title compound as an off white solid, mp 121 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.48 (s, 2H), 5.41 (s, 1H), 3.83-3.58 (m, 7H), 2.42-2.38 (m, 4H), 1.90 (pentet, 2H, J = 6.6 Hz), 1.80-1.77 (m, 2H), 1.70-1.66 (m, 2H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for CsgH^NC^: 686.3913 (M+H) ⁺ . Found: 686.3909. Anal. Calcd. C39H59NO5S2: C, 68.28; H, 8.67; N, 2.04; S, 9.35. Found: C, 68.53; H, 8.70; N, 2.10; S, 9.05. Example 45: 4-[4-(3,5-Di-tert-butyl-4-hydroxy-phenylsuIfanyl)-4-(3,5-di- teri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-hydroxy-4-oxo-buty ric acid

Ex. 45a: In a 10 mL round bottom flask (S)-(+)-2,2-dimethyl-5-oxo-l,3-dioxolane-4-acetic acid (0.46 g, 2.62 mmol) was combined with dichloromethane (3.3 mL), DMF (1 drop), and oxalyl chloride (0.34 g, 3.94 mmol) at 0 °C and the resulting mixture was stirred rapidly to rt. NMR analysis indicated the reaction was complete after 2 h. The reaction mixture was concentrate in vacuo to provide 0.50 g (100%) of (S)-(+)-2,2-dimethyl-5-oxo-l,3-dioxolane- 4-acetic chloride as an off white solid. The material was carried forward without any further purification.

Ex. 45b: In a 100 mL round bottom flask, 2,6-di-tert-butyl-4-[4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.66 g, 1.15 mmol) was combined with anhydrous THF (28 mL) and DIPEA (0.60 mL, 7.56 mmol) and the resulting mixture was treated with (S)-(+)-2,2-dimethyl-5-oxo-l,3-dioxolane-4-acetic chloride (Ex. 45a, 0.22 g, 1.15 mmol). TLC indicated that the reaction was complete in 5 min. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed 1 : 1 watenbrine solution, dried over Na ₂ S04, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (25% EtOAc in hexanes) to provide 0.34 g (43%) of 5-{2-[4-(3,5-di-feri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5- di-feri-butyl-4- methoxy-phenylsulfanyl)-piperidin- 1 -yl]-2-oxo-ethyl} -2,2-dimethyl-[ 1 ,3]dioxolan-4-one as an off white solid, mp 107 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (d, 2H, J = 2.1 Hz), 7.48 (d, 2H, J = 2.1 Hz), 5.41 (s, 1H), 4.86-4.83 (m, 1H), 3.85-3.56 (m, 7H), 2.94-2.88 (m, 1H), 2.74-2.66 (m, 1H), 1.79-1.64 (m, 4H), 1.60 (s, 3H), 1.56 (s, 3H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C4iH ₆ iN0 ₆ S2: 750.3838 (M+Na) ⁺ . Found: 750.3826.

In a 100 niL round bottom flask, 5-{2-[4-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5- di-½r/-butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl]-2-ox o-ethyl}-2,2-dimethyl- [l,3]dioxolan-4-one (Ex. 45b, 0.34 g, 0.46 mmol) was combined with THF (5 mL) and a solution of IN NaOH (2.3 mL, 2.3 mmol) and the resulting mixture was stirred rapidly at rt. HPLC indicated that the reaction was complete after 40 min. The reaction mixture was diluted with water and EtOAc. This reaction mixture was acidified to a pH of 2 with 3N HCl. The organic portion was collected, washed with 1 : 1 water:brine solution, dried over sodium sulfate, concentrated, and dried. The crude material was purified by silica gel chromatography (10%-30% MeOH in dichloromethane) to provide 0.22 g of product bound to silica gel. This mix was suspended in EtOAc and washed with IN NaOH. The organic portion was washed with IN HCl, 1 :1 water:brine solution, dried over magnesium sulfate, concentrated, and dried to provide 92 mg (29%) of the title compound as a white solid, mp 126 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (d, 2H, J = 3.3 Hz), 7.49 (d, 2H, J = 2.4 Hz), 5.43 (s, 1H), 4.42-4.38 (m, 1H), 3.89-3.57 (m, 7H), 3.04-2.98 (m, 1H), 2.76-2.66 (m, 1H), 1.81-1.72 (m, 5H), 1.45-1.44 (m, 36H). HRMS (ESI) Calcd. for 710.3525 (M+Na) ⁺ . Found: 710.3521. Anal. Calcd. CssHjvNOeSa: C, 66.34; H, 8.35; N, 2.04; S, 9.32. Found: C, 66.52; H, 8.43; N, 2.03; S, 8.85.

Example 46: l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yI]-4-hydroxy-butan-l-on e

Ex. 46a: In a 100 mL round bottom flask, 2,6-di-teri-butyl-4-[4-(3,5-di-fe -butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.75 g, 1.31 mmol) was combined with anhydrous THF (33 mL) and DIPEA (0.68 mL, 3.93 mmol) and the resulting mixture was treated with 3-chIorocarbonyl-propionic acid methyl ester (0.16 mL, 1.31 mmol). HPLC indicated that the reaction was over in 1 h. The reaction mixture was quenched with 0.5N HC1 and extracted with EtOAc. The organic was washed 1:1 water:brine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (25% EtOAc in hexanes) to provide 0.61 g (68%) of 4-[4-(3,5-di- eri- butyl-4-hyo^oxy-phenylsulfanyl)-4-(3,5-di-fe^bu1yl-4-methoxy -phenylsulfanyl)-piperidin-l- yl]-4-oxo-butyric acid methyl ester as an off white solid, mp 87 °C. Ή-NMR (300 MHz, CDC1 ₃ ) 6 7.59 (s, 2H), 7.48 (d, 2H), 5.40 (s, 1H), 3.77-3.61 (m, 10H), 2.64-2.58 (m, 4H), 1.81-1.77 (m, 2H), 1.70-1.66 (m, 2H), 1.45-1.43 (m, 36H). HRMS (ESI) Calcd. for C39H59NO5S2: 708.3732 (M+Na) ⁺ . Found: 708.3741. Anal. Calcd. C, 68.28; H, 8.67; N, 2.04; S, 9.35. Found: C, 68.24; H, 8.61; N, 2.11; S, 9.21.

In a 50 mL round bottom flask, 4-[4-(3,5-di-/er/-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- ½r/'-butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo- butyric acid methyl ester (Ex. 46a, 0.55 g, 0.8 mmol) was combined with anhydrous THF (11 mL) and lithium borohydride (1.6 mL, 3.2 mmol, 2M in THF). After 5 h, additional lithium borohydride (1.6 mL, 3.2 mmol, 2M in THF) was added followed by another addition of lithium borohydride (2.2 mL, 4.5 mmol) and the resulting reaction stirred overnight. The reaction mixture was heated to 40 °C for 1 h 30 min, charged with additional lithium borohydride (1.6 mL, 3.2 mmol, 2M in THF), and continued to heat at 40 °C overnight; HPLC indicated that the reaction was complete. The reaction mixture was quenched with IN HC1 and extracted with EtOAc. The organic was washed with water, 1 : 1 watenbrine solution, dried over magnesium sulfate, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (2% MeOH in dichloromethane) to provide 0.36 g (70%) of the title compound as an off white solid, mp 103 °C. 1H-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.48 (d, 2H), 5.41 (s, 1H), 3.79-3.60 (m, 9H), 2.76 (t, 1H, J = 5.1 Hz), 2.45 (t, 2H, J = 6.6 Hz), 1.87-1.65 (m, 6H), 1.45-1.43 (m, 36H). HRMS (ESI) Calcd. for C38H59NO4S2: 658.3964 (M+H) ⁺ . Found: 658.3969. Anal. Calcd. C ₃ 8H ₅ 9N0 ₄ S2: C, 69.36; H, 9.04; N, 2.13; S, 9.75. Found: C, 69.44; H, 9.02; N, 2.22; S, 9.49. Example 47: l-[4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- teri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yI]-3,4-dihydroxy-butan- l-one

In a 50 mL round bottom flask, 5-{2-[4-(3,5-di-½r?-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5- di-z'er/'-butyl-4-methoxy-phenylsulfanyl)-piperidin- 1 -yl]-2-oxo-ethyl} -2,2-dimethyl- [l,3]dioxolan-4-one (Ex. 45b, 0.37 g, 0.51 mmol) was combined with anhydrous THF (8 mL) and lithium borohydride (0.51 mL, 1.02 mmol, 2M in THF). HPLC indicated that the reaction was complete after 1 h 40 min. The reaction mixture was quenched with IN HCl and extracted with EtOAc. The organic was washed with water, 1 : 1 water:brine solution, dried over magnesium sulfate, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (2% MeOH in dichloromethane) to provide 0.21 g (61%) of the title compound as an off white solid, mp 109 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (d, 2H, J = 2.4 Hz), 7.47 (d, 2H, J = 1.5 Hz), 5.42 (s, 1H), 4.33-4.32 (m, 1H), 4.09 (brs, 1H), 3.74- 3.53 (m, 9H), 2.46-2.45 (m, 2H), 2.11-2.10 (m, 1H), 1.79-1.68 (m, 4H), 1.45-1.44 (m, 36H). HRMS (ESI) Calcd. for C ₃₈ H ₅₉ N0 ₅ S ₂ : 696.3732 (M+Na) ⁺ . Found: 696.3746. Anal. Calcd. C ₃₈ H ₅₉ N0 ₅ S ₂ : C, 67.72; H, 8.82; N, 2.08; S, 9.51. Found: C, 67.75; H, 9.07; N, 2.01; S, 9.12.

Example 48: l-{4-(3,5-Di-fe i-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-½ri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-4-hydroxy-b utan-l-one

In a 50 mL round bottom flask, 4-[4,4-bis-(3,5-di-teri-butyl-4-hydroxy- phenylsulfanyl)piperidin-l-yl]-4-oxo-butyric acid methyl ester (Ex. 9a, 0.60 g, 0.82 mmol) was combined with anhydrous THF (11 mL) and lithium borohydride (1.6 mL, 3.29 mmol, 2M in THF). HPLC indicated that the reaction was complete after 5 h 35 min. The reaction mixture was quenched with IN HCl and extracted with EtOAc. The organic was washed with water, 1;1 water:brine solution, dried over magnesium sulfate, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (2% MeOH in dichloromethane) to provide 0.16 g (28%) of the title compound as an off white solid, mp 103 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.41 (s, 1H), 3.91-3.84 (m, 4H), 3.75-3.72 (m, 2H), 3.65-3.59 (m, 4H), 2.85-2.82 (m, 1H), 2.46-2.42 (m, 2H), 2.18-2.09 (m, 2H), 1.88-1.76 (m, 5H), 1.67-1.64 (m, 2H), 1.45-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₄ oH ₆ 3N0 ₅ S2: 724.4045 (M+Na) ⁺ . Found: 724.4045. Anal. Calcd. C ₄ oH ₆ 3N0 ₅ S ₂ : C, 68.43; H, 9.04; N, 2.00; S, 9.13. Found: C, 69.18; H, 9.24; N, 2.02; S, 8.90.

Example 49 : 4-(3,5-Di-fert-butyl-4-hydroxyphenylsuIfanyl)-4- [3,5-di-fert-butyl-4-(3- pyrazol-l-yl-propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester

To a solution of 4-(3,5-di-ieri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-ieri -butyl-4-(3- methane-sulfonyloxypropoxy)phenylsulfanyl]piperidine-l-carbo xylic acid ethyl ester (Ex. 10a, 0.50 g, 0.66 mmol) and pyrazole (0.067 g, 0.99 mmol) in DMF (5 mL) at rt was added NaH in one portion (0.050 g, 1.98 mmol). The resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with saturated ammonium chloride (5 mL) and diluted with H ₂ 0 (50 mL) and EtOAc (50 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1:3) afforded 0.42 g (83%) of the title compound as an off-white solid, mp 85-87 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.56 (s, 2H), 7.50 (d, 1H, J= 2.1 Hz), 7.47 (s, 2H), 7.40 (d, 1H, J= 2.1 Hz), 6.25 (t, 1H, J = 2.1 Hz), 5.39 (s, 1H), 4.30 (t, 2H, J = 7.2 Hz), 4.08 (q, 2H, J= 7.8 Hz), 3.74 (t, 2H, J= 7.2 Hz), 3.53-3.65 (m, 4H), 2.45 (pentet, 2H, J= 7.2 Hz), 1.70 (brs, 4H), 1.43 (s, 18H), 1.37 (s, 18H), 1.21 (t, 3H, J= 7.8 Hz). HRMS (ESI) Calcd. for C ₄ 2H ₆ 3N30 ₄ S2: 738.4338 (M+H) ⁺ . Found: 738.4325. Anal. Calcd. for C ₄₂ H ₆ 3N ₃ 0 ₄ S ₂ : C, 68.34; H, 8.60; N, 5.69; S, 8.69. Found: C, 68.40; H, 8.64; N, 5.54; S, 8.55.

Example 50: 2,6-Di-tert-butyl-4-{4-[3,5-di-tert-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol

To a solution of 4-(3,5-di-½r/-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-½ri -butyl-4-(3- pyrazol-l-yl-propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester (Ex. 49, 0.50 g, 0.66 mmol) in z-PrOH (5 mL) was added solid KOH (pellets, 0.74 g, 13.1 mmol). The resulting solution was heated to 85 °C for 24 h. Upon completion, as determined by HPLC, the reaction was acidified with IN HCl and partitioned between H ₂ 0 (50 mL) and EtOAc (50 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 30 mL). The combined organic cuts were washed with a saturated NaHC0 ₃ solution (1 x 30 mL), 50% aqueous brine solution (1 x 30 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (MeOH/CH ₂ Cl ₂ , 1:9) afforded 0.34 g (75%) of 2,6-di-½r/-butyl-4-{4-[3,5-di-½r -butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]piperidin-4-ylsulfanyl}phenol as an off-white solid, mp 108-111 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.50 (d, 1H, J= 2.1 Hz), 7.48 (s, 2H), 7.40 (d, 1H, J= 2.1 Hz), 6.25 (t, 1H, J= 2.1 Hz), 5.40 (s, 1H), 4.29 (t, 2H, J= 12 Hz), 3.74 (t, 2H, J = 7.2 Hz), 3.16 (brs, 4H), 2.45 (pentet, 2H, J= 7.2 Hz), 1.86-1.88 (m, 5H), 1.44 (s, 18H), 1.36 (s, 18H). HRMS (ESI) Calcd. for C39H59N3O2S2: 666.4127 (M+H) ⁺ . Found: 666.4139. Anal. Calcd. for C ₃₉ H59N ₃ 0 ₂ S2-½H ₂ 0: C, 66.90; H, 9.40; N, 5.85; S, 8.93. Found: C, 67.24; H, 8.73; N, 6.03; S, 9.12.

Example 51 : l-{4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-t ert-butyl-4-(3- pyrazol-l-yl-propoxy)phenylsulfanyl]piperidin-l-yl}-2-hydrox yethanone

Ex 51a: To a solution of 2,6-di-½rr-butyl-4-{4-[3,5-di-ter/-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl} phenol (Ex. 50, 0.70 g, 1.01 mmol) in THF (15 mL) was added DIPEA (0.52 mL, 3.03 mmol) followed by acetoxyacetyl chloride (0.12 mL, 1.12 mmol) and the resulting solution was stirred at rt for 1 h. Upon completion, as determined by HPLC, the reaction was quenched with saturated ammonium chloride (3 mL) and partitioned between H ₂ 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 15 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1 :3 to 1:1) afforded 0.67 g (89%) of acetic acid 2-{4-(3,5-di-/err-butyl-4-hydroxyphenylsulfanyl)-4-[3,5- di-teri-butyl-4-(3-pyrazol- 1 -ylpropoxy)phenyl-sulfanyl]-piperidin- 1 -yl} -2-oxo-ethyl ester as an off-white foam, mp 62-65 °C. *H-NMR (300 MHz, CDC1 ₃ ) δ 7.56 (s, 2H), 7.50 (d, 1H, J= 1.8 Hz), 7.47 (s, 2H), 7.40 (d, 1H, J= 1.8 Hz), 6.25 (t, 1H, J= 1.8 Hz), 5.42 (s, 1H), 4.66 (s, 2H), 4.30 (t, 2H, J= 7.2 Hz), 3.70-3.78 (m, 4H), 3.49 (brs, 2H), 2.46 (pentet, 2H, J= 7.2 Hz), 2.15 (s, 3H), 1.71 (brs, 2H), 1.68-1.71 (m, 2H), 1.44 (s, 18H), 1.37 (s, 18H). HRMS (ESI) Calcd. for C4 ₃ H ₆₃ N ₃ 0 ₅ S2: 766.4287 (M+H) ⁺ . Found: 766.4294. Anal. Calcd. for

C ₄₃ H ₆₃ N ₃ 0 ₅ S2: C, 67.41; H, 8.29; N, 5.48; S, 8.37. Found: C, 67.37; H, 8.30; N, 5.39; S, 8.13.

To a solution of acetic acid 2- {4-(3,5-di-ier/-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-/er i- butyl-4-(3-pyrazol-l-ylpropoxy)phenyl-sulfanyl]-piperidin-l- yl}-2-oxo-ethyl ester (Ex. 51a, 0.66 g, 0.83 mmol) in THF (8 mL) was added a 2 mL aqueous LiOH solution (0.11 g, 2.51 mmol) followed by a few drops of MeOH for solubility (0.3 mL) and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was neutralized with IN HCl and partitioned between H ₂ 0 (25 mL) and EtOAc (25 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 20 mL). The combined organic cuts were washed with a 50% brine solution (1 x 25 mL), brine (1 x 25 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1 :3) afforded 0.57 g (96%) of the title compound as an off-white solid, mp 89-92 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.56 (s, 2H), 7.50 (d, 1H, J = 1.8 Hz), 7.46 (s, 2H), 7.40 (d, 1H, J = 1.8 Hz), 6.25 (t, 1H, J = 1.8 Hz), 5.42 (s, 1H), 4.30 (t, 2H, J = 7.8 Hz), 4.09 (s, 2H), 3.73-3.81 (m, 4H), 3.60 (brs, 1H), 3.36-3.39 (m, 2H), 2.45 (pentet, 2H, J = 7.8 Hz), 1.70-1.78 (m, 4H), 1.44 (s, 18H), 1.37 (s, 18H). HRMS (ESI) Calcd. for C ₄ iH ₆ iN ₃ 0 ₄ S2: 724.4181 (M+H) ⁺ . Found: 724.4183. Anal. Calcd. for C ₄ iH ₆₁ N ₃ 0 ₄ S ₂ : C, 68.01; H, 8.49; N, 5.80; S, 8.86. Found: C, 68.28; H, 8.67; N, 5.49; S, 8.34.

Example 52 : {4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyI)-4-[3,5-di-ter i-butyl-4-(3- pyrazol-l-yI-propoxy)phenylsuIfanyl]piperidin-l-yI}acetic acid

Ex. 52a: To a solution of 2,6-di-?er?-butyl-4-{4-[3,5-di-ferr-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl} phenol (Ex. 50, 0.70 g, 1.01 mmol) in THF (15 mL) was added DIPEA (0.52 mL, 3.03 mmol) followed by ethyl bromoacetate (0.12 mL, 1.12 mmol) and the resulting solution was stirred at it for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with saturated ammonium chloride (3 mL) and partitioned between H ₂ 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 15 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1 :3) afforded 0.36 g (50%) of {4-(3,5-di-½r -butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-reri-butyl- 4-(3-pyrazol-l-yl-propoxy)phenylsulfanyl]piperidin-l-yl}acet ic acid ethyl ester as an off- white solid, mp 78-81 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.56 (s, 2H), 7.51 (d, 1H, J = 2.1 Hz), 7.44 (s, 2H), 7.40 (d, 1H, J = 2.1 Hz), 6.24 (t, 1H, J = 2.1 Hz), 5.36 (s, 1H), 4.30 (t, 2H, J = 7.2 Hz), 4.17 (q, 2H, J = 7.5 Hz), 3.75 (t, 2H, J = 7.2 Hz), 3.20 (s, 2H), 2.72 (brs, 4H), 2.45 (pentet, 2H, J= 7.2 Hz), 1.86-1.89 (m, 4H), 1.43 (s, 18H), 1.36 (s, 18H), 1.26 (t, 3H, J = 7.5 Hz). HRMS (ESI) Calcd. for C ₄₃ H ₆₅ N ₃ 0 ₄ S2: 752.4494 (M+H) ⁺ . Found: 752.4481. Anal. Calcd. for C ₄₃ H ₆ 5N ₃ 0 ₄ S2: C, 68.67; H, 8.71; N, 5.59; S, 8.53. Found: C, 68.63; H, 8.57; N, 5.52; S, 8.39.

To a solution of {4-(3,5-di-½r -butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-½r/-butyl-4-(3- pyrazol-l-yl-propoxy)phenylsulfanyl]piperidin-l-yl} acetic acid ethyl ester (Ex. 52a, 0.35 g, 0.45 mmol) in THF:¾0:MeOH (4: 1 : 1, 8 mL) was added solid LiOH H ₂ 0 (0.057 g, 1.35 mmol) in one portion and the resulting solution was stirred at rt for 4 h. Upon completion, as determined by HPLC, the reaction was acidified with IN HC1 and partitioned between H ₂ 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic cuts were washed with a 50% brine solution (1 x 20 mL), brine (1 x 20 mL), dried over Na ₂ S0 , and concentrated under reduced pressure. The crude foam was taken up in hexanes and stirred for 2 h at rt and the resulting precipitate was collected and rinsed with fresh hexanes to afford 0.32 g (95%) of the title compound as an off-white solid, mp 140-143 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.51 (d, 1H, J = 2.1 Hz), 7.49 (s, 2H), 7.41 (d, 1H, J = 2.1 Hz), 6.25 (t, 1H, J = 2.1 Hz), 5.44 (brs, 1H), 4.30 (t, 2H, J = 7.2 Hz), 3.71 -3.76 (m, 4H), 3.46 (brs, 4H), 2.44 (pentet, 2H, J= 7.2 Hz), 2.08-2.17 (m, 4H), 1.44 (s, 18H), 1.36 (s, 18H). HRMS (ESI) Calcd. for C ₄ iH ₆ iN ₃ 0 ₄ S ₂ : 724.4181 (M+H)\ Found: 724.4193. Anal. Calcd. for C ₄ iH ₆ iN ₃ 0 ₄ S ₂ -½H ₂ 0: C, 64.99; H, 8.96; N, 5.41 ; S, 8.26. Found: C, 65.19; H, 5.89; N, 5.31 ; S, 7.83.

