Details for Patent: 9,296,763

Title:	Cyclic boronic acid ester derivatives and therapeutic uses thereof
Abstract:	Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to 1 cyclic boronic acid ester derivatives and their use as therapeutic agents.
Inventor(s):	Hirst; Gavin (San Diego, CA), Reddy; Raja (San Diego, CA), Hecker; Scott (Del Mar, CA), Totrov; Maxim (San Diego, CA), Griffith; David C. (San Marcos, CA), Rodny; Olga (Mill Valley, CA), Dudley; Michael N. (San Diego, CA), Boyer; Serge (San Diego, CA)
Assignee:	Rempex Pharmaceuticals, Inc. (San Diego, CA)
Filing Date:	Jul 29, 2013
Application Number:	13/953,647
Claims:	1. A compound having the structure of formula I: ##STR00214## or a pharmaceutically acceptable salt thereof, wherein: Y is a 2-4 atom alkenylene linker, optionally substituted by one or more substituents selected from the group consisting of Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9, wherein said alkenylene linker is optionally fused to an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R.sup.1 is selected from a group consisting of --C.sub.1-9alkyl, --C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --NR.sup.9R.sup.10, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, -carbocyclyl-R.sup.11, --CH(OH)C.sub.1-9alkylR.sup.9, --CH(OH)C.sub.2-9alkenylR.sup.9, --CH(OH)C.sub.2-9alkynylR.sup.9, --CH(OH)carbocyclyl-R.sup.9, --C(.dbd.O)R.sup.9, --C(.dbd.O)C.sub.1-9alkylR.sup.9, --C(.dbd.O)C.sub.2-9alkenylR.sup.9, --C(.dbd.O)C.sub.2-9alkynylR.sup.9, --C(.dbd.O)C.sub.2-9carbocyclyl-R.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)OR.sup.9, --N(R.sup.9)C(.dbd.O)C(.dbd.NR.sup.10)R.sup.9, --N(R.sup.9)C(.dbd.O)C(.dbd.CR.sup.9R.sup.10)R.sup.9, --N(R.sup.9)C(.dbd.O)C.sub.1-4alkylN(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.NR.sup.10)R.sup.9, --C(.dbd.NR.sup.10)NR.sup.9NR.sup.10, --N.dbd.C(R.sup.9)NR.sup.9R.sup.10, --N(R.sup.9)SO.sub.2R.sup.9, --N(R.sup.9)SO.sub.2NR.sup.9R.sup.10, --N.dbd.CHR.sup.9, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; R.sup.6 is selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, carbocyclyl, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, carbocyclyl-R.sup.11, --C(.dbd.O)OR.sup.9, --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, --C.sub.2-9alkynylCO.sub.2R.sup.9, and -carbocyclyl-CO.sub.2R.sup.9, or alternatively: (i) R.sup.6 and an R.sup.7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) R.sup.6 and a carbon atom in Y are taken together with intervening atoms to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, or (iii) R.sup.6 is absent when the carbon to which it is attached is a ring atom in an aryl or heteroaryl ring; each R.sup.7 is independently selected from a group consisting of H, halo, --C.sub.1-9alkyl, --C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --NR.sup.9R.sup.10, --OR.sup.9, --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, --C.sub.2-9alkynylCO.sub.2R.sup.9, and -carbocyclyl-CO.sub.2R.sup.9, or independently: (i) R.sup.6 and an R.sup.7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) R.sup.7 and an R.sup.8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (iii) an R.sup.7 and a carbon atom in Y are taken together with intervening atoms to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (iv) each of the following conditions are met: (a) Y is a 3-4 atom alkenylene linker, (b) R.sup.6 is absent, (c) R.sup.7 and a carbon atom in Y are taken together with intervening atoms to form a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, and (d) each R.sup.8 attached to a ring atom forming part of the substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl formed by R.sup.7 and Y is absent; each R.sup.8 is independently selected from a group consisting of H, halo, --C.sub.1-9alkyl, --C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --NR.sup.9R.sup.10, --OR.sup.9, --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, --C.sub.2-9alkynylCO.sub.2R.sup.9, -carbocyclyl-CO.sub.2R.sup.9, or independently: (i) an R.sup.7 and an R.sup.8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) a geminal