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  Quinazolinone modulators of nuclear receptorsThe Patent Description & Claims data below is from USPTO Patent Application 20080070864. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001]Quinazolinones, compositions containing quinazolinones and methods for modulating the activity of nuclear receptors using quinazolinones are provided. In particular, quinazolinones are provided for modulating the activity of FXR and orphan nuclear receptors. BACKGROUND OF THE INVENTION [0002]Nuclear Receptors [0003]Nuclear receptors are a superfamily of regulatory proteins that are structurally and functionally related and are receptors for, e.g., steroids, retinoids, vitamin D and thyroid hormones (see, e.g., Evans (1988) Science 240:889-895). These proteins bind to cis-acting elements in the promoters of their target genes and modulate gene expression in response to ligands for the receptors. [0004]Nuclear receptors can be classified based on their DNA binding properties (see, e.g., Evans, supra and Glass (1994) Endocr. Rev. 15:391-407). For example, one class of nuclear receptors includes the glucocorticoid, estrogen, androgen, progestin and mineralocorficoid receptors which bind as homodimers to hormone response elements (HREs) organized as inverted repeats (see, e.g., Glass, supra). A second class of receptors, including those activated by retinoic acid, thyroid hormone, vitamin D.sub.3, fatty acids/peroxisome proliferators (i.e., peroxisome proliferator activated receptor (PPAR)) and ecdysone, bind to HREs as heterodimers with a common partner, the retinoid X receptors (i.e., RXRs, also known as the 9-cis retinoic acid receptors; see, e.g., Levin et al. (1992) Nature 355:359-361 and Heyman et al., (1992) Cell 68:397-406). [0005]RXRs are unique among the nuclear receptors in that they bind DNA as a homodimer and are required as a heterodimeric partner for a number of additional nuclear receptors to bind DNA (see, e.g., Mangelsdorf et al. (1995) Cell 83:841-850). The latter receptors, termed the class II nuclear receptor subfamily, include many which are established or implicated as important regulators of gene expression. There are three RXR genes (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329-344), coding for RXR.alpha., -.beta., and -.gamma., all of which are able to heterodimerize with any of the class II receptors, although there appear to be preferences for distinct RXR subtypes by partner receptors in vivo (see, e.g., Chiba et al. (1997) Mol. Cell. Biol. 17:3013-3020). In the adult liver, RXR.alpha. is the most abundant of the three RXRs (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329-344), suggesting that it might have a prominent role in hepatic functions that involve regulation by class II nuclear receptors. See also, Wan et al. (2000) Mol. Cell. Biol. 20:4436-4444. [0006]Orphan Nuclear Receptors [0007]Included in the nuclear receptor superfamily of regulatory proteins are nuclear receptors for whom the ligand is known and those which lack known ligands. Nuclear receptors falling in the latter category are referred to as orphan nuclear receptors. The search for activators for orphan receptors has led to the discovery of previously unknown signaling pathways (see, e.g., Levin et al., (1992), supra and Heyman et al., (1992), supra). For example, it has been reported that bile acids, which are involved in physiological processes such as cholesterol catabolism, are ligands for FXR (infra). [0008]Since it is known that products of intermediary metabolism act as transcriptional regulators in bacteria and yeast, such molecules may serve similar functions in higher organisms (see, e.g., Tomkins (1975) Science 189:760-763 and O'Malley (1989) Endocrinology 125:1119-1120). For example, one biosynthetic pathway in higher eukaryotes is the mevalonate pathway, which leads to the synthesis of cholesterol, bile acids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitamin D, steroid hormones and farnesylated proteins. [0009]FXR [0010]FXR (originally isolated as RIP14 (retinoid X receptor-interacting protein-14), see, e.g., Seol et al. (1995) Mol. Endocrinol. 9:72-85) is a member of the nuclear hormone receptor superfamily and is primarily expressed in the liver, kidney and intestine (see, e.g., Seol et al., supra and Forman et al. (1995) Cell 81:687-693). It functions as a heterodimer with the retinoid X receptor (RXR) and binds to response elements in the promoters of target genes to regulate gene transcription. The FXR-RXR heterodimer binds with highest affinity to an inverted repeat-1 (IR-1) response element, in which consensus receptor-binding hexamers are separated by one nucleotide. FXR is part of an interrelated process, in that FXR is activated by bile acids (the end product of cholesterol metabolism) (see, e.g., Makishima et al. (1999) Science 284:1362-1365, Parks et al. (1999) Science 284:1365-1368, Wang et al. (1999) Mol. Cell. 3:543-553), which serve to inhibit cholesterol catabolism. See also, Urizar et al. (2000) J. Biol. Chem. 275:39313-39317. [0011]Nuclear Receptors and Disease [0012]Nuclear receptor activity, including FXR and/or orphan nuclear receptor activity has been implicated in a variety of diseases and disorders, including, but not limited to, hypercholesterolemia, and