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Isoxazole Beta-Lactamase Inhibitors Isoxazol-Beta-Lactamase-Hemmer Inhibiteurs Des Beta-Lactamases Dérivés D’Isoxazole

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Isoxazole Beta-Lactamase Inhibitors Isoxazol-Beta-Lactamase-Hemmer Inhibiteurs Des Beta-Lactamases Dérivés D’Isoxazole (19) TZZ ¥_Z_T (11) EP 2 831 069 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 451/06 (2006.01) A61K 31/46 (2006.01) 12.07.2017 Bulletin 2017/28 A61P 31/00 (2006.01) C07D 471/08 (2006.01) A61K 45/06 (2006.01) A61K 31/407 (2006.01) (2006.01) (2006.01) (21) Application number: 13769389.1 A61K 31/427 A61K 31/546 (22) Date of filing: 29.03.2013 (86) International application number: PCT/US2013/034589 (87) International publication number: WO 2013/149136 (03.10.2013 Gazette 2013/40) (54) ISOXAZOLE BETA-LACTAMASE INHIBITORS ISOXAZOL-BETA-LACTAMASE-HEMMER INHIBITEURS DES BETA-LACTAMASES DÉRIVÉS D’ISOXAZOLE (84) Designated Contracting States: • ALEXANDER, Dylan, C. AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Watertown, MA 02472 (US) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • CROSS, Jason, B. PL PT RO RS SE SI SK SM TR Acton, MA 01718 (US) Designated Extension States: • METCALF, Chester, A., III. BA ME Needham, MA 02492 (US) • BUSCH, Robert (30) Priority: 30.03.2012 US 201261618127 P Wakefield, MA 01880 (US) 15.03.2013 US 201361790248 P (74) Representative: Böhles, Elena et al (43) Date of publication of application: Merck Sharp & Dohme Limited 04.02.2015 Bulletin 2015/06 Hertford Road Hoddesdon, Herts EN11 9BU (GB) (73) Proprietor: Merck Sharp & Dohme Corp. Rahway, NJ 07065 (US) (56) References cited: WO-A1-2009/133442 WO-A1-2010/038115 (72) Inventors: KR-A- 20100 130 176 •GU,Yu Gui Acton, MA 01720 (US) • IAN K. MANGION ET AL.: ’A Concise of a • HE, Yong beta-Lactamase Inhibitor’ ORGANIC LETTERS Bedford, MA 01730 (US) vol.13, no. 20, 21 October 2011, pages 5480 - 5483, • YIN, Ning XP055033007 Lexington, MA 02420 (US) 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 2 831 069 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 831 069 B1 Description TECHNICAL FIELD 5 [0001] This disclosure is directed to β-lactamase inhibitors (BLIs) which are effective as inhibitors ofβ -lactamases and, when used in combination with β-lactam antibiotics are useful in the treatment of bacterial infections. The compounds when combined with a β-lactam antibiotic are effective in treating infections caused by bacteria that are resistant to β- lactam antibiotics due to the presence ofβ -lactamases. Pharmaceutical compositions comprising such compounds, methods of using such compounds, and processes for preparing such compounds are also disclosed. 10 BACKGROUND [0002] Bacterial resistance to β-lactam antibiotics, especially in Gram-negative bacteria, is most commonly mediated by β-lactamases. β-lactamases are enzymes that catalyze the hydrolysis of theβ -lactam ring, which inactivates the 15 antibacterial activity of the β-lactam antibiotic and allows the bacteria to become resistant. Inhibition of the β-lactamase with a BLI slows or prevents degradation of the β-lactam antibiotic and restores β-lactam antibiotic susceptibility to β- lactamase producing bacteria. Many of these β-lactamases are not effectively inhibited by BLIs currently on the market rendering the β-lactam antibiotics ineffective in treating bacteria that produce these β-lactamases. There is an urgent need for novel BLIs that inhibit β-lactamases that are not effectively inhibited by the current clinical BLIs (e.g. KPC, class 20 C and class D β-lactamases) and that could be used in combination with β-lactam antibiotics to treat infections caused by β-lactam resistant bacteria. SUMMARY OF INVENTION 25 [0003] The present invention provides, in one aspect, compounds of chemical formula (I), or pharmaceutically-accept- able salts thereof, which are BLIs and are useful in combination with β-lactam antibiotics for the treatment of bacterial infections. 30 35 40 wherein R is selected from 45 50 and R1 is selected from: a. 55 2 EP 2 831 069 B1 wherein R2 is selected from 5 3 4 5 wherein each of R , R and R is independently selected from hydrogen, (C1-C3)-alkyl, aminoalkyl, aminocy- 10 cloalkyl, and hydroxyalkyl, and n is selected from 1, 2 and 3; b. 15 20 wherein R6 is selected from H and 25 c. 30 35 7 wherein R is selected from H, (C 1-C3)-unsubstituted alkyl, amino-(C 2-C3)-alkyl, aminocycloalkyl, hydroxyalkyl, and 40 45 and wherein each of p and q is independently selected from 1 and 2. [0004] In another aspect, the invention provides compounds of chemical Formula (A-I) or a pharmaceutically acceptable salt thereof, which are BLIs and are useful in combination with β-lactam antibiotics for the treatment of bacterial infections. 