(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 i 1 m 19 May 2011 (19.05.2011) 2011/058582 Al (51) International Patent Classification: Road, Sholinganallur, Chennai 600 119 (IN). CHEN- C07C 259/06 (2006.01) A61P 31/00 (2006.01) NIAPPAN, Vinoth Kumar [IN/IN]; Orchid Research C07D 277/46 (2006.01) A61K 31/426 (2006.01) Laboratories Ltd., R & D Centre: Plot No: 476/14, Old C07D 277/48 (2006.01) A61K 31/55 (2006.01) Mahabalipuram Road, Sholinganallur, Chennai 600 119 C07D 487/08 (2006.01) (IN). GANESAN, Karthikeyan [IN/IN]; Orchid Re search Laboratories Ltd., R & D Centre: Plot No: 476/14, (21) International Application Number: Old Mahabalipuram Road, Sholinganallur, Chennai 600 PCT/IN20 10/000738 119 (IN). NARAYANAN, Shridhar [IN/IN]; Orchid Re (22) International Filing Date: search Laboratories Ltd., R & D Centre: Plot No: 476/14, 12 November 2010 (12.1 1.2010) Old Mahabalipuram Road, Sholinganallur, Chennai 600 119 (IN). (25) Filing Language: English (74) Agent: UDAYAMPALAYAM PALANISAMY, (26) Publication Language: English Senthilkumar; Orchid Chemicals & Pharmaceuticals (30) Priority Data: LTD., R & D Centre: Plot No: 476/14, Old Mahabalipu 2810/CHE/2009 16 November 2009 (16. 11.2009) IN ram Road, Sholinganallur, Chennai 600 119 (IN). (71) Applicant (for all designated States except US): OR¬ (81) Designated States (unless otherwise indicated, for every CHID RESEARCH LABORATORIES LTD. [IN/IN]; kind of national protection available): AE, AG, AL, AM, Orchid Towers, 313, Valluvar Kottam High Road, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, Nungambakkam, Chennai 600 034 (IN). CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (72) Inventors; and HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (75) Inventors/ Applicants (for US only): RAJAGOPAL, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, Sridharan [IN/IN]; Orchid Research Laboratories Ltd., R ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, & D Centre: Plot No: 476/14, Old Mahabalipuram Road, NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, Sholinganallur, Chennai 600 119 (IN). THANGA- SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, PAZHAM, Selvakumar [IN/IN]; Orchid Research Labo TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. ratories Ltd., R & D Centre: Plot No: 476/14, Old Maha balipuram Road, Sholinganallur, Chennai 600 119 (IN). (84) Designated States (unless otherwise indicated, for every PAUL-SATYASEELA, Maneesh [IN/IN]; Orchid Re kind of regional protection available): ARIPO (BW, GH, search Laboratories Ltd., R & D Centre: Plot No: 476/14, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, Old Mahabalipuram Road, Sholinganallur, Chennai 600 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 119 (IN). BALASUBRAMANIAN, Gopalan [IN/IN]; TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Orchid Research Laboratories Ltd., R & D Centre: Plot EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, No: 476/14, Old Mahabalipuram Road, Sholinganallur., LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Chennai 600 119 (IN). SHAKTI SINGH, Solanki SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, TG). [IN/IN]; Orchid Research Laboratories Ltd., R & D Cen GW, ML, MR, NE, SN, TD, tre: Plot No: 476/14, Old Mahabalipuram Road, Sholin Declarations under Rule 4.17 : ganallur, Chennai 600 119 (IN). KUPPUSAMY, — of inventorship (Rule 4.1 7(iv)) Bharathimohan [IN/IN]; Orchid Research Laboratories Ltd., R & D Centre: Plot No: 476/14, Old Mahabalipuram Published: Road, Sholinganallur, Chennai 600 119 (IN). KACHHA- — with international search report (Art. 21(3)) DIA, Virendra [IN/IN]; Orchid Research Laboratories Ltd., R & D Centre: Plot No: 476/14, Old Mahabalipuram [Continued on next page] (54) Title: HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF FUNGAL INFECTIONS :2 4 ∞ (I) ∞ o (57) Abstract: Described are bridged compounds of the formula (I), their analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and pro- drugs thereof. The invention relates to compositions and methods to treat fungal infection. These compounds are selective HDAC Q inhibitors that act as inherent antifungal compounds or enhance the activity of other antifungal compounds such as azoles. w o 2011/058582 A l II 11 II I 1 Illlll I lll l l ll l l II il II I II before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF FUNGAL INFECTIONS Field Described are bridged compounds of the formula (I), their analogs, tautomeric forms, stereoisomers, geometrical isomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. Provided herein are also the compositions and methods to treat fungal infection. These compounds are selective HDAC inhibitors that act as inherent antifungal compounds or augment the activity of other antifungal compounds such as azoles. Background Fungal infections (mycoses), are not as frequent as bacterial or viral infections, but have nonetheless been increasing in incidence in the human population over the past several years. This trend is largely as a consequence of increased number of cancer and immunocompromised patients who, owing to weakened immune system and the chronic nature of the diseases, are at greater risk. The fungi, like bacteria, have unique characteristics, distinct from their mammalian hosts, but at the same time they being eukaryotic like mammals, are much more complex organisms. Consequently, only a few drugs are aimed at interfering with cell division and have limited use. Most antifungal drugs are targeted to the cell membrane. The principal predisposing factors for C. albicans infection are diabetes mellitus, general debility, immunodeficiency, indwelling catheters, antibiotics that alter normal bacterial flora and corticosteroids. Of these the infection of the skin occurs in moist, warm parts of the body such as the axilla, intergluteal folds, groin, or inframammary folds; it is most common in the obese and diabetic individuals. Interdigital web infection is common among those that work in wet conditions. (Jawetz Microbiology 19th ed; Antimicrobial Agents and Chemotherapy, 2002: 46(1 1): 3532- 3539). Candidiasis is treated with antifungal azoles such as topical agents and oral or intravenous fluconazole and itraconazole. The major limitation of antifungal azoles is their lack of fungicidal activity. Furthermore surviving yeasts provide a reservoir for the development of Azole resistance. (Antimicrobial Agents and Chemotherapy 2002; 46:3532-3539). Azole class of antifungal agents includes the imidazoles (clotrimazole, miconazole, and ketoconazole) and the triazoles (fluconazole, itraconazole, isavucanazole, ravucanazole, posoconazole, voriconazole and terconazole). Mechanism of action: Azoles interfere with the biosynthesis of major fungal membrane component ergosterol by inhibiting sterol C14-demethylation of cytochrome P-450 3-A dependent enzyme 14-a-lanosterol-demethylase, one of the about 20 enzymes involved in the biosynthesis of ergosterol. Inhibition of this critical enzyme in the ergosterol synthesis pathway leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols, causing increased membrane permeability and inhibition of fungal growth. Azole antifungals can also inhibit many mammalian cytochrome P450-dependent enzymes involved in hormone synthesis or drug metabolism. Therefore, they are particularly susceptible to clinically significant drug interactions with other medications metabolized through the cytochrome P450 pathway. One of the major differences is that the fungi rely on endogenous ergosterol biosynthesis, in contrast to mammalian cells that have the ability to incorporate exogenous sterol. This property may account for the selectivity of the azoles against fungi. (Lorian V. Antibiotics in Laboratory medicine. 4th ed; Crit. Rev. Biochem. Mol. Biol. 1999: 34:159-166; Curr. Opin. Microbiol. 2001, 4:540-545). Azole resistance has been documented in several species of Candida. The proposed mechanisms include alteration of 14-a-demethylase and upregulation of genes that encode for efflux pumps. In vitro, Azoles not only fail to kill but also fail to suppress growth of Candida completely, resulting in trailing growth as observed in broth microdilution assays. (Antimicrobial Agents and Chemotherapy, 2002; 46:3532- 3539) HDACs (Histone deacetylases) are validated targets for anticancer and antiprotozoal therapy. The chromatin at any given point of time is controlled by opposing actions of two types of enzymes: Histone acetyltransferases, which transfer an acetyl group from acetyl CoA to an ε-amino group of lysine residues of histones loosening the nucleosomes, and HDACs that catalyze the hydrolysis of acetamides by removing acetyl groups and lead to the compaction of chromatin (The Oncologist, 2003; 8:389-391). It has been recognized in recent years that histone acetylation and deacetylation play important roles in eukaryotic gene regulation. The ε-amino groups of lysine residues within the flexible amino-terminal tails of the core histones are the primary targets for acetylation.