Example 53: 2,6-Di-teri-butyl-4-[4-[3,5-di-teri-butyl-4-(3-pyrazol-l- ylpropoxyphenylsulfanyI]-l-(2-hydroxyethyl)piperidin-4-ylsul fanyl]phenol

To a solution of 2,6-di-½ri-butyl-4-{4-[3,5-di-ieri-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 50, 0.50 g, 1.01 mmol) in THF (10 mL) was added DIPEA (0.38 niL, 2.16 mmol) followed by (2-bromoethoxy)-tert- butyldimethylsilane (0.17 mL, 0.80 mmol) and the resulting solution was stirred at rt for 48 h. Upon completion, as determined by HPLC, TBAF (1.44 mL, 1.44 mmol, 1.0 M in THF) was added to the reaction and allowed to stir at rt for 30 min. The reaction was partitioned between H ₂ 0 (25 mL) and EtOAc (25 mL). The layers were cut and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (5% MeOH/CH ₂ Cl ₂ ) afforded 0.40 g (80%) of the title compound as a white solid, mp 74-77 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.50 (d, 1H, J = 1.8 Hz), 7.48 (s, 2H), 7.40 (d, 1H, J = 1.8 Hz), 6.25 (t, 1H, J = 1.8 Hz), 5.38 (s, 1H), 4.30 (t, 2H, J = 7.2 Hz), 3.75 (t, 2H, J = 7.2 Hz), 3.56 (t, 2H, J = 5.4 Hz), 2.66 (brt, 4H, J = 4.8 Hz), 2.56 (t, 2H, J = 5.4 Hz), 2.45 (pentet, 2H, J = 7.2 Hz), 1.80 (brs, 5H), 1.44 (s, 18H), 1.37 (s, 18H). HRMS (ESI) Calcd. for C ₄₁ H ₆₃ N ₃ 0 ₃ S2: 710.4389 (M+H) ⁺ . Found: 710.4382. Anal. Calcd. for C ₄ iH63N ₃ 0 ₃ S ₂ : C, 69.35; H, 8.94; N, 5.92; S, 9.03. Found: C, 69.65; H, 9.19; N, 5.75; S, 8.64. Example 54: l-(2-{4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-d i-teri-butyl-4- (3-pyrazoI-l-ylpropoxy)phenylsulfanyl]piperidin-l-yl}-2-oxoe thyl)-lH-pyrazole-4- carboxylic acid

Ex. 54a: To a solution of 2,6-di-½r -butyl-4-{4-[3,5-di-½rt-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 50, 3.0 g, 4.36 mmol) in THF (50 mL) was added DIPEA (2.3 mL, 13.1 mmol) followed by chloroacetyl chloride (0.38 mL, 4.79 mmol) and the resulting solution was stirred at rt for 30 min. Upon completion, as determined by HPLC, the reaction was quenched with saturated ammonium chloride (5 mL) and partitioned between H ₂ 0 (75 mL) and EtOAc (75 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1 :2) afforded 3.31 g (99%) of 2-chloro-l-{4-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)-4- [3,5- di-½ri-butyl-4-(3-pyrazol-l-ylpropoxy)phenylsulfanyl]-piper idin-l-yl}ethanone as an off- white solid, mp 83-86 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.55 (s, 2H), 7.50 (d, 1H, J = 2.1 Hz), 7.46 (s, 2H), 7.40 (d, 1H, J = 2.1 Hz), 6.25 (t, 1H, J = 2.1 Hz), 5.41 (s, 1H), 4.30 (t, 2H, J = 7.2 Hz), 4.00 (s, 2H), 3.66-3.81 (m, 4H), 3.62 (t, 2H, J = 5.4 Hz), 2.45 (pentet, 2H, J = 7.2 Hz), 1.85-1.87 (m, 2H), 1.69 (t, 2H, J = 5.4 Hz), 1.44 (s, 18H), 1.37 (s, 18H). HRMS (ESI) Calcd. for C ₄₁ H ₆₀ ClN ₃ O ₃ S2: 742.3843 (M+H) ⁺ . Found: 742.3842. Anal. Calcd. for C ₄ iH ₆₀ ClN ₃ O ₃ S ₂ : C, 66.32; H, 8.14; N, 5.66; S, 8.64. Found: C, 66.12; H, 8.25; N, 5.43; S, 8.36.

Ex. 54b: To a solution of 2-chloro-l-{4-(3,5-di-½r/-butyl-4-hydroxyphenylsulfanyl)-4- [3,5- di-½rt-butyl-4-(3-pyrazol-l-ylpropoxy)phenylsulfanyl]-piper idin-l-yl}ethanone (Ex. 54a, 0.75 g, 0.98 mmol) in THF (10 mL) was added ethyl 4-pyrazolecarboxylate (0.21 g, 1.47 mmol) followed by NaH (0.071 g, 2.94 mmol, 60% dispersion in mineral oil) and the resulting solution was stirred at rt for 1 h. Upon completion, as determined by HPLC, the reaction was quenched with saturated ammonium chloride (5 mL) and partitioned between H ₂ 0 (25 mL) and EtOAc (25 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 25 mL). The combined organic cuts were washed with a 50% brine solution (1 x 25 mL), brine (1 x 25 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1:1) afforded 0.84 g (98%) of l-(2-{4-(3,5-di- ½^bu1yl-4-hydroxyphenylsulfanyl)-4-[3,5-di-feri-butyl-4-(3- pyrazol-l-ylpropoxy)-phenyl- sulfanyl]piperidin-l -yl}-2-oxoethyl)-lH-pyrazole-4-carboxylic acid ethyl ester as an off- white form, mp 107-110°C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.98 (s, 1H), 7.90 (s, 1H), 7.57 (s, 2H), 7.50 (d, 1H, J= 2.1 Hz), 7.47 (s, 2H), 7.40 (d, 1H, J= 2.1 Hz), 6.25 (t, 1H, J= 2.1 Hz), 5.42 (s, 1H), 4.94 (s, 2H), 4.24-4.32 (m, 4H), 3.64-3.81 (m, 6H), 2.45 (pentet, 2H, J = 7.2 Hz), 1.79-1.81 (m, 2H), 1.69-1.73 (m, 2H), 1.44 (s, 18H), 1.37 (s, 18H), 1.32 (t, 3H, J = 7.2 Hz). HRMS (ESI) Calcd. for C47H67N5O5S2: 846.4662 (M+H) ⁺ . Found: 846.4648. Anal. Calcd. for C ₄ 7H67N ₅ 0 ₅ S ₂ : C, 66.71; H, 7.98; N, 8.28; S, 7.58. Found: C, 66.68; H, 8.09; N, 8.06; S, 7.43.

To a solution of l-(2-{4-(3,5-di-ieri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-d i-teri-butyl-4- (3-pyrazol- 1 -ylpropoxy)-phenyl-sulfanyl]piperidin-l -yl} -2-oxoethyl)- lH-pyrazole-4- carboxylic acid ethyl ester (Ex. 54b, 0.75 g, 0.86 mmol) in THF:H ₂ 0:MeOH (4:1:1, 12 mL) was added solid LiOH-H ₂ 0 (0.11 g, 2.58 mmol) in one portion and the resulting solution was stirred at rt for 24 h. Upon completion, as determined by HPLC, the reaction was acidified with IN HCl and partitioned between H ₂ 0 (25 mL) and EtOAc (25 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 20 mL). The combined organic cuts were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Silica gel chromatography (5% MeOH/CH ₂ CH ₂ containing 0.07% AcOH) afforded 0.62 g (85%) of the title compound as an off-white solid, mp 132-135 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 8.02 (s, 1H), 7.92 (s, 1H), 7.52 (s, 3H), 7.48 (s, 2H), 7.42 (d, 1H, J= 2.1 Hz), 6.27 (t, 1H, J= 2.1 Hz), 5.43 (s, 1H), 4.96 (dd, 2H, J = 15.3, 10.8 Hz), 4.33 (t, 2H, J = 7.2 Hz), 3.74-3.82 (m, 4H), 3.66 (brs, 2H), 2.44 (pentet, 2H, J = 7.2 Hz), 1.65-1.78 (m, 4H), 1.44 (s, 18H), 1.36 (s, 18H). HRMS (ESI) Calcd. for QsH^NsOsS^ 818.4349 (M+H) ⁺ . Found: 818.4331. Anal. Calcd. for C ₄₅ H ₆ 3N ₅ 0 ₅ S2: C, 64.64; H, 7.84; N, 8.38; S, 7.67. Found: C, 64.66; H, 7.87; N, 7.85; S, 7.08. Example 55 : 4- [4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-ter i-butyl-4- methoxy-phenylsulfanyl)-piperidine-l-carbonyl]-3-ethyl-5-met hyl-lH-pyrrole-2- carboxylic acid ethyl ester

To a solution of the 3-ethyl-5-methyl-lH-pyrrole-2,4-dicarboxylate acid 2-ethyl ester (0.40 g, 1.78 mmol) in CH ₂ C1 ₂ (5 mL) was added SOCl ₂ (0.15 mL, 2.13 mmol) followed by two drops of DMF and the resulting solution was stirred at rt for 18 h. The volatiles were removed under reduced pressure to give a crude off-white foam. The acid chloride was then added to a solution of 2,6-di-tert-butyl-4-{4-[3,5-di-tert-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 50, 0.88 g, 1.47 mmol) and DIPEA (1.0 mL, 5.88 mmol) in THF (10 mL) and the resulting solution was stirred at rt for 1 h. Upon completion, as determined by HPLC, the reaction was quenched with saturated ammonium chloride (3 mL) and partitioned between H ₂ 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 15 mL). The combined organic cuts were washed with a 50% brine solution (1 x 20 mL), brine (1 x 20 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1 :2) afforded 0.68 g (60%) of the title compound as a pale yellow solid, mp 119-122 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 8.72 (brs, 1H), 7.65 (s, 1H), 7.53 (d, 2H, J = 2.4 Hz), 7.41 (s, 1H), 5.40 (d, 1H, J= 5.4Hz), 4.29 (q, 2H, J = 7.2 Hz), 4.11 (q, 2H, J= 7.0 Hz), 3.69 (d, 3H, J = 4.2 Hz), 3.04-3.10 (m, 1H), 2.77-2.81 (m, 1H), 2.51-2.53 (m, 2H), 2.05 (d, 3H, J = 14.4 Hz), 1.63-1.78 (m, 4H), 1.41-1.45 (m, 36H), 1.33 (t, 3H, J = 12 Hz), 1.23 (t, 3H, J = 7.0 Hz). Anal. Calcd. for C ₄₅ H ₆ 6N ₂ 0 ₅ S ₂ -½H ₂ 0: C, 67.80; H, 8.60; N, 3.51; S, 8.04. Found: C, 67.98; H, 8.26; N, 3.17; S, 7.21.

Example 56: 4-[4-(3,5-Di-te7-/-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di- teri-butyl-4- methoxy-phenylsulfanyl)piperidine-l-carbonyl]-3-ethyl-5-meth yI-lH-pyrrole-2- carboxylic acid

To a solution of 4-[4-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-� �r -butyl-4- methoxy-phenylsulfanyl)-piperidme-l-carbonyl]-3-ethyl-5-meth yl-lH-pyrrole-2-carboxylic acid ethyl ester (Ex. 55, 0.47 g, 0.58 mmol) in THF:H ₂ 0:MeOH (4: 1 : 1, 6 mL) was added solid LiOH H ₂ 0 (0.074 g, 1.76 mmol) in one portion and the resulting solution was stirred at rt for 5 h. Upon completion, as determined by HPLC, the reaction was acidified with IN HCl and partitioned between H ₂ 0 (20 mL) and EtOAc (20 mL). The layers were cut and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic cuts were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Silica gel chromatography (5% MeOH/CH ₂ CH ₂ ) afforded 0.28 g (65%) of the title compound as an off white solid, mp 161- 164 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 8.84 (brs, 1H), 7.58 (d, 2H, J= 8.4 Hz)), 7.46 (d, 2H, J= 9.9 Hz), 5.41 (s, 1H), 4.30 (q, 2H, J= 7.0 Hz), 3.70 (s, 3H), 3.11 (brs, 1H), 2.62-2.74 (m, 3H), 2.10 (d, 3H, J= 11.7 Hz), 1.64-1.88 (m, 4H), 1.42-1.43 (m, 36H), 1.34 (t, 3H, J= 7.0 Hz). Anal. Calcd. for C ₄ 3H ₆₂ N ₂ 0 ₅ S ₂ -½H ₂ 0: C, 67.15; H, 8.39; N, 3.64; S, 8.34. Found: C, 67.17; H, 8.29; N, 3.22; S, 8.31.

Example 57: 4-[3,5-Di-tert-butyl-4-(3-carboxy-3-hydroxypropoxy)phenylsul fanyl]-4- (3,5-di-ieri-butyl-4-hydroxyphenylsuIfanyl)piperidine-l-carb oxylic acid ethyl ester

Ex. 57a: A solution of ((S)-(+)-2,2-dimethyl-5-oxo-[l,3]dioxolan-4-yl)acetic acid (15.0 g, 86.1 mmol) in THF (46 mL) was cooled to 0 °C followed by addition of BH ₃ -THF (112 mL, 112 mmol, 1M in THF) dropwise over 30 min. The reaction mixture was allowed to stir at 0 °C for 30 min, warmed up to rt and continued to stir for 4 h. The reaction was then quenched at 0 °C by addition of MeOH (60 mL). The solution was allowed to stir at the same temperature and concentrated under reduced pressure on a rotatory evaporator with a temperature not exceeding 18 °C. Additional MeOH (100 mL) was added to the oily residue and the solution was concentrated under reduced pressure. The process was repeated three times to afford 14.3 g (100%) of (S 5-(2-hydroxyethyl)-2,2-dimethyl-[l,3]dioxolan-4-one as a clear oil. Ή-NMR (300 MHz, CDC1 ₃ ) δ 4.55-4.60 (m, 1H), 3.80-3.90 (m, 2H), 2.80-3.00 (m, 1H), 2.10-2.20 (m, 1H), 1.95-2.08 (m, 1H), 1.63 (s, 3H), 1.56 (s, 3H). The crude product was used immediately in the next step without further purification.

Ex. 57b: To a solution of 4,4-bis-(3,5-di-teri-butyl-4-hydroxyphenylsulfanyl)piperidin e-l- carboxylic acid ethyl ester (Ex. la, 18.2 g, 28.9 mmol), (5)-5-(2-hydroxyethyl)-2,2-dimethyl- [l,3]dioxolan-4-one (Ex. 57a, 6.03 g, 37.6 mmol), and triphenylphosphine (15.2 g, 57.9 mmol) in THF (155 mL) was added diethyl azodicarboxylate (9.12 mL, 57.9 mmol) dropwise at 0 °C. The reaction mixture was allowed to stir overnight at rt. The reaction mixture was concentrated under reduced pressure, redissolved in CH ₂ CI ₂ , and purified by silica gel chromatography (EtOAc/hexane, 1 :5) to afford a mixture (5.05 g) containing 4- {3,5-di-teri- butyl-4-[2-(S)-(2,2-dimethyl-5-oxo-[l,3]-dioxolan-4-yl)ethox y]-phenylsulfanyl}-4-(3,5-di- ½ri-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester (85% HPLC) and unreacted starting carbamate. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.39 (s, 1H), 4.55-4.60 (m, 1H), 4.09 (q, 2H, J = 7.3 Hz), 3.90-4.00 (m, 1H), 3.80-3.90 (m, 1H), 3.55-3.70 (m, 4H), 2.45-2.60 (m, 1H), 2.10-2.25 (m, 1H), 1.65-1.75 (m, 4H), 1.45 (s, 18H), 1.42 (s, 18H), 1.22 (t, 3H, J= 7.3 Hz). The material was used without further purification. To a solution of 4-{3,5-di-½ri-butyl-4-[2-(5)-(2,2-dimethyl-5-oxo-[l,3]-diox olan-4- yl)ethoxy]-phenylsulfanyl}-4-(3,5-di-teri-butyl-4-hydroxyphe nylsulfanyl)piperidine-l- carboxylic acid ethyl ester (Ex. 57b, 5.05 g, 5.56 mmol, 85% HPLC) in THF (50 mL) was added NaOH (25 mL, 25 mmol, 1M) at 0 °C. The reaction mixture was allowed to warm up to rt, stir for 1.5 h and was acidified to pH = 3 with concentrated HC1 (9 mL). The resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with a 10%) brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/hexanes, 1:2; then 10% MeOH/CH ₂ Cl ₂ ) gave 2.78 (66%) of the title compound as a white solid, mp 165-169 °C. ^-NMR (DMSO- ₆ ) δ 7.49 (s, 2H), 7.33 (s, 2H), 4.30 (brs, 1H), 3.92 (q, 2H, J = 7.6 Hz), 3.60-3.80 (m, 3H), 3.40-3.50 (m, 4H), 2.12-2.25 (m, 2H), 1.80-1.95 (m, 1H), 1.50-1.60 (m, 4H), 1.33 (s, 36H), 1.05 (t, 3H, J = 7.6 Hz). HRMS (ESI) Calcd. for C ₄ oH ₆₁ N0 ₇ S ₂ : 754.3787 (M+Na) ⁺ . Found: 754.3762.

Example 58: 4-[3,5-Di-teri-butyl-4-((5}-3,4-dihydroxybutoxy)phenylsulfan yl]-4-(3,5-di- teri-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester

To a solution of 4-[3,5-di-/er -butyl-4-(3-carboxy-3-hydroxypropoxy)phenylsulfanyl]-4-(3,5- di-/er/'-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxyl ic acid ethyl ester (Ex. 57, 2.34 g, 3.2 mmol) in THF (17 mL) was added BH ₃ THF (16 mL, 16 mmol, 1M in THF) dropwise. The reaction mixture was allowed to stir at rt for 7 h and cooled to 0 °C followed by addition of MeOH (15 mL). The resulting solution was allowed to stir for 10 min at the same temperature and then concentrated under reduced pressure. The residue was redissolved in CH ₂ Ci ₂ and concentrated under reduced pressure to afford a white fluffy foam (2.16 g, 94%). A portion of the foam (300 mg) was purified by Silica gel chromatography (0-10% MeOH/CH ₂ Cl ₂ ; then 3% MeOH/CH ₂ Cl ₂ ) to give 0.21 g of the title compound as a white fluffy foam. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.39 (s, 1H), 4.08 (q, 2H, J= 7.1 Hz), 3.89-4.02 (m, 4H), 3.70-3.77 (m, 1H), 3.50-3.65 (m, 4H), 2.50 (d, 1H, J= 3.7 Hz), 1.95-2.15 (m, 2H), 1.88 (t, 1H, J= 5.6 Hz), 1.66-1.78 (m, 4H), 1.44 (s, 18H), 1.43 (s, 18H), 1.22 (t, 3H, 7.1 Hz). HRMS (ESI): Calcd. for C ₄ oH ₆₃ N0 ₆ S ₂ : 740.3995 (M+Na) ⁺ .

Found: 740.3987.

Example 59: 4-{2,6-Di-tert-butyl-4-[4-(3,5-di-ieri-butyl-4- hydroxyphenylsulfany^piperidin^-ylsulfanyll-phenoxyJbutane-^ -l^-diol

To a solution of 4-[3,5-di- eri-butyl-4-((S)-3,4-dihydroxybutoxy)phenylsulfanyl]-4-(3,5- di- ½r/-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester (Ex. 58, 0.98 g, 1.36 mmol) in z ^' -PrOH (13 mL) was added solid KOH (1.53 g, 27.3 mmol). The reaction mixture was heated at 87 °C overnight, concentrated under reduced pressure and treated with water (20 mL). The aqueous solution was acidified to pH = 6 with 3M HC1 and extracted with CH ₂ C1 ₂ . The combined organic extracts were washed with a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The material was purified by silica gel chromatography (0-10% MeOH/CH ₂ Cl ₂ ) to afford 0.50 g (58%) of the title compound as a white fluffy foam. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.47 (s, 2H), 5.38 (s, 1H), 3.89-4.02 (m, 3H), 3.70-3.75 (m, 1H), 3.51-3.57 (m, 1H), 3.00-3.10 (m, 4H), 1.95-2.07 (m, 5H), 1.73-1.80 (m, 4H), 1.44 (s, 18H), 1.43 (s, 18H).

HRMS (ESI) Calcd. for C ₃ 7H59NO ₄ S2: 646.3964 (M+H) ⁺ . Found: 646.3959. Example 60: [4-[3,5-Di-feri-butyl-4-((S)-3,4-dihydroxybutoxy)phenylsuIfa nyl]-4-(3,5-di- fert-butyl-4-hydroxyphenylsulfanyl)piperidin-l-yl] acetic acid

Ex. 60a: To a solution of 4-{2,6-di-?ert-butyl-4-[4-(3,5-di-½rt-butyl-4- hydroxyphenylsulfanyl)piperidin-4-ylsulfanyl]-phenoxy}butane -(5)-l,2-diol (Ex. 59, 0.36 g, 0.56 mmol) and DIPEA (0.29 mL, 1.69 mmol) in THF (10 mL) was added ethyl bromoacetate (0.1 1 g, 0.67 mmol). The reaction mixture was allowed to stir overnight at rt and then was diluted with water. The resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with 0.5M HCl, a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The material was purified by silica gel chromatography (0-10% MeOH/CHbCh) to give 0.33 g (80%) of [4-[3,5-di-½ri-butyl-4-((S)-3,4-dihydroxybutoxy)-phenylsulf anyl]-4-(3,5-di-½r - butyl-4-hydroxyphenyl-sulfanyl)piperidin-l-yl] acetic acid ethyl ester as an off-white foam. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.45 (s, 2H), 5.63 (s, 1H), 4.17 (q, 2H, J = 7.0 Hz), 3.85-4.05 (m, 3H), 3.66-3.77 (m, 1H), 3.50-3.60 (m, 1H), 3.21 (s, 2H), 2.68-2.77 (m, 4H), 2.52 (brs, 1H), 1.80-2.19 (m, 7H), 1.43 (s, 36H), 1.26 (t, 3H, J = 7.0 Hz). HRMS (ESI) Calcd. for C4iH ₆₅ N0 ₆ S ₂ : 732.4331 (M+H) ⁺ . Found: 732.4321.

To a solution of [4-[3,5-di-½ri-butyl-4-((S)-3,4-dihydroxybutoxy)-phenylsulf anyl]-4-(3,5-di- ½^-butyl-4-hydroxyphenyl-sulfanyl)piperidin-l-yl]acetic acid ethyl ester (Ex. 60a, 0.33 g, 0.45 mmol) in THF (6 mL) was added NaOH (3 mL, 3 mmol, 1M). The reaction mixture was allowed to stir at rt for 45 min, at 50 °C for 15 min and then concentrated under reduced pressure. Water was added to the residue. The pH of the resulting solution was adjusted to 7 by 0.5M HCl. The aqueous mixture was extracted with a mixture of EtOAc and i-PrOH (4/1, v/v). The combined organic extracts were washed with a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (0-10% MeOH/CH ₂ Cl ₂ ) afforded 0.20 g (75%) of the title compound as a clear oil which was titurated to form an off-white solid in aqueous EtOH (30%), mp 131-134°C. 'H-NMR (300 MHz, CDC1 ₃ ) 5 7.51 (s, 2H), 7.49 (s, 2H), 5.44 (s, 1H), 3.80-3.97 (m, 3H), 3.64-3.76 (m, 2H), 3.46-3.52 (m, 2H), 3.29 (s, 2H), 3.10-3.20 (m, 4H), 1.89-2.00 (m, 6H), 1.45 (s, 18H), 1.41 (s, 18H). HRMS (ESI) Calcd. for C ₃ 9H6iN0 ₆ S ₂ : 704.4018 (M+H) ⁺ . Found: 704.4010.

Example 61 : 4-{2,6-Di-teri-butyl-4-[4-(3,5-di-teri-butyl-4-hydroxyphenyl sulfanyl)-l-(2- hydroxyacetyl)-piperidin-4-ylsulfanyl]phenoxy}-(S)-2-hydroxy butyric acid

Ex. 61a: To a solution of 4,4-bis-(3,5-di-ter/-butyl-4-hydroxyphenylsulfanyl)piperidin e-l- carboxylic acid ethyl ester (Ex. la, 2.0 g, 3.58 mmol) in THF (20 mL) was added acetic acid chlorocarbonylmethyl ester (0.46 mL, 4.30 mmol). The reaction mixture was allowed to stir for 3 h and diluted with water. The resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with 0.5M HC1, a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure to afford 2.63 g (100%) of acetic acid 2-[4,4-bis-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)piper idin-l-yl]- 2-oxo-ethyl ester as a clear oil and was used without further purification. *H-NMR (300 MHz, CDC1 ₃ ) δ 7.49 (s, 4H), 5.41 (s, 2H), 4.66 (s, 2H), 3.70-3.80 (m, 2H), 3.45-3.55 (m, 2H), 2.15 (s, 3H), 1.74-1.80 (m, 2H), 1.65-1.74 (m, 2H), 1.44 (s, 36H). HRMS (ESI) Calcd. for C ₃ 7Hs ₅ N0 ₅ S ₂ : 680.3419 (M+Na) ⁺ . Found: 680.3428.

