Cyclic boronic acid ester derivatives and therapeutic uses thereof
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.
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, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , wherein said alkylene or alkenylene linker is optionally fused to an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, or optionally substituted heterocyclyl;
R 1 is selected from a group consisting of —NR 9 R 10 , —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , —CH(OH)C 1-9 alkylR 9 , —CH(OH)C 2-9 alkenylR 9 , —CH(OH)C 2-9 alkynylR 9 , —CH(OH)carbocyclyl-R 9 , —C(═O)R 9 , —C(═O)C 1-9 alkylR 9 , —C(═O)C 2-9 alkenylR 9 , —C(═O)C 2-9 alkynylR 9 , —C(═O)C 2-9 -carbocyclyl-R 9 , —C(═O)NR 9 R 10 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)NR 9 R 10 , —N(R 9 )C(═O)OR 9 , —N(R 9 )C(═O)C(═NR 10 )R 9 , —N(R 9 )C(═O)C(═CR 9 R 10 )R 9 , —N(R 9 )C(═O)C 1-4 alkylN(R 9 )C(═O)R 9 , —N(R 9 )C(═NR 10 )R 9 , —C(═NR 10 )NR 9 R 10 , —N═C(R 9 )NR 9 R 10 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 NR 9 R 10 , —N═CHR 9 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
R 6 is selected from a group consisting of H, —C 1-9 alkyl, C 2-9 alkenyl, —C 2-9 alkynyl, carbocyclyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , carbocyclyl-R 11 , —C(═O)OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , and -carbocyclyl-CO 2 R 9 , or alternatively:
(i) R 6 and an R 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 6 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) R 6 is absent when the carbon to which it is attached is a ring atom in an aryl or heteroaryl ring;
each R 7 is independently selected from a group consisting of H, halo, —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , and -carbocyclyl-CO 2 R 9 , or independently:
R 6 and an R 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 7 and an R 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 7 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) R 6 is absent,
(c) R 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 8 attached to a ring atom forming part of the substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl formed by R 7 and Y is absent;
each R 8 is independently selected from a group consisting of H, halo, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 R 10 , —OR 9 , —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , —C 2-9 alkynylCO 2 R 9 , -carbocyclyl-CO 2 R 9 , or independently:
an R 7 and an R 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 7 and R 8 together form —C 2-9 alkenylenylCO 2 R 9 , or
(iii) each R 8 attached to a ring atom forming part of a substituted or unsubstituted aryl is absent;
each R 9 is independently selected from a group consisting of H, —C 1-9 alkyl, C 2-9 alkenyl, —C 2-9 alkynyl, carbocyclyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , -carbocyclyl-R 11 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each R 10 is independently selected from a group consisting of H, —C 1-9 alkyl, —OR 9 , —CH(═NH), —C(═O)OR 9 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
each R 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 2 R 12 , and carboxylic acid isosteres;
R 12 is selected from a group consisting of H, C 1-9 alkyl, —(CH 2 ) 0-3 —R 11 , —C(R 13 ) 2 OC(O)C 1-9 alkyl, —C(R 13 ) 2 OC(O)R 11 , —C(R 13 ) 2 OC.(O)OC 1-9 alkyl and —C(R 13 ) 2 OC(O)OR 11 ;
each R 13 is independently selected from a group consisting of H and C 1-4 -alkyl; and
m is independently an integer from 1 to 2,
wherein each C 1-9 alkyl, C 2-9 alkenyl, and C 2-9 alkynyl 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;
R 2 and R 4 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; or alternatively, R 2 and R 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 3 and R 5 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; 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:
R 1 is selected from a group consisting of —NR 9 R 10 , —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , —CH(OH)C 1-9 alkylR 9 , —CH(OH)C 2-9 alkenylR 9 , —CH(OH)C 2-9 alkynylR 9 , —C(═O)R 9 , —C(═O)C 1-9 alkylR 9 , —C(═O)C 2-9 alkenylR 9 , —C(═O)C 2-9 alkynylR 9 , —C(═O)NR 9 R 10 , —N(R 9 )C(═O)R 9 , —N(R 9 )C(═O)NR 9 R 10 , —N(R 9 )C(═O)OR 9 , —N(R 9 )C(═O)C(═NR 10 )R 9 , —N(R 9 )C(═O)C 1-4 -alkylN(R 9 )C(═O)R 9 , —N(R 9 )C(═NR 10 )R 9 , —C(═NR 10 )NR 9 R 10 , —N═C(R 9 )NR 9 R 10 , —N(R 9 )SO 2 R 9 , —N(R 9 )SO 2 NR 9 R 10 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl;
R 6 is selected from a group consisting of H, —C 1-9 alkyl, C 2-9 alkenyl, —C 2-9 alkynyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , —C(═O)OR 9 , and —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 , or alternatively R 6 and an R 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 7 is independently selected from a group consisting of H, —NR 9 R 10 , —OR 9 , and —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 , or independently, R 6 and an R 7 or independently an R 7 and an R 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 8 is independently selected from a group consisting of H, —NR 9 R 10 , —OR 9 , and —C 1-9 alkylCO 2 R 9 , —C 2-9 alkenylCO 2 R 9 , and —C 2-9 alkynylCO 2 R 9 , or independently, an R 7 and an R 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 9 is independently selected from a group consisting of H, C 2-9 alkenyl, —C 2-9 alkynyl, —C 1-9 alkylR 11 , —C 2-9 alkenylR 11 , —C 2-9 alkynylR 11 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted —(CH 2 ) 0-3 -carbocyclyl, and substituted or unsubstituted heterocyclyl;
each R 10 is independently selected from a group consisting of H, —C 1-9 alkyl, —OR 9 , —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 —CO 2 H and carboxylic acid isosteres.
6. The compound of claim 2 , wherein n is 1.
7. The compound of claim 2 , wherein R 2 , R 3 , R 4 , and R 5 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 R 2 and R 4 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; or alternatively, an R 2 and R 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 3 and R 5 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 .
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 R 2 and each R 4 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 ; or alternatively, an R 2 and an R 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 3 and each R 5 are independently selected from a group consisting of Cl, F, CN, CF 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 .
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 R 6 and each R 7 and R 8 is hydrogen.
15. The compound of claim 14 , wherein m is 1.
16. The compound of claim 15 , wherein R 1 is —NHC(═O)C 1-9 alkylR 11 .
17. The compound of claim 16 , wherein R 11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
18. The compound of claim 17 , wherein R 11 is thien-2-yl.
19. The compound of claim 1 , wherein R 1 is —NHC(═O)C(═NOR 9 )R 9′ , wherein R 9′ is selected from the group consisting of C 1-9 alkyl, 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 —CO 2 H.
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)(OR 9 ) 2 , —P(O)(R 9 )(OR 9 ), —P(O)(OR 12′ ) 2 , —P(O)(R 9 )(OR 12′ ), —CON(R 9 )OH, —SO 3 H, —SO 2 N(R 9 )OH, and
wherein R 12 ′ is selected from the group consisting of H, R 11 , —C(R 13 ) 2 OC(O)C 1-9 alkyl, —C(R 13 ) 2 OC(O)R 11 , —C(R 13 ) 2 OC(O)OC 1-9 alkyl and —C(R 13 ) 2 OC(O)OR 11 .
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.