Heterocyclic boronic acid ester derivatives and therapeutic uses thereof

1. A compound having the structure of formula I:

or pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from a group consisting of —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 , —C(R 9 R 10 )C(═O)NR 9 R 10 , —C(R 9 R 10 )N(R 9 )C(═O)R 9 ;

G 1 is selected from a divalent group consisting of —C(R a R b )—, —C(═R a ′)—, —C(R a R b )C(R c R d )—, —C(R a )═C(R c )—, —C(═O)C(R a R b )—, —C(R a R b )C(═O)—, and a bond;

G 2 is selected from a divalent group consisting of —C(R e R f )—, —C(═R e ′)—, ═C(R e )—, —C(R e R f )C(R g R h )—, —C(R e R f )C(R g R h )C(R i R j )—, —C(═O)—, —C(═O)C(R e R f )—, —C(R e R f )C(═O)—, —C(═O)C(R e R f )C(R g R h )—, —C(R e R f )C(R g R h )C(═O)—, —C(═O)C(R e R f )C(R g R h )C(R i R j )—, —C(R e R f )C(R g R h )C(R i R j )C(═O)—, —C(R e )═C(R g )—, —C(R e )═C(R g )C(R i R j )— and —C(R e R f )C(R g )═C(R j )—;

R a , R b , R c , R d , R e , R f , R g , R h , R i , and R j are independently selected from a group consisting of H, Cl, F, CN, CF 3 , —R 9 , —OR 9 , NR 9 R 10 , —C(═O)NR 9 R 10 , and —C(═O)OR 9 , or independently: R a and R c , R e and an R 7 , R e and R 6 , R k and R c , R k and R e , R e and R g , and R g and R j are taken together with the atoms to which they are attached and any intervening atoms to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, or independently R e and R f are taken together with the atoms to which they are attached and any intervening atoms to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

R a′ and R e′ are ═CR 9 R 10 or independently R a′ and R k , or R e ′ and R k , 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;

Z is selected from a divalent group consisting of —O—, —S—, —N(R 9 )—, —N[C(═O)R 9 ]—, —N[C(═O)NR 9 R 10 ]—, —N[C(═O)OR 9 ]—, —N[C(═NR 10 )R 9 ]—, —N[SO 2 R 9 ]—, —N[SO 2 NR 9 R 10 ]—, —N(R 9 )C(═O)—, and —N(R k );

R k and R c , R k and R e , R a′ and R k , or R e′ and R k are taken together with any intervening atoms to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

Y is selected from a group consisting of N, CR 6 , and C, with the proviso that when Z is a bond, —C(R 9 R 10 )—, —C(R 9 R k )—, or —C(═R k )—, then Y is N;

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 and ——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 R 6 and an R 7 or R 6 and R e are taken together with the atoms to which they are attached and any intervening atoms to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl;

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 or an R 7 and an R 8 are taken together with the atoms to which they are attached and any intervening atoms to form a substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl, or independently an R 7 and R e are taken together with intervening atoms to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl;

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 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, 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, or independently, each R 8 attached to a ring atom forming part of a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl 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 , —C 1-9 alkylCO 2 R 12 , C 2-9 alkenylCO 2 R 12 , —C 2-9 alkynylCO 2 R 12 , -carbocyclyl-CO 2 R 12 , —C 1-9 alkyl-N(R 12 )OR 12 , C 2-9 alkenyl-N(R 12 )OR 12 , —C 2-9 alkynyl-N(R 12 )OR 12 , -carbocyclyl-N(R 12 )OR 12 , —C 1-9 alkyl-OR 12 , C 2-9 alkenyl-OR 12 , —C 2-9 alkynyl-OR 12 , -carbocyclyl-OR 12 , 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;

each R 12 is independently 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;

each X is independently selected from a group consisting of —CO 2 R 12 , and carboxylic acid isosteres;

m is independently zero or an integer from 1 to 2;

the bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond; and

each C 1-9 alkyl, C 2-9 alkenyl, and C 2-9 alkynyl is optionally substituted.

2. The compound of claim 1 , having the defined stereochemistry at 3-position shown in formula Ia:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein Y is CR 6 , having the defined 3,7-trans-stereochemistry shown in formula Ib:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein Y is CR 6 , having the defined 3,7-cis-stereochemistry shown in formula Ic:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein R 1 is —NHC(═O)R 9 .

6. The compound of claim 5 , wherein R 9 is —C 1-9 alkylR 11 .

7. The compound of claim 6 , wherein R 11 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

8. The compound of claim 7 , wherein R 11 is thien-2-yl.

9. The compound of claim 1 , wherein R 1 is —N(R 9 )C(═O)C(═NR 10 )R 9 .

10. The compound of claim 1 , wherein R 1 is —N(R 9 )C(═O)C(═C R 9 R 10 )R 9 .

11. The compound of claim 1 , wherein R 9 is —C 1-9 alkyl.

12. The compound of claim 1 , wherein R 9 is —C 1-9 alkylR 11 .

13. The compound of claim 1 , wherein R 9 is —C 1-9 alkylCO 2 R 12 .

14. The compound of claim 1 , wherein R 9 is substituted or unsubstituted heteroaryl.

15. The compound of claim 1 , wherein G 1 is a bond.

16. The compound of claim 1 , wherein G 2 is —C(R e R f )—.

17. The compound of claim 1 , wherein G 2 is —C(═O)—.

18. The compound of claim 1 , wherein G 2 is —C(═O)C(R e R f )—.

19. The compound of claim 1 , wherein G 1 is —C(R a R b )— and G 2 is —C(R e R f )—.

20. The compound of claim 1 , wherein Z is —O—.

21. The compound of claim 1 , wherein Z is —S—.

22. The compound of claim 1 , wherein Z is —N(R 9 )—.

23. The compound of claim 1 , wherein Z is —N[C(═O)R 9 ]—.

24. The compound of claim 1 , wherein Z is —N[C(═O)OR 9 ]—.

25. The compound of claim 1 , wherein Z is —N(R k )—.

26. The compound of claim 1 , wherein Y is CR 6 .

27. The compound of claim 1 , wherein Y is N.

28. The compound of claim 1 , wherein m is 1.

29. The compound of claim 1 , wherein R 7 and R 8 are H.

30. The compound of claim 1 , wherein R 10 is —OR 9 —.

31. The compound of claim 1 , wherein R 10 is —C(═O)OR 9 —.

32. The compound of claim 1 , wherein R 11 is substituted or unsubstituted aryl.

33. The compound of claim 1 , wherein R 11 is substituted or unsubstituted heteroaryl.

34. The compound of claim 1 , wherein R 11 is substituted or unsubstituted carbocyclyl.

35. The compound of claim 1 , wherein R 11 is substituted or unsubstituted heterocyclyl.

36. The compound of claim 1 , wherein X is —CO 2 R 12 or carboxylic acid isosteres.

37. The compound of claim 36 , wherein X is —CO 2 H.

38. The compound of claim 1 , having a structure selected from the group consisting of:

39. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.