A solution of acetic acid 2-[4,4-bis-(3,5-di-ieri-butyl-4-hydroxy-phenylsulfanyl)piper idin-l- yl]-2-oxo-ethyl ester (Ex. 61a, 1.12 g, 1.70 mmol), (S)-5-(2-hydroxyethyl)-2,2-dimethyl- [l,3]dioxolan-4-one (Ex. 57a, 0.36 g, 2.25 mmol), triphenylphosphine (0.89 g, 3.40 mmol) and diethyl azodicarboxylate (0.59 g, 3.4 mmol) in THF (12 mL) was allowed to stir for 1.5 days at rt. The reaction mixture was then concentrated under reduced pressure. Silica gel chromatography (0-10% EtOAc/CH ₂ Cl ₂ ) afforded a mixture (0.97 g) which was redissolved in THF (15 mL). To the resulting solution of THF was added NaOH (4.5 mL, 4.5 mmol, 1M). The reaction mixture was allowed to stir for 1.5 h at rt and was treated with 3M HC1 (1.5 mL). The aqueous mixture was extracted with EtOAc (lx) and EtOAc/ -PrOH (3/1, v/v, 3x). The combined organic extracts were washed with a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc/CH ₂ Cl ₂ , 1: 10; then 10% MeOH/CH ₂ Cl ₂ ) gave a slightly impure fraction which was subjected to a second purification using silica gel chromatography (0-10% MeOH/CH ₂ Cl ₂ ) to afford 0.16 g (38%) of the title compound as an off-white fluffy foam. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.56 (s, 1H), 7.53 (s, 1H), 7.48 (s, 2H), 5.43 (s, 1H), 4.45-4.49 (m, 1H), 4.04-4.13 (m, 3H), 3.70-4.01 (m, 6H), 3.30-3.43 (m, 2H), 2.40-2.52 (m, 1H), 2.20-2.35 (m, 1H), 3.67-3.80 (m, 4H), 1.45 (s, 18H), 1.42 (s, 9H), 1.41 (s, 9H). HRMS (ESI) Calcd. for C ₃ 9H ₅₉ N0 ₇ S ₂ : 718.3811 (M+H) ⁺ . Found: 718.3792.

Example 62: [4-[3,5-Di-teri-butyl-4-(4-hydroxybutoxy)phenylsulfanyl]-4-( 3,5-di-tert- butyl-4-hydroxy-phenylsulfanyl)piperidin-l-yI] acetic acid

Ex. 62a: To a mixture of 4,4-bis-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)piperidin e-l- carboxylic acid ethyl ester (Ex. la, 30 g, 47.6 mmol) and K ₂ C0 ₃ (16.4 g, 119.1 mmol) in DMF (100 mL) was added ethyl bromobutyrate (18.0 g, 92.5 mmol). The reaction mixture was allowed to stir at 85 °C for 4.5 h and diluted with water. The resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with 0.5M HC1 (2x), a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S04, and concentrated under reduced pressure. The residue (39.2 g) was redissolved in a mixture of THF (150 mL) and water (60 mL). To the resulting aqueous solution was added LiOH H ₂ 0 (10.6 g, 239.7 mmol). The reaction mixture was allowed to stir for 9 h at rt and poured into 3M HC1 (100 mL). The aqueous mixture was then extracted with EtOAc. The combined organic extracts were washed with a saturated NH ₄ C1 solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Consecutive silica gel chromatographies (CH ₂ Cl ₂ /hexane, 5: 1; then 10% MeOH/CH ₂ Cl ₂ followed by 10-55% EtOAc/hexane) afforded 13.7 g (40%) of 4-[3,5-di-½r/-butyl-4-(3-carboxypropoxy)phenyl-sulfanyl]-4- (3,5-di-/er - butyl-4-hydroxyphenylsulfanyl)-piperidine-l-carboxylic acid ethyl ester as an off-white fluffy foam. ^J H-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.39 (s, 1H), 4.05-4.14 (m, 3H), 3.78 (t, 2H, J = 7.1 Hz), 3.49-3.65 (m, 4H), 2.55 (t, 2H, J = 7.1 Hz), 2.18-2.23 (m, 2H), 1.64-1.77 (m, 4H), 1.44 (s, 18H), 1.41 (s, 18H), 1.21 (t, 3H, J = 6.8 Hz). HRMS (ESI) Calcd. for C ₄ oH ₆₁ N0 ₆ S ₂ : 738.3838 (M+Na) ⁺ . Found: 738.3828.

Ex. 62b: To a solution of 4-[3,5-di-½ri-butyl-4-(3-carboxypropoxy)phenyl-sulfanyl]-4- (3,5- di-½ri-butyl-4-hydroxyphenylsulfanyl)-piperidine-l-carboxyl ic acid ethyl ester (Ex. 62a, 12.2 g, 17.0 mmol) in THF (50 mL) was added BH ₃ -Me ₂ S (42.5 mL, 85 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction was then quenched with MeOH. The resulting solution was concentrated under reduced pressure. The residue was treated with MeOH and concentrated under reduced pressure again. The residue was dissolved in a mixture of EtOAc/hexane (1/2, v/v). The resulting solution was filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to afford 11.7 g (98%) of 4- [3,5-di-ieri-butyl-4-(4-hydroxybutoxy)phenylsulfanyl]-4-(3,5 -di-reri-butyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester as an off-white fluffy foam and was used without further purification. 1H-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.39 (s, 1H), 4.09 (q, 2H, J = 6.8 Hz), 3.70-3.78 (m, 4H), 3.57-3.65 (m, 4H), 1.93- 2.00 (m, 2H), 1.60-1.80 (m, 7H), 1.44 (s, 18H), 1.42 (s, 18H), 1.21 (t, 3H, J = 6.8 Hz). HRMS (ESI) Calcd. for C ₄ oH ₆₃ N0 ₅ S ₂ : 724.4045 (M+Na) ⁺ . Found: 724.4046.

Ex. 62c: To a solution of 4-[3,5-di-½ri-butyl-4-(4-hydroxybutoxy)phenylsulfanyl]-4-(3 ,5-di- teri-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester (Ex. 62b, 13.3 g, 18.9 mmol) in z ^' -PrOH (115 mL) was added solid KOH (21.2 g, 377.8 mmol). The reaction mixture was allowed to stir at 85 °C overnight and concentrated under reduced pressure to dryness. The residue was treated with water. The pH of the resulting solution was adjusted to 6 and the aqueous mixture was extracted with EtOAc. The combined organic extracts were washed with a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (10% MeOH/CH ₂ Cl ₂ ) afforded 10.2 g (85%) of 2,6-di-teri-butyl-4-{4-[3,5-di-tert-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]piperidin-4-ylsulfanyl} phenol as an off-white fluffy foam. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.48 (s, 2H), 5.38 (s, 1H), 3.70-3.78 (m, 4H), 3.08 (brs, 4H), 1.85-2.00 (m, 2H), 1.80 (brs, 4H), 1.62-1.73 (m, 4H), 1.44 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₃₇ H ₅₉ N0 ₃ S ₂ : 630.4014 (M+H) ⁺ . Found: 630.4020.

Ex. 62d: To a solution of 2,6-di-te^butyl-4-{4-[3,5-di-tert-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]piperidin-4-ylsulfanyl} phenol (Ex. 62c, 70 mg, 0.11 mmol) and diisopropylethyl amine (0.058 mL, 0.33 mmol) in THF (2 mL) was added ethyl bromoacetate (0.015 mL, 0.13 mmol). The reaction mixture was allowed to stir overnight at rt and diluted with EtOAc. The solution of EtOAc was washed with 0.5M HC1, a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (0-6% MeOH/CH ₂ Cl ₂ ) afforded 0.057 g (72%) of [4- [3,5-di-½r/-butyl-4-(4-hydroxy-butoxy)-phenyl-sulfanyI]-4-( 3,5-di-½r/-butyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid ethyl ester as an off-white fluffy foam. 1H- NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.38 (s, 1H), 4.19 (q, 2H, J = 7.2 Hz), 3.72-3.80 (m, 4H), 3.23 (s, 2H), 2.73-2.76 (m, 4H), 1.89-2.00 (m, 6H), 1.52-1.75 (m, 3H), 1.45 (s, 18H), 1.44 (s, 18H), 1.28 (t, 3H, J = 7.2 Hz). HRMS (ESI) Calcd. for C ₄ iH ₆₅ N0 ₅ S2: 716.4382 (M+H) ⁺ . Found: 716.4378.

To a solution of [4-[3,5-di-z'er?-butyl-4-(4-hydroxy-butoxy)-phenyl-sulfanyl] -4-(3,5-di-/eri- butyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid ethyl ester (Ex. 62d, 0.44 g, 0.61 mmol) in a mixture of THF (5.5 mL) and MeOH (1 mL) was added NaOH (3.7 mL, 3.7 mmol, 1M). The reaction mixture was allowed to stir for 4.5 h at 65 °C and was concentrated under reduced pressure. The residue was treated with water and the aqueous solution was then neutralized to pH = 7. The water was decanted and the insoluble oily material was redissolved in MeOH. The solution of MeOH was concentrated under reduced pressure. The residue was dissolved in EtOAc. The solution of EtOAc was then washed with a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (0-10% MeOH/CH ₂ Cl ₂ ) afforded an oily fraction which was titurated in hexane to give 0.28 g (67%) of the title compound as a white solid, mp 125-128 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.48 (s, 2H), 5.42 (s, 1H), 3.69-3.78 (m, 4H), 3.31 (s, 2H), 3.10-3.20 (m, 4H), 1.85-2.05 (m, 6H), 1.60-1.75 (m, 3H), 1.44 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₃₉ H ₆ iN0 ₅ S ₂ : 688.4069 (M+H) ⁺ . Found: 688.4075.

Example 63: 2,6-Di-fer^butyl-4-[4-[3,5-di-ter*-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]-l-(2-hydroxy-ethyl)piperidin-4 -ylsulfanyl]phenol

To a solution of [4-[3,5-di-½r -butyl-4-(4-hydroxy-butoxy)-phenyl-sulfanyl]-4-(3,5-di-/eri- butyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid ethyl ester (Ex. 62d, 0.44 g, 0.62 mmol) in THF (10 mL) was added lithium aluminum hydride (1.0M, 1.5 mL, 1.5 mmol). The reaction mixture was allowed to stir for 2.5 h at rt. The reaction was then quenched with a saturated solution of potassium sodium tartrate (Rochelle's Salt). The resulting mixture was allowed to stir for 1 h at rt and extracted with EtOAc. The combined organic extracts were washed with 0.5M HC1, a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ SC>4, and concentrated under reduced pressure. Silica gel chromatography (0-10% MeOH/CH ₂ Cl ₂ ) afforded 0.34 g (82%) of the title compound as an off-white fluffy foam. NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.49 (s, 2H), 5.37 (s, 1H), 3.70-3.78 (m, 4H), 3.56 (t, 2H, J= 5.1 Hz), 2.62-2.68 (m, 4H), 2.56 (t, 2H, J= 5.1 Hz), 1.90-1.98 (m, 3H), 1.78-1.82 (m, 4H), 1.66-1.74 (m, 3H), 1.45 (s, 18H), 1.42 (s, 18H). HRMS Calcd. for C ₃ 9H ₆₃ N0 ₄ S ₂ : 674.4277 (M+H) ⁺ . Found: 674.4271. Example 64: 2,6-Di-te^butyl-4-[4-[3,5-di-tert-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]-l-(3-hydroxy-propyl)piperidin- 4-ylsulfanyl]phenol

To a solution of 2,6-di-/er/-butyl-4-{4-[3,5-di-feri-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]piperidin-4-ylsulfanyl}phenol (Ex. 62c, 0.44 g, 0.69 mmol) and diisopropylethyl amine (0.36 mL, 2.09 mmol) in MeOH was added 3-bromopropanol (0.12 mL, 1.39 mmol). The reaction mixture was heated at 120 °C for 5 min, then 150 °C for 10 min under microwave radiation and diluted with EtOAc. The solution of EtOAc was washed with 0.5M HCl, a saturated NaHCOs solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (0-10% MeOH/CH ₂ Cl ₂ ) afforded 0.24 g (50%) of the title compound as an off-white fluffy foam. Ή- NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.49 (s, 2H), 5.37 (s, 1H), 3.69-3.79 (m, 6H), 2.62- 2.67 (m, 6H), 1.90-2.05 (m, 3H), 1.79 (brs, 4H), 1.60-1.75 (m, 5H), 1.44 (s, 18H), 1.42 (s, 18H). HRMS Calcd. for C ₄ oH ₆ 5N0 ₄ S2: 688.4433 (M+H) ⁺ . Found: 688.4426.

Example 65: 2,6-Di-fer^butyl-4-[4-[3,5-di-fert-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]-l-(4-hydroxy-butyl)piperidin-4 -yIsulfanyl]phenol

Ex. 65a: To a solution of 2,6-di-/ert-butyl-4-{4-[3,5-di-fert-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]piperidin-4-ylsulfanyl}phenol (Ex. 62c, 0.61 g, 0.97 mmol) and diisopropylethyl amine (0.34 mL, 1.94 mmol) in THF (10 mL) was added 3- chlorocarbonylpropionic acid ethyl ester (0.13 mL, 0.92 mmol). The reaction mixture was allowed to stir for 15 min at rt and diluted with EtOAc. The solution of EtOAc was washed with 0.5M HCl, a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (100% CH2CI2; then 0-10% MeOH/CH ₂ Cl ₂ ) afforded 0.84 g (100%) of 4-[4-[3,5-di-½ri-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]-4-(3 ,5-di-/er -butyl-4-hydroxyphenyl-sulfanyl)piperidin- 1 - yl]-4-oxobutyric acid ethyl ester as an off-white fluffy foam. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.56 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 4.13 (q, 2H, J= 7.2 Hz), 3.66-3.81 (m, 6H), 3.60-3.63 (m, 2H), 2,56-2.63 (m, 4H), 1.91-1.98 (m, 3H), 1.77-1.80 (m, 2H), 1.59-1.74 (m, 4H), 1.44 (s, 18H), 1.42 (s, 18H), 1.25 (t, 3H, J = 7.2 Hz). HRMS Calcd. for C ₄₃ H ₆ 7N0 ₆ S2: 758.4488 (M+H) ⁺ . Found: 758.4483.

To a solution of 4-[4-[3,5-di-/eri-butyl-4-(4-hydroxybutoxy)phenylsulfanyl]-4 -(3,5-di-½r - butyl-4-hydroxyphenyl-sulfanyl)piperidin-l-yl]-4-oxobutyric acid ethyl ester (Ex. 65a, 0.84 g, 0.97 mmol) in anhydrous THF (15 mL) was added lithium aluminum hydride (1.0M, 3.5 mL, 3.5 mmol). The reaction mixture was refluxed for 2 h during which additional THF (15 mL) was added due to difficulty of stirring. The reaction mixture was then cooled to 0 °C and a saturated solution of Rochelle's salt (potassium sodium tartrate) was added. The aqueous mixture was allowed to stir at this temperature for 30 min followed by addition of EtOAc. The resulting mixture was allowed to stir vigorously at rt overnight. The mixture was then partitioned. The organic layer was washed with a 10% brine solution, dried over Na2S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (10% MeOH/C^Cb) afforded 0.37 g (40%) of the title compound as an off-white fluffy foam. ^-NMR (300 MHz, CDCI3) δ 7.59 (s, 2H), 7.51 (s, 2H), 5.36 (s, 1H), 3.70-3.77 (m, 4H), 3.51 (brs, 2H), 2.60-2.70 (m, 4H), 2.42 (brs, 2H), 1.90-1.97 (m, 2H), 1.81 (brs, 4H), 1.65-1.75 (m, 8H), 1.44 (s, 18H), 1.42 (s, 18H). Anal. Calcd. for C41H67NO4S2: C, 70.14; H, 9.62; N, 1.99; S, 9.13. Found: C, 69.88; H, 9.45; N, 1.99; S, 8.99.

Example 66: l-[4-[3,5-Di-fe -i-butyl-4-(4-hydroxy-butoxy)-phenylsulfanyl]-4-(3,5-di-ieri - butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-4-hydroxy-bu tan-l-one

Ex. 66a: In a 100 mL round bottom flask, 2,6-di-½ri-butyl-4-{4-[3,5-di-½ri-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]piperidin-4-ylsulfanyl}phenol (Ex. 62c, 1.06 g, 1.68 mmol) was combined with anhydrous THF (42 mL) and DIPEA (0.88 mL, 5.04 mmol) and the resulting mixture was treated with 3-chlorocarbonyl-propionic acid methyl ester (0.21 mL, 1.68 mmol). HPLC indicated that the reaction was over in 30 min. The reaction mixture was quenched with 0.5N HC1 and extracted with EtOAc. The organic was washed 1 :1 watenbrine solution, dried over Na ₂ S0 ₄ , filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (50% EtOAc in hexanes) to provide 0.79 g (63%) of 4- [4-[3,5-di-½ri-butyl-4-(4-hydroxy-butoxy)-phenylsulfanyl]-4 -(3,5-di-½ri-butyl-4-hydroxy- phenylsulfanyl)-piperidin-l-yl]-4-oxo-butyric acid methyl ester as a light brown solid, mp 86 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 3.80-3.60 (m, 11H), 2.64-2.55 (m, 4H), 2.01-1.91 (m, 2H), 1.79-1.63 (m, 6H), 1.44-1.42 (s, 36H). HRMS (ESI) Calcd. for C ₄₂ H ₆₅ N0 ₆ S ₂ : 744.4331 (M+H) ⁺ . Found: 744.4330. Anal. Calcd. C ₄₂ H ₆₅ N0 ₆ S ₂ : C, 67.79; H, 8.80; N, 1.88; S, 8.62. Found: C, 68.05; H, 8.96; N, 2.05; S, 8.43. In a 50 mL round bottom flask, 4-[4-[3,5-di-/ert-butyl-4-(4-hydroxy-butoxy)- phenylsulfanyl]-4-(3,5-di-/e^bu1yl-4-hydroxy-phenylsulfanyl) -piperidm-l-yl]-4-oxo-butyric acid methyl ester (Ex. 66a, 0.79 g, 1.06 mmol) was combined with anhydrous THF (15 mL) and lithium borohydride (2.12 mL, 4.24 mmol, 2M in THF). HPLC indicated that the reaction was complete after 3 h. The reaction mixture was quenched with 0.5N HCl and extracted with EtOAc. The organic was washed with water, 1 : 1 watenbrine solution, dried over magnesium sulfate, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (5% MeOH in dichloromethane) to provide 0.33 g (44%) of the title compound as an off white solid, mp 1 10 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.48 (s, 2H), 5.41 (s, 1H), 3.83-3.61 (m, 10H), 2.77 (t, 1H, J = 5.4 Hz), 2.45 (t, 2H, J = 6.6 Hz), 2.01-1.61 (m, 1 1H), 1.45-1.42 (m, 36H). HRMS (ESI) Calcd. for C41H65NO5S2: 716.4382 (M+H) ⁺ . Found: 716.4373. Anal. Calcd. C ₄ iH ₆₅ N0 ₆ S2: C, 68.77; H, 9.15; N, 1.96; S, 8.96. Found: C, 68.73; H, 9.18; N, 1.93; S, 8.69.

Example 67: 4-[l-[2-(3,5-Bis-hydroxymethylpyrazol-l-yl)-ethyl]-4-(3,5-di -tert-butyl-4- methoxy-phenylsulfanyl)piperidin-4-ylsulfanyl]-2,6-di-teri-b utylphenol

Ex. 67a: To a solution of lH-pyrazole-3,5-dicarboxylic acid diethyl ester (1.0 g, 4.71 mmol), 2-bromoethanol (0.40 mL, 5.65 mmol) and triphenylphosphine (2.47 g, 9.42 mmol) in THF (20 mL) was added diethyl azodicarboxylate (1.48 mL, 9.42 mmol) at 0 °C. The reaction mixture was allowed to stir at rt for 1.5 h and concentrated under reduced pressure. Silica gel chromatography (10-24% EtOAc/hexane) afforded 1.14 g (76%) of l-(2-bromoethyl)-lH- pyrazole-3,5-dicarboxylic acid diethyl ester as an off-white fluffy foam. Ή-NMR (300 MHz, CDCI ₃ ) δ 7.35 (s, 1H), 5.03 (t, 2H, J = 7.1 Hz), 4.34-4.45 (m, 4H), 3.73 (t, 2H, J = 7.0 Hz), 1.32-1.44 (m, 6H). MS (EI): 318 (M ⁺ ).

Ex. 67b: To a mixture of l-(2-bromoethyl)-lH-pyrazole-3,5-dicarboxylic acid diethyl ester (Ex. 67a, 0.47 g, 1.49 mmol), ₂ C0 ₃ (0.62 g, 4.46 mmol) and KI (0.49 g, 2.97 mmol) in DMF (20 mL) was added 2,6-di-½rt-butyl-4-[4-(3,5-di-½rt-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 1.70 g, 2.97 mmol). The reaction mixture was allowed to stir at 120 °C for 3 h and poured into water. The resulting aqueous mixture was extracted with EtOAc/z ^' -PrOH (4/1, v/v). The combined organic solution was washed with 0.5M HCl, a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (15-45% EtOAc/hexane) afforded 0.61 g (51%) of l-{2-[4-(3,5-di-terr-butyl-4- hy droxypheny lsulfany l)-4-(3 , 5 -di- er -butyl-4-methoxyphenylsulfany l)piperidin- 1 -y 1] ethyl } - lH-pyrazole-3,5-dicarboxylic acid diethyl ester as an off-white fluffy foam. ^-NMR (300 MHz, CDCI ₃ ) δ 7.59 (s, 2H), 7.48 (s, 2H), 7.30 (s, 1H), 5.36 (s, 1H), 4.74 (t, 2H, J= 7.0 Hz), 4.30-4.44 (m, 4H), 3.70 (s, 3H), 2.83 (t, 2H, J = 7.0 Hz), 2.66-2.69 (m, 4H), 1.76 (brs, 4H), 1.44 (s, 18H), 1.43 (s, 18H), 1.35-1.42 (m, 6H). Anal. Calcd. for C ₄ 5H ₆ 7N30 ₆ S2: C, 66.71; H, 8.34; N, 5.19; S, 7.92. Found: C, 66.48; H, 8.38; N, 4.99; S, 7.77.

