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WO 2013/033310 Al 7 March 2013 (07.03.2013) P O P C T

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WO 2013/033310 Al 7 March 2013 (07.03.2013) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/033310 Al 7 March 2013 (07.03.2013) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, H04N 9/07 (2006.01) C07D 409/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C07D 495/02 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (21) International Application Number: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, PCT/US20 12/053006 NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 30 August 2012 (30.08.2012) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/529,433 31 August 201 1 (3 1.08.201 1) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicants : KAMENECKA, Theodore Mark [US/US]; MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 50 Stoney Drive, Palm Beach Gardens, Florida 33410 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (US). BURRIS, Thomas [US/US]; 163 10 75th Avenue ML, MR, NE, SN, TD, TG). North, Palm Beach Gardens, Florida 33418 (US). Published: (74) Agents: PERDOK SHONKA, Monique M., USPTO — with international search report (Art. 21(3)) Reg. No. 42,989 et al; Schwegman, Lundberg & Woess- ner, P.A., P. O. Box 2938, Minneapolis, Minnesota 55402 — before the expiration of the time limit for amending the (US). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, — with sequence listing part of description (Rule 5.2(a)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: MODULATORS OF REV-ERB < © © (57) Abstract: The subject matter herein concerns the identification and development of potent synthetic REV-ERB ligands, such as o in vivo agonists and antagonists. These compounds allow for characterization of the effects of modulation of this receptor in vivo specifically on circadian behavior and metabolism, and have suitable characteristics for development of medicinal compounds useful for treatment of malconditions such as diabetes, obesity, atherosclerosis, dyslipidemia, a circadian rhythm disorder, coronary artery disease, bipolar disorder, depression, cancer, a sleep disorder, an anxiety disorder, an addiction disorder, or an autoimmune disorder. MODULATORS OF REV-ERB CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. provisional application serial number 61/529,433, filed August , 20 1, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under grant number DK0802Q1, awarded by the National Institutes of Health. The U.S. government certain rights in the invention. Synchronizing rhythms of behavior and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors RE V ERBa and -E play an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Administration of synthetic REV-ERB ligands alters circadian behavior and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle, and adipose tissue was also altered resulting in increased energy expenditure. Treatment of diet -induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dysiipidemia and hyperglycemia. These results suggest that ligands that pharmaco logically target the circadian rhythm may hold utility in the treatment of sleep disorders as we l as metabolic diseases. In mammals, most if not all tissues display a self-sustaining circadian molecular pacemaker that is responsible for aligning rhythms in various physiological functions. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian pacemaker synchronizing behavioral and physiological rhythms to the environmental light-dark cycle1. The regulation of clocks residing outside of the SCN in peripheral tissues is less clear. Optimal coordination of rhythms in metabolic processes with nutrient availability involves signals emanating from the SCN and hypothalamus, as well as autonomous inputs from nutrient-sensors responding to metabolic flux and body temperature 2. The mammalian molecular clock is composed of a transcriptional feedback loop where the heterodimers of the transcription factors BMAL1 (brain and muscle ARNT-iike protein 1) and CLOCK (circadian locomotor output cycles kaput) or NPAS2 (Neuronal PAS domain-containing protein 2) activate the transcription of the Period (Perl, Perl and Peri) and Crytochrome (Cry] and Cry!) genes. Subsequently the PER/CRY proteins feedback to