Claims for Patent: 8,680,136

Summary for Patent: 8,680,136

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):	Gavin Hirst, Raja Reddy, Scott Hecker, Maxim Totrov, David C. Griffith, Olga Rodny, Michael N. Dudley, Serge Boyer
Assignee:	Melinta Subsidiary Corp
Application Number:	US13/205,112
Patent Claims:	1. A compound having the structure of formula I: or a pharmaceutically acceptable salt thereof, wherein: Y is a 1-4 atom alkylene, optionally substituted by one or more substituents selected from the group consisting of Cl, F, CN, CF3, —R9, —OR9, —C(═O)NR9R10, and —C(═O)OR9, wherein said alkylene or alkenylene linker is optionally fused to an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl; R1 is selected from a group consisting of —NR9R10, —C1-9alkylR11, —C2-9alkenylR11, —C2-9alkynylR11, -carbocyclyl-R11, —CH(OH)C1-9alkylR9, —CH(OH)C2-9alkenylR9, —CH(OH)C2-9alkynylR9, —CH(OH)carbocyclyl-R9, —C(═O)R9, —C(═O)C1-9 alkylR9, —C(═O)C2-9alkenylR9, —C(═O)C2-9alkynylR9, —C(═O)C2-9-carbocyclyl-R9, —C(═O)NR9R10, —N(R9)C(═O)R9, —N(R9)C(═O)NR9R10, —N(R9)C(═O)OR9, —N(R9)C(═O)C(═NR10)R9, —N(R9)C(═O)C(═CR9R10)R9, —N(R9)C(═O)C1-4alkylN(R9)C(═O)R9, —N(R9)C(═NR10)R9, —C(═NR10)NR9R10, —N═C(R9)NR9R10, —N(R9)SO2R9, —N(R9)SO2NR9R10, —N═CHR9, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; R6 is selected from a group consisting of H, —C1-9alkyl, C2-9alkenyl, —C2-9alkynyl, carbocyclyl, —C1-9alkylR11, —C2-9alkenylR11, —C2-9alkynylR11, carbocyclyl-R11, —C(═O)OR9, —C1-9alkylCO2R9, —C2-9alkenylCO2R9, —C2-9alkynylCO2R9, and -carbocyclyl-CO2R9, or alternatively: (i) R6 and an R7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) R6 and a carbon atom in Y are taken together with intervening atoms to form a substituted or unsubstituted carbocyclyl or substituted or unsubstitued heterocyclyl, or (iii) R6 is absent when the carbon to which it is attached is a ring atom in an aryl or heteroaryl ring; each R7 is independently selected from a group consisting of H, halo, —C1-9alkyl, —C2-9alkenyl, —C2-9alkynyl, NR9R10, —OR9, —C1-9alkylCO2R9, —C2-9alkenylCO2R9, —C2-9alkynylCO2R9, and -carbocyclyl-CO2R9, or independently: R6 and an R7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, (ii) R7 and an R8 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 R7 and a carbon atom in Y are taken together with intervening atoms to form a substituted or unsubstituted carbocyclyl or substituted or unsubstitued heterocyclyl, (iv) each of the following conditions are met: (a) Y is a 3-4 atom alkylene or 3-4 atom alkenylene linker, (b) R6 is absent, (c) R7 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 R8 attached to a ring atom forming part of the substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl formed by R7 and Y is absent; each R8 is independently selected from a group consisting of H, halo, —C2-9alkenyl, —C2-9alkynyl, —NR9R10, —OR9, —C1-9alkylCO2R9, —C2-9alkenylCO2R9, —C2-9alkynylCO2R9, -carbocyclyl-CO2R9, or independently: an R7 and an R8 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 R7 and R8 together form —C2-9 alkenylenylCO2R9, or (iii) each R8 attached to a ring atom forming part of a substituted or unsubstituted aryl is absent; each R9 is independently selected from a group consisting of H, —C1-9alkyl, C2-9alkenyl, —C2-9alkynyl, carbocyclyl, —C1-9alkylR11, —C2-9alkenylR11, —C2-9alkynylR11, -carbocyclyl-R11, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; each R10 is independently selected from a group consisting of H, —C1-9alkyl, —OR9, —CH(═NH), —C(═O)OR9, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; each R11 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 —CO2R12, and carboxylic acid isosteres; R12 is selected from a group consisting of H, C1-9alkyl, —(CH2)0-3—R11, —C(R13)2OC(O)C1-9alkyl, —C(R13)2OC(O)R11, —C(R13)2OC.(O)OC1-9alkyl and —C(R13)2OC(O)OR11; each R13 is independently selected from a group consisting of H and C1-4-alkyl; and m is independently an integer from 1 to 2, wherein each C1-9alkyl, C2-9alkenyl, and C2-9alkynyl is independently optionally substituted. 2. The compound of claim 1, having the structure of formula II: or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents; R2 and R4 are independently selected from a group consisting of Cl, F, CN, CF3, —R9, —OR9, —C(═O)NR9R10, and —C(═O)OR9; or alternatively, R2 and R4 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; R3 and R5 are independently selected from a group consisting of Cl, F, CN, CF3, —R9, —OR9, —C(═O)NR9R10, and —C(═O)OR9; and n is independently zero or an integer from 1 to 2. 3. The compound of claim 2 having the defined 3,6-cis-stereochemistry shown in formula IIa: or a pharmaceutically acceptable salt thereof. 4. The compound of claim 2 having the defined 3,6-trans-stereochemistry shown in formula IIb: or a pharmaceutically acceptable salt thereof. 