R.sup.7 and R.sup.8 together form --C.sub.2-9 alkenylenylCO.sub.2R.sup.9, or (iii) each R.sup.8 attached to a ring atom forming part of a substituted or unsubstituted aryl is absent; each R.sup.9 is independently selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, carbocyclyl, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, -carbocyclyl-R.sup.11, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; each R.sup.10 is independently selected from a group consisting of H, --C.sub.1-9alkyl, --OR.sup.9, --CH(.dbd.NH), --C(.dbd.O)OR.sup.9, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; each R.sup.11 is independently selected from a group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; X is selected from a group consisting of --CO.sub.2R.sup.12 and carboxylic acid isosteres; R.sup.12 is selected from a group consisting of H, C.sub.1-9alkyl, --(CH.sub.2).sub.0-3--R.sub.11, --C(R.sup.13).sub.2OC(O)C.sub.1-9alkyl, --C(R.sup.13).sub.2OC(O)R.sup.11, --C(R.sup.13).sub.2OC(O)OC.sub.1-9alkyl and --C(R.sup.13).sub.2OC(O)OR.sup.11; each R.sup.13 is independently selected from a group consisting of H and C.sub.1-4alkyl; and m is independently zero or an integer from 1 to 2, wherein each C.sub.1-9alkyl, C.sub.2-9alkenyl, and C.sub.2-9alkynyl is independently optionally substituted. 2. The compound of claim 1, having the structure of formula II: ##STR00215## or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents a double bond; R.sup.2 and R.sup.4 are independently selected from a group consisting of Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9; or alternatively, R.sup.2 and R.sup.4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; R.sup.3 and R.sup.5 are absent; and n is 1. 3. The compound of claim 2 having the defined 3,6-cis-stereochemistry shown in formula IIa: ##STR00216## or a pharmaceutically acceptable salt thereof. 4. The compound of claim 2 having the defined 3,6-trans-stereochemistry shown in formula IIb: ##STR00217## or a pharmaceutically acceptable salt thereof. 5. The compound of claim 2, wherein: R.sup.1 is selected from a group consisting of --C.sub.1-9alkyl, --C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --NR.sup.9NR.sup.10, C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, --CH(OH)C.sub.1-9alkylR.sup.9, --CH(OH)C.sub.2-9alkenylR.sup.9, --CH(OH)C.sub.2-9alkynylR.sup.9, --C(.dbd.O)R.sup.9, --C(.dbd.O)C.sub.1-9alkylR.sup.9, --C(.dbd.O)C.sub.2-9alkenylR.sup.9, --C(.dbd.O)C.sub.2-9alkynylR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.O)NR.sup.9R.sup.10, --N(R.sup.9)C(.dbd.O)OR.sup.9, --N(R.sup.9)C(.dbd.O)C(.dbd.NR.sup.10)R.sup.9, --N(R.sup.9)C(.dbd.O)C.sub.1-4alkylN(R.sup.9)C(.dbd.O)R.sup.9, --N(R.sup.9)C(.dbd.NR.sup.10)R.sup.9, --C(.dbd.NR.sup.10)NR.sup.9R.sup.10, --N.dbd.C(R.sup.9)NR.sup.9R.sup.10, --N(R.sup.9)SO.sub.2R.sup.9, --N(R.sup.9)SO.sub.2NR.sup.9R.sup.10, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; R.sup.6 is selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --C.sub.1-9alkylR.sup.11, --C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, --C(.dbd.O)OR.sup.9, and --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, and --C.sub.2-9alkynylCO.sub.2R.sup.9, or alternatively R.sup.6 and an R.sup.7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R.sup.7 is independently selected from a group consisting of H, --NR.sup.9R.sup.10, --OR.sup.9, and --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, and --C.sub.2-9alkynylCO.sub.2R.sup.9, or independently, R.sup.6 and an R.sup.7 or independently an R.sup.7 and an R.sup.8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R.sup.8 is independently selected from a group consisting of H, --NR.sup.9R.sup.10, --OR.sup.9, and --C.sub.1-9alkylCO.sub.2R.sup.9, --C.sub.2-9alkenylCO.sub.2R.sup.9, and --C.sub.2-9alkynylCO.sub.2R.sup.9, or independently, an R.sup.7 and an R.sup.8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R.sup.9 is independently selected from a group consisting of H, --C.sub.1-9alkyl, C.sub.2-9alkenyl, --C.sub.2-9alkynyl, --C.sub.1-9alkylR.sup.11, C.sub.2-9alkenylR.sup.11, --C.sub.2-9alkynylR.sup.11, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted --(CH.sub.2).sub.0-3carbocyclyl, and substituted or unsubstituted heterocyclyl; each R.sup.10 is independently selected from a group consisting of H, --C.sub.1-9alkyl, --OR.sup.9, --CH(.dbd.NH), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; and X is selected from a group consisting of --CO.sub.2H and carboxylic acid isosteres. 