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WO 2009/049018 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 16 April 2009 (16.04.2009) WO 2009/049018 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/33 (2006.01) C07D 213/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, (21) International Application Number: CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, PCT/US2008/079298 EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, (22) International Filing Date: 9 October 2008 (09.10.2008) IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, (25) Filing Language: English MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, (26) Publication Language: English RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (30) Priority Data: ZW 60/978,955 10 October 2007 (10.10.2007) US (71) Applicant (for all designated States except US): SYN- (84) Designated States (unless otherwise indicated, for every DAX PHARMACEUTICALS, INC. [US/US]; 11260 El kind of regional protection available): ARIPO (BW, GH, Camino Real, Suite 220, San Diego, CA 92130 (US). GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (72) Inventors; and European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (75) Inventors/Applicants (for US only): KEANNA, John, FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, F.W. [US/US]; 1253 University Of Oregon, Eugene, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, OR 97403 (US). ORDENTLICH, Peter [US/US]; 4043 CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Grayson Drive, San Diego, CA 92130 (US). GOODE- NOW, Bob [US/US]; 38 Calle Ameno, San Clemente, CA Published: 92672 (US). — with international search report (74) Agents: ELAMRANI, Samir et al; Wilson Sonsini — before the expiration of the time limit for amending the Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA claims and to be republished in the event of receipt of 94304-1050 (US). amendments (54) Title: NOVEL COMPOUNDS AND METHODS OF USING THEM (57) Abstract: The present invention relates to novel compounds and their pharmaceutically acceptable salts, prodrugs, solvates, polymorphs, tautomers and isomers. In some embodiments, the compounds described herein may be used to modulate sirtuins (SIRT). The present invention also relates to methods for modulating sirtuins. The present invention also relates to methods useful in the treatment of diseases. NOVEL COMPOUNDS AND METHODS OF USING THEM CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 60/978,955, filed October 10, 2007, which is incorporated by reference in its entirety. BACKGROUND OF THE INVENTION [0002] Sirtuins are members of the Silent Information Regulator (SIR) family of genes. They are found in both prokaryotes and eukaryotes. The yeast Sir2 protein belongs to a family of histone deacetylases. The Sir2 protein is a deacetylase which can use NAD as a cofactor. Unlike other deacetylases, many of which are involved in gene silencing, Sir2 is relatively insensitive to histone deacetylase inhibitors like trichostatin A (TSA). Mammalian Sir2 homologs, such as SIRTl, have NAD-dependent deacetylase activity, which is involved in gene expression and gene silencing. [0003] Exemplary mammalian sirtuins include SIRTl, SIRT2, and SIRT3. A compound described herein may inhibit one or more activities of a mammalian sirtuin. For example, the compound may inhibit deacetylase activity, e.g., with respect to a natural or artificial substrate (e.g. histones, p53, FoxO transcription, deacetylate histones, deacetylate lysines, tubulin, cytochrome c, etc.). Histone deacetylation alters local chromatin structure and consequently can regulate the transcription of a gene in that vicinity. Many of the SIRTl binding partners are transcription factors, e.g., proteins that recognize specific DNA sites. For example, SIRTl deacetylates and down regulates forkhead proteins (i.e., FoxO proteins). Interaction between SIRTl and SIRTl binding partners can deliver SIRTl to specific regions of a genome and can result in a local manifestation of substrates, e.g., histones and transcription factors localized to the specific region. [0004] The present invention relates to novel compounds and compositions containing these compounds. In some embodiments, these compounds of the present invention affect sirtuin activity. Due to its role in the transcriptional mechanism to affect gene expression, compounds affecting sirtuin are useful as a therapeutic or ameliorating agent for diseases involving cellular growth such as malignant tumors, autoimmune diseases, skin diseases, infections, other anti-proliferative therapies, cancer, etc. They are also useful as therapeutic or prophylactic agent for diseases caused by abnormal gene expression such as inflammatory disorders, homozygous thalassemia, fibrosis, cirrhosis, acute promyelocytic leukaemia (APL), organ transplant rejections, protozoal infections, etc. They also have therapeutic effects in autoimmune diseases (e.g. HIV, AIDS), ocular diseases, neurodegenerative diseases (e.g. Alzheimer), and blood coagulation disorders. They also effects metabolism and be useful as therapeutic agents for treatment of diabetes, diabetic complications, and general obesity control. Compounds affecting sirtuin also have anti-aging effects and can extend cellular life in both prokaryotes and eukaryotes. SUMMARY OF THE INVENTION [0005] The present invention relates to novel compounds and their pharmaceutically acceptable salts, prodrugs, solvates, polymorphs, tautomers and isomers. In some embodiments, the compounds described herein may be used to modulate sirtuins (SIRT). The present invention also relates to compositions comprising novel compounds and their pharmaceutically acceptable salts, prodrugs, solvates, polymorphs, tautomers and isomers. The present invention also relates to methods for modulating sirtuins. The methods described herein may be used for modulating SIRTl, SIRT2 and/or SIRT3, or homologs thereof. The present invention also relates to methods useful in the treatment of diseases. The compounds and compositions described herein may be useful in the treatment of diseases. [0006] The compounds described herein may be useful in the treatment of diseases such as cancer and other hyperproliferative diseases. The compounds desribed herein may also be useful in increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress (including increasing radiosensitivity and/or chemosensitivity), diabetes, obesity (including stimulation of appetite or weight gain), neurodegenerative diseases, cardiovascular disease, blood clotting disorders, stroke, ischemia, inflammation, flushing, infections including viral infections (e.g. herpes, HIV, adenovirus, and HTLV-I associated malignant and benign disorders), autoimmune disorders (e.g., systemic lupus erythematosus, scleroderma, and arthritis, in which autoimmune cells should be removed), fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, carcinomas, metabolic diseases, malignant diseases, stimulation of appetite, and/or stimulation of weight gain. [0007] Compounds of Formula I-XXI, pharmaceutically acceptable salts, pharmaceutically active metabolites, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable solvates thereof, may modulate the activity of sirtuin enzymes; and, as such, are useful for treating diseases or conditions in which aberrant sirtuin enzyme activity contributes to the pathology and/or symptoms of a disease or condition. [0008] Provided herein are compounds and pharmaceutically acceptable salts of Formula I: [0009] Provided herein are compounds and pharmaceutically acceptable salts of Formulas IIA-IIC: [0010] Provided herein are compounds and pharmaceutically acceptable salts of Formulas IIIA-IIIC: [0011] Provided herein are compounds and pharmaceutically acceptable salts of Formulas IVA-IVC: [0012] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VA-VC: [0013] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VIA-VIC: [0014] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VIA' -VIC: [0015] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VIIA-VIIC: [0016] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VIIA'-VIIC: . [0017] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VIIIA-VIIIC: [0018] Provided herein are compounds and pharmaceutically acceptable salts of Formulas IXA-IXC: [0019] Provided herein are compounds and pharmaceutically acceptable salts of Formulas XA-XC: [0020] Provided herein are compounds and pharmaceutically acceptable salts of Formulas XIA-XIC: [0021] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VIIA-VIIC: [0022] Provided herein are compounds and pharmaceutically acceptable salts of Formulas VIIA' -VIIC: [0023] Provided herein are compounds and pharmaceutically acceptable salts
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