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WO 2013/053372 Al 18 April 2013 (18.04.2013) P O P C T

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WO 2013/053372 Al 18 April 2013 (18.04.2013) 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 2013/053372 Al 18 April 2013 (18.04.2013) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07F 5/02 (2006.01) A61P 31/04 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/69 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, PCT/EP20 11/005 142 HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 13 October 201 1 (13.10.201 1) MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (26) Publication Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): (84) Designated States (unless otherwise indicated, for every THERABOR PHARMACEUTICALS [IT/IT]; via kind of regional protection available): ARIPO (BW, GH, Campi 183, 1-41 125 Modena (IT). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, (72) Inventors; and TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (75) Inventors/ Applicants (for US only): PRATI, Fabio DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, [IT/IT]; via Antonelli 9/00, 1-42123 Reggio Emilia (IT). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, CASELLI, Emilia [IT/IT]; via della Pace 53, 1-41049 Sas- SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, suolo (Mo) (IT). GW, ML, MR, NE, SN, TD, TG). (74) Agent: GRAF VON STOSCH, Andreas; Graf von Stosch Published: Patentanwaltsgesellschaft mbH, Prinzregentenstrasse 22, — with international search report (Art. 21(3)) 80538 Munchen (DE). l © o- (54) Title: BORONIC ACID INHIBITORS OF BETA-LACTAMASES (57) Abstract: The invention relates to novel boronic acid compounds, a method for the preparation of such compounds, intermedi - ate compounds for the preparation of such compounds, intermediate compounds for the use in a method for preparation of such com- pounds, a pharmaceutical composition, the use of one or more compounds discussed above or of a pharmaceutical composition in S the manufacture of a medicament for the treatment of a bacterial infection, and a screening method. Boronic acid inhibitors of beta-lactamases The invention relates to novel boronic acid compounds, a method for the preparation of such compounds, intermediate compounds for the preparation of such compounds, intermediate compounds for the use in a method for preparation of such compounds, a pharmaceutical composition, the use of one or more compounds discussed above or of a pharmaceutical composition in the manufacture of a medicament for the treatment of a bacterial infection, and a screening method. FIELD OF INVENTION The present disclosure relates to boronic acids containing at least one heterocyle. These compounds act as beta-lactamase enzyme inhibitors. BACKGROUND OF THE INVENTION Bacterial resistance to antibiotics represents today one of the most alarming aspects of the pharmacotherapy: in fact, the number of therapeutic options for serious, life-threatening bacterial infections are becoming increasingly limited because of multidrug resistance. Multidrug resistant pathogens are now characterized by their heterogeneity, increasing virulence, rsistance even to reserve agents and spread within and between hospitals and the community. Examples are the meticillin-resistance Staphylococcus aureus (MRSA) and enterococci, extended spectrum β-lactamases (ESBL) and carbapenemase- producing coliform, and toxin-hyperproducing Clostridium difficile. Resistance to β-lactams in Staphylococcus aureus is mainly caused by acquisition of a low affinity penicillin-binding protein, PBP 2a, but is accompained by other resistance factors that provide resistance to most of clinically used antibiotics.. A number of relatevly new drugs such as linezolid, daptomycin and tigecycline are now available to treat infections caused by β-lactam-resistant Gram positive cocci. Thus attention has shfted to the drug resistant gram-negative bacteria that have been acquiring mobile genetic elements associated with multiple resistance determinants for most antibiotic classes. In Gram negative bacteria, the most common β-lactam resistance mechanism involves β-lactamase-mediated hydrolysis resulting in subsequent inactivation of the antibiotic.