US 2006O128764A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0128764 A1 DOWnes et al. (43) Pub. Date: Jun. 15, 2006 (54) NON-STEROIDAL FARNESOD X Publication Classification RECEPTOR MODULATORS AND METHODS FOR THE USE THEREOF (51) Int. Cl. A61K 31/4433 (2006.01) (75) Inventors: Michael R Downes, San Diego, CA A6II 3/44 (2006.01) (US); Ronald M Evans, La Jolla, CA A6II 3 L/353 (2006.01) (US) A6II 3/16 (2006.01) (52) U.S. Cl. ........................... 514/357: 514/456; 514/625 Correspondence Address: FOLEY & LARDNER LLP P.O. BOX 80278 (57) ABSTRACT SAN DIEGO, CA 92138-0278 (US) The efficient regulation of cholesterol synthesis, metabo (73) Assignee: THE SALK INSTITUTE FOR BIO lism, acquisition, and transport is an essential component of LOGICAL STUDES lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of (21) Appl. No.: 10/535,043 cholesterol metabolism. Accordingly, the development of potent, selective, Small molecule agonists, partial agonists, (22) PCT Fed: Nov. 14, 2003 and antagonists of FXR would be an important step in PCT No.: PCT/USO3/36137 further deconvoluting FXR physiology. In accordance with (86) the present invention, the identification of novel potent FXR Related U.S. Application Data activators is described. Two derivatives of invention com pounds, bearing stilbene or biaryl moieties, contain mem (60) Provisional application No. 60/426,664, filed on Nov. bers that are the most potent FXR agonists reported to date 15, 2002. in cell-based assays. These compounds are useful as chemi cal tools to further define the physiological role of FXR as (30) Foreign Application Priority Data well as therapeutic leads for the treatment of diseases linked to cholesterol, bile acids and their metabolism and homeo Sep. 8, 2003 (US)......................................... 10/658,115 Stasis. Patent Application Publication Jun. 15, 2006 US 2006/0128764 A1 NER response element Cell based Assay FKRRXR on a FXRRE 2. d 2000 D OOOOO h R - - S GM ugh Conc of CDCA FXR efficacy on a 384 well plate. Figure 1 US 2006/0128764 A1 Jun. 15, 2006 NON-STEROIDAL FARNESOD X RECEPTOR 0005. In this circuit FXR induces the expression of a MODULATORS AND METHODS FOR THE USE transcriptional repressor SHP (small heterodimer partner) THEREOF which in turn binds to LRH-1 (liver receptor homolog), which is required in CYP7A activation. Additionally, both FIELD OF THE INVENTION LXR and FXR are implicated in the regulation of several other gene products involved in cholesterol absorption, 0001. The present invention relates to new chemical metabolism and transport. entities. In a particular aspect, the present invention relates to non-steroidal modulators of farnesoid X receptors (FXR). 0006 Thus, the identification of potent, selective, small In another aspect, the present invention relates to methods molecule FXR agonists, partial agonists and antagonists for modulating FXR-mediated processes employing the would be powerful tools and would have many potential novel compounds described herein. applications. For example, such compounds would facilitate the in vivo analysis of FXR physiology in vivo. In addition, BACKGROUND OF THE INVENTION Such compounds, in conjunction with DNA arraying tech nology, might allow for the discovery of new gene products 0002 The following discussion of the background of the under the control of FXR. Further, FXR modulators might invention is merely provided to aid the reader in understand find potential utility in the treatment of cholestasis and other ing the invention and is not admitted to describe or constitute disease states associated with aberrant levels, flow and prior art to the present invention. release of bile acids. Moreover, in the absence of a crystal 0003. The efficient regulation of cholesterol biosynthesis, structure of FXR, a thorough structure-activity relationship metabolism, acquisition and transport is an essential func (SAR) study of ligands that modulate the activity of FXR tion of mammalian cells. High levels of cholesterol are would allow for the delineation of the structural require associated with atherosclerosis, a leading cause of death in ments for ligand binding and might aid in the design of the western world and a major risk factor correlated with the future ligands and potential therapeutics. occurrence of coronary heart disease and stroke. Until SUMMARY OF THE INVENTION recently, recommendations for the treatment of hypercho 0007. In accordance with the present invention, the iden lestemia were focused on the use of statins, which inhibit the tification of novel potent FXR activators is described. Initial de novo biosynthesis of cholesterol, and the use of bile acid screening of a 