To a solution of l-{2-[4-(3,5-di-½r/-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-d i-½ri-butyl-4- methoxyphenylsulfanyl)piperidin-l-yl]ethyl}-lH-pyrazole-3,5- dicarboxylic acid diethyl ester (Ex. 67b, 0.56 g, 0.69 mmol) in THF (18 mL) was added lithium aluminum hydride (2.8 mL, 5.6 mmol, 2M in THF) at 0 °C. The reaction mixture was allowed to warm up to rt, stir for 2.5 h and was treated with saturated solution of Rochelle's salt. The resulting mixture was allowed to stir for 10 min at rt and extracted with EtOAc. The combined organic extracts were washed with 0.5M HCl, a saturated NaHC0 ₃ solution, a 10% brine solution, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Three consecutive silica gel chromatographies (60-100% EtOAc/hexane; then 0-10% MeOH/CH ₂ Cl ₂ x2) afforded 0.32 g (63%) of the title compound as an off-white foam. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.47 (s, 2H), 6.13 (s, 1H), 5.36 (s, 1H), 4.62 (d, 2H, J= 5.4 Hz), 4.40 (s, 2H), 4.18-4.20 (m, 2H), 3.70 (s, 3H), 2.77-2.79 (m, 2H), 2.56 (brs, 4H), 1.77 (brs, 4H), 1.44 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄ iH ₆ 3N ₃ 0 ₄ S2: 726.4338 (M+H) ⁺ . Found: 726.4341. Example 68: 2,6-Di-teri-butyl-4-[4-[3,5-di-teri-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]-l-(5-hydroxymethyl-l-methyl-l H-pyrrole-2- sulfonyl)piperidine-4-ylsulfanyl]phenol

Ex. 68a: To a solution of 2,6-di-½ri-butyl-4-{4-[3,5-di-feri-butyl-4-(3-hydroxy-propo xy)- phenylsulfanyl]-piperidin-4-ylsulfanyl} -phenol (Ex. 5, 2.29 g, 3.7 mmol) in THF (50 mL) at rt was added DIPEA (1.8 mL, 10.3 mmol). Methyl (5-chlorosulfonyl)-l-methyl-lH-pyrrole- 2-carboxylate (0.88 g, 3.7 mmol) was added to the reaction and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (50 mL) and diluted with H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 0: 1 to 1 :0) afforded 2.34 g (77%) of 5 {4-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-½r i-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine- 1 -sulfonyl} - 1 -methyl- lH-pyrrole-2-carboxylic acid methyl ester as an off-white solid, mp 103-105 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.49 (s, 2H), 7.38 (s, 2H), 7.19 (d, 1H, J = 1.9 Hz), 7.13 (d, 1H, J = 1.2 Hz), 5.41 (s, 1H), 4.05 (s, 3H), 3.86-3.92 (m, 7H), 3.09-3.17 (m, 4H), 2.10 (ddd, 2H, J = 19.2, 13.2, 6.1 Hz), 1.85-1.86 (m, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄₃ H ₆₄ N ₂ 0 ₇ S ₃ : 817.3954 (M+H) ⁺ . Found: 817.3961. Anal. Calcd. for C ₄₃ H ₆₄ N ₂ 0 ₇ S ₃ -½H ₂ 0: C, 62.51; H, 7.93; N, 3.39; S, 11.64. Found: C, 62.74; H, 7.90; N, 3.31 ; S, 11.42.

To a solution of 5 {4-(3,5-di-ter -butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-/eri-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine- 1 -sulfonyl} - 1 -methyl- lH-pyrrole-2-carboxylic acid methyl ester (Ex. 68a, 0.78 g, 0.97 mmol) in THF (15 mL) was added lithium borohydride (0.08 g, 3.7 mmol) and the resulting solution was stirred at rt for 18 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (50 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with a H ₂ 0 (1 x 50 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc :hexanes, 1 : 1) afforded 0.37 g (50%) of the title compound as an off-white foam, mp 105-106 °C. Ή-ΝΜΡ (300 MHz, CDC1 ₃ ) δ 7.49 (s, 2H), 7.38 (s, 2H), 7.09 (d, 1H, J = 1.2 Hz), 6.33 (d, 1H, J = 1.3 Hz), 5.41 (s, 1H), 4.61 (d, 2H, J= 5.9 Hz), 3.90 (dd, 4H, J= 13.2, 6.3 Hz), 3.76 (m, 3H), 3.19-3.10 (m, 4H), 2.18-2.12 (m, 3H), 1.81-1.88 (m, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄₂ H ₆ 4N ₂ 0 ₆ S3: 811.3824 (M+Na) ⁺ . Found: 811.3820. Anal. Calcd. for C ₄₂ H ₆ 4N ₂ 06S3: C, 63.92; H, 8.17; N, 3.55; S, 12.19. Found: C, 63.93; H, 8.33; N, 3.24; S, 11.33.

Example 69: 5-{4-(3,5-Di-feri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-t eri-butyl-4-(3- hydroxy-propoxy)phenylsulfanyI]piperidine-l-suIfonyl}-l-meth yHH-pyrrole-2- carboxylic acid

To a solution of 5 {4-(3,5-di-½r?-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-ier /-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine- 1 -sulfonyl} - 1 -methyl- lH-pyrrole-2-carboxylic acid methyl ester (Ex. 68a, 0.78 g, 0.97 mmol) in THF (9 mL), MeOH (3 mL), and H ₂ 0 (3 mL) was added lithium hydroxide (0.12 g, 4.9 mmol) and the resulting solution was stirred at rt for 18 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (50 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1:20) afforded 0.23 g (29%) of the title compound as an off-white foam, mp 122-125 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.48 (s, 2H), 7.40 (s, 2H), 7.24 (d, 1H, J = 2.5 Hz), 7.21 (d, 1H, J= 1.3 Hz), 5.41 (s, 1H), 4.0 (s, 3H), 3.89 (t, 4H, J = 6.1 Hz), 3.12-3.23 (m, 4H), 2.09-2.18 (m, 2H), 1.79-1.90 (m, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄₂ H6 ₂ N ₂ 0 ₇ S3 : 825.3617 (M+Na) ⁺ . Found: 825.3629. Anal. Calcd. for C ₄₂ H ₆₂ N ₂ 0 ₇ S ₃ : C, 62.81; H, 7.78; N, 3.49; S, 11.98. Found: C, 62.81; H, 7.75; N, 3.33; S, 11.24.

Example 70: [4-(3,5-Di-ieri-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-ter t-butyl-4- methoxy-phenylsulfanyl)piperidin-l-yl] acetic acid ethyl ester

To a solution of 2,6-di-ier -butyl-4-[4-(3,5-di-½ri-butyl-4-methoxy-phenylsulfanyl)- piperidin-4-ylsulfanyl] -phenol (Ex. 17, 8.0 g, 14.0 mmol) in THF (350 mL) was added DIPEA (7.3 mL, 42.0 mmol) followed by ethyl bromoacetate (1.7 mL, 15.4 mmol) and the resulting solution was stirred at rt for 18 h. Upon completion, as determined by HPLC, the reaction was quenched with H ₂ 0 (250 mL) and EtOAc (250 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 15 mL). The combined organic cuts were washed with IN HCl (300 mL) and saturated NaHC0 ₃ (1 x 250 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc :hexanes, 1 :20 to 1 :5) afforded 7.5 g (82%) of the title compound as an off-white foam, mp 69-70 °C. ^! H-NMR (300 MHz, CDCI ₃ ) δ 7.59 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 4.17 (dd, 2H, J = 15.2, 7.5 Hz), 3.70 (s, 3H), 3.21 (s, 2H), 2.73 (t, 4H, J = 6.1 Hz), 1.88-2.00 (m, 4H), 1.43 (s, 18H), 1.42 (s, 18H), 1.26 (t, 3H, J = 7.0 Hz). HRMS (ESI) Calcd. for C _3g H ₅₉ N0 ₄ S ₂ : 658.3964 (M+H) ⁺ . Found: 658.3957. Anal. Calcd. for C ₃₈ H ₅₉ NO ₄ S ₂ : C, 69.36; H, 9.04; N, 2.13; S, 9.75. Found: C, 69.36; FL 9.11; N, 2.17; S, 9.67.

Example 71 : 2-[4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-f e ^, i-butyl-4- methoxy-phenylsulfanyl)piperidin-l-yl]acetamide

To a solution of 2,6-di-½ri-butyl-4-[4-(3,5-di-½ri-butyl-4-methoxy-phenylsu lfanyl)- piperidin-4-ylsulfanyl] -phenol (Ex. 17, 0.7 g, 1.2 mmol) in THF (30 mL) was added DIPEA (0.63 mL, 3.6 mmol) followed by 2-bromoacetamide (0.18 g, 1.3 mmol) and the resulting solution was stirred at rt for 18 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with saturated NaHC0 ₃ (1 x 50 mL), brine (1 x 25 mL) dried over Na ₂ S04, and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 :20) afforded 0.55 g (73%) of the title compound as an off-white foam, mp 187 °C. 'H-NMR (300 MHz, CDCI ₃ ) δ 7.61 (s, 2H), 7.50 (s, 2H), 6.95 (brs, 1H), 5.39 (s, 1H), 5.33 (brs, 1H), 3.70 (s, 3H), 3.03 (s, 2H), 2.70 (t, 4H, J = 5.1 Hz), 1.79-1.83 (m, 4H), 1.45 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C ₃₆ H ₅₆ N ₂ O ₃ S ₂ : 629.3610 (M+H) ⁺ . Found: 629.3809. Anal. Calcd. for C ₃₆ H ₅₆ N ₂ O ₃ S ₂ : C, 68.74; H, 8.97; N, 4.45; S, 10.20. Found: C, 68.52; H, 9.07; N, 4.48; S, 9.98.

Example 72: 3-[4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-f e *i-butyl-4- methoxy-phenylsulfanyl)piperidin-l-yl]-3-oxo-propionic acid

Ex. 72a: To a solution of 2,6-di-½ri-butyl-4-[4-(3,5-di-ieri-butyl-4-methoxy-phenylsu lfanyl)- piperidin-4-ylsulfanyl] -phenol (Ex. 17, 0.65 g, 1.1 mmol) in THF (25 mL) at rt was added DIPEA in one portion (0.59 mL, 3.4 mmol). Methyl-3-chlorooxoprionate (0.13 mL, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 2.5 h. Upon completion, as determined by HPLC, the reaction was quenched with 0.5N HCl (50 mL) and diluted with EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with saturated NaHC0 ₃ solution (1 x 50 mL), brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 :5 to 1:3) afforded 0.47 g (50%) of 3- [4-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-ier i-butyl-4- methoxyphenylsulfanyl]piperidin-l-yl]-3-oxo-propionic acid methyl ester as an off-white solid, mp 65-67 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.47 (s, 2H), 5.41 (s, 1H), 3.62-3.75 (m, 6H), 3.56 (t, 4H, J= 5.3 Hz), 3.42 (s, 2H), 1.81 (t, 2H, J= 5.3 Hz), 1.71 (t, 2H, J = 5.5 Hz), 1.45 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C ₃ 8H ₅₇ N0 ₅ S ₂ : 694.3576 (M+Na) ⁺ . Found: 694.3564.

To a solution of 3-[4-(3,5-di-/eri-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-� �r -butyl-4- methoxyphenylsulfanyl]piperidin-l-yl]-3-oxo-propionic acid methyl ester (Ex. 71a, 0.47 g, 0.77 mmol) in THF (24 mL), MeOH (8 mL), H ₂ 0 (8 mL) was added lithium hydroxide (0.09 g, 3.6 mmol) and the resulting solution was stirred at rt for 3 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (50 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 :20) afforded 0.14 g (28%) of the title compound as an off-white foam, mp 160 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.47 (s, 2H), 5.40 (s, 1H), 3.80 (brs, 1H), 3.69 (s, 3H), 3.58 (brs, 2H), 3.30 (brs, 2H), 1.71-1.77 (m, 6H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C37H55NO5S2: 680.3419 (M+H) ⁺ . Found: 680.3410. Anal. Calcd. for C ₃ 7H ₅₅ N0 ₅ S2-2H ₂ OlNa: C, 62.07; H, 8.17; N, 1.96; S, 8.96. Found: C, 62.35; H, 8.02; N, 2.00; S, 8.89.

Example 73 : 3-{4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-t ert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-sulfonyl}thiophe ne-2-carboxylic acid

Ex. 73a: To a solution of 2,6-di-ier/-butyl-4-{4-[3,5-di-feri-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl} phenol (Ex. 5, 0.75 g, 1.2 mmol) in THF (15 mL) at rt was added DIPEA (0.63 mL, 3.6 mmol). 2-Carbomethoxy-3-thiophene sulfonyl chloride (0.29 g, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 1 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (50 mL) and diluted with H ₂ 0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 :4 to 1 :3) afforded 0.85 g (86%) of 3-{4-(3,5- di-ieri-butyl-4-hydroxyphenylsulfanyl)-4- [3 ,5 -di- r?-butyl-4-(3 -hydroxy - propoxy)phenylsulfanyl]piperidine-l-sulfonyl}thiophene-2-car boxylic acid methyl ester as an off-white solid, mp 88-90 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.52 (s, 2H), 7.49 (d, 1H, J = 5.1 Hz), 7.40-7.42 (m, 3H), 5.40 (s, 1H), 3.86-3.92 (m, 7H), 3.44-3.50 (m, 4H), 2.11-2.16 (m, 2H), 1.80-1.84 (m, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄ 2H ₆ iN0 ₇ S4: 842.3229 (M+Na) ⁺ . Found: 842.3224. Anal. Calcd. for G^^NO^^hexanes: C, 62.25; H, 7.80; N, 1.65; S, 15.11. Found: C, 62.01; H, 7.64; N, 1.74; S, 15.17. To a solution of 3-{4-(3,5-di-ieri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-� �ri-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine- 1 -sulfonyl} thiophene-2-carboxylic acid methyl ester (Ex. 73a, 0.83 g, 1.0 mmol) in THF (9 mL), MeOH (3 mL), and H ₂ 0 (3 mL) was added lithium hydroxide (0.12 g, 5.0 mmol) and the resulting solution was stirred at rt for 1.5 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (200 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 :20) afforded 0.26 g (33%) of the title compound as an off-white foam, mp 190-192 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.49 (s, 3H), 7.41 (s, 3H), 5.39 (s, 1H), 3.82-3.87 (m, 4H), 3.20-3.40 (m, 4H), 2.02-2.13 (m, 5H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C41H59NO7S4: 806.3252 (M+H) ⁺ . Found: 806.3243 Anal. Calcd. for C ₄ iH ₅₉ N0 ₇ S4-2H ₂ 0: C, 58.47; H, 7.54; N, 1.66; S, 15.23. Found: C, 58.88; H, 7.19; N, 1.59; S, 14.66.

Example 74: 4-{4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-t e/*i-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-suIfonyl}-3,5-di methyl-lH-pyrrole-2- carboxylic acid

Ex. 74a: To a solution of 2,6-di-½r/-butyl-4-{4-[3,5-di- eri-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 1.0 g, 1.6 mmol) in THF (15 mL) at rt was added DIPEA (0.84 mL, 4.8 mmol). Ethyl 4-(chlorosulfonyl)-3, 5-dimethyl- lH-pyrrole-2-carboxylate (0.43 g, 1.6 mmol) was added to the reaction and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (50 mL) and diluted with H ₂ 0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 :10 to 1 :3) afforded 0.90 g (67%) of 4 {4-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-fer i-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine-l-sulfonyl}-3,5-dim ethyl-lH-pyrrole-2- carboxylic acid ethyl ester as an off-white solid, mp 213-215 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 9.09 (s, 1H), 7.49 (s, 2H), 7.41 (s, 2H), 5.41 (s, 1H), 4.35 (dd, 1H, J = 14.0, 7.1 Hz), 3.85-3.92 (m, 4H), 3.22-3.27 (m, 4H), 2.47 (s, 3H), 2.43 (s, 3H), 2.10-2.20 (m, 2H), 1.74-1.90 (m, 7H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C45H68N2O7S3: 867.4086 (M+H) ⁺ . Found: 867.4088. Anal. Calcd. for C ₄ 5H _6g N ₂ 0 ₇ S3: C, 63.95; H, 8.11; N, 3.31; S, 11.38. Found: C, 64.08; H, 8.22; N, 3.31; S, 11.07.

To a solution of 4{4-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-½ ri-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine-l-sulfonyl}-3,5-dim ethyl-lH-pyrrole-2- carboxylic acid ethyl ester (Ex. 74a, 0.87 g, 1.0 mmol) in THF (9 mL), MeOH (3 mL), and H ₂ 0 (3 mL) was added sodium hydroxide (0.20 g, 5.0 mmol) and the resulting solution was stirred at 50 °C for 48 h. Upon completion, as determined by HPLC, the reaction was quenched with saturated IN HCl (50 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1:1 to MeOH:CH ₂ Cl ₂ , 1 :5) afforded 0.35 g (43%) of the title compound as an off-white foam, mp 162 °C. H-NMR (300 MHz, CDCI ₃ ) δ 9.36 (s, 1H), 7.47 (s, 2H), 7.42 (s, 2H), 5.41 (s, 1H), 3.90-3.94 (m, 4H), 3.29 (brs, 4H), 2.48 (s, 3H), 2.11-2.23 (m, 6H), 1.77-1.87 (m, 4H), 1.42 (m, 36H). HRMS (ESI) Calcd. for C ₄₃ H ₆ 4N ₂ 0 ₇ S3: 817.3954 (M+H) ⁺ . Found: 817.3936. Anal. Calcd. for C ₄₃ H ₆₄ N ₂ 0 ₇ S ₃ : C, 63.20; H, 7.89; N, 3.43; S, 11.77. Found: C, 63.46; H, 8.26; N, 3.12; S, 10.71.

Example 75: 5-{4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-i ert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-sulfonyl}furan-2 -carboxylic acid

Ex. 75a: To a solution of 2,6-di-½r/-butyl-4-{4-[3,5-di-½r/-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 0.75 g, 1.2 mmol) in THF (15 mL) at rt was added DIPEA (0.63 mL, 3.6 mmol). Methyl-5-(chlorosulfonyl)-2-furoate (0.27 g, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (50 mL) and diluted with ¾0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 : 10 to 1 :1.25) afforded 0.84 g (87%) of 5-{4-(3,5-di-½ri- butyl-4-hyQroxyphenylsulfanyl)-4-[3,5-di-½r/-butyl-4-(3-hyd roxy-pro- poxy)phenylsulfanyl]piperidine-l-sulfonyl}furan-2-carboxylic acid methyl ester as an off- white solid, mp 84-86 °C. 1H-NMR (300 MHz, CDC1 ₃ ) δ 7.53 (s, 2H), 7.42 (s, 2H), 7.24 (d, 1 H, J = 3.5 Hz), 7.02 (d, 1 H, J= 3.9 Hz), 5.42 (s, 1H), 3.88-3.94 (m, 7H), 3.35-3.44 (m, 4H), 2.08-2.18 (m, 2H), 1.81-1.85 (m, 4H), 1.43 (s, 18H), 1.42 (s, 18H) HRMS (ESI) Calcd. for C ₄₂ H6iN0 ₈ S ₃ : 826.3457 (M+Na) ⁺ . Found: 826.3453. Anal. Calcd. for

C, 62.04; H, 7.69; N, 1.72; S, 11.83. Found: C, 62.32; H, 7.71; N, 1.74; S, 11.40.

To a solution of 5-{4-(3,5-di-½r -butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-½r/-butyl-4-(3- hydroxy-pro-poxy)phenylsulfanyl]piperidine-l-sulfonyl}furan- 2-carboxylic acid methyl ester (Ex. 75a, 0.81 g, 1.0 mmol) in THF (9 mL), MeOH (3 mL), and H ₂ 0 (3 mL) was added lithium hydroxide (0.12 g, 5.0 mmol) and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (200 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 : 1 to MeOH:CH ₂ Cl ₂ , 1 : 10) afforded 0.17 g (22%) of the title compound as an off-white foam, mp 159-161 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.49 (s, 2H), 7.43 (s, 2H), 7.27 (s, 1H), 7.02 (s, 1H), 5.42 (s, 1H), 3.88 (brs, 2H), 3.42 (brs, 2H), 2.65-2.90 (m, 4H), 2.14 (brs, 2H), 1.83 (brs, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄₁ H ₅₉ N0 ₈ S ₃ : 812.3301 (M+Na) ⁺ . Found: 812.3293 Anal. Calcd. for C ₄ iH ₅₉ N0 ₈ S ₃ -lH ₂ 0: C, 60.94; H, 7.61; N, 1.73; S, 11.90. Found: C, 60.53; H, 7.81 ; N, 1.65; S, 10.61.

Example 76: 5-{4-(3,5-Di-teri-butyl-4-hydroxyphenyIsulfanyl)-4-[3,5-di-t eri-butyI-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-sulfonyl}4-methy lthiophene-2-carboxylic acid

Ex. 76a: To a solution of 2,6-di-fert-butyl-4-{4-[3,5-di-tert-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 0.75 g, 1.2 mmol) in THF (15 mL) at rt was added DIPEA (0.63 mL, 3.6 mmol). Methyl-5-(chlorosulfonyl)-4-methyl-2- thiophene carboxylate (0.31 g, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 1 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (50 mL) and diluted with ¾0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 : 10 to 1 :3) afforded 0.76 g (76%) of 5-{4-(3,5-di-ieri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-f er/-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine- 1 -sulfonyl} -4-methyl-thiophene-2-carboxylic acid methyl ester as an off-white solid, mp 90-92 °C. ^! H- MR (300 MHz, CDC1 ₃ ) δ 7.62 (s, 1H), 7.50 (s, 2H), 7.40 (s, 2H), 5.42 (s, 1H), 3.87-3.92 (m, 7H), 3.27-3.33 (m, 4H), 2.45 (s, 3H), 2.12-2.16 (m, 2H), 1.85 (brs, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄₃ H6 ₃ N0 ₇ S4: 856.3385 (M+Na) ⁺ . Found: 856.3395. Anal. Calcd. for C ₄ 3H ₆₃ N0 ₇ S ₄ - ¹ / ₂ hexanes: C, 62.98; H, 8.04; N, 1.60; S, 14.62. Found: C, 62.69; H, 7.86; N, 1.68; S, 15.00.

Ex. 76b: To a solution of 5-{4-(3,5-di-fer/-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-f eri- butyl-4-(3-hydroxypropoxy)phenylsulfanyl]piperidine-l-sulfon yl}-4-methyl-thiophene-2- carboxylic acid methyl ester (Ex. 76a, 0.74 g, 0.9 mmol) in THF (9 mL), MeOH (3 mL), and H ₂ 0 (3 mL) was added lithium hydroxide (0.11 g, 4.5 mmol) and the resulting solution was stirred at rt for 1.5 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (200 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 : 1 to 1 :1.25 and MeOH:CH ₂ Cl ₂ , 1:20 to 1:5) afforded 0.33 g (45%) of the title compound as an off-white foam, mp 199 °C. ^] H-NMR (300 MHz, CDC1 ₃ ) δ 7.41 (brs, 5H), 5.40 (s, 1H), 3.86 (brs, 4H), 3.20-3.43 (m, 4H), 2.05-2.30 (m, 6H), 1.75-1.86 (m, 4H), 1.42 (s, 18H), 1.38 (s, 18H). HRMS (ESI) Calcd. for C ₄ 2H ₆₁ N0 ₇ S ₄ : 842.3229 (M+Na) ⁺ . Found: 842.3229 Anal. Calcd. for C ₄₂ H ₆₁ N0 ₇ S ₄ -2H ₂ 0: C, 58.92; H, 7.65; N, 1.64; S, 14.98. Found: C, 59.20; H, 7.41; N, 1.62; S, 14.09.

