Cyclic boronic acid ester derivatives and therapeutic uses thereof

1. A compound having the structure of formula I:

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 3 , —R 9 , —OR 9 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , wherein said 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 —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —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 NR 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 unsubstituted 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:

(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 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 unsubstituted heterocyclyl,

(iv) each of the following conditions are met:

(a) Y is a 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 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 , -carbocyclyl-CO 2 R 9 , or independently:

(i) 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 zero or 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 a double bond;

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 absent; and

n is 1.

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 —C 1-9 alkyl, —C 2-9 alkenyl, —C 2-9 alkynyl, —NR 9 NR 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 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 , 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 R 2 and R 4 are hydrogen.

7. The compound of claim 1 , having the structure of formula IIIa or IIIb:

or a pharmaceutically acceptable salt thereof, wherein:

the bond represented by a dashed and solid line represents a double 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 is 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 , with the proviso that the R 3 attached to the carbon atoms bonded to the bond represented by a dashed and solid line are absent; and

R 5 is absent.

8. The compound of claim 7 , having the 3,7-cis-stereochemistry shown in formula IIIc and IIId:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 7 , having the 3,7-trans-stereochemistry shown in formula IIIe and IIIf:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , having the structure of formula IVa, IVb, or IVc:

or a pharmaceutically acceptable salt thereof, wherein:

the bond represented by a dashed and solid line represents a double 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 , with the proviso that the R 3 and R 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:

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:

or a pharmaceutically acceptable salt thereof.

13. The compound claim 1 , wherein R 6 and each R 7 and R 8 is hydrogen.

14. The compound of claim 13 , wherein m is 1.

15. The compound of claim 14 , wherein R 1 is —NHC(═O)C 1-9 alkylR 11 .

16. The compound of claim 15 , wherein R 11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

17. The compound of claim 16 , wherein R 11 is thien-2-yl.

18. 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.

19. The compound of claim 1 , wherein X is —CO 2 H.

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 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 .

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:

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.