US008883797B2 (12) United States Patent (10) Patent No.: US 8,883,797 B2 Hoekstra et al. (45) Date of Patent: *Nov. 11, 2014 (54) METALLOENZYME INHIBITOR (2013.01); A61 K3I/4725 (2013.01); C07D COMPOUNDS 401/06 (2013.01); A61K 31/428 (2013.01); C07D 403/06 (2013.01) (75) Inventors: William J. Hoekstra, Durham, NC USPC ........... 514/256; 514/365: 514/372: 514/374; (US); Robert J. Schotzinger, Raleigh, 514/378; 544/333; 548/252: 548/235; 548/237; NC (US) 548/203: 548/214: 548/255 (58) Field of Classification Search (73) Assignee: Viamet Pharmaceuticals, Inc., Durham, None NC (US) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 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FOREIGN PATENT DOCUMENTS 23, 2011, provisional application No. 61/611,917, WO WO921.7474 A1 * 10, 1992 filed on Mar. 16, 2012. WO WO-2008064311 A2 S/2008 WO WO 2011 133875 A2 * 10, 2011 (51) Int. Cl. OTHER PUBLICATIONS AOIN 43/54 (2006.01) C07D 239/52 (2006.01) F. Qin 27 Electrophoresis 1050-1059 (2006).* CO7D40 L/04 (2006.01) J.H Poupaert, Drug Design: Basic Principles and Applications, in 2 A6 IK3I/506 (2006.01) Encyclopedia of Pharmaceutical Technology 1362-1369, 1367 A6 IK3I/427 (2006.01) (James Swarbrick ed., 3rd ed., 2007).* B.A. Chabner et al., Chemotherapy of Neoplastic Diseases, A6 IK3I/50 (2006.01) Neoplastic Agents in, Goodman & Gilman'S: The Pharmacological A 6LX3L/2197 (2006.01) Basis of Therapeutics 1315-1403, 1315 (L.L. Brunton et al., eds. A6 IK3I/4I (2006.01) 11th ed., 2006).* CO7D 409/06 (2006.01) H. 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A61K 45/06 (2013.01); A61 K3I/506 (57) ABSTRACT (2013.01); A61 K3I/427 (2013.01); A61 K The instant invention describes compounds having metal 31/501 (2013.01); A61 K3I/497 (2013.01); loenzyme modulating activity, and methods of treating dis A6 IK3I/4I (2013.01); C07D 409/06 eases, disorders or symptoms thereof mediated by Such met (2013.01); A61 K3I/498 (2013.01); C07D alloenzymes. 257/04 (2013.01); C07D 417/06 (2013.01); A6 IK3I/4439 (2013.01); A61 K3I/4709 15 Claims, No Drawings US 8,883,797 B2 1. 2 METALLOENZYME INHIBITOR inhibition of off-target metalloenzymes due to indiscriminate COMPOUNDS binding of the hydroxamic acid group to Zinc in the off-target active sites. CROSS-REFERENCE TO RELATED Therefore, the search for metal-binding groups that can APPLICATIONS achieve a betterbalance of potency and selectivity remains an important goal and would be significant in the realization of The present application claims priority benefit under 35 therapeutic agents and methods to address currently unmet U.S.C. S119(e) of U.S. Provisional Patent Application Ser. needs in treating and preventing diseases, disorders and No. 61/500,372, filed Jun. 23, 2011; and U.S. Provisional symptoms thereof. Patent Application Ser. No. 61/611,917, filed Mar. 16, 2012. 10 Fungicides are compounds, of natural or synthetic origin, The disclosures of these applications are incorporated herein which act to protect and cure plants against damage caused by by reference. agriculturally relevant fungi. Generally, no single fungicide is useful in all situations. Consequently, research is ongoing to BACKGROUND 15 produce fungicides that may have better performance, are easier to use, and cost less. Living organisms have developed tightly regulated pro The present disclosure relates to compounds of Formula I, cesses that specifically import metals, transport them to intra shown below, and their derivatives and their use as fungicides. cellular storage sites and ultimately transport them to sites of The compounds of the present disclosure may offer protec use. One of the most important functions of metals such as tion against ascomycetes, basidiomycetes, deuteromycetes Zinc and iron in biological systems is to enable the activity of and oomycetes. metalloenzymes. Metalloenzymes are enzymes that incorpo rate metal ions into the enzyme active site and utilize the BRIEF SUMMARY OF THE INVENTION metal as a part of the catalytic process. More than one-third of The invention is directed towards compounds (e.g., any of all characterized enzymes are metalloenzymes. 