Example 77: 4-{4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-t e/-i-butyl-4-(3- hydroxy-propoxy)phenylsuIfanyl]piperidine-l-sulfonyl}-2,5-di methylfuran-3-carboxylic acid

Ex. 77a: To a solution of 2,6-di-/eri-butyl-4-{4-[3,5-di-½r/-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 0.75 g, 1.2 mmol) in THF (15 mL) at rt was added DIPEA (0.63 mL, 3.6 mmol). Methyl-4-(chlorosulfonyl)-2,5-dimethyl-3- furoate (0.30 g, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 1 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (50 mL) and diluted with H ₂ 0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 : 10 to 1:3) afforded 0.89 g (89%) of 4-{4-(3,5- di-fer^buty l-4-hydroxyphenylsulfanyl)-4- [3 ,5 -di-teri-butyl-4-(3 - hydroxypropoxy)phenylsulfanyl]piperidine- 1 -sulfonyl} -2,5-dimethylfuran-3-carboxylic acid methyl ester as an off-white solid, mp 87-89 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.55 (s, 2H), 7.44 (s, 2H), 5.40 (s, 1H), 3.86-3.92 (m, 4H), 3.76 (s, 3H), 3.38-3.46 (m, 4H), 2.52 (s, 3H), 2.48 (s, 3H), 2.12-2.16 (m, 2H), 2.05 (s, 1H), 1.81 (brs, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C44H65NO8S3: 854.3770 (M+Na) ⁺ . Found: 854.3790. Anal. Calcd. for C44H65N08S3- ₂ H20: C, 62.82; H, 7.91; N, 1.67; S, 11.44. Found: C, 63.10; H, 7.78; N, 1.69; S, 11.05.

Ex. 77b: To a solution of 4-{4-(3,5-di-ter/-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-� �ri- bu1yl-4-(3-hydroxypropoxy)phenylsulfanyl]piperidine-l-sulfon yl}-2,5-dimethylfuran-3- carboxylic acid methyl ester (Ex. 77a, 0.86 g, 1.0 mmol) in THF (9 mL), MeOH (3 mL), and H ₂ 0 (3 mL) was added lithium hydroxide (0.12 g, 5.0 mmol) and the resulting solution was stirred at rt for 18 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (200 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc :hexanes, 1: 1 to MeOH:CH ₂ Cl ₂ , 1:5) afforded 0.35 g (43%) of the title compound as an light pink foam, mp 126 °C. ^! H-NMR (300 MHz, CDCI3) δ 7.50 (s, 2H), 7.42 (s, 2H), 5.42 (s, 1H), 3.89 (dd, 4H, J= 12.7, 6.1 Hz), 3.29 (brs, 4H), 2.57 (d, 6H, J = 17.5 Hz), 2.11-2.16 (m, 3H), 1.84 (brs, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄₃ H ₆₃ N0 ₈ S ₃ : 840.3614 (M+Na) ⁺ . Found: 840.3613 Anal. Calcd. for C ₄₃ H ₆₃ N0 ₈ S3- ¹ /3hexanes: C, 63.82; H, 8.05; N, 1.65; S, 11.36. Found: C, 64.04; H, 8.22; N, 1.70; S, 11.03. Example 78 : 5-{4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4- [3,5-di-fert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-sulfonyl}4-methy lthiophene-2-carboxylic acid

Ex. 78a: To a solution of 2,6-di-fert-butyl-4-{4-[3,5-di-tert-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl} henol (Ex. 5, 0.75 g, 1.2 mmol) in THF (15 mL) at rt was added DIPEA (0.63 mL, 3.6 mmol). Methyl-5-(chlorosulfonyl)-4-methoxy- thiophene-3-carboxylate (0.33 g, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (50 mL) and diluted with H ₂ 0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ SC> ₄ , and concentrated under reduced pressure. Silica gel chromatography (acetone:hexanes, 1 :20 to 1 : 10 then acetone:EtOAc:hexanes, 1 :0.5:10) afforded 0.92 g (90%) of 5-{4-(3,5-di-½rr-butyl-4- hydroxyphenylsulfanyl)-4-[3,5-di-½ri-butyl-4-(3-hydroxyprop oxy)-phenyl- sulfanyl]piperidine-l-sulfonyl}-4-methoxythiophene-3-carboxy lic acid methyl ester as an off-white solid, mp 106-108 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 8.23 (s, 1H), 7.51 (s, 2H), 7.40 (s, 2H), 5.41 (s, 1H), 3.98 (s, 3H), 3.85-3.91 (m, 7H), 3.30-3.37 (m, 4H), 2.09-2.16 (m, 3H), 1.84 (brs, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄ 3H ₆ 3N0 ₈ S ₄ : 872.3334 (M+Na) ⁺ . Found: 872.3322 Anal. Calcd. for C, 61.85; H, 7.90; N, 1.57; S, 14.36. Found: C, 61.49; H, 7.66; N, 1.70; S, 14.68.

Ex. 78b: To a solution of 5-{4-(3,5-di-½rt-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-� �ri- butyl-4-(3-hydroxypropoxy)-phenyl-sulfanyl]piperidine-l-sulf onyl}-4-methoxythiophene-3- carboxylic acid methyl ester (Ex. 78a, 0.90 g, 0.9 mmol) in THF (9 mL), MeOH (3 mL), H ₂ 0 (3 mL) was added lithium hydroxide (0.13 g, 5.5 mmol) and the resulting solution was stirred at rt for 3.5 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (200 mL) and partitioned between H ₂ 0 (100 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 0: 1 to 1 : 10) afforded 0.50 g (56%) of the title compound as an off-white foam, mp 162-164 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 8.29 (brs, 1H), 7.47 (brs, 2H), 7.42 (brs, 2H), 5.42 (s, 1H), 3.84-3.94 (m, 7H), 3.40 (brs, 4H), 2.13-2.18 (m, 3H), 1.84 (brs, 4H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₄₂ H ₆ iN0 ₈ S ₄ : 858.3178 (M+Na) ⁺ . Found: 858.3176 Anal. Calcd. for C ₄₂ H ₆ iN0 ₈ S ₄ -lH ₂ 0: C, 59.05; H, 7.43; N, 1.64; S, 15.02. Found: C, 59.12; H, 7.40; N, 1.66; S, 14.27.

Example 79 : 5- [4,4-Bis-(3,5-di-te/-i-butyl-4-hydroxyphenylsulfanyl)-piperi dine-l- sulfonyl]-l-methyl-lH-pyrrole-2-carboxylic acid

Ex. 79a: To a solution of 4,4-bis-(3,5-di-½ri-butyl-4-hydroxylphenylsulfanyl)piperidi ne (Ex. lb, 7.7 g, 13.8 mmol) in THF (100 mL) at rt was added DIPEA (7.2 mL, 41.4 mmol). Methyl (5-chlorosulfonyl)-l-methyl-lH-pyrrole-2-carboxylate (3.6 g, 15.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with 1M citric acid and ice and diluted with EtOAc (250 mL). The organic layer was washed with brine (1 x 100 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc :hexanes, 1 :5 to 1 : 1) afforded 5.98 g (95% pure by HPLC) the expected product. Recrystallization using 20:80 THF:hexanes (1 g to 20 mL) afforded 5.4 g (70% yield) of 5[4,4-bis-(3,5-di-te -butyl-4- hydroxyphenylsulfanyl)-piperidine- 1 -sulfonyl} - 1 -methyl- lH-pyrrole-2-carboxylic acid methyl ester as a white solid, mp 165-167 °C. Ή-NM (300 MHz, CDC1 ₃ ) δ 7.39 (s, 4H), 7.20 (d, 1H, J = 1.6 Hz), 7.13 (d, 1H, J = 1.9 Hz), 5.40 (s, 2H), 4.00 (s, 3H), 3.86 (s, 3H), 3.12-3.14 (m, 4H), 1.83-1.87 (m, 4H), 1.43 (s, 36H). HRMS (ESI) Calcd. for C ₄₀ H ₅₈ N ₂ O ₆ S ₃ : 781.3355 (M+Na) ⁺ . Found: 781.3362. To a solution of 5[4,4-bis-(3,5-di-½ri-butyl-4-hydroxyphenylsulfanyl)-piperi dine-l- sulfonyl}-l-methyl-lH-pyrrole-2-carboxylic acid methyl ester (Ex. 79a, 0.50 g, 0.66 mmol) in THF (9 mL), MeOH (3 mL), and H ₂ 0 (3 mL) was added lithium hydroxide (0.08 g, 3.3 mmol) and the resulting solution was stirred at rt for 18 h. Upon completion, as determined by HPLC, the reaction was quenched with 1M citric acid (50 mL) and diluted with EtOAc (100 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 0: 1 to 1 : 1 then MeOILCEkC^, 1 :20) afforded 0.22 g (44%) of the title compound as an off-white foam, mp 216-218 °C. Ή-ΝΜΡ (300 MHz, CDC1 ₃ ) δ 7.39 (s, 4H), 7.28 (d, 1H, J = 2.2 Hz), 7.25 (brs, 1H), 5.40 (s, 2H), 4.01 (s, 3H), 3.14-3.18 (m, 4H), 1.85 (t, 4H, J = 5.1 Hz), 3.12-3.23 (m, 4H), 2.09-2.18 (m, 2H), 1.79-1.90 (m, 4H), 1.43 (s, 36H). HRMS (ESI) Calcd. for C39H56N2O6S3: 767.3198 (M+Na) ⁺ . Found: 767.3211. Anal. Calcd. for C, 62.37; H, 7.60; N, 3.73; S, 12.81. Found: C, 62.52; H, 7.49; N, 3.61; S, 12.43.

Example 80: 4-(3,5-Di-teri-butyl-4-carboxymethoxy-phenylsulfanyl)-4-(3,5 -di-teri-butyl- 4-hydroxy-phenylsulfanyI)-piperidine-l-carboxylic acid ethyl ester

To a solution of 4,4-bis-(3,5-di-ieri-butyl-4-hydroxyphenylsulfanyl)piperidin e-l-carboxylic acid ethyl ester (Ex. la, 31.5 g, 50 mmol) in DMF (400 mL) were added bromoacetic acid ethyl ester (16.7 g, 100 mmol) and K ₂ C0 ₃ (13.8 g, 100 mmol). The mixture was immediately heated to 85 °C for ca. 3 h. Upon completion, as determined by HPLC, the mixture was poured into 2 L of ice/water and acidified to pH = 6 with 3N HC1. The precipitate was filtered and washed with water. The wet cake obtained was dissolved in 200 mL of THF, 100 mL of MeOH and 50 mL of 5N NaOH. The mixture was stirred at rt for 1 h. Upon completion, as determined by HPLC, the mixture was poured into 2 L of ice/water and acidified to pH = 6 with 3N HC1. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (1 x 200 mL), dried over sodium sulfate, and concentrated to a light brown oil. Silica gel chromatography (EtOAc:hexanes, 1 :2 and then 1 : 1) afforded 12.0 g (33%) of the title compound as a white solid, mp 160-162 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.64 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 4.45 (s, 2H), 4.10 (q, 2H, J= 7 Hz), 3.57-3.64 (m, 4H), 1.71-1.74 (m, 4H), 1.45 (s, 18H), 1.44 (s, 18H), 1.22 (t, 3H, J = 7 Hz). Anal. Calcd. for C38H57NO6S2: C, 66.34; H, 8.35; N, 2.04; S, 9.32. Found: C, 66.45; H, 8.42; N, 2.09; S, 9.28.

Example 81 : l-[4,4-Bis-(3,5-di-feri-butyl-4-hydroxy-phenylsulfanyl)-pipe ridin-l-yl]-2- imidazol-l-yl-ethanone

Ex. 81a: To a solution of 4,4-bis-(3,5-di-½r -butyl-4-hydroxylphenylsulfanyl)piperidine (Ex. lb, 5.6 g, 10 mmol) in THF (100 mL) were added chloroacetyl chloride (1.2 g, 10.5 mmol) and N,N-diisopropylethylarnine (3.9 g, 30 mmol). The mixture was stirred at rt for 10 min. Upon completion, as determined by TLC, the mixture was filtered, and the filtrate was concentrated to ca. 40 mL. The mixture obtained was then diluted with 100 mL of CH2CI2, washed with brine, dried over MgS0 ₄ , and concentrated to dryness. Crystallization of the residue from CH ₂ Cl ₂ /hexanes gave 5.3 g (83%) of l-[4,4-bis-(3,5-di-½r -butyl-4-hydroxy- phenylsulfanyl)-piperidin-l-yl]-2-chloro-ethanone as a white solid. ^! H-NMR (300 MHz, CDCI ₃ ) 5 7.48 (s, 4H), 5.41 (s, 2H), 4.01 (s, 2H), 3.74 (brs, 2H), 3.63 (brs, 2H), 1.87 (brs, 2H), 1.69 (brs, 2H), 1.45 (s, 36H).

To a solution of l-[4,4-bis-(3,5-di-ieri-butyl-4-hydroxy-phenylsulfanyl)-pipe ridin-l-yl]-2- chloro-ethanone (Ex. 81a, 2.0 g, 3.15 mmol) in THF (30 mL) was added imidazole (1.07 g, 15.75 mmol) and DIPEA (2.03 g, 15.75 mmol). The mixture was heated to reflux for 5 h. Upon completion, as determined by HPLC, the mixture was poured into water and extracted with CH ₂ CI ₂ . The combined organic phase was washed with brine, dried over MgS0 ₄ , and concentrated to dryness. Silica gel chromatography (Μβ0Η:Ο¾θ ₂ , 1 : 10) afforded 1.5 g (68%) of the title compound as a white foam, mp 250-252°C. ^J H-NMR (300 MHz, CDC1 ₃ ) δ 7.49 (s, 4H), 7.46 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 5.49 (brs, 2H), 4.72 (s, 2H), 3.77 (brs, 2H), 3.58 (brs, 2H) 1.72-1.76 (m, 4H), 1.45 (s, 36H). HRMS (ESI) Calcd. for C ₃ 8H55N3O3S2: 666.3763 (M+H) ⁺ . Found: 666.3774.

Example 82: l-[4,4-Bis-(3,5-di-¾ i-butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-2- pyrrolidin-l-yl-ethanone

l-[4,4-Bis-(3,5-di-½^butyl-4-hydroxy-phenylsulfanyl)-piperi dm-l-yl]-2-chloro-eth

(Ex. 81a, 0.32g, 0.5 mmol) and pyrrolidine (1 mL) in THF (4 mL) was placed in a 5 mL Biotage vial. The mixture was heated to 60 °C for 10 min. using a Biotage microwave synthesizer. The reaction mixture from three combined runs was poured into water and extracted with CH2CI2. The combined organic extracts was washed with brine, dried over MgS0 ₄ , and concentrated to dryness. Silica gel chromatography (MeOH:CH ₂ Ci2, 1 :10) afforded 0.85 g (84%) of the title compound as a white foam, mp 221-223°C. ^-NMR (300 MHz, CDCI3) δ 7.48 (s, 4H), 5.39 (s, 2H), 3.75 (brs, 2H), 3.68 (brs, 2H), 3.23 (s, 2H), 2.45 (brs, 4H), 1.69-1.73 (m, 4H), 1.66 (brs, 4H), 1.44 (s, 36H). Anal. Calcd. for C ₃ 9H6oN ₂ 0 ₃ S2: C, 70.01; H, 9.04; N, 4.19; S, 9.52. Found: C, 70.00; H, 8.93; N, 4.21; S, 9.45.

Example 83: l-[4,4-Bis-(3,5-di-tei-i-butyl-4-hydroxy-phenylsulfanyl)-pip eridin-l-yI]-2- hydroxy-ethanone

Ex. 83a: To a solution of 4,4-bis-(3,5-di-½r/-butyl-4-hydroxylphenylsulfanyl)piperidi ne (Ex. lb, 2.6 g, 4.7 mmol) in THF (100 mL) was added acetic acid chlorocarbonylmethyl ester (0.67 g, 4.9 rnmol) and triethylamine (1.8 g, 14 mmol). The mixture was stirred at rt for 30 min. Upon completion, as determined by TLC, the reaction mixture was filtered and the filtrate was concentrated to ca. 40 mL. The mixture was then diluted with 100 mL of CH ₂ C1 ₂ , washed with brine, dried over MgS0 ₄ , and concentrated to dryness. The residue was then recrystallized from CH ₂ Cl ₂ :hexane to give 2.6 g (86%) of acetic acid 2-[4,4-bis-(3,5-di-tert- butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl ester as a white solid. ¹ H-NMR (300 MHz, CDC1 ₃ ) 5 7.49 (s, 4H), 5.41 (s, 2H), 4.66 (s, 2H), 3.74 (brs, 2H), 3.50 (brs, 2H), 2.15 (s, 3H), 1.79 (brs, 2H), 1.70 (brs, 2H) 1.45 (s, 36H).

To a solution of acetic acid 2-[4,4-bis-(3,5-di-½r -butyl-4-hydroxy-phenylsulfanyl)-piperidin- l-yl]-2-oxo-ethyl ester (Ex. 83a, 2.6 g, 4.0 mmol) in 50 mL of THF and 25 mL of MeOH was added 20 mL of a 5N LiOH solution in water. The mixture was stirred at rt for 3 h. The reaction mixture was acidified to pH = 5 with 3N HC1 and extracted with CH ₂ C1 ₂ . The combined organic extracts were washed with brine, dried over MgS0 ₄ , and concentrated under reduced pressure to a colorless oil which was recrystallized from CH ₂ Cl ₂ /hexane to give 2.2 g (92%) of the title compound as a white solid, mp 221-223 °C. ^-NMR (300 MHz, CDCI ₃ ) δ 7.48 (s, 4H), 5.42 (s, 2H), 4.09 (s, 2H), 3.79 (brs, 2H), 3.49 (s, 1H), 3.38 (brs, 2H), 1.74 (m, 4H), 1.45 (s, 36H). Anal. Calcd. for C, 67.59; H, 8.70; N, 2.25; S, 10.31. Found: C, 67.78; H, 8.76; N, 2.35; S, 10.03.

Example 84: {2,6-Di-teri-butyl-4-[4-(3,5-di-tert-butyl-4-hydroxy-phenyls ulfanyl)-l-(2- hydroxy-acetyl)-piperidin-4-ylsulfanyl]-phenoxy}-acetic acid

Starting from 2- [4,4-bis-(3 ,5-di- er -butyl-4-hydroxy-phenylsulfanyl)-piperidin- 1 -yl] -2-oxo- ethyl ester (Ex. 83 a) the title compound was prepared in an analogous fashion as Ex. 80, white foam (18.5% over two steps), mp 218-221 °C. ¹ H-NMR (300 MHz, CDC1 ₃ ) δ 7.63 (s, 2H), 7.47 (s, 2H), 5.44 (s, 1H), 4.46 (s, 2H), 4.12 (s, 2H), 3.78-3.82 (m, 2H), 3.40 (brs, 2H), 1.73-1.80 (m, 4H), 1.45 (s, 18H), 1.44 (s, 18H). Anal. Calcd. for C ₃ 7H ₅ 5N0 ₆ S ₂ : C, 65.94; H, 8.23; N, 2.08; S, 9.52. Found: C, 65.88; H, 8.39; N, 2.12; S, 9.22.

Example 85: 3-[4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- tert-butyl-4- methoxy-phenylsulfanyl)-piperidine-l-sulfonyl]-benzoic acid

To a solution of 2,6-di-/eri-butyl-4-[4-(3,5-di-ieri-butyl-4-methoxy-phenylsu lfanyl)- piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.87 g, 1.5 mmol) in THF (15 mL) was added 3- chlorosulfonyl-benzoic acid (0.33 g, 1.5 mmol) and TEA (0.77 g, 7.5 mmol). The mixture was stirred at rt for 30 min. Upon completion, as determined by TLC, the reaction mixture was filtered, and the filtrate was concentrated to ca. 10 mL. The mixture was then diluted with 100 mL of CH2CI2, washed with brine, dried over MgSC^, and concentrated to dryness. Silica gel chromatography ((MeOH:CH ₂ Cl ₂ , 1:10) afforded 0.82 g (71%) of the title compound as a white foam, mp 119-123 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 8.51 (s, 1H), 8.40 (d, 1H, J = 8 Hz), 8.00 (d, 1H, J = 7 Hz), 7.72 (t, 1H, J= 7.Hz), 7.46 (s, 2H), 7.36 (s, 2H), 5.41 (brs, 1H), 3.70 (s, 3H), 3.15-3.27 (m, 4H), 1.86 (brs, 4H),1.41 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C41H57NO ₆ S3: 754.3270 (M-H). Found: 754.3279

Example 86: 2,6-Di-½rt-butyl-4-[4-(3,5-di-feri-butyl-4-methoxy-phenylsu lfanyl)-l-(l- methyl-lH-imidazole-2-sulfonyl)-piperidin-4-ylsulfanyl]-phen ol

The title compound was prepared in an analogous fashion as Ex. 85 using 1 -methyl- 1H- imidazole-2-sulfonyl chloride; white foam in 72% yield, mp 215-217 °C. ^-NMR (300 MHz, CDClj) δ 7.51 (s, 2H), 7.50 (d, IH, J= 2 Hz), 7.42 (d, IH, J= 2 Hz), 7.41 (s, 2H), 5.40 (s, IH), 3.77 (s, 3H), 3.71 (s, 3H), 3.34-3.39 (m, 4H), 1.83 (brs, 4H),1.44 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for CssH^NaC Ss: 738.3409 (M+Na) ⁺ . Found: 738.3411.

Example 87: 2,6-Di-½ri-butyl-4-[4-(3,5-di-fe -i-butyl-4-methoxy-phenylsulfanyl)-l-(3,5- dimethyl-isoxazole-4-sulfonyl)-piperidin-4-ylsulfanyl]-pheno l

The title compound was prepared in an analogous fashion as Ex. 85 using 3,5-dimethyl- isoxazole-4-sulfonyl chloride; white foam in 55% yield, mp 179-181 °C. ^! H-NMR (300 MHz, CDCI3) δ 7.52 (s, 2H), 7.41 (s, 2H), 5.43 (s, IH), 3.71 (s, 3H), 3.24-3.31 (m, 4H), 2.61 (s, 3H), 2.35 (s, 3H), 1.85 (brs, 4H), 1.40 (s, 18H), 1.39 (s, 18H). HRMS (ESI) Calcd. for C39H58N2O5S3: 729.3430 (M-H). Found: 729.3439.

Example 88: 2,6-Di-feri-butyl-4-[4-(3,5-di-½ri-butyl-4-methoxy-phenylsu lfanyl)-l-(l,2- dimethyl-lH-imidazole-4-sulfonyl)-piperidin-4-ylsulfanyl]-ph enol

The title compound was prepared in an analogous fashion as Ex. 85 using 1,2-dimethyl-lH- imidazole-4-sulfonyl chloride; white foam in 41% yield, mp 168-170 °C. ^! H-NMR (300 MHz, CDCI3) δ 7.52 (s, 2H), 7.42 (s, 2H), 7.33 (s, 1H), 5.40 (s, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 3.32-3.24 (m, 4H), 2.43 (s, 3H), 1.83 (brs, 4H), 1.44 (s, 18H), 1.43 (s, 18H). Anal. Calcd. for C39H59N3O4S3: C, 64.16; H, 8.15; N, 5.76; S, 13.18. Found: C, 64.18; H, 8.08; N, 5.64; S, 12.98.

Example 89: 5-[4-(3,5-Di-reri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- teri-butyl-4- methoxy-phenylsuIfanyl)-piperidine-l-sulfonyl]-l-methyl-lH-p yrrole-2-carboxylic acid

Ex. 89a: 5-[4-(3,5-Di-feri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- feri-butyl-4-methoxy- phenylsulfanyl)-piperidine-l-sulfonyl]-l -methyl- lH-pyrrole-2-carboxylic acid methyl ester was prepared in an analogous fashion as Ex. 85 using 5-chlorosulfonyl-l -methyl- lH-pyrrole- 2-carboxylic acid methyl ester; white foam in 58% yield. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.53 (s, 2H), 7.42 (s, 2H), 7.23 (d, 1H, J= 2 Hz), 7.17 (d, 1H, J= 2 Hz), 5.45 (s, 1H), 4.04 (s, 3H), 3.90 (s, 3H), 3.75 (s, 3H), 3.13-3.21 (m, 4H), 1.90 (brs, 4H), 1.47 (s, 18H), 1.45 (s, 18H).

