(19) TZZ ¥_T (11) EP 2 566 853 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 257/04 (2006.01) C07D 401/06 (2006.01) 25.01.2017 Bulletin 2017/04 C07D 401/12 (2006.01) C07D 403/06 (2006.01) C07D 403/12 (2006.01) C07D 407/12 (2006.01) (2006.01) (2006.01) (21) Application number: 11731538.2 C07D 413/06 C07D 413/12 C07D 417/04 (2006.01) C07D 417/06 (2006.01) A61K 31/41 (2006.01) A61P 3/00 (2006.01) (22) Date of filing: 04.05.2011 A61P 29/00 (2006.01) A61P 35/00 (2006.01) (86) International application number: PCT/US2011/035141 (87) International publication number: WO 2011/140190 (10.11.2011 Gazette 2011/45) (54) TETRAZOLONES AS INHIBITORS OF FATTY ACID SYNTHASE TETRAZOLONE ALS FETTSÄURESYNTHASEHEMMER TÉTRAZOLONES UTILISÉS EN TANT QU’INHIBITEURS D’ACIDE GRAS SYNTHASE (FASN) (84) Designated Contracting States: • KEANEY, Gregg, F. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Lexington GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO MA 02421 (US) PL PT RO RS SE SI SK SM TR • NEVALAINEN, Marta Weymouth (30) Priority: 02.12.2010 US 419174 P MA 02189 (US) 06.04.2011 US 472566 P • NEVALAINEN, Vesa 28.01.2011 US 437564 P Weymouth 05.05.2010 US 331644 P MA 02189 (US) 05.05.2010 US 331575 P • PELUSO, Stephane Brookline (43) Date of publication of application: MA 02446 (US) 13.03.2013 Bulletin 2013/11 • SNYDER, Daniel, A. Somerville (60) Divisional application: MA 02145 (US) 16183011.2 • TIBBITTS, Thomas, T. Westford (73) Proprietor: Infinity Pharmaceuticals, Inc. MA 01886 (US) Cambridge, MA 02139 (US) (74) Representative: Savic, Bojan et al (72) Inventors: Jones Day • BAHADOOR, Adilah Rechtsanwälte Attorneys-at-Law Patentanwälte Cambridge Prinzregentenstraße 11 MA 02140 (US) 80538 München (DE) • CASTRO, Alfredo, C. Winchester (56) References cited: MA 01890 (US) EP-A1- 0 712 850 EP-A1- 0 902 028 • CHAN, Lawrence, K. WO-A1-02/28843 JP-A- 9 087 281 Brookline US-A- 5 589 439 US-A- 5 641 727 MA 02446 (US) US-A- 5 652 198 US-A- 5 654 257 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 566 853 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 566 853 B1 US-A- 5 686 392 US-A- 5 767 286 US-A- 5 776 858 US-B1- 6 277 790 • KRIDEL S J ET AL: "Fatty acid synthase inhibitors: New directions for oncology", EXPERT OPINION ON INVESTIGATIONAL DRUGS 200711 GB LNKD- DOI:10.1517/13543784.16.11.1817, vol. 16, no. 11, November 2007 (2007-11), pages 1817-1829, XP002655531, ISSN: 1354-3784 2 EP 2 566 853 B1 Description BACKGROUND 5 [0001] Fatty acid synthase (FASN) is a key enzyme for the synthesis of long-chain fatty acids from acetyl-coenzyme A (CoA) and malonyl-CoA that uses reduced nicotinamide adenine dinucleotidephosphate as a cofactor. FASN is min- imally expressed in most normal human tissues except the liver and adipose tissue, where it is expressed at high levels. [0002] Since FASN expression is markedly increased in several human cancers compared with the corresponding normal tissue, and FASN overexpression in tumors has been associated with a poor prognosis, FASN inhibitors have 10 long been viewed as potential therapeutics for the treatment of cancer. Kridel et al. (Expert Opinion on Investigational Drugs, 16(11): 1817-1829 (2011)) reviews the preclinical development of FASN Inhibitors, their antitumor effects and the strategies underway to develop novel inhibitors. FASN inhibitors have also shown promise in the treatment of other FASN-mediated diseases, disorders or conditions, such as obesity, lack of appetite control and inflammatory conditions. [0003] Furthermore, FASN has been identified as a target for treatment of microbial infections. In particular, it was 15 reported that fatty acid synthesis or the level of fatty acid is critical in viral pathogenesis. For example, it was reported that the formation of a novel vesicular compartment ( i.e., remodelled golgi apparatus), on the surface of which viral RNA replication takes place, requires fatty acid biosynthesis. See( Cherry et al., PLoS Pathogens, 2(10): e102 (2006)). In addition, fatty acid biosynthesis has been indentified as a target for antiviral therapy using a metabolic profiling of the hosts upon viral infection. (See Munger et al., Nature Biotechnology, 26: 1179-1186 (2008). It was also reported that 20 inhibition of fatty acid biosynthesis (e.g., inhibition of fatty acid synthase) results in reduced replication of human cy- tomegalomous virus (HCMV) and influenza A viruses. ( Id.). [0004] Reports establishing FASN as a valid target for the treatment of viral infections are available