(Bush, K., Curr. Op. Microbiol., 2010, 13, 558-564) A recent compilation of β-lactamases cataloged over 950 unique, naturally occurring enzymes (see Lahey Clinic β-lactamase website). The simplest classification of this class of enzymes is based on the protein sequence whereby the β-lactamases are classified into four molecular classes A , B, C, and D, based on the conserved and distinguishing amino acids motif. Clas A , C and D include enzymes that hydrolyze their substrate by forming an acyl enzyme through an active site serine, whereas class B β-lactamases are metalloenzymes that utilize at least one-active site Zinc ion to facilitate hydrolysis. The concept of achieving antibacterial activity, without accelerating resistance development and without compromising safety, by synergism between a β-lactam antibiotic and a β-lactamase inhibitor (inactivator) is proven by decades of clinical success with the amoxicillin/clavulanic acid (Augmentin®), ticarcillin/clavulanic acid (Timentin®), ampicillin/sulbactam (Unasyn®), cefoperazone/ sulbactam (Sulperazone®) and piperacillin/tazobactam (Zosyn®). combinations. With the forward evolution of β-lactamase capability resulting in the diminished effectiveness of clavulate and the penam sulfone against these enzymes, there is a rapidly growing unmet medical need and hence a renewed opportunity for β-lactamase inhibitors discovery. Specifically, recognizing the emergence of β-lactamases capable of carbapenem hydrolysis, future identification of an effective carbapenemase inhibitor has the potential to establish clinical longevity for existing carbapenems, as clavulate and the penicillin sulfone have accomplished for the penicillin. Boronic acids have been known since the late '80 to inhibit β-lactamases (Crompton, I. E., Cuthbert, B. K., Lowe, G., Waley, S. G., Biochem. J., 1988, 251, 453-9.). They are compounds that replace the β-lactam ring with boronic acid. The boron atom forms of a reversible, dative covalent bond with the active site serine of class A and C and D β-lactamases, assuming a geometry that resembles the tetrahedral transition state of the β-lactamase hydrolytic reaction. By modifying the boronic acid substituents to resemble in structure, distance, and stereochemical arrangement the R 1 side chains of natural substrates, affinities in the nM range against class C enzymes of Escherichia coli were achieved (U.S. Patent No. 7,271 ,186). Ness et al. (Biochemistry (2000) 39:5312-21) discloses β-lactamase inhibitors that target TEM-1 (a non-ESBL TEM variant from class A ; one of approximately 140 known TEM-type betalactamase variants). More recently patent WO201 0/1 30708 disclosed a-aminoacyl-p-boron (3-carboxyphenyl) as broad spectrum β-lactamases inhibitors. Taking respect to the rapidly evolving β-lactamase capability of bacteria, it is the object of the invention to provide novel compounds for inhibition of β-lactamase activity. As a solution the invention provides compounds featuring a boronic acid structure bearing a heterocycle. These compounds act as β-lactamase inhibitors and are useful in several pathological conditions either used alone or in combination with a therapeutically effective agent. A compound, particularly a boronic acid containing at least one heterocyle, having the general formula (I) is a bond or a C1-C8 saturated or unsaturated linear or branched aliphatic chain, optionally substituted with one or more groups chosen from hydroxyl, alkyl, cycloalkyi, alkoxy, alkenyl, alkynyl, amino, aminocarbonyl, carbonyl, aminosulfonyl, alkylaryl, aryl, aryloxy, carboxyl, cyano, guanidine, halogen, heteroaryl, heterocyclyl, sulfide, sulfonyl, sulfoxido, sulfonic acid, sulfate and thiol; is chosen from hydrogen, linear or branched C1-C12 alkyl, linear or branched C1-C12 alkenyl, or C3-C8 cycloalkyi; said linear or branched C1-C12 alkyl, linear or branched C1-C12 alkenyl, or C3- C8 cycloalkyi being optionally substituted with one or more groups independently chosen from the group consisting of hydroxyl, halogen, carboxyl, cyano, C(0)R 4, C(0)NR 4R5, thiol, sulfonic acid, sulfate, alkyl, cycloalkyi, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, alkylaryl, heteroarylalkyl, alkylheteroaryl, cycloalkoxy, heterocyclyloxy, aryloxy, heteroaryloxy, amino, carbonyl, aminocarbonyl, oxycarbonyl, aminosulfonyl, sulfonyl, guanidino, sulfido, and sulfoxido; is 0, 1, 2, 3, 4, 5, or 6; and X 2 are independently hydroxyl, halogen, NR1R2, C1-C6 alkoxy, or acyloxy; or and X 2 together form a cyclic boron ester, a cyclic boron amide, or a cyclic boron amide-ester, said cyclic boron ester, boron amide or boron amide-ester having a chain or a ring containing from 2 to 12 carbon atoms and, optionally, 1-3 heteroatoms which can be O, N , or S ; is chosen
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