To a solution of 5-[4-(3,5-di-½r/-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- ½ri-butyl-4- methoxy-phenylsulfanyl)-piperidine- 1 -sulfonyl]- 1 -methyl- lH-pyrrole-2-carboxylic acid methyl ester (Ex. 89a, 0.45 g, 0.58 mmol) in 10 mL of THF and 5 mL of MeOH was added 5 mL of KOH (5N). The mixture was stirred at rt overnight.

The reaction mixture was acidified to pH = 5 with HC1 (3N), extracted with CH ₂ C1 ₂ . The combined organic phase was washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil which was recrystallized from CH ₂ Cl ₂ :hexanes to give 0.36 g (82%) of the title compound as a white solid, mp 128-135 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.50 (s, 2H), 7.39 (s, 2H), 7.25-7.27 (m, 2H), 5.41 (s, 1H), 4.01 (s, 3H), 3.70 (s, 3H), 3.10-3.22 (m, 4H), 1.86 (brs, 4H), 1.43 (s, 18H), 1.42 (s, 18H). Anal. Calcd. for C ₄ oH58N ₂ 0 ₆ S ₃ .H ₂ 0: C, 61.82; H, 7.78; N, 3.60; S, 13.28. Found: C, 62.02; H, 7.57; N, 3.67; S, 10.36. Example 90 : [4-(3,5-Di-iert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-te ri-butyI-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-oxo-acetic acid

Ex. 90a: To a solution of 2,6-di-teri-butyl-4-[4-(3,5-di-feri-butyl-4-methoxy-plienyls ulfanyl)- piperidin-4-ylsulfanyl] -phenol (Ex. 17, 1.14 g, 2.0 mmol) in THF (25 mL) was added chloro- oxo-acetic acid ethyl ester (0.28 g, 2.0 mmol) and TEA (1.0 g, 10 mmol). The mixture was stirred at rt for 15 rnin. Upon completion, as determined by TLC, the reaction mixture was filtered and the filtrate was concentrated to ca. 10 mL. The mixture was then diluted with 30 mL of CH2CI2, washed with brine, dried over MgS0 ₄ , and concentrated to dryness to give [4- (3,5-di-/eri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-¾ri- butyl-4-methoxy-phenylsulfanyl)- piperidin-l-yl]-oxo-acetic acid ethyl ester. This material was used without further purification. 1H-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.42 (s, 1H), 4.29 (q, 2H, J = 7 Hz), 3.71-3.77 (m, 2H), 3.71 (s, 3H), 3.52-3.56 (m, 2H) 1.85 (brs, 2H), 1.73 (brs, 2H), 1.44 (s, 18H), 1.43 (s, 18H), 1.32 (t, 3H, J= 7 Hz).

[4-(3,5-Di-½r/ ¹ -butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-ierr-butyl- 4-methoxy- phenylsulfanyl)-piperidin-l-yl]-oxo-acetic acid ethyl ester (Ex. 90a) was dissolved in 25 mL of THF and 10 mL of MeOH and 5 mL of NaOH (5N) was added. The mixture was stirred at rt for 30 min. The reaction mixture was acidified to pH = 5 with HC1 (3N) and extracted with CH2CI2. The combined organic phase was washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil which was recrystallized from CH2Cl2/hexanes to give 0.75 g (58.5%, two step overall yield) of the title compound as a white solid, mp 118-125 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.49 (s, 2H), 5.39 (s, 1H), 3.98 (brs, 2H), 3.75- 3.77 (m, 2H), 3.70 (s, 3H), 1.82 (brs, 2H), 1.74 (brs, 2H), 1.43 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₃ 6H ₅₃ N0 ₅ S ₂ : 642.3287 (M-H). Found: 642.3275.

Example 91 : {4-(3,5-Di-iert-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-te ri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-oxo-acetic acid

Ex. 91a: To a solution of 2,6-di-tert-butyl-4-{4-[3,5-di-ter/-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 0.81 g, 1.3 mmol) in THF (20 mL) was added chloro-oxo-acetic acid ethyl ester (0.39 g, 2.9 mmol) and TEA (0.66 g, 6.6 mmol). The mixture was stirred at rt for 15 min. Upon completion, as determined by TLC, the reaction mixture was filtered, and the filtrate was concentrated to ca. 10 mL. The mixture was then diluted with 30 mL of CH ₂ C1 , washed with brine, dried over MgS0 ₄ , and concentrated to dryness. Silica gel chromatography (EtOAc:hexanes, 1:3) afforded 0.89 g (83%) of oxalic acid 3-{2,6-di-½ri-butyl-4-[4-(3,5-di-ieri-butyl-4-hydroxy-pheny lsulfanyl)- l-ethoxyoxalyl-piperidin-4-ylsulfanyl]-phenoxy} -propyl ester ethyl ester as a white solid. NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.47 (s, 2H), 5.43 (s, 1H), 4.48 (t, 2H, J = 7 Hz), 4.35 (q, 2H, J= 7 Hz), 4.29 (q, 2H, J= 7 Hz), 3.87 (t, 2H, J= 7 Hz), 3.72-3.76 (m, 2H), 3.53 (brs, 2H), 2.30-2.34 (m, 2H), 1.85 (brs, 2H), 1.73 (brs, 2H), 1.44 (s, 18H), 1.42 (s, 18H), 1.28-1.40 (m, 6H).

Oxalic acid 3-{2,6-di-ier -butyl-4-[4-(3,5-di-½r/-butyl-4-hydroxy-phenylsulfanyl)-l- ethoxyoxalyl-piperidin-4-ylsulfanyl]-phenoxy}-propyl ester ethyl ester (Ex. 91a) was dissolved in 25 mL of THF and 10 mL of MeOH and 5 mL of NaOH (5N) was added. The mixture was stirred at rt for 10 min. The reaction mixture was acidified to pH = 5 with HC1 (3N) and extracted with CH ₂ C1 ₂ . The combined organic phase was washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil which was recrystallized from CH ₂ Cl ₂ /hexanes to give 0.70 g (78%, two step overall yield) the title compound as a white solid, mp 136-138 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.48 (s, 2H), 5.43 (s, 1H), 4.09-4.13 (m, 2H), 3.83-3.91 (m, 4H), 3.81 (brs, 2H), 2.12-2.16 (m, 2H), 1.83 (brs, 4H), 1.45 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for 710.3525 (M-H). Found: 710.3527 Example 92: 2,6-Di-tert-butyl-4-[4-(3,5-di-feri-butyl-4-methoxy-phenylsu lfanyl)-l-(3- pyrrolidin-l-yl-propane-l-sulfonyI)-piperidin-4-ylsulfanyl]- phenol

Ex. 92a: To a solution of 2,6-di-teri-butyl-4-[4-(3,5-di-¾ri-butyl-4-methoxy-phenylsu lfanyl)- piperidin-4-ylsulfanyl] -phenol (Ex. 17, 3.0 g, 5.2 mmol) in THF (100 mL) was added 3- chloro-propane-l-sulfonyl chloride (0.93 g, 5.2 mmol) and TEA (2.65 g, 26.2 mmol). The mixture was stirred at rt for 30 min. Upon completion, as determined by TLC, the reaction mixture was filtered, and the filtrate was concentrated to ca. 30 mL. The mixture was then diluted with 30 mL of CH2CI2, washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil which was recrystallized from Ct^CL^hexanes to give 2.9 g (78%) of 2,6- di-tert-bu yl-4- [ 1 -(3 -chloro-propane- 1 -sulfonyl)-4-(3 ,5-di-½ri-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol as a white solid. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.46 (s, 2H), 5.42 (s, 1H), 3.71 (s, 3H), 3.68 (t, 2H, J = 7 Hz), 3.45 (brs, 4H), 3.07 (t, 2H, J= 7 Hz), 2.26-2.30 (m, 2H), 1.85 (brs, 4H), 1.45 (s, 18H), 1.44 (s, 18H).

To a solution of 2,6-di-fert-butyl-4-[l-(3-chloro-propane-l-sulfonyl)-4-(3,5- di-fer/-butyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 92a, 0.5 g, 0.7 mmol) in 25 mL of THF was added pyrrolidine (2.0 g, 28.0 mmol). The mixture was heated to reflux overnight. Upon completion, as determined by TLC, the reaction mixture was then diluted with 50 mL of CH2CI2, washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1:10) afforded 0.24 g (46%) of the title compound as a white foam, mp 102-106 °C. ^-NMR (300 MHz, CDCI3) δ 7.57 (s, 2H), 7.45 (s, 2H), 5.42 (s, 1H), 3.71 (s, 3H), 3.44 (brs, 4H), 2.98-3.03 (m, 2H), 2.50-2.59 (m, 6H), 1.99-2.04 (m, 2H), 1.85 (brs, 4H), 1.78 (brs, 4H), 1.44 (s, 18H), 1.43 (s, 18H). Anal. Calcd. for C ₄ iH ₆ 6N ₂ 0 ₄ S3: C, 65.91; H, 8.90; N, 3.75; S, 12.87. Found: C, 66.08; H, 8.67; N, 3.84; S, 12.58. Example 93 : 4-(3,5-Di-iei-/-butyl-4-cyanomethoxy-phenylsulfanyl)-4-(3,5- di-teri-butyl-4- hydroxy-phenylsulfanyl)-piperidine-l-carboxylic acid ethyl ester

To a solution of 4,4-bis-(3,5-di-½r^bu1yl-4-hydroxyphenylsulfanyl)piperidine -l-carboxylic acid ethyl ester (Ex. la, 12.6g, 20 mmol) in 200 mL of DMF was added bromo-acetonitrile (2.4 g, 20 mmol) and K ₂ C0 ₃ (4.0 g, 29.0 mmol). The mixture was heated to ca. 85 °C overnight. The mixture was poured into 1000 mL of ice water. The precipitate was filtered, washed with water and dried. Silica gel chromatography (EtOAc:hexanes, 3: 100 to 10:100) afforded 3.0 g (22%) of the title compound as a white solid, mp 159-161 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.64 (s, 2H), 7.46 (s, 2H), 5.41 (s, 1H), 4.5(s, 2H), 4.09 (q, 2H, J = 7 Hz), 3.56-3.63 (m, 4H), 1.68 (brs, 4H), 1.45 (s, 18H), 1.44 (s, 18H), 1.22 (t, 3H, J = 1 Hz). Anal. Calcd. for C ₃ 8H ₅₆ N20 ₄ S ₂ : C, 68.22; H, 8.44; N, 4.19; S, 9.59. Found: C, 68.51; H, 8.22; N, 4.25; S, 9.53.

Example 94: [4-(3,5-Di-¾ri-butyl-4-cyanomethoxy-phenylsulfanyl)-4-(3,5- di-iert-butyl-4- hydroxy-phenylsulfanyl)-piperidin-l-yl]-oxo-acetic acid ethyl ester

Ex. 94a. Starting from 4,4-bis-(3,5-di-teri-butyl-4-hydroxylphenylsulfanyl)piperidi ne (Ex. lb), [4,4-bis-(3,5-di-½r -butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-oxo-acetic acid ethyl ester was prepared in an analogous fashion as Ex. 90a; white foam in 48% yield. ^l H- NMR (300 MHz, CDC1 ₃ ) δ 7.49 (s, 4H), 5.42 (s, 2H), 4.29 (q, 2H, J = 8 Hz), 3.75 (brs, 2H), 3.54 (brs, 2H), 1.83 (brs, 2H), 1.72 (brs, 2H), 1.44 (s, 36H), 1.33 (t, 3H, J= 8 Hz).

The title compound was prepared from [4,4-bis-(3,5-di-te^butyl-4-hydroxy-phenylsulfanyl)- piperidin-l-yl]-oxo-acetic acid ethyl ester (Ex. 94a) in an analogous fashion as Ex. 93; white foam in 11% yield, mp 105-108 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.62 (s, 2H), 7.46 (s, 2H), 5.44 (s, 1H), 4.51(s, 2H), 4.29 (q, 2H, J = 7 Hz), 3.73 (brs, 2H), 3.53 (brs, 2H), 1.83 (brs, 2H), 1.72 (brs, 2H), 1.45 (s, 18H), 1.44 (s, 18H), 1.33 (t, 3H, J = 7 Hz). Anal. Calcd. for C39H56N2O5S2: C, 67.20; H, 8.10; N, 4.02; S, 9.20. Found: C, 67.39; H, 8.18; N, 3.93; S, 9.02.

Example 95: 2,6-Di-teri-butyl-4-[4-(3,5-di-teri-butyl-4-methoxy-phenylsu lfanyl)-l-(2- hydroxy-ethyl)-piperidin-4-ylsulfanyl]-phenol

Ex. 95a: To a solution of 2,6-di- err-butyl-4-[4-(3,5-di-fer/-butyl-4-methoxy-phenylsulfanyl)- piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.57 g, 1.0 mmol) in 15 mL of DMF was added 2- bromoethoxy)-½rt-butyldimethylsilane (0.20, 1.5 mmol) and 2CO3 (0.28 g, 2.0 mmol). The mixture was stirred at rt overnight. Upon completion, as determined by TLC, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried over MgS0 ₄ , and concentrated to give 2,6-di-ieri-butyl-4-[l-[2- (½rr-butyl-dimethyl-silanyloxy)-ethyl]-4-(3,5-di-½rt-butyl -4-methoxy-phenylsulfanyl)- piperidin-4-ylsulfanyl]-phenol as a colorless oil which was used without further purification.

2,6-Di-½^bu†yl-4-[l-[2-(½^bu1yl-dimethyl-silanyloxy)- ethyl]-4-(3,5-di-/er^utyl-4- methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl] -phenol (Ex. 95a) was dissolved in 20 mL of THF, and TBAF (1.3 g, 5 mmol) was added. The mixture was stirred at rt overnight. Upon completion, as determined by TLC, the mixture was concentrated to give a colorless oil. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 : 10) afforded 0.22 g (37%, over two steps) of the title compound as a white foam, mp 115-120 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.49 (s, 2H), 5.38 (s, 1H), 3.70 (s, 3H), 3.57 (t, 2H, J = 6 Hz), 2.67 (brs, 4H), 2.57(t, 2H, J = 6 Hz) 1.82 (brs, 4H), 1.45 (s, 18H), 1.44 (s, 18H). Anal. Calcd. for C ₃ 6H ₅₇ N0 ₃ S2

C, 69.69; H, 9.34; N, 2.26; S, 10.34. Found: C, 69.69; H, 9.32; N, 2.22; S, 9.97.

Example 96: 2,6-Di-fe/*i-butyl-4-[4-[3,5-di-teri-butyl-4-(3-hydroxy-prop oxy)- phenylsulf anyl] - l-(2-hy dr oxy-ethyl)-pip eridin-4-ylsulf anyl] -phenol

Ex. 96a: Starting from [4,4-bis-(3,5-di-fer -butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]- oxo-acetic acid ethyl ester (Ex. 94a), {4-(3,5-di-½r/-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5- di-te -buty l-4-(3 -hy droxy-propoxy)-phenylsulfany 1] -piperidin- 1 -yl } -oxo-acetic acid ethyl ester was prepared in an analogous fashion as Ex. 4; white foam in 25% yield. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.47 (s, 2H), 5.42 (s, 1H), 4.29 (q, 2H, J = 7 Hz), 3.89-3.92 (m, 4H), 3.72-3.76 (m, 2H), 3.54 (brs, 2H), 2.12-2.16 (m, 2H), 1.84 (brs, 2H), 1.72 (brs, 2H), 1.44 (s, 18H), 1.43 (s, 18H), 1.35 (t, 3H, J = 7 Hz).

To a solution of {4-(3,5-di- eri-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-ier/-butyl-4-( 3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl} -oxo-acetic acid ethyl ester (Ex. 96a, 0.5 g, 0.7 mmol) in 25 mL of THF was added 2.1 mL of LAH (2.1 mmol, 1.0 M in THF). The mixture was heated to reflux immediately and kept at reflux for ca. 4 h. Upon completion, as determined by HPLC. The reaction mixture was quenched by adding Rochelle's salt solution slowly, and the mixture was stirred for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSC^ and concentrated to a colorless oil. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 : 10) afforded 0.28 g (61%) of the title compound as a white foam, mp 160- 163 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.38 (s, 1H), 3.85-3.92 (m, 4H), 3.56 (t, 2H, J = 5 Hz), 2.66 (brs, 4H), 2.56 (t, 2H, J = 5 Hz), 2.11-2.15 (m, 2H), 1.80 (brs, 4H), 1.45 (s, 18H), 1.43 (s, 18H). Anal. Calcd. for C ₃₈ H ₆ iN0 ₄ S ₂ : C, 69.15; H, 9.32; N, 2.12; S, 9.72. Found: C, 69.42; H, 9.56; N, 2.19; S, 9.48.

Example 97: 2,6-Di-tert-butyl-4-[4-(3,5-di-feri-butyl-4-methoxy-phenylsu lfanyl)-l-(3- hydroxy-propyI)-piperidin-4-yIsuIfanyI]-phenoI

To a solution of 2,6-di-½ri-butyl-4-[4-(3,5-di-ieri-butyl-4-methoxy-phenylsu lfanyl)- piperidin-4-ylsulfanyl]-phenol (Ex. 17, 0.57 g, 1.0 mmol) in 25 mL of DMF was 3- bromopropan-l-ol (0.20 mL, 1.5 mmol) and K2CO3 (0.28 g, 2.0 mmol). The mixture was stirred at rt overnight. Upon completion, as determined by TLC, the reaction mixture was poured into water, extracted with CH2CI2. The combined organic phase was washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 :10) afforded 0.14 g (22%) of the expected product as a white foam, mp 123-126 °C. ^-NMR (300 MHz, CDCI3) δ 7.60 (s, 2H), 7.49 (s, 2H), 5.38 (s, 1H), 3.75 (t, 2H, J = 5 Hz), 3.70 (s, 3H), 2.62-2.67 (m, 6H), 1.79 (brs, 4H), 1.65-1.70 (m, 2H), 1.44 (s, 18H), 1.43 (s, 18H). Anal. Calcd. for Csv^NC^: C, 70.54; H, 9.44; N, 2.22; S, 10.18. Found: C, 70.50; H, 9.61; N, 2.31; S, 10.11.

Example 98: 2,6-Di-fe/*/-butyl-4-[4-(3,5-di-teA-i-butyI-4-methoxy-phenyl sulfanyl)-l-(4- hydroxy-butyl)-piperidin-4-ylsulfanyl]-phenol

Ex. 98a: Starting from 2,6-di-/err-butyl-4-[4-(3,5-di-ieri-butyl-4-methoxy-phenylsu lfanyl)- piperidin-4-ylsulfanyl] -phenol (Ex. 17), 4-[4-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-4- (3,5-di-ieri-butyl-4-methoxy-phenylsulfanyl)-piperidin-l-yl] -4-oxo-butyric acid ethyl ester was prepared in an analogous fashion as Ex. 81a; white solid in 64% yield. ^-NMR (300 MHz, CDCI3) δ 7.59 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 4.13 (q, 2H, J= 7 Hz), 3.75-3.77 (m, 2H), 3.71 (s, 3H), 3.62 (brs, 2H), 2.58-2.60 (m, 4H), 1.79 (brs, 2H), 1.67 (brs, 2H), 1.44 (s, 18H), 1.43 (s, 18H), 1.25 (t, 3H, J = 7 Hz). Starting from 4-[4-(3,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- ½rt-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo-butyric acid ethyl ester (Ex. 98a), the title compound was prepared in an analogous fashion as Ex. 96; white solid in 73% yield, mp 130-132 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.61 (s, 2H), 7.51 (s, 2H), 5.36 (s, 1H), 3.70 (s, 3H), 3.52 (brs, 2H), 2.66 (brs, 4H), 2.42 (brs, 2H), 1.82 (brs, 4H), 1.63 (brs, 4H), 1.44 (s, 18H), 1.43 (s, 18H). Anal. Calcd. for C38H61NO3S2: C, 70.87; H, 9.55; N, 2.17; S, 9.96. Found: C, 71.03; H, 9.44; N, 2.26; S, 9.89.

Example 99: 2,6-Di-teri-butyl-4-[4-[3,5-di-teri-butyl-4-(3-hydroxy-propo xy)- phenylsulfanyl]-l-(3-hydroxy-propyl)-piperidin-4-ylsulfanyl] -phenol

Starting from 2,6-di-½ri-butyl-4-{4-[3,5-di-½r -butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5), the title compound was prepared in an analogous fashion as Ex. 97 after the crude material was purified by semi-prep HPLC; white foam in 65% yield, mp 115-119 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) 5 7.58 (s, 2H), 7.49 (s, 2H), 5.40 (s, 1H), 3.81-3.89 (m, 4H), 3.73 (brs, 2H), 2.64 (brs, 6H), 2.09-2.13 (m, 2H), 1.78 (brs, 4H), 1.63 (brs, 2H), 1.44 (s, 18H), 1.43 (s, 18H). Anal. Calcd. for C ₃ 9H ₆₃ N0 ₄ S ₂ -½H ₂ 0: C, 68.58; H, 9.44; N, 2.05; S, 9.39. Found: C, 68.74; H, 9.29; N, 2.12; S, 9.30.

Example 100: 2,6-Di-tert-butyI-4-[4-[3,5-di-te *i-butyl-4-(3-hydroxy-propoxy)- phenylsulfanyl]-l-(4-hydroxy-butyl)-piperidin-4-ylsulfanyl]- phenol

Ex. 100a: To a solution of 2,6-di-½r?-butyl-4-{4-[3,5-di-½ri-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 0.92 g, 1.5 mmol) in THF (30 mL) was added 3-chlorocarbonylpropionic acid ethyl ester (0.26 g, 1.65 mmol) and DIPEA (0.97 g, 7.5 mmol). The mixture was stirred at rt for 30 min. Upon completion, as determined by TLC, the reaction mixture was filtered, and the filtrate was concentrated to ca. 10 mL. The mixture was then diluted with 100 mL of CH ₂ C1 ₂ , washed with brine, dried over MgS0 ₄ , and concentrated to dryness. Silica gel chromatography (EtOAc:hexanes, 1 :2) afforded 0.95 g (86%) of 4-{4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di- ½rr-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-4-oxo-butyr ic acid ethyl ester as a white foam. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.48 (s, 2H), 5.41 (s, 1H), 4.13 (q, 2H, J = 7 Hz), 3.86-3.92 (m, 4H), 3.73 (brs, 2H), 2.60 (brs, 6H), 2.57-2.62 (m, 4H), 2.12-2.16 (m, 2H), 1.78 (brs, 2H), 1.67 (brs, 2H), 1.44 (s, 18H), 1.43 (s, 18H), 1.25 (t, 3H, J = 7 Hz).

Starting from 4- {4-(3,5-di-ferr-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-/e r/-butyl-4-(3- hydroxy-propoxy)-phenylsuIfanyl]-piperidin-l-yl}-4-oxo-butyr ic acid ethyl ester (Ex. 100a), the title compound was prepared in an analogous fashion as Ex. 96; white foam in 55% yield, mp 90-95 °C. *H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.50 (s, 2H), 5.37 (s, 1H), 3.85- 3.91 (m, 4H), 3.51 (brs, 2H), 2.63-2.67 (m ,4H), 2.41 (brs, 2H), 2.07-2.14 (m, 2H), 1.70 (brs, 4H), 1.60 (brs, 4H), 1.44 (s, 18H), 1.43 (s, 18H). Anal. Calcd. for C ₄ oH ₆ 5N0 ₄ S2: C, 69.82; H, 9.52; N, 2.04; S, 9.32. Found: C, 70.05; H, 9.49; N, 2.09; S, 9.08.