for various viruses. For example, the role of FASN has been implicated in the pathogenesis of an enveloped virus such as human cytome- galomous virus (HCMV), influenza A and Heptatitis C (HCV). ( See Munger et al., Nature Biotechnology, 26: 1179-1186 25 (2008); Syed et al., Trends in Endocrinology and Metabolism, 21: 33-40 (2009); Sakamoto et al., Nature Chemical Biology, 1: 333-337 (2005); Yang et al., Hepatology, 48: 1396-1403 (2008)). With regard to HCV, it was reported that an elevated level of fatty acid biosynthesis enzymes, including FASN, contributes to liver steatosis, leading to cirrhosis and hepatocellular carcinoma, upon HCV infection. (Fukusawa et al., Biol. Pharm. Bull., 29(9): 1958-1961 (2006)). HCV replication was reported to be regulated by, among others, fatty acid biosynthesis. (Kapadia et al., Proc. Natl. Acad. 30 Sci., 102(7): 2561-2566 (2005)). Other reports establishing FASN as a potential host-target against HCV have also been published. (See, e.g., Hepatology, 48: 1396 (2008); Trends Endocrine Metabol., 21: 33 (2010); and Virology, 394: 130 (2009)). [0005] With regard to other various viruses, it was reported that the FASN expression is increased in the cells infected by coxsackievirus B3 (CVB3), a picornavirus, and the replication of CVB3 is blocked by FASN inhibitors. ( See Rassmann 35 et al., Antiviral Research, 76: 150-158(2007)). FASN was reported to be important in lytic viral replication of Epstein- Barr virus (EBV), and it was suggested that FASN inhibition may be a novel approach for blocking the EBV replication. (Li et al., Journal of Virology, 78(8): 4197-4206 (2004)). The role of FASN in the replication of dengue virus has also been implicated. (See, e.g., Heaton et al., Pro. Natl. Acad. Sci., 107(40): 17345-17350 (2010); and Samsa et al., PLoS Pathegens, 5(10): e1000632 (2009)). 40 [0006] Moreover, aside from being a potential target for anti-viral therapy, the role of FASN has also been implicated in diabetes or regulation of the general wellness of the Seeliver., e .g(., Wu et al., PNAS Early Edition, www.pnas.org/cgi/doi/10.1073/pnas.1002588108 (2011)) U.S. patent 5,686,392 discloses a process and intermediates for preparing substituted N-carbamoyl-tetrazolinones, which are known to be compounds having herbicidal activity. Thus, there is a need for effective inhibitors of FASN, which can be potentially used as therpies for microbial infections, including , 45 but not limited to viral infections, or other diseases and disorders. SUMMARY [0007] Provided herein are tetrazolone FASN inhibitors of the formula (I): 50 55 3 EP 2 566 853 B1 5 10 or a pharmaceutically acceptable form thereof; wherein: 15 A R is selected from C6-14 aryl and 5-14 membered heteroaryl; B R is selected from C6-14 aryl and 5-14 membered heteroaryl; C R is selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, 3-14 membered heteroaliphatic, C C3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, with the proviso that R is not -CH3; 20 or RB and R C together with the nitrogen (N) atom to which each is attached are joined to form a 5-14 membered ring; wherein: RB is substituted with the group: 25 -L-RD wherein: L is a covalent bond or a divalent C 1-10 hydrocarbon chain, wherein one, two or three methylene units of L 30 are optionally and independently replaced with one or more -O-, -S-,-NR B8-, -(C=NRB8)-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, divalent carbocyclyl, divalent heterocyclyl, divalent aryl or divalent heteroaryl group; D B7 B9 B7 B7 R is selected from -N3, -SO2H, -SO3H, -C(=O)R , -CO2H, -CHO, -C(OR )2,-CO2R , -OC(=O)R , B7 B8 B8 B8 B7 B8 B7 B8 B8 -OCO2R , -C(=O)N(R )2, -OC(=O)N(R )2, -NR C(=O)R ,-NR CO2R , -NR C(=O)N(R )2, B8 B7 B8 B7 B8 B7 B8 B8 B8 B8 -C(=NR )OR , -OC(=NR)R , -OC(=NR)OR ,-C(=NR )N(R )2, -OC(=NR)N(R )2, 35 B8 B8 B8 B8 B7 B8 B7 B8 B7 B7 -NR C(=NR )N(R )2, -C(=O)NRSO2R ,-NR SO2R , -SO2N(R )2, -SO2R , -SO2OR , 7 B7 B7 B8 B7 B7 B7 B7 -OSO2B , -S(=O)R , -OS(=O)R ,-C(=S)N(R )2, -C(=O)SR , -C(=S)SR , -SC(=S)SR , -P=O)2R , B7 B7 B7 B9 B8 -OP(=O)2R ,-P(=O)(R )2, -OP(=O)(R)2, -OP(=O)(OR)2, 2N(R-P(=O))2, B8 B8 B8 B8 B9 B8 B8 -OP(=O)2N(R )2,-P(=O)(NR )2, -OP(=O)(NR)2, -NRP(=O)(OR )2, -NRP(=O)(NR )2, B9 B7 B9 -B(OR )2,-BR (OR ), and tetrazolyl; 40 B7 each instance of R is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, 3-14 membered heteroaliphatic, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl; B8 B7 B9 B7 each instance of R is, independently, selected from hydrogen, -OH, -OR , -N(R )2, -CN, -C(=O)R