10,000-membered, diversity-orientated sequestering agents. While statin-based agents are still in library of benzopyran containing small molecules for FXR widespread use as cholesterol-lowering drugs, an evolving activation utilizing a cell-based reporter assay led to the understanding of the mechanisms controlling cholesterol identification of several lead compounds owning low micro homeostasis has led to new molecular targets as candidates molar activity (ECss=5-10 uM. These compounds were in therapeutic intervention. systematically modified employing parallel solution-phase 0004 Cholesterol metabolism is controlled through a synthesis and solid-phase synthesis to provide numerous complex feedback loop involving cholesterol itself and bile compounds that potently activate FXR. Two derivatives of acids (which are primary oxidation products), and through invention compounds, bearing Stilbene or biaryl moieties, secretion in the gut, the single most critical regulators of contain members that are the most potent FXR agonists cholesterol absorption. The nuclear receptors LXR (liver X reported to date in cell-based assays. These compounds are receptor) and FXR (farnesoid X receptor) are the specialized useful as chemical tools to further define the physiological sensors of cholesterol and bile acids that control transcrip role of FXR as well as therapeutic leads for the treatment of tion of networks encoding key metabolic enzymes. For diseases linked to cholesterol, bile acids and their metabo example activation of LXR by oxysterols (i.e., mono-oxy lism and homeostasis. genated cholesterol metabolites) leads to the up-regulation of CYP7A1, the enzyme that catalyzes the rate limiting step BRIEF DESCRIPTION OF THE FIGURE in the conversion of cholesterol to bile acids. In turn, bile 0008 FIG. 1 summarizes the efficacy of the functional acids such as chenodeoxycholic acid (CDCA, 1, a low assay for the identification of FXR agonists, using the affinity endogenous agonist for FXR, whose structure is known FXR agonist, chenodeoxycholic acid (CDCA). shown below) are potent ligands for FXR, whose activation DETAILED DESCRIPTION OF THE leads to down-regulation of CYP7A1, leading to the INVENTION completion of the feedback circuit. 0009. In accordance with the present invention, there are provided compounds having the structure: US 2006/0128764 A1 Jun. 15, 2006 wherein: 0022. As employed herein, “alkenyl refers to straight or branched chain hydrocarbyl groups having at least one 0010) A is a C3 up to C8 branched chain alkyl or carbon-carbon double bond, and having in the range of about substituted alkyl group, a C3 up to C7 cycloalkyl or sub 2 up to 20 carbon atoms, and “substituted alkenyl refers to stituted cycloalkyl, an optionally Substituted aryl or an alkenyl groups further bearing one or more Substituents as optionally substituted heteroaryl, set forth above. 0011 X is C(O) or -CH , 0023. As employed herein, “alkoxy' refers to —O-alkyl groups having in the range of 2 up to 20 carbon atoms and 0012 R is methyl or ethyl, “substituted alkoxy” refers to alkoxy groups further bearing 0013) R' is H, hydroxy, alkoxy, benzoyloxy, mesityloxy, one or more substituents as set forth above. or —OCHC(O)OCH, 0024. As employed herein, "cycloalkyl refers to a cyclic 0014) R is H or R can cooperate with R to form a ring-containing groups containing in the range of about 3 up to about 8 carbon atoms, and “substituted cycloalkyl refers benzopyran, wherein the pyran ring has the structure: to cycloalkyl groups further bearing one or more substitu ents as set forth above. 0025. As employed herein, "heterocyclic” refers to cyclic (i.e., ring-containing) groups containing one or more het eroatoms (e.g., N, O, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and “substituted heterocyclic” refers to heterocyclic groups further bearing one or more substituents as set forth above. 0026. As employed herein, “aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms and “substituted aryl refers to aryl groups further bearing one or more substituents as set forth above. 0.015 wherein: 0027. As employed herein, “aryloxy” refers to O-aryl 0016 R is not present if the pyran ring is unsatur groups having in the range of 6 up to 14 carbon atoms and ated, or, if present, is selected from H. —OR, “substituted aryloxy' refers to aryloxy groups further bear wherein R is alkyl or acyl, or R can cooperate with ing one or more Substituents as set forth above. R” to form a cyclic acetal, a cyclic ketal, or a 0028. As employed herein, “arylalkenyl refers to aryl cyclopropyl moiety, and substituted alkenyl groups and “substituted arylalkenyl 0017 only one of R7 and R is present if the pyran refers