Example 101: 4-[3,5-Di-teri-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl]-4- (3,5-di-teri- butyl-4-hydroxy-phenylsulfanyl)-piperidine-l-carboxylic acid ethyl ester

To a solution 4-(3,5-di-½r/-butyl-4-carboxymethoxy-phenylsulfanyl)-4-(3,5 -di-½ri-butyl-4- hydroxy-phenylsulfanyl)-piperidine-l-carboxylic acid ethyl ester (Ex. 80, 12.0 g, 16.4 mmol) in 500 mL of THF was added 42 mL of BH ₃ -Me ₂ S (2.0 M in THF) dropwise at 0 °C. The mixture was stirred at rt overnight. Upon completion, as determined by HPLC, the reaction mixture was quenched by adding MeOH slowly at 0 °C. The mixture was then concentrated under reduced pressure, and redissolved in 100 mL of MeOH and concentrated to dryness 3-4 times. The residue was recrystallized from CH ₂ Cl ₂ :hexanes to give 10.5 g (95%) of the title compound as a white solid, mp 184-186 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.40 (s, 1H), 4.08 (q, 2H, J = 1 Hz), 4.03-4.06 (m, 2H), 3.93 (t, 2H, J = 5 Hz), 3.57- 3.61 (m, 4H), 1.71 (brs, 4H), 1.44 (s, 36H), 1.21 (t, 3H, J = 7 Hz). HRMS (ESI) Calcd. for C ₃₈ H ₅₉ N0 ₅ S ₂ : 696.3732 (M+Na) ⁺ . Found: 696.3727.

Example 102 : 2,6-Di-¾rt-butyl-4-{4-[3,5-di-feri-butyl-4-(2-hydroxy-ethox y)- phenylsulfanyl]-piperidin-4-ylsulfanyl}-phenol

To a solution of 4-[3,5-di-½ri-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl]-4- (3,5-di-½ri- butyl-4-hydroxy-phenylsulfanyl)-piperidine-l-carboxylic acid ethyl ester (Ex. 101, 10.5 g, 15.6 mmol) in 500 mL of propan-2-ol was added OH (17.4 g, 312 mmol). The mixture was heated to reflux overnight. .Upon completion, as determined by HPLC, the mixture was poured into 2 L of ice water The precipitate was filtered, washed with water, and recrystallized from CH ₂ Cl2:hexanes to give 7.81 g (83%) of the title compound as a white solid, mp 145-152 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.61 (s, 2H), 7.47 (s, 2H), 5.37 (s, 1H), 4.02 (t, 2H, J= 4 Hz), 3.92 (t, 2H, J= 4 Hz), 3.00-3.03 (m, 4H), 1.75 (brs, 4H), 1.43 (s, 36H). Anal. Calcd. for C ₃₃ H ₅₅ N0 ₃ S ₂ : C, 69.84; H, 9.21 ; N, 2.33; S, 10.65. Found: C, 69.91; H, 9.31; N, 2.43; S, 10.50.

Example 103: [4-[3,5-Di-teri-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl]-4 -(3,5-di-i'e -i- butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-acetic acid

Ex. 103a: To a solution of 2,6-di-rer/-butyl-4-{4-[3,5-di-rer/-butyl-4-(2-hydroxy-ethox y)- phenylsulfanyl]-piperidin-4-ylsulfanyl}-phenol (Ex. 102, 0.9 g, 1.5 mmol) in 30 mL of THF was added bromoacetic acid ethyl ester (0.28 g, 1.65 mmol) and DIPEA (0.97 g, 7.5 mmol). The mixture was heated to reflux for 2 h. Upon completion, as determined by HPLC, the mixture was poured into water, extracted with CH ₂ CI ₂ . The organic phases were combined, and washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil. Silica gel chromatography (EtOAc:hexanes, 1: 1) afforded 0.78 g (77%) of [4-[3,5-di-tert-butyl-4-(2- hy droxy-ethoxy)-phenylsulfany 1] -4-(3 , 5 -di-½r/-butyl-4-hydroxy-pheny lsulfany l)-piperidin- 1 - yl]-acetic acid ethyl ester as a white foam. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 4.17 (q, 2H, J = 7 Hz), 4.03 (t, 2H, J = 5 Hz), 3.94 (t, 2H, J = 5 Hz), 3.21 (s, 2H), 2.73 (brs, 4H), 1.88 (brs, 4H), 1.44 (s, 36H), 1.26 (t, 3H, J= 7 Hz).

To a solution of [4-[3,5-di-z'er -butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl]-4-(3,5-di- eri- butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-acetic acid ethyl ester (Ex. 103a, 0.35 g, 0.5 mmol) in 20 mL of THF and 10 mL of MeOH was added 5mL of NaOH (5N). The mixture was stirred at rt overnight. The reaction mixture was acidified to pH = 5 with HC1 (3N), extracted with CH ₂ CI ₂ . The combined organic phase was washed with brine, dried over MgS0 ₄ , and concentrated to give a colorless oil. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 :10) afforded 0.29 g (85%) of the title compound as a white foam, mp 173-175 °C. ^] H-NMR (300 MHz, CDCI ₃ ) δ 7.59 (s, 2H), 7.50 (s, 2H), 5.43 (s, 1H), 4.01 (t, 2H, J = 5 Hz), 3.91 (t, 2H, J = 5 Hz), 3.57 (s, 2H), 3.35 (brs, 4H), 2.03 (brs, 4H), 1.43 (s, 18H), 1.42, (s, 18H). HRMS (ESI) Calcd. for C ₃ 7H5 ₇ N0 ₅ S ₂ : 660.3756 (M+H) ⁺ . Found: 660.3751.

Example 104: 2,6-Di-tert-butyl-4-[4-[3,5-di-fe/-i-butyl-4-(2-hydroxy-etho xy)- phenylsulfanyl]-l-(2-hydroxy-ethyl)-piperidin-4-ylsulfanyl]- phenol

To a solution of [4-[3,5-di-/ert-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl]-4 -(3,5-di-½r - butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl] -acetic acid ethyl ester (Ex. 103a, 0.45 g, 0.65 mmol) in 30 mL of THF was added 1.5 mL of LAH (1.5 mmol, 1.0 M in THF). The mixture was stirred at rt for 1.5 h. Upon completion, as determined by TLC, the reaction mixture was quenched by adding Rochelle's salt solution slowly, and the mixture was stirred for 30 min. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgS0 ₄ and concentrated to a colorless oil. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1 : 10) afforded 0.33 g (79%) of the title compound as a white foam, mp 211-213 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.61 (s, 2H), 7.48 (s, 2H), 5.38 (s, 1H), 4.02 (t, 2H, J= 5 Hz), 3.93 (t, 2H, J = 5 Hz), 3.57 (t, 2H, J = 5 Hz), 2.67 (brs, 4H), 2.57 (t, 2H, J = 5 Hz), 1.82 (brs, 4H), 1.44 (s, 36H). Anal. Calcd. for C37H59NO4S2: C, 68.79; H, 9.21 ; N, 2.17; S, 9.93. Found: C, 68.74; H, 9.14; N, 2.08; S, 9.70.

Example 105: l-{4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di- feri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-2-hydroxy-e thanone

Ex. 105a: Starting from acetic acid 2-[4,4-bis-(3,5-di-/eri-butyl-4-hydroxy-phenylsulfanyl)- piperidin-l-yl]-2-oxo-ethyl ester (Ex. 83a), acetic acid 2-{4-(3,5-di-½ri-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di-ier^u1yl-4-(3-hydroxy-propoxy)-phe nylsulfanyl]-piperidin-l-yl}- 2-oxo-ethyl ester was prepared in an analogous fashion as Ex. 4; white foam in 20% yield.

'H-NMR (300 MHz, CDCI ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.42 (s, 1H), 4.66 (s, 2H), 3.87-3.92 (m, 4H), 3.71-3.75 (m, 2H), 3.49 (brs, 2H), 2.15 (s, 3H), 1.79 (brs, 2H), 1.70 (brs, 4H), 1.45 (s, 18H), 1.43 (s, 18H).

Starting from acetic acid 2-{4-(3,5-di-½r -butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-/eri- butyl-4-(3-hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}- 2-oxo-ethyl ester (Ex. 105a), the title compound was prepared in an analogous fashion as Ex. 83; white foam in 60% yield, mp 176-179 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.47 (s, 2H), 5.42 (s, 1H), 4.08 (d, 2H, J = 4 Hz), 3.87-3.92 (m, 4H), 3.77-3.81 (m, 2H), 3.59 (t, 1H, J = 4 Hz), 3.37 (brs, 2H), 2.12-2.16 (m, 2H), 1.71-1.78 (m, 4H), 1.45 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C ₃ 8H ₅₉ N0 ₅ S ₂ : 696.3732 (M+Na) ⁺ . Found: 696.3733. Example 106: 4-[4-[3,5-Di-tert-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl]

butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo-but yric acid

Ex. 106a: Starting from 2,6-di-½ri-butyl-4-{4-[3,5-di-½ri-butyl-4-(2-hydroxy-ethox y)- phenylsulfanyl]-piperidin-4-ylsulfanyl}-phenol (Ex. 102), 4-[4-[3,5-di-½ri-butyl-4-(2- hydroxy-ethoxy)-phenylsulfanyl]-4-(3,5-di-½^butyl-4-hydroxy -phenylsulfanyl)-piperidin-l- yl]-4-oxo-butyric acid ethyl ester was prepared in an analogous fashion as Ex. 100a; white foam in 74% yield. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.41 (s, 1H), 4.14 (q, 2H, J = 7 Hz), 4.01-4.04 (m, 2H), 3.93 (t, 2H, J = 5 Hz), 3.71-3.76 (m, 2H), 3.62, (brs, 2H), 2.58-2.61 (m, 4H), 1.80(t, 1H, J = 5 Hz), 1.79 (brs, 2H), 1.68 (brs, 2H), 1.44 (s, 36H), 1.26 (t, 3H, J= 7 Hz).

Starting from 4- [4- [3 , 5 -άϊ-tert- uty l-4-(2-hydroxy-ethoxy)-phenylsulfany 1] -4-(3 ,5 -di-fe - butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo-butyri c acid ethyl ester (Ex. 106a), the title compound was prepared in an analogous fashion as Ex. 103; white foam in 62% yield, mp 120-125 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.43 (s, 1H), 4.02 (t, 2H, J = 4 Hz), 3.90 (t, 2H, J = 4 Hz), 3.74 (brs, 2H), 3.59, (brs, 2H), 2.55-2.57 (m, 4H), 1.76 (brs, 2H), 1.69 (brs, 2H), 1.44 (s, 18H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C ₃₉ H ₅₉ N0 ₆ S ₂ : 724.3682 (M+H) ⁺ . Found: 724.3681.

Example 107: 2,6-Di-tert-butyl-4-[4-[3,5-di-tert-butyl-4-(2-hydroxy-ethox y)- phenylsulfanyl]-l-(4-hydroxy-butyl)-piperidin-4-ylsulfanyl]- phenol

Starting from 4-[4-[3,5-di-ier/-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-½r/- butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo-butyri c acid ethyl ester (Ex. 106a), the title compound was prepared in an analogous fashion as Ex. 100; white foam in 71% yield, mp 88-90 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.62 (s, 2H), 7.51 (s, 2H), 5.36 (s, 1H), 4.02 (brs, 2H), 3.93 (brs, 2H), 3.74 (brs, 2H), 3.51, (brs, 2H), 2.66 (brs, 4H), 2.42 (brs, 2H), 1.82 (brs, 4H), 1.57 (brs, 4H), 1.44 (s, 36H). Anal. Calcd. for C ₃ 9H ₆₃ N0 ₄ S ₂ : C, 69.49; H, 9.42; N, 2.08; S, 9.51. Found: C, 69.24; H, 9.44; N, 2.17; S, 9.27.

Example 108: 2,6-Di-ieri-butyl-4-[4-[3,5-di-teri-butyl-4-(2-hydroxy-ethox y)- phenylsulf anyl] - 1 -(3-hy dr oxy-propyl)-pip eridin-4-ylsulf anyl] -phenol

To a solution of 2,6-di-½r/-butyl-4-{4-[3,5-di-½r/-butyl-4-(2-hydroxy-ethox y)- phenylsulfanyl]-piperidin-4-ylsulfanyl} -phenol (Ex. 102, 1.0 g, 1.66 mmol) in 25mL of THF was added 3-bromopropan-l-ol (0.46 g, 3.32 mmol) and DIPEA (1.07g, 8.31 mmol). The mixture was heated to reflux for 48 h. Upon completion, as determined by TLC, the reaction mixture was poured into water. The precipitate was filtered and washed with water. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1: 10) afforded 0.82 g (78%) of the title compound as a white foam, mp 169-174 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.49 (s, 2H), 5.38 (s, 1H), 4.02 (t, 2H, J= 4 Hz), 3.92 (t, 2H, J= 4 Hz), 3.75 (brs, 2H), 2.62-2.68, (m, 6H), 1.79 (brs, 4H), 1.65-1.69 (m, 2H), 1.44 (s, 36H). Anal. Calcd. for C ₃₈ H ₆ iN0 ₄ S2: C, 69.15; H, 9.32; N, 2.12; S, 9.72. Found: C, 69.34; H, 9.47; N, 2.25; S, 9.50.

Example 109: l-[4-[3,5-Di-tert-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-feri- butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-2-hydroxy-et hanone

Ex. 109a. Starting from 2,6-di-½r/-butyl-4-{4-[3,5-di- eri-butyl-4-(2-hydroxy-ethoxy)- phenylsulfanyl]-piperidin-4-ylsulfanyl} -phenol (Ex. 102), acetic acid 2-[4-[3,5-di-feri-butyl- 4-(2-hydroxy-ethoxy)-phenylsulfanyl]-4-(3,5-di-/er/-butyl-4- hydroxy-phenylsulfanyl)- piperidin-l-yl]-2-oxo-ethyl ester was prepared in an analogous fashion as Ex. 83a, which was used without purification.

Starting from acetic acid 2-[4-[3,5-di- er/-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl]-4- (3,5-di-?eri-butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl] -2-oxo-ethyl ester (Ex. 109a), the title compound was prepared in an analogous fashion as Ex. 83; white foam in 34% yield (over two steps), mp 222-224°C. ^! H-NM (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.47 (s, 2H), 5.42 (s, 1H), 4.09 (d, 2H, J = 4 Hz), 4.03 (t, 2H, J = 5 Hz), 3.93 (t, 2H, J = 5 Hz), 3.82 (m, 2H), 3.58, (t, 1H, J = 4 Hz), 3.38 (brs, 2H) 1.89, (t, 1H, J = 4 Hz), 1.76 (brs, 4H), 1.69 (brs, 2H), 1.44 (s, 36H). Anal. Calcd. for C, 67.33; H, 8.71; N, 2.12; S, 9.72. Found: C, 67.52; H, 8.82; N, 2.19; S, 9.48.

Example 110: l-[4-[3,5-Di-tert-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-tert- butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-4-hydroxy-bu tan-l-one

Ex. 110a: In a 100 mL round bottom flask 2,6-di-tert-butyl-4-{4-[3,5-di-tert-butyl-4-(2- hydroxy-ethoxy)-phenylsulfanyl]-piperidin-4-ylsulfanyl} -phenol (Ex. 102, 0.88 g, 1.46 mmol) was combined with anhydrous THF (36 mL) and DIPEA (0.76 mL, 4.38 mmol) and the resulting mixture was treated with 3-chlorocarbonyl-propionic acid methyl ester (0.18 mL, 1.46 mmol). HPLC indicated that the reaction was complete in 1 h. The reaction mixture was quenched with 0.5N HC1 and extracted with EtOAc. The organic was washed 1 :1 brine:water solution, dried over Na ₂ SC>4, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (50% EtOAc in hexanes) to provide 0.77 g (73%) of 4-[4-[3,5-di-½ri-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-¾ri-butyl-4- hydroxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo-butyric acid methyl ester as an off white solid, mp 98 °C. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.61 (s, 2H), 7.48 (s, 2H), 5.41 (s, 1H), 4.06- 4.01 (m, 2H), 3.95-3.92 (m, 2H), 3.81-3.61 (m, 7H), 2.64-2.56 (m, 4H), 1.90-1.92 (m, 3H), 1.66-1.70 (m, 2H), 1.44 (s, 36H). HRMS (ESI) Calcd. for C ₄ oH ₆ iN0 ₆ S2: 716.4018 (M+Fff. Found: 716.4023. Anal. Calcd. for C ₄ oH ₆ iN0 ₆ S ₂ : C, 67.09; H, 8.59; N, 1.96; S, 8.96. Found: C, 67.13; H, 8.62; N, 1.99; S, 8.80.

In a 50 mL round bottom flask, 4-[4-[3,5-di-½r/-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] - 4-(3 ,5-di-½ri-butyl-4-hydroxy-phenylsulfanyl)-piperidin- 1 -yl]-4-oxo-butyric acid methyl ester (Ex. 110a, 0.76 g, 1.07 mmol) was combined with anhydrous THF (15 mL) and lithium borohydride (2.13 mL, 4.27 mmol, 2M in THF). HPLC indicated that the reaction was complete after 1 h. The reaction mixture was quenched with 0.5N HC1 and extracted with EtOAc. The organic was washed with water, 1 :1 watenbrine solution, dried over magnesium sulfate, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (50% EtOAc in hexanes) to provide 0.36 g (49%) of the title compound as an off white solid, mp 1 17 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.60 (s, 2H), 7.48 (s, 2H), 5.41 (s, 1H), 4.08-3.91 (m, 4H), 3.82-3.59 (m, 6H), 2.76 (t, 1H, J = 5.4 Hz), 2.45 (t, 2H, J = 6.3 Hz), 1.93-1.77 (m, 5H), 1.70-1.66 (m, 2H), 1.44-1.43 (m, 36H). HRMS (ESI) Calcd. for C ₃ 9H ₆₁ N0 ₅ S2: 688.4069 (M+H) ⁺ . Found: 688.4047. Anal. Calcd. for C ₃ 9H ₆ iN0 ₅ S2: C, 68.08; H, 8.94; N, 2.04; S, 9.32. Found: C, 68.25; H, 9.08; N, 2.03; S, 9.03.

Example 111: l-[4-[3,5-Di-tert-butyI-4-(4-hydroxy-butoxy)-phenylsulfanyl] -4-(3,5-di- teri-butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-2-hydro xy-ethanone

Ex. 111a: Starting from 2,6-di-tert-butyl-4-{4-[3 ₅ 5-di-tert-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]piperidin-4-ylsulfanyl} phenol (Ex. 62c), acetic acid 2-[4- [3,5-di-½ri-butyl-4-(4-hydroxy-butoxy)-phenylsulfanyl]-4-(3 ,5-di-fer/-butyl-4-hydroxy- phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl ester was prepared in an analogous fashion as Ex. 83a; white foam in 85% yield. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.58 (s, 2H), 7.48 (s, 2H), 5.42 (s, 1H), 4.66 (s, 2H),3.74-3.79 (m, 6H), 3.50, (brs, 2H), 2.15 (s, 3H), 1.91-1.99, (m, 2H) 1.80 (brs, 2H), 1.70-1.74 (m, 4H), 1.44 (s, 18H), 1.42 (s, 18H). Starting from acetic acid 2-[4-[3,5-di-½ri-butyl-4-(4-hydroxy-butoxy)-phenylsulfanyl] -4- (3,5-di-ie^bu1yl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-2 -oxo-ethyl ester (Ex. 111a), the title compound was prepared in an analogous fashion as Ex. 83; a white foam in 34% yield (over two steps), mp 100-103 °C. Ή- M (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.47 (s, 2H), 5.42 (s, 1H), 4.08 (d, 2H, J= 4 Hz), 3.72-3.81 (m, 6H), 3.59 (t, 1H, J= 4 Hz), 3.38 (brs, 2H), 1.93-1.99 (m, 2H), 1.70-1.77 (m, 6H), 1.44 (s, 18H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C ₃ 9H ₆₁ N0 ₅ S2: 710.3889 (M+Na) ⁺ . Found: 710.3881.

Example 112: 5-[4-[3,5-Di-tert-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-feri- butyl-4-hydroxy-phenylsulfanyl)-piperidine-l-sulfonyl]-l-met hyl-lH-pyrrole-2- carboxylic acid

Ex. 112a: To a solution of 2,6-di-fer/-butyl-4-{4-[3,5-di-feri-butyl-4-(2-hydroxy-ethox y)- phenylsulfanyl]-piperidin-4-ylsulfanyl} -phenol (Ex. 102, 2.0 g, 3.3 mmol) in THF (50 mL) at rt was added DIPEA (1.7 mL, 10.0 mmol). Methyl (5-chlorosulfonyl)-l -methyl- lH-pyrrole- 2-carboxylate (0.87 g, 3.6 mmol) was added to the reaction and the resulting solution was stirred at rt for 2 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HCl (50 mL) and diluted with H ₂ 0 (200 mL) and EtOAc (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 100 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 0: 1 to 1:0) afforded 1.90 g (71%) of 5-[4-[3,5-di-ieri-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-½rr-butyl-4- hydroxy-phenylsulfanyl)-piperidine- 1 -sulfonyl]- 1 -methyl- 1 H-pyrrole-2-carboxylic acid methyl ester as an amorphous solid. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.50 (s, 2H), 7.38 (s, 2H), 7.19 (d, 1H, J = 1.2 Hz), 7.13 (d, 1H, J = 2.7 Hz), 5.41 (s, 1H), 4.04-3.92 (m, 7H), 3.86 (s, 3H), 3.17-3.10 (m, 4H), 2.05 (s, 1H), 1.92-1.84 (m, 4H), 1.43 (s, 36H). HRMS (ESI) Calcd. for C ₄₂ H ₆₂ N ₂ 0 ₇ S ₃ : 803.3797 (M+H) ⁺ . Found: 803.3817. Anal. Calcd. for C ₄ 2H ₆₂ N ₂ 0 ₇ S3: C, 62.81; H, 7.78; N, 3.49; S, 11.98. Found: C, 62.68; H, 7.85; N, 3.45; S, 11.71. To a solution of 5-[4-[3,5-di-/er/-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-/er - butyl-4-hydroxy-phenylsulfanyl)-piperidine- 1 -sulfonyl]- 1 -methyl- 1 H-pyrrole-2-carboxylic acid methyl ester (Ex. 112a, 0.70 g, 0.87 mmol) in THF (12 mL), MeOH (4 mL) and H ₂ 0 (4 mL) was added lithium hydroxide (0.10 g, 4.4 mmol) and the resulting solution was stirred at rt for 18 h. Upon completion, as determined by HPLC, the reaction was quenched with saturated 1 N HC1 (50 mL) and partitioned between H ₂ 0 (200 mL) and EtOAc (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 100 mL). The combined organic cuts were washed with saturated sodium bicarbonate solution (100 mL), dried over Na ₂ SC>4, and concentrated under reduced pressure. The solid was redissolved in EtOAc (200 mL), washed with 3 N HC1 (100 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 0: 1 to 1: 10) afforded 0.47 g (68%) of the title compound as a white solid, mp 126-129 °C. 'H-NMR (300 MHz, CDC1 ₃ ) δ 7.50 (s, 2H), 7.39 (s, 2H), 7.26-7.24 (m, 2H), 5.41 (s, 1H), 4.05-3.91 (m, 7H), 3.20-3.12 (m, 4H), 2.05 (s, 1H), 1.88-1.84 (m, 4H), 1.43 (s, 36H). HRMS (ESI) Calcd. for C ₄ iH ₆ oN ₂ 0 ₇ S ₃ : 789.3641 (M+H) ⁺ . Found: 789.3641. Anal. Calcd. for C ₄₁ H ₆₀ N ₂ O ₇ S ₃ -½H ₂ O: C, 61.70; H, 7.70; N, 3.51, S, 12.05. Found: C, 61.94; H, 7.74; N, 3.41; S, 11.46.