complications thereof, including without limitation coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis and xanthoma, (see, e.g., International Patent Application Publication No. WO 00/57915), osteoporosis and vitamin deficiency (see, e.g., U.S. Pat. No. 6,316,5103), hyperlipoproteinemia (see, e.g., International Patent Application Publication No. WO 01/60818), hypertriglyceridemia, lipodystrophy, peripheral occlusive disease, ischemic stroke, hyperglycemia and diabetes mellitus (see, e.g., International Patent Application Publication No. WO 01/82917), disorders related to insulin resistance including the cluster of disease states, conditions or disorders that make up "Syndrome X" such as glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, hypertension, hyperuricemia, smaller denser low-density lipoprotein particles, and higher circulating levels of plasminogen activator inhibitor-1, atherosclerosis and gallstones (see, e.g., International Patent Application Publication No. WO 00/37077), disorders of the skin and mucous membranes (see, e.g., U.S. Pat. Nos. 6,184,215 and 6,187,814, and International Patent Application Publication No. WO 98/32444), obesity, acne (see, e.g., International Patent Application Publication No. WO 00/49992), and cancer, Parkinson's disease and Alzheimer's disease (see, e.g., International Patent Application Publication No. WO 00/17334). The activity of nuclear receptors, including FXR and/or orphan nuclear receptors, has been implicated in physiological processes including, but not limited to, bile acid biosynthesis, cholesterol metabolism or catabolism, and modulation of cholesterol 7.alpha.-hydroxylase gene (CYP7A1) transcription (see, e.g., Chiang et al. (2000) J. Biol. Chem. 275:10918-10924), HDL metabolism (see, e.g., Urizar et al. (2000) J. Biol. Chem. 275:39313-39317), hyperlipidemia, cholestasis, and increased cholesterol efflux and increased expression of ATP binding cassette transporter protein (ABC1) (see, e.g., International Patent Application Publication No. WO 00/78972). [0013]Thus, there is a need for compounds, compositions and methods of modulating the activity of nuclear receptors, including FXR and/or orphan nuclear receptors. Such compounds are useful in the treatment, prevention, or amelioration of one or more symptoms of diseases or disorders in which nuclear receptor activity is implicated. SUMMARY OF THE INVENTION [0014]Compounds for use in compositions and methods for modulating the activity of nuclear receptors are provided. In particular, compounds for use in compositions and methods for modulating famesoid X receptor (FXR) and/or orphan nuclear receptors, are provided. In certain embodiments, the compounds are quinazolinones. In one embodiment, the compounds provided herein are agonists of FXR. In another embodiment, the compounds provided herein are antagonists of FXR. Agonists that exhibit low efficacy are, in certain embodiments, antagonists Antagonists include both competitive and non-competitive antagonists. In another embodiment the compound is an inverse agonist, partial agonist or partial antagonist [0015]In one embodiment, the compounds for use in the compositions and methods provided herein have formula (I): wherein: [0016]m is an integer from 0 to 4; [0017]R.sup.1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, --OR.sup.7 or --N(R.sup.8)R.sup.9, with the proviso that R.sup.1 is not 3- or 4-(1,1,1,3,3,3-hexafluoro-2-hydroxy-2-propyl)phenyl; [0018]R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are selected from (a) and (b) as follows: [0019](a) R.sup.2 and R.sup.3 are selected from (i) and (ii) as follows: (i) R.sup.2 and R.sup.6 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocyclylalkyl; or (ii) R.sup.2 and R.sup.6 together form optionally substituted alkylene or optionally substituted alkenylene; and [0020]R.sup.4 and R.sup.5 are selected from (i) and (ii) as follows: (i) R.sup.4 and R.sup.5 are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, --N(R.sup.8)R.sup.9, --OR.sup.7, --S(O).sub.jR.sup.11 where j is 1 or 2, --B(R.sup.22).sub.2, --P(R.sup.22).sub.2, --P(O)(R.sup.22).sub.2 and --C(E)R.sup.23, where E is selected from O, S and NR.sup.7; or (ii) R.sup.4 and R.sup.5 together form optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkyleneoxyalkylene or optionally substituted alkyleneazaalkylene; or [0021](b) R.sup.2 and R.sup.5, or R.sup.2 and R.sup.4, or R.sup.6 and R.sup.5, or R.sup.6 and R.sup.4, together form a 4, 5, 6 or 7 membered optionally substituted heterocyclyl group, or a 5 or 6 membered optionally substituted heteroaryl group; and the remainder of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are each independently selected as in (i) above; [0022]each R.sup.3 is independently selected from the group consisting of halo, pseudohalo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, --N(R.sup.12)R.sup.13, --OR.sup.14, --C(E)R.sup.15 where E is O, S or NR.sup.7, and --S(O).sub.yR.sup.16 where y is 0, 1 or 2; [0023]or any two R.sup.3 groups, which substitute adjacent carbons on the ring, together form optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkylenedioxy, optionally substituted thioalkylenoxy, or optionally substituted alkylenedithioxy; Continue reading... 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