Boronic acid derivatives and therapeutic uses thereof

1. A compound having the structure of Formula (I-1) or Formula (I-2):

or pharmaceutically acceptable salts thereof, wherein:

J, L, and M are each independently selected from the group consisting of CR 7 and N;

Y is selected from the group consisting of —S—, —S(O)—, —S(O) 2 —, —O—and —CH 2 —;

G is selected from the group consisting of —NR 1 R 2 , —N 3 , —C(O)NR 1 R 2 , —S(O) 2 NR 1 R 2 , —SR 3 , —OR 3 , —CH 2 NR 1 C(O)R 5 , —C(═NOR 3 )—X, —C(═NOR 3 )—Z, —C(O)OR 3 , —S(O 2 )R 3 , —C(O)NR 1 (OR 3 ), —NR 1 (OR 3 ), —NR 1 C(O)R 5 , —NR 1 C(O)NR 2 R 1a , —NR 1 C(O)OR 3 , —NR 1 S(O) 2 R 3 , —NR 1 S(O) 2 NR 2 R 1a , —NR 1 NR 2 R 1a , —C(O)NR 1 NR 2 R 1a , —S(O) 2 NR 1 NR 2 R 1a , —C(═NR 1 )R 5 , —C(═NR 1 )NR 2 R 1a , —NR 1 CR 5 (═NR 2 ), —NR 1 C(═NR 2 )NR 1a R 2a , optionally substituted —C 1-10 alkyl, optionally substituted —C 2-10 alkenyl, optionally substituted —C 2-10 alkynyl, optionally substituted —C 3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted —C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl;

R 7 is present 1 to 5 times and each R 7 is independently selected from the group consisitng of —H, —OH, halogen, —CF 3 , —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 1 -C 6 heteroalkyl, —C 3 -C 7 carbocyclyl, 5-10 membered heterocyclyl, aryl, 5-10 membered heteroaryl, cyano, —C 1 -C 6 alkoxy(C 1 -C 6 )alkyl, aryloxy, sulfhydryl (mercapto), and —(CH 2 ) m —Y′—(CH 2 ) p M′;

m and p are independently 0 to 3;

Y′ is selected from the group consisting of —S—, —S(O)—, —S(O) 2 —, —O—, —CR 5 R 6 —, and —NR 1 —;

M′ is selected from the group consisting of —C(O)NR 1 R 2 ; —C(O)NR 1 OR 3 ; —NR 1 C(O)R 5 ; —NR 1 C(O)NR 2 R 1a ; —NR 1 C(O)OR 3 ; —NR 1 S(O) 2 R 3 ; —NR 1 S(O) 2 NR 2 R 1a ; —C(═NR 1 )R 5 ; —C(═NR 1 )NR 2 R 1a ; —NR 1 CR 5 (═NR 2 ); —NR 1 C(═NR 2 )NR 1a R 2a ; —C 1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting of —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; —C 3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of —C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; —C 6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of —C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of —C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of —C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ;

X is hydrogen or optionally substituted C 1-9 alkyl;

Z is selected from the group consisting of optionally substituted C 3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R is selected from the group consisting of —H, —C 1-9 alkyl, —CR 5 R 6 OC(O)C 1-9 alkyl, —CR 5 R 6 OC(O)OC 1-9 alkyl, and

each R 1 , R 2 , R 1a and R 2a are independently selected from the group consisting of —H, optionally substituted —C 1-10 alkyl, optionally substituted —C 2-10 alkenyl, optionally substituted —C 2-10 alkynyl, optionally substituted —C 3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted —C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl;

R 3 is hydrogen, optionally substituted —C 1-10 alkyl, -optionally substituted —C 1-10 alkyl—COOH, optionally substituted —C 2-10 alkenyl, optionally substituted —C 2-10 alkynyl, optionally substituted —C 3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted —C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl;

each R 5 , R 6 , R 8 and R 9 are independently selected from the group consisting of —H, —OH, -optionally substituted alkoxyl, optionally substituted —C 1-10 alkyl, optionally substituted —C 2-10 alkenyl, optionally substituted —C 2-10 alkynyl, optionally substituted —C 3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted —C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl; and

each n is independently 0-3.