Example 113: 2,6-Di-teri-butyl-4-[4-[3,5-di-teri-butyl-4-(2-hydroxy-ethox y)- phenylsulfanyI]-l-(5-hydroxymethyl-l-methyl-lH-pyrroIe-2-sul fonyl)-piperidin-4- ylsulfanyl] -phenol

To a solution of 5-[4-[3,5-di-½ri-butyl-4-(2-hydroxy-ethoxy)-phenylsulfanyl] -4-(3,5-di-/'eri- butyl-4-hydroxy-phenylsulfanyl)-piperidine- 1 -sulfonyl]- 1 -methyl- 1 H-pyrrole-2-carboxylic acid methyl ester (Ex. 112a, 0.75 g, 0.93 mmols) in THF (25 mL) was added lithium borohydnde (2.8 mL, 5.6 mmol, 2.0M in THF) and the resulting solution was stirred at rt for 48 h. Additional lithium borohydnde (4.2 mL, 8.4 mmol, 2.0M in THF) was added and the resulting solution was stirred at rt for an additional 18 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (100 mL) and partitioned between H ₂ 0 (200 mL) and EtOAc (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 100 mL). The combined organic cuts were washed with brine (1 x 100 mL), dried over Na ₂ S0 _4, and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes 1 : 1) afforded 0.58 g (80%) of the title compound as a white solid, mp 109- 112 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.50 (s, 2H), 7.38 (s, 2H), 7.09 (d, 1H, J = 2.1 Hz), 6.33 (d, 1H, J = 1.8 Hz), 5.41 (s, 1H), 4.62 (d, 2H, J = 6.6 Hz), 4.09-3.92 (m, 4H), 3.76 (s, 3H), 3.17-3.08 (m, 4H), 2.04 (s, 1H), 1.90-1.80 (m, 4H), 1.43 (s, 36H). HRMS (ESI) Calcd. for C ₄ iH ₆₂ N ₂ 0 ₆ S ₃ : 797.3668 (M+Na) ⁺ . Found: 797.3675. Anal. Calcd. for C ₄ iH ₆₂ N ₂ 0 ₆ S ₃ : C, 63.53; H, 8.06; N, 3.61; S, 12.41. Found: C, 63.30; H, 8.23; N, 3.42; S, 11.32.

Example 114: 3-{4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di- teri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl}-3-oxo-propi onic acid

Ex. 114a: To a solution of 2,6-di-½r/-butyl-4-{4-[3,5-di-½ri-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 1.0 g, 1.7 mmol) in THF (40 mL) at rt was added DIPEA in one portion (0.90 mL, 5.2 mmol). Methyl-3- chlorooxopropionate (0.27 mL, 2.5 mmol) was added to the reaction and the resulting solution was stirred at rt for 3 hours. Upon completion, as determined by HPLC, the reaction was quenched with 0.5N HCl (75 mL) and diluted with EtOAc (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 100 mL). The combined organic cuts were washed with saturated NaHC0 ₃ solution (1 x 100 mL), brine (1 x 100 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1:5 to 1:1) afforded 0.84 g (62%) of malonic acid 2,6-di-/ert-butyl-4-[4- [3,5-di-iert-butyl-4-(3-hydroxy-propoxy)-phenylsulfanyl]-l-( 2-methoxycarbonyl-acetyl)- piperidin-4-ylsulfanyl] -phenyl ester methyl ester as an off-white solid, mp 57-61 °C. 1H- NMR (300 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.49 (s, 2H), 5.41 (s, 1H), 4.34 (t, 2H, J = 6.2 Hz), 3.83 (t, 4H, J= 7.0 Hz), 3.74 (s, 3H), 3.67 (s, 3H), 3.55 (t, 2H, J= 5.0 Hz), 3.42 (s, 2H), 3.39 (s, 2H), 2.24-2.20 (m, 2H), 1.81 (t, 2H, J = 5.3 Hz), 1.70 (t, 2H, J = 5.7 Hz), 1.56 (s, 1H), 1.43 (s, 36H). HRMS (ESI) Calcd. For C ₄₄ H ₆₅ N0 ₉ S ₂ : 816.4179. Found: 816.4163. To a solution of malonic acid 2,6-di-½r/-butyl-4-[4-[3,5-di-ieri-butyl-4-(3-hydroxy-propo xy)- phenylsulfanyl]- 1 -(2-methoxycarbonyl-acetyl)-piperidin-4-ylsulfanyl]-phenyl ester methyl ester (Ex. 114a, 0.85 g, 1.1 mmol) in THF (15 mL), MeOH (5 mL), H ₂ 0 (5 mL) was added lithium hydroxide (0.14 g, 5.9 mmol) and the resulting solution was stirred at rt for 3 h. Upon completion, as determined by HPLC, the reaction was quenched with IN HC1 (75 mL) and partitioned between H ₂ 0 (200 mL) and EtOAc (200 mL). The layers were cut and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic cuts were dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (MeOH:CH ₂ Cl ₂ , 1:20) afforded 0.18 g (25%) of the title compound as an off-white solid, mp 132-135 °C. ^! H-NMR (300 MHz, CDC1 ₃ ) δ 7.57 (s, 2H), 7.48 (s, 2H), 5.44 (s, 1H), 3.90-3.76 (m, 6H), 3.58 (t, 2H, J= 3.4 Hz), 3.29 (s, 2H), 2.16-2.12 (m, 2H), 1.79-1.74 (m, 4H), 1.44 (s, 36H). HRMS (ESI) Calcd. For Cs^NOeSz: 702.3844 (M+H) ⁺ . Found: 702.3862. Anal. Calcd. for C39H ₅₉ N0 ₆ S ₂ -lNa: C, 64.61; N, 8.20; N, 1.93; S, 8.85. Found: C, 64.63; H, 8.22; N, 1.98; S, 8.69.

Example 115: 2-{4-(3,5-Di-ieri-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di- tert-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidine-l-sulfonyl}-3H-i midazole-4-carbox lic acid

Ex. 115a: To a solution of 2,6-di-/ert-butyl-4-{4-[3,5-di-tert-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 0.40 g, 0.65 mmol) in THF (10 mL) at rt was added DIPEA (0.34 mL, 1.95 mmol). 2-Chlorosulfonyl-3H-imidazole-4- carboxylic acid ethyl ester (0.17 g, 0.72 mmol) was added to the reaction and the resulting solution was stirred at rt for 15 min. Upon completion, as determined by HPLC, the reaction was quenched with 0.1M citric acid (20 mL) and diluted with H ₂ 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic cuts were washed with brine (1 x 25 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1:1) afforded 0.45 g (85%) of 2-{4-(3,5-di-ierr-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di- ½rr- butyl-4-(3-hydroxy-propoxy)-phenylsulfanyl]-piperidine- 1 -sulfonyl} -3H-imidazole-4- carboxylic acid ethyl ester as a white foam, mp 148-150 °C. ^! H-NMR (400 MHz, CDC1 ₃ ) δ 7.75 (brs, 1H), 7.52 (s, 2H), 7.41 (s, 2H), 5.41 (s, 1H), 4.39 (q, 2H, J= 6.8 Hz), 3.86-3.90 (m, 4H), 3.44-3.48 (m, 4H), 2.13 (pentet, 2H, J= 6.4 Hz), 1.80-1.87 (m, 4H), 1.64 (t, 1H, J= 5.2 Hz), 1.43 (s, 18H), 1.41 (s, 18H), 1.39 (t, 3H, J = 6.8 Hz). HRMS (ESI) Calcd. for C ₄ 2H ₆ 3N30 ₇ S3: 731.4127 (M+H) ⁺ . Found: 731.4120. Anal. Calcd. for C ₄₂ H ₆₃ N ₃ 0 ₇ S3- ¹ ₄ hexanes: C, 62.40; H, 8.05; N, 4.96; S, 11.36. Found: C, 62.33; H, 8.15; N, 4.91; S, 11.24.

To a solution of 2-{4-(3,5-di-½r -butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-½ri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidine-l-sulfonyl}-3H-i midazole-4-carboxylic acid ethyl ester (Ex. 115a, 0.42 g, 0.51 mmol) in THF (5 mL), and MeOH (2 mL) was added a solution of sodium hydroxide (0.20 g, 5.1 mmol) in water (2 mL) and the resulting solution was stirred at rt for 3 days. Upon completion, as determined by HPLC, the reaction was quenched with 0.1M citric acid (30 mL) and partitioned between H ₂ 0 (30 mL) and EtOAc (30 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 30 mL). The combined organic cuts were washed with a 1:1 brine:water solution (1 x 25 mL), brine (1 x 25 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (10% MeOH:CH ₂ Cl ₂ to 15% MeOH/CH ₂ Cl ₂ containing 0.1% AcOH) provided a white foam. The solid was dissolved in EtOAc and washed with water (lx), filtered, concentrated under reduced pressure, and dried in a vacuum oven (60 °C, 30 psi) to afford 0.25 g (65%) of the title compound as an off-white solid, mp 84-86 °C. H-NMR (400 MHz, DMSO-ik) δ 8.44 (brs, 1H), 8.06 (s, 2H), 7.94 (s, 2H), 4.32 (t, 2H, J= 7.2 Hz), 4.17 (t, 2H, J= 6.4 Hz), 3.87-3.90 (m, 4H), 2.54 (pentet, 2H, J= 7.0 Hz), 2.27-2.29 (m, 4H), 1.89 (s, 18H), 1.88 (s, 18H). HRMS (ESI) Calcd. for C ₄₀ H59N3O ₇ S3: 790.3593 (M+H) ⁺ . Found: 790.3615. Anal. Calcd. for C, 61.61; H, 7.84; N, 5.13 S, 11.75. Found: C, 61.57; H, 7.90; N, 4.96; S, 11.43. Example 116: 3-({4-(3,5-Di-feri-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di -iert-butyl-4- (3-hydroxy-propoxy)-phenylsulfanyl]-piperidine-l-carbonyl}-a mino)-propionic acid

Ex. 116a: To a solution of 2,6-di-tert-butyl-4-{4-[3,5-di-/er/-butyl-4-(3-pyrazol-l-yl- propoxy)phenylsulfanyl]-piperidin-4-ylsulfanyl}phenol (Ex. 5, 0.75 g, 0.1.22 mmol) in THF (10 mL) was added 3-isocyanatopropionic acid ethyl ester (0.18 mL, 1.34 mmol) and the resulting solution was stirred at rt for 30 min. Upon completion, as determined by HPLC, the reaction was concentrated under reduced pressure. Silica gel chromatography (EtOAc:hexanes, 1 : 1 to 2:1) afforded 0.83 g (90%) of 3-({4-(3,5-di-½ri-butyl-4-hydroxy- phenylsulfanyl)-4-[3,5-di-½r/-butyl-4-(3-hydroxy-propoxy)-p henylsulfanyl]-piperidine-l- carbonyl}-amino)-propionic acid ethyl ester as a white foam, mp 158-160 °C. ^-NMR (400 MHz, CDC1 ₃ ) δ 7.59 (s, 2H), 7.47 (s, 2H), 5.39 (s, 1H), 5.13 (t, 2H, J = 6.0 Hz), 4.13 (q, 2H, J = 7.2 Hz), 3.86-3.91 (m, 4H), 3.44-3.52 (m, 6H), 2.51 (t, 2H, J = 6.0 Hz), 2.14 (t, 2H, J = 6.8 Hz), 1.72-1.75 (m, 4H), 1.44 (s, 18H), 1.43 (s, 18H), 1.26 (t, 3H, J = 7.2 Hz). HRMS (ESI) Calcd. for C42H66N2O7S2: 759.4440 (M+H) ⁺ . Found: 759.4446. Anal. Calcd. for C ₄₂ H ₆ 6N20 ₇ S2- ¹ / ₄ hexanes: C, 67.08; H, 9.04; N, 3.56; S, 8.14. Found: C, 66.94; H, 9.04; N, 3.65; S, 8.00.

To a solution of 3-({4-(3,5-di-/eri-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di -½ri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidine-l-carbonyl}-amin o)-propionic acid ethyl ester (Ex. 116a, 0.81 g, 1.1 mmol) in THF (3 mL), and MeOH (1 mL) was added a solution of lithium hydroxide (0.13 g, 5.3 mmol) in water (1 mL) and the resulting solution was stirred at rt for 1 h. Upon completion, as determined by HPLC, the reaction was quenched with 0.1M citric acid (20 mL) and partitioned between ¾0 (20 mL) and EtOAc (20 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 20 mL). The combined organic cuts were washed with a 1 : 1 brine:water solution (1 x 25 mL), brine (1 x 25 mL), dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. Silica gel chromatography (10% MeOH/CH ₂ Cl ₂ ) afforded 0.38 g (50%) of the title compound as a white solid, mp 130- 131 °C. ^! H-NMR (400 MHz, DMSO-t¼) δ 7.50 (s, 2H), 7.34 (s, 2H), 6.48 (d, 1H, J = 4.8 Hz), 4.53 (s, 1H), 3.73 (t, 2H, J = 7.2 Hz), 3.52 (t, 2H, J = 6.0 Hz), 3.35-3.38 (m, 4H), 3.09- 3.12 (m, 2H), 2.23-2.27 (t, 2H, J= 7.2 Hz), 1.94 (pentet, 2H, J= 12 Hz), 1.53 (brs, 4H), 1.37 (s, 18H), 1.36 (s, 18H). HRMS (ESI) Calcd. for C ₄ oH6 ₂ N ₂ 0 ₇ S ₂ : 790.3593 (M+H) ⁺ . Found: 790.3615. Anal. Calcd. for C ₄ oH62N ₂ 0 ₇ S ₂ : C, 66.39; H, 8.84; N, 3.69; S, 8.44. Found: C, 66.10; H, 8.88; N, 3.59; S, 8.14.

Example 117: 5-[4-[3,5-Di-ieri-butyl-4-(4-hydroxy-butoxy)-phenylsulfanyl] -4-(3,5-di- tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-l-sulfonyl]- l-methyl-lH-pyrrole-2- carboxylic acid

Ex. 117a: Starting from ,6-di-fe? -butyl-4-{4-[3,5-di-teri-butyl-4-(4- hydroxybutoxy)phenylsulfanyl]piperidin-4-ylsulfanyl}phenol (Ex. 62c), 5-[4-[3> ,5-di-tert- butyl-4-(4-hydroxy-butoxy)-phenylsulfanyl]-4-(3,5-di-tert-bu tyl-4-hydroxy-phenylsulfanyl)- piperidine-l-sulfonyl]-l -methyl- lH-pyrrole-2-carboxylic acid methyl ester was prepared in an analogous fashion as Ex. 68a; white foam in 81% yield. ^-NMR (300 MHz, CDC1 ₃ ) δ 7.47 (s, 2H), 7.38 (s, 2H), 7.19 (d, 1H, J = 1.8 Hz), 7.12 (d, 1H, J = 1.8 Hz), 5.41 (s, 1H), 4.00 (s, 3H), 3.86 (s, 3H), 3.77-3.72 (m, 4H), 3.19-3.13 (m, 2H), 3.13-3.07 (m, 2H), 1.98- 1.93 (m, 2H), 1.89-1.82 (m, 4H), 1.72-1.67 (m, 2H), 1.43 (s, 18H), 1.40 (s, 18H). HRMS (ESI) Calcd. for C ₄₄ H ₆₆ N ₂ 0 ₇ S3 : 853.3930 (M+Na) ⁺ . Found: 853.3920.

Starting from 5 - [4- [3 ,5 -di-½ri-butyl-4-(4-hydroxy-butoxy)-pheny lsulfany 1] -4-(3 ,5 -di-tert- butyl-4-hydroxy-phenylsulfanyl)-piperidine- 1 -sulfonyl] - 1 -methyl- lH-pyrrole-2-carboxylic acid methyl ester (Ex. 117a), the title compound was prepared in an analogous fashion as Ex. 69; white foam in 75% yield, mp 1 15-120 °C. Ή-NMR (300 MHz, CDC1 ₃ ) δ 7.45 (s, 2H), 7.36 (s, 2H), 7.23 (d, 1H, j = 1.4 Hz), 7.22 (d, 1H, J = 1.4Hz), 5.39 (s, 1H), 3.99 (s, 3H), 3.73-3.71 (m, 4H), 3.20-3.13 (m, 2H), 3.12-3.06 (m, 2H), 1.96-1.90 (m, 2H), 1.88-1.78 (m, 4H), 1.70-1.64 (m, 2H), 1.40 (s, 18H), 1.37 (s, 18H). HRMS (ESI) Calcd. for C ₄₃ H ₆₄ N ₂ 0 ₇ S ₃ : 839.3733 (M+Na) ⁺ . Found: 839.3792. EA Calcd. for C ₄ 3H ₆ 4N20 ₇ S3 : C, 63.20; H, 7.89; N, 3.43; S, 11.77. Found: C, 62.98; H, 7.80; N, 3.39; S, 11.55.

Example 118 In vitro cytokine assays

Compounds at dosing concentrations (with 0.2% DMSO vehicle) were incubated in EGM2MV cell media at 37°C for overnight, added to 96-well plates seeded with confluent human pulmonary artery endothelial cells (HPAEC) for 20 hrs at 37°C, and then replaced with fresh dosing media containing 2ng/ml tumor necrosis factor alpha for additional 4 hrs at 37°C. Afterwards, media was removed and used in ELISA assay to quantify the amount of IL-6 and IL-8 secreted by the cells using R&D Systems Duoset ELISA kits. Data of compounds from this assay is reported in Table 1.

Example 119 Asthma model in vivo

Male 5-6 week old Balb/CJ mice were obtained from Jackson Laboratories (Bar Harbor, ME). All experimental animals were used in accordance to Institutional Animal Care and Use Committee of AtheroGenics, Inc. Mice were sensitized by administering an intraperitoneal injection of 20 μg of ovalbumin (Calbiochem, La Jolla, Ca) adsorbed in 2 mg of alum (Imject Alum; Pierce, Rockford, 111) on day 0 and 14. A group of mice received saline and served as negative control animals. The mice were challenged by aerosol exposure to ovalbumin (1% [wt/vol]) for 25 minutes on 3 consecutive days (days 28, 29, and 30) in a plexiglas exposure chamber coupled to an Aeroneb nebulizer (Buxco Electronics,

Wilmington, NC). Experimental compounds were dissolved in Glycofurol/PEG 300/Tween (35%/55%/10%) (Sigma-aldrich; Milwaukee, WI). Animals were dosed orally with either test compound or vehicle (6 ml/kg dosing volume) on days 26 - 32 of study. Compound or vehicle was administered 2 hour before the aerosol challenge on days 28, 29, and 30 and 1 hour before airway reactivity measurement on day 32.

Methacholine-induced airway reactivity was assessed on day 32. Methacholine was administered in increasing concentrations (0.375, 0.77, 1.5, 3, 6, 12, 25, and 50 mg/ml) to unrestrained mice. Increases in airway resistance to Methacholine were determined as enhanced pause, (Penh) values, during and after the exposure (6-minute total analysis time). Mice were then humanely euthanized with an overdose of ketamine/xylazine and plasma samples collected for determination of drug levels. The data is presented as the % inhibition of the PenH vs McH dose AUC compared with the vehicle control. Data analysis was conducting using the software package, JMP (SAS Institute Inc; Cary, NC). The Dunnett's multiple comparison test was used to compare treatment group means to the vehicle control group. P values of less than 0.05 were considered statistically significant. The data (Table 1) is presented as the % inhibition of the PenH vs McH dose AUC compared with the vehicle control.

Table 1. Biological data of compounds

Example Inhibition (%) of lL- Inhibition (%) of IL-6 at 10 Reduction of Penh

No. 8 at 10 microM microM AUC at 50 mg/kg p.o.

1 62 56, 18 3

2 not tested not tested 3

3 not tested not tested not tested

4 not tested not tested 2

5 not tested not tested 2

6 not tested not tested 3

7 not tested not tested 2

8 80, 56 100, 76 3

9 61, 51 58, 0 3

10 30, 27 40, 37 3

11 0 0 2

12 not tested not tested 2

13 90 63, 57 1

14 80, 99 97, 100 3

15 63, 34 89, 80 2

16 16, 10 20, 34 2

17 not tested not tested 3

18 0, 0 53, 53 3

19 0, 0 60, 60 not tested

20 not tested 28, 28 2

21 0, 0 45, 45

22 3

23 21, 40 27, 20 2

24 100, 100 100, 100 not tested 82, 79 78, 67 2

0, 69 66, 84 3

9,21 18,7 2

25,0 10, 10 2

100 83,93 1

69 6 2

53, 16 66,56 2

61 9 3

21,2 78,54 3

0,0 44, 44 3

0,0 34, 34 not tested

64 59 3

15,0 0,0 2

62, 29 88,73 2

66, 64 100, 99 2 t tested not tested 2

0,0 51, 16 2

34, 27 96, 81 2

18,0 13,9 2

42,6 0,0 3

12, 10 29, 54 2

80, 66 100, 94 3 t tested not tested 3

69, 59 75,0 3

23, 10 26, 36 3 t tested not tested 3 t tested not tested 3

57,0 34, 62 3

76, 83 97, 92 2

0, 54 0,38 3 t tested not tested not tested t tested not tested 2

50, 20 66, 77 2 92, 68 100, 100 2 100, 100 100, 100 2 17,0 10, 89 3 23,0 28,40 1 100, 68 100, 82

100, 33 93,81 2 100, 59 93, 89 3 100,9 89, 82 3 100, 55 77, 81 2ot tested not tested 3ot tested not tested 2 89 81 1 ot tested not tested 3 ot tested not tested 3 ot tested not tested 2 92 51 2 ot tested not tested 2 ot tested not tested 2

99 98 3

53 19 3 ot tested not tested 3 ot tested not tested not tested 0,0 0,0 3 54 6 2 ot tested not tested not tested ot tested not tested not tested 34,33 25,0 2 0,0 55, 55 3 ot tested not tested not tested ot tested not tested not tested 0, 15 40,37 3 0,0 0,0 2 23, 10 26, 19 3 91 85, 0, 6 2

92 100 96, 53 2

93 0, 0 59, 33 3

94 0, 0 0, 5 not tested

95 66, 0 85, 57 3

96 1

97 100, 100 100, 100 3

98 50, 0 87, 69 3

99 99, 100 98, 100 3

100 100, 89 99, 95 3

101 15, 38 100, 58 2

102 100, 100 100, 100 2

103 52, 2 31, 15 3

104 98, 100 100, 100 3

105 56, 65 58, 68 3

106 not tested not tested 3

107 100, 97 100,100 2

108 not tested not tested 1

109 66, 38 92, 88 2

110 84, 17 94, 89 2

111 78, 65 91, 94 3

112 not tested not tested 3

113 not tested not tested 3

114 not tested not tested 3

115 not tested not tested not tested

116 not tested not tested not tested

117 not tested not tested 2 : >40% and statistically significant

: 20-40% and either statistically significant or not

: <20% (no significant activity)