6. The compound of claim 2, wherein R.sup.2 and R.sup.4 are hydrogen. 7. The compound of claim 1, having the structure of formula IIIa or IIIb: ##STR00218## or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents a double bond; each R.sup.2 and R.sup.4 are independently selected from a group consisting of Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9; or alternatively, an R.sup.2 and R.sup.4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R.sup.3 is independently selected from a group consisting of Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9, with the proviso that the R.sup.3 attached to the carbon atoms bonded to the bond represented by a dashed and solid line are absent; and R.sup.5 is absent. 8. The compound of claim 7, having the 3,7-cis-stereochemistry shown in formula IIIc and IIId: ##STR00219## or a pharmaceutically acceptable salt thereof. 9. The compound of claim 7, having the 3,7-trans-stereochemistry shown in formula IIIe and IIIf: ##STR00220## or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1, having the structure of formula IVa, IVb, or IVc: ##STR00221## or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents a double bond; each R.sup.2 and each R.sup.4 are independently selected from a group consisting of Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9; or alternatively, an R.sup.2 and an R.sup.4 are taken together with the atoms to which they are attached to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R.sup.3 and each R.sup.5 are independently selected from a group consisting of Cl, F, CN, CF.sub.3, --R.sup.9, --OR.sup.9, --C(.dbd.O)NR.sup.9R.sup.10, and --C(.dbd.O)OR.sup.9, with the proviso that the R.sup.3 and R.sup.5 attached to the carbon atoms bonded to the bond represented by a dashed and solid line are absent. 11. The compound of claim 10, having the 3,8-cis-stereochemistry shown in formula IVd, IVe, and IVf: ##STR00222## or a pharmaceutically acceptable salt thereof. 12. The compound of claim 10, having the 3,8-trans-stereochemistry shown in formula IVg, IVh, and IVi: ##STR00223## or a pharmaceutically acceptable salt thereof. 13. The compound claim 1, wherein R.sup.6 and each R.sup.7 and R.sup.8 is hydrogen. 14. The compound of claim 13, wherein m is 1. 15. The compound of claim 14, wherein R.sup.1 is --NHC(.dbd.O)C.sub.1-9alkylR.sup.11. 16. The compound of claim 15, wherein R.sup.11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. 17. The compound of claim 16, wherein R.sup.11 is thien-2-yl. 18. The compound of claim 1, wherein R.sup.1 is --NHC(.dbd.O)C(.dbd.NOR.sup.9)R.sup.9', wherein R.sup.9' is selected from the group consisting of C.sub.1-9alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl. 19. The compound of claim 1, wherein X is --CO.sub.2H. 20. The compound of claim 1, wherein X is a carboxylic acid isostere. 21. The compound of claim 20, wherein the carboxylic acid isostere is selected from the group consisting of --P(O)(OR.sup.9).sub.2, --P(O)(R.sup.9)(OR.sup.9), --P(O)(OR.sup.12').sub.2, --P(O)(R.sup.9)(OR.sup.12'), --CON(R.sup.9)OH, --SO.sub.3H, --SO.sub.2N(R.sup.9)OH, and ##STR00224## wherein R.sup.12' is selected from the group consisting of H, R.sub.11, --C(R.sup.13).sub.2OC(O)C.sub.1-9alkyl, --C(R.sup.13).sub.2OC(O)R.sup.11, --C(R.sup.13).sub.2OC(O)OC.sub.1-9alkyl and --C(R.sup.13).sub.2OC(O)OR.sup.11. 22. The compound of claim 1, wherein m is 1. 23. The compound of claim 1, having a structure selected from the group consisting of: ##STR00225## ##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232## or a pharmaceutically acceptable salt thereof. 24. The compound of claim 1, having the structure: ##STR00233## or a pharmaceutically acceptable salt thereof.