5. The compound of claim 2, wherein: R1 is selected from a group consisting of —NR9R10, —C1-9alkylR11, —C2-9alkenylR11, —C2-9alkynylR11, —CH(OH)C1-9alkylR9, —CH(OH)C2-9alkenylR9, —CH(OH)C2-9alkynylR9, —C(═O)R9, —C(═O)C1-9alkylR9, —C(═O)C2-9alkenylR9, —C(═O)C2-9alkynylR9, —C(═O)NR9R10, —N(R9)C(═O)R9, —N(R9)C(═O)NR9R10, —N(R9)C(═O)OR9, —N(R9)C(═O)C(═NR10)R9, —N(R9)C(═O)C1-4-alkylN(R9)C(═O)R9, —N(R9)C(═NR10)R9, —C(═NR10)NR9R10, —N═C(R9)NR9R10, —N(R9)SO2R9, —N(R9)SO2NR9R10, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl; R6 is selected from a group consisting of H, —C1-9alkyl, C2-9alkenyl, —C2-9alkynyl, —C1-9alkylR11, —C2-9alkenylR11, —C2-9alkynylR11, —C(═O)OR9, and —C1-9alkylCO2R9, —C2-9alkenylCO2R9, and —C2-9alkynylCO2R9, or alternatively R6 and an R7 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R7 is independently selected from a group consisting of H, —NR9R10, —OR9, and —C1-9alkylCO2R9, —C2-9alkenylCO2R9, and —C2-9alkynylCO2R9, or independently, R6 and an R7 or independently an R7 and an R8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R8 is independently selected from a group consisting of H, —NR9R10, —OR9, and —C1-9alkylCO2R9, —C2-9alkenylCO2R9, and —C2-9alkynylCO2R9, or independently, an R7 and an R8 are taken together with the atoms to which they are attached to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl; each R9 is independently selected from a group consisting of H, C2-9alkenyl, —C2-9alkynyl, —C1-9alkylR11, —C2-9alkenylR11, —C2-9alkynylR11, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —(CH2)0-3-carbocyclyl, and substituted or unsubstituted heterocyclyl; each R10 is independently selected from a group consisting of H, —C1-9alkyl, —OR9, —CH(═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 —CO2H and carboxylic acid isosteres. 6. The compound of claim 2, wherein n is 1. 7. The compound of claim 2, wherein R2, R3, R4, and R5 are hydrogen. 8. The compound of claim 1, having the structure of formula IIIa: or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents a single bond; each R2 and R4 are independently selected from a group consisting of Cl, F, CN, CF3, —R9, —OR9, —C(═O)NR9R10, and —C(═O)OR9; or alternatively, an R2 and R4 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 R3 and R5 are independently selected from a group consisting of Cl, F, CN, CF3, —R9, —OR9, —C(═O)NR9R10, and —C(═O)OR9. 9. The compound of claim 8, having the 3,7-cis-stereochemistry shown in formula IIIe: or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1, having the 3,7-trans-stereochemistry shown in formula IIIe: or a pharmaceutically acceptable salt thereof. 11. The compound of claim 1, having the structure of formula IVa: or a pharmaceutically acceptable salt thereof, wherein: the bond represented by a dashed and solid line represents a single bond; each R2 and each R4 are independently selected from a group consisting of Cl, F, CN, CF3, —R9, —OR9, —C(═O)NR9R10, and —C(═O)OR9; or alternatively, an R2 and an R4 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 R3 and each R5 are independently selected from a group consisting of Cl, F, CN, CF3, —R9, —OR9, —C(═O)NR9R10, and —C(═O)OR9. 12. The compound of claim 11, having the 3,8-cis-stereochemistry shown in formula IVd: or a pharmaceutically acceptable salt thereof. 13. The compound of claim 11, having the 3,8-trans-stereochemistry shown in formula IVg: or a pharmaceutically acceptable salt thereof. 14. The compound claim 1, wherein R6 and each R7 and R8 is hydrogen. 15. The compound of claim 14, wherein m is 1. 16. The compound of claim 15, wherein R1 is —NHC(═O)C1-9alkylR11. 17. The compound of claim 16, wherein R11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. 18. The compound of claim 17, wherein R11 is thien-2-yl. 19. The compound of claim 1, wherein R1 is —NHC(═O)C(═NOR9)R9′, wherein R9′ is selected from the group consisting of C1-9alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl. 20. The compound of claim 1, wherein X is —CO2H. 21. The compound of claim 1, wherein X is a carboxylic acid isostere. 22. The compound of claim 21, wherein the carboxylic acid isostere is selected from the group consisting of —P(O)(OR9)2, —P(O)(R9)(OR9), —P(O)(OR12′)2, —P(O)(R9)(OR12′), —CON(R9)OH, —SO3H, —SO2N(R9)OH, and wherein R12′ is selected from the group consisting of H, R11, —C(R13)2OC(O)C1-9alkyl, —C(R13)2OC(O)R11, —C(R13)2OC(O)OC1-9alkyl and —C(R13)2OC(O)OR11. 23. The compound of claim 1, wherein m is 1. 24. The compound of claim 1, having a structure selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 25. The compound of claim 1, having a structure selected from the group consisting of: and or a pharmaceutically acceptable salt thereof. 26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient. 27. The compound of claim 1, having the structure: or a pharmaceutically acceptable salt thereof.