inhibit BMALI /CLOCK activity resulting in a rhythmic, circadian pattern of expression of these genes3. Members of the REV-ERB group of nuclear receptors also have an important role in feedback regulation of the circadian oscillator. Both Bmail and Clock are direct REV-ERB target genes , and loss of REV-E B alters circadian behavior 4. The physiological iigand for REV-ERBa and β was recently identified as heme, and the suppression of expression of REV-ERB target genes is heme-dependent"' '. Based on observations that REV-ERB activity is regulated by a small molecule ligand, we and others have sought to identify and characterize synthetic ligand s. Unfortunately, the characteristics of the compounds identified thus far- ruled out evaluating their effects on modulating REV-ERB activity in vivo8 i j . Anxiety disorders are among the most common mental disorders and nearly 30% of individuals will be directly affected by an anxiety disorder at some point in their lifetime, thus these disorders significantly burden our society. Common pharmacological treatments for anxiety are γ-aminobutyric acid (GABA) receptor agonists (e.g. benzodiazapenes), selective serotonin and/or norepinephrine reuptake inhibitors (SSRls/SNRls; e.g. fiuoxitene, duloxitine) and serotonin (5-HT) receptor agonists (e.g. buspirone). GABA receptor agonists typically act very rapidly and exhibit very good efficacy, but are associated with dependence/tolerance and sedation. SSRI/SNRI antidepressants are utilized for long-term treatment of anxiety disorders and typically display broad anxiolytic activity, but their onset of anxiolytic activity ' takes several weeks. Similarly, buspirone, a 5- T A partial agonist, can take several weeks to display activity and is only effective in treatment of a subset of anxiety disorders. Given the predominance of anxiety disorders in our society, there continues to be a focus on development of novel anxiolytic agents with improved efficacy and/or side effect profiles. SUMMARY We describe the identification and development of potent synthetic EV-E B ligands, such as in vivo agonists and antagonists. These compounds allow for characterization of the effects of modulation of this receptor in vivo specifically on circadian behavior and metabolism, and have suitable characteristics for development of medicinal compounds useful for treatment of malconditions such as diabetes, obesity, atherosclerosis, dyslipidemia, circadian rhythm disorders, coronary artery disease, bipolar disorder, depression, cancer, sleep disorders, anxiety disorders, and autoimmune disorders. In various embodiments, the invention provides a modulator of a REV-ERB receptor in vitro and in vivo, The modulator of the invention can be a compound of formula (Ϊ), wherein 2 2 is CR2, CO, S0 2, or CR with a (CR2) bridge wherein n = 1, 2, 3 to Ar , X Y, orX 3; 1 1 X is CR2, CO, S0 2, or CR with a (CR2) bridge wherein n = , 2, 3 to Ar , X Y, or X3; 3 1 X is CR2, CO, S0 2, or CR with a (CR2) bridge wherein n = , 2, 3 to Ar Ar2, X , or X2; or X3 is absent; each independently selected R is H or (Cl-C6)alkyl; Ar 1 is alkyl, alkoxy, cycloalkyl, cycioalkoxy, aryi, aryloxy, aryialkenyi, heterocyclyl, heterocylyloxy, heteroaiyi, or heteroaryloxy, wherein Ar 1 is substituted with 0-3 J ; or X l Arl is H ; Ar2 is cycloalkyl, aryl, or heteroaryl, wherein Ar2 is substituted with 0-3 J; Y is II, hydroxy(Cl-C6)alkyl, aryloxy(Cl-C6)alkyL arylalkoxy(Cl-C6)alkyl, heteroaryloxy(Cl-C6)alkyl, heteroarylalkoxy(Cl-C6)alkyl, wherein any alkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy is substituted with 0-3 J; or Y is C(=0)W wherein W is OR or NR2; CN; cycloalkyi, heterocyclyi, aryl, arvlalkyl, heteroaryi, or heteroarylalkyi, wherein any cycloalkyi, heterocyclyi, aryl, arvlalkyl, heteroaryi, or hetero arvlalkyl, is substituted with 0-3 J; J is R, hydr y(Cl -C6)aikyi, R2N-(C1 ~C6)aIkyl, halo, halo(Cl -C6)alkyL nitro, cyano, RS(0) or RN(R)S(0 )q wherein q = 0, 1, or 2, C(=0)OR, C( 0)R, C(=0)NR 2, N(R)C(=0)OR, N(R)C(=0)R, or N(R)C(=0)NR 2; each independently selected R is II, (Cl-C6)alkyl, (Cl-C6)acyl, aryl, aroyl, or aryl(Cl -C6)alkyl, wherein any alkyl, acyl, aryl, aroyl, or aralkyl is substituted with 0- 3 J ; or a pharmaceutically acceptable salt thereof; chlorophenyi or 3,4-dichlorophenyl.
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