25 those delineated herein), methods of modulating activity of The function of metalloenzymes is highly dependent on the metalloenzymes, and methods of treating diseases, disorders presence of the metalion in the active site of the enzyme. It is or symptoms thereof. The methods can comprise the com well recognized that agents which bind to and inactivate the pounds herein. active site metalion dramatically decrease the activity of the A method of controlling a pathogen-induced disease in a enzyme. Nature employs this same strategy to decrease the 30 plant that is at risk of being diseased from the pathogen activity of certain metalloenzymes during periods in which comprising contacting one of the plant and an area adjacent to the enzymatic activity is undesirable. For example, the pro the plant with a composition of Formula I, or salt, Solvate, tein TIMP (tissue inhibitor of metalloproteases) binds to the hydrate or prodrug thereof, wherein: Zinc ion in the active site of various matrix metalloprotease enzymes and thereby arrests the enzymatic activity. The phar 35 maceutical industry has used the same strategy in the design of therapeutic agents. For example, the azole antifungal agents fluconazole and Voriconazole contain a 1-(1,2,4-tria Zole) group that binds to the heme iron present in the active MBG site of the target enzymelanosterol demethylase and thereby 40 inactivates the enzyme. Another example includes the zinc binding hydroxamic acid group that has been incorporated into most published inhibitors of matrix metalloproteinases MBG is optionally substituted tetrazolyl, optionally sub and histone deacetylases. Another example is the zinc-bind 45 stituted triazolyl, optionally substituted oxazolyl, optionally ing carboxylic acid group that has been incorporated into substituted pyrimidinyl, optionally substituted thiazolyl, or most published angiotensin-converting enzyme inhibitors. optionally substituted pyrazolyl, In the design of clinically safe and effective metalloen R is H, halo, alkyl or haloalkyl: Zyme inhibitors, use of the most appropriate metal-binding R is H. halo, alkyl or haloalkyl: group for the particular target and clinical indication is criti 50 R is 1,1'-biphenyl substituted with 4'-OCHCF or 4-F, or cal. If a weakly binding metal-binding group is utilized, heteroaryl, which may be optionally substituted with 1, 2 or 3 potency may be suboptimal. On the other hand, if a very independent Rs. tightly binding metal-binding group is utilized, selectivity for R is aryl, heteroaryl, alkyl or cycloalkyl, optionally Sub the target enzyme versus related metalloenzymes may be stituted with 0, 1, 2 or 3 independent R: suboptimal. The lack of optimal selectivity can be a cause for 55 each Rs is independently H, halo, aryl optionally Substi clinical toxicity due to unintended inhibition of these off tuted with 1, 2 or 3 independent R. heteroaryl, haloalkyl, target metalloenzymes. One example of such clinical toxicity haloalkoxy, cyano, nitro, alkyl, alkoxy, alkenyl, haloalkenyl, is the unintended inhibition of human drug metabolizing arylalkenyl, alkynyl, haloalkynyl, alkylaryl, arylalkynyl, ary enzymes such as cytochrome P450 2C9 (CYP2C9), lalkyl, cycloalkyl, halocycloalkyl, thioalkyl, SF, SF SCN, CYP2C19 and CYP3A4 by the currently-available azole anti 60 SOR, C(O)alkyl, C(O)OH, C(O)Oalkyl: fungal agents such as fluconazole and Voriconazole. It is each R is independently alkyl, thioalkyl, cyano, haloalkyl, believed that this off-target inhibition is caused primarily by hydroxy, alkoxy, halo, haloalkoxy, —C(O)alkyl, —C(O)OH, the indiscriminate binding of the currently utilized 1-(1,2,4- —C(O)Calkyl, SF, SF SCN, SOH; and SOR: triazole) to iron in the active site of CYP2C9, CYP2C19 and R, is independently alkyl, aryl. Substituted aryl, heteroaryl CYP3A4. Another example of this is the joint pain that has 65 or substituted heteroaryl; been observed in many clinical trials of matrix metallopro Rs is H.