2. The compound of claim 1 , wherein R 8 is H and R 9 is H.

3. The compound of claim 1 , wherein:

Y is selected from the group consisting of —S—, —O—, —CH 2 —;

G is selected from the group consisting of —C(O)NR 1 R 2 ; —C(O)NR 1 OR 3 ; —NR 1 C(O)R 5 ; —NR 1 C(O)NR 2 R 1a ; —NR 1 C(O)OR 3 ; —NR 1 S(O) 2 R 3 ; —NR 1 S(O) 2 NR 2 R 1a ; —C(═NR 1 )R 5 ; —C(═NR 1 )NR 2 R 1a ; —NR 1 CR 5 (═NR 2 ); —NR 1 C(═NR 2 )NR 1a R 2a ; —C 6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of —C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; 5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of —C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; and 5-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of —C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ;

R is selected from the group consisting of —H, —C 1-9 alkyl, —CR 5 R 6 OC(O)C 1-9 alkyl, and

each R 1 , R 2 , R 1a , R 2a , R 3 , R 5 and R 6 are independently selected from —H and —C 1-4 alkyl; and

R 7 is selected from the group consisting of —H, —C 2-4 alkyl, —OH, —OC 1-4 alkyl, and halogen.

4. The compound of claim 1 , having the structure of Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id)

or pharmaceutically acceptable salts thereof.

5. The compound of claim 1 , wherein Y is —CH 2 —, —O— or —S—.

6. The compound of claim 1 , wherein:

Y is —O— or —S—;

G is selected from the group consisting of phenyl, imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted by 0-2 substituents selected from the group consisting of C 1-4 alkyl, —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 , wherein R 1 , R 2 and R 5 in G are independently selected from —H and —C 1-4 alkyl; and

J, L and M are CR 7 .

7. The compound of claim 1 , wherein n is 0 or 1.

8. The compound of claim 1 , wherein the compound of formula (I) has the structure of formula (Ie):

or pharmaceutically acceptable salts thereof,

wherein n is 0;

R 7 is selected from t ie group consisting of H, F, Cl, —CF 3 , and —Y′—(CH 2 ) p M′; and

p is 0 or 1.

9. The compound of claim 1 , wherein G is selected from the group consisting of thiadiazole; thiadiazole optionally substituted with —NR 1 R 2 or —NR 1 C(O)R 5 ; triazole optionally substituted with —NR 1 R 2 or C 1-4 alkyl; tetrazole optionally substituted with methyl; pyridine; thiazole; phenyl; or azetidine; and wherein R 1 , R 2 and R 5 in G are independently —H or —C 1-4 alkyl.

10. The compound of claim 1 , wherein:

Y is —S—;

n is 1 or 2;

G is —C(O)NR 1 R 2 ; and

J, L and M are CR 7 .

11. The compound of claim 1 , wherein:

Y is —CH 2 —;

n is 0 to 2;

G is —C(O)NR 1 R 2 ; and

J, L and M are CR 7 .

12. The compound of claim 1 , wherein R 7 is selected from the group consisting of —H, —OH, —C 1-4 alkyl, —O—C 1-4 alkyl, —S—C 1-4 alkyl, halogen, —CF 3 , and cyano.

13. The compound of claim 1 , wherein R is —CR 5 R 6 OC(O)C 1-9 alkyl or —CR 5 R 6 OC(O)OC 1-9 alkyl.

14. The compound of claim 1 , wherein M′ is selected from the group consisting of —C(O)NR 1 R 2 ; —C(O)NR 1 OR 3 ; —NR 1 C(O)R 5 ; —NR 1 C(O)NR 2 R 1a ; —NR 1 C(O)OR 3 ; —NR 1 S(O) 2 R 3 ; —NR 1 S(O) 2 NR 2 R 1a ; —C(═NR 1 )NR 2 R 1a ; —NR 1 CR 5 (═NR 2 ); —NR 1 C(═NR 2 )NR 1a R 2a ; C 6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; 5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; and 4-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of —OR 3 , —NR 1 R 2 , halogen, —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 .

15. The compound of claim 1 , wherein R 1 is H and R 2 is H.

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

or pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

18. The composition of claim 17 , wherein the pharmaceutically acceptable excipient is meglumine.

19. The pharmaceutical composition of claim 17 , further comprising an additional medicament, and wherein the additional medicament is selected from the group consisting of an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, and an anti-allergic agent.

20. The composition of claim 19 , wherein the additional medicament is a β-lactam antibacterial agent, and wherein the β-lactam antibacterial agent is selected from the group consisting of Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, and Carumonam.

21. A method of treating or preventing a bacterial infection, comprising administering to a subject in need thereof, a compound according to claim 1 .

22. The method of claim 21 , further comprising administering to the subject an additional medicament, wherein the additional medicament is selected from an antibacterial agent, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or an antiallergic agent.

23. The method of claim 21 , wherein the additional medicament is a β-lactam antibacterial agent, and wherein the β-lactam antibacterial agent is selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.

24. A chemical complex, comprising a complex between a monosaccharide or monosaccharide derivative and a compound of claim 1 .

25. The chemical complex of claim 24 , wherein the monosaccharide derivative is meglumine.

26. A compound having the structure of:

or pharmaceutically acceptable salts thereof.