50 55 3 EP 2 831 069 B1 5 10 wherein 15 R* is selected from 20 and R1* is selected from: 25 a. 30 wherein R2* is selected from 35 40 3* R is selected from hydrogen, (C1-C3)-alkyl, aminoalkyl, aminocycloalkyl, hydroxyalkyl, 45 4* 5* 6* 7* each of R , R , R and R is independently selected from hydrogen, (C 1-C6)-alkyl, aminoalkyl, aminoc- ycloalkyl, and hydroxyalkyl, provided that at least one of R4*, R5*, R6* and R7* is hydrogen , 50 n is selected from 1, 2, 3 and 4, and m is selected from 1, 2 and 3; b. 55 4 EP 2 831 069 B1 8 * wherein R is selected from -NH(C1-C3)-alkyl and 5 wherein each of R4*, R5*, R6* and R7* is as described previously; 10 c. 15 20 wherein Z is selected from CR9R10 and NR11, 9 10 * each of R and R is independently selected from H, NH 2, -NH(C1-C3)-alkyl and 25 30 wherein each of R4*, R5*, R6* and R7* is as described previously, alternatively, R 9 and R 10 together with the carbon to which they are attached, form a cycloalkylor heterocyclyl ring containing 4-6 ring members, R11 is selected from H and 35 40 12 13 14 each of R , R and R is independently selected from hydrogen, (C1-C6)-alkyl, aminoalkyl, aminocy- cloalkyl, and hydroxyalkyl, provided that at least one of R 12 , R13 and R14 is hydrogen, 15 * R is selected from NH2 and 45 50 wherein each of R4*, R5*, R6* and R7 is as described previously, each of p* and q* is independently selected from 0, 1, 2 and 3, T is selected from NH and O, 55 t is selected from 0, 1, 2, 3, and 4, and each of r and y is independently selected from 0 and 1; d. 5 EP 2 831 069 B1 5 16 wherein R is selected from NH2, -NH(C1-C3)-alkyl and 10 15 wherein each of R4*, R5*, R6* and R7* is as described previously, s is selected from 0 and 1, and, v is selected from 0, 1, 2, and 3; 20 e. 25 18 * wherein R is selected from NH2 and 30 35 wherein each of R4*, R5*, R6* and R7* is as described previously, R17 is selected from amino and hydroxyl, and w is selected from 0 and 1; 40 f. 45 g. 50 55 wherein M is selected from NR19, CR20R21 and O, wherein R19 is selected from H and 6 EP 2 831 069 B1 5 where each of R12, R13 and R14 is as described previously, 20 21 each of R and R is independently selected from H, NH2 and 10 15 wherein each of R4*, R5*, R6* and R7* is as described previously, and u is selected from 0, 1 and 2; and h. 20 25 [0005] In one embodiment, the invention provides a compound of Formula I for use in inhibiting β-lactamases. [0006] In one embodiment, the invention provides a compound of Formula A-I for use in inhibiting β-lactamases. [0007] In one embodiment, the present invention also provides antibacterial compositions comprising compounds of Formula I and at least one β-lactam antibiotic. 30 [0008] In one embodiment, the present invention also provides antibacterial compositions comprising compounds of Formula A-I and at least one β-lactam antibiotic. [0009] Methods of use of the compounds of Formula I to treat bacterial infections in a subject, and methods of use of the compounds of Formula A-I to treat bacterial infections in a subject are disclosed. 35 BRIEF DESCRIPTION OF THE DRAWINGS [0010] Figures 1A-1D show Table I, Representative Compounds of Formula A-II 40 Figures 2A-2B show Table II, Standard BLI potentiation MIC assay against a panel of isogenic and clinical strains expressing β-lactamases. Figures 3A-3B show Table III, the synergy MIC of representative compounds of Formula II-A against a panel of isogenic and clinical strains expressing β-lactamases. Figure 4 shows Table IV, an assay to determine inhibition kinetics of representative compounds of Formula II-A for 45 the KPC-2 β-lactamase. Figures 5A-5B show Table V, Synergy MICof Comparator Compounds Against a Panel of Isogenic and Clinical Strains Expressing β-lactamases DETAILED DESCRIPTION 50 Definitions: [0011] Molecular terms, when used in this application, have their common meaning unless otherwise specified. [0012] The term "alkyl" is defined as a linear or branched, saturated radical having one to about twenty carbon atoms 55 unless otherwise specified. Preferred alkyl radicals are "lower alkyl" radicals having one to about five carbon atoms.
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