Oxaborole esters and uses thereof

1. A compound of formula 1:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen or C 1-6 aliphatic;

R 1a is hydrogen or C 1-6 aliphatic; or

R 1 and R 1a are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered spiro carbocyclic ring;

each R 2 is independently hydrogen, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from the group consisting of C 1-6 aliphatic and 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl;

R 3 is hydrogen or optionally substituted C 1-6 aliphatic;

R 4 is hydrogen, a natural or unnatural amino acid side-chain group, or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and phenyl; or

R 3 and R 4 are taken together with the carbon atom attached to R 4 and the nitrogen atom attached to R 3 to form an optionally substituted 3- to 6-membered heterocyclyl ring having 0-1 additional heteroatoms selected from oxygen, nitrogen, or sulfur;

R 5 is hydrogen or optionally substituted C 1-6 aliphatic; or

R4 and R5 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6- membered spiro heterocyclic ring having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

each R is independently hydrogen or optionally substituted C 1-6 aliphatic;

and L is selected from:

2. The compound of claim 1 , wherein R 6 is an optionally substituted group selected from:

3. The compound of claim 1 , wherein the compound is of formula II:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is of formula III:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein the compound is of formula III-a:

or a pharmaceutically acceptable salt thereof.

6. A compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen or C 1-6 aliphatic;

R 1a is hydrogen or C 1-6 aliphatic; or

R 1 and R 1a are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6-membered spiro carbocyclic ring;

each R 2 is independently hydrogen, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from the group consisting of C 1-6 aliphatic and 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl;

R 4 is hydrogen, a natural or unnatural amino acid side-chain group, or an optionally substituted group selected from the group consisting of C 1-6 aliphatic, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, and phenyl; or

R 3 and R 4 are taken together with the carbon atom attached to R 4 and the nitrogen atom attached to R 3 to form an optionally substituted 3- to 6-membered heterocyclyl ring having 0-1 additional heteroatoms selected from oxygen, nitrogen, or sulfur;

R 5 is hydrogen or optionally substituted C 1-6 aliphatic; or

R4 and R5 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6- membered spiro heterocyclic ring having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur;

R 6 is hydrogen, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R), —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, —OC(O)N(R), an optionally substituted group selected from the group consisting of C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 8- to 10-membered bicyclic aryl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and bridged bicyclic;

each R a is independently R, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, or —OC(O)N(R) 2 ;

R b is hydrogen or methyl; and

R b1 is hydrogen or methyl; and, each R is independently hydrogen or optionally substituted C 1-6 aliphatic.

7. The compound of claim 6 , wherein the compound is of formula V:

or a pharmaceutically acceptable salt thereof, wherein

each R a is independently R, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, or —OC(O)N(R) 2 ;

R b is hydrogen or methyl; and

R b1 is hydrogen or methyl.

8. The compound of claim 6 , wherein the compound is of formula V-a or V-b:

or a pharmaceutically acceptable salt thereof, wherein

each R a is independently R, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR,

—S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR, —N(R)SO 2 R, or —OC(O)N(R) 2 .

9. The compound of formula VI-a, VI-b, VI-c, VI-d, VI-e, or VI-f:

or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R,

—C(O)N(R), —SO 2 N(R), —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR,

—N(R)SO 2 R, —OC(O)N(R), an optionally substituted group selected from the group consisting of C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 3- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 8- to 10-membered bicyclic aryl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and bridged bicyclic;

each R is independently hydrogen or optionally substituted C 1-6 aliphatic;

each R a is independently R, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR,

—S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR,

—N(R)SO 2 R, or —OC(O)N(R) 2 ; and

n is 0, 1, 2 or 3.

10. The compound of claim 1 , wherein the compound is of formula VII-a, VII-b or VII-c:

or a pharmaceutically acceptable salt thereof, wherein:

R 6 is hydrogen, -halogen, —OR, —NO 2 , —CN, —SR, —N(R), —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R,

—C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR,

—N(R)SO 2 R, —OC(O)N(R) 2 , an optionally substituted group selected from the group consisting of C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 8- to 10-membered bicyclic aryl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur, and bridged bicyclic;

each R is independently hydrogen or optionally substituted C 1-6 aliphatic;

each R a is independently R, -halogen, —OR, —NO 2 , —CN, —SR, —N(R) 2 , —C(O)R, —C(O)OR,

—S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)C(O)OR,

—N(R)SO 2 R, or —OC(O)N(R) 2 ; and

n is 0, 1, 2 or 3.

11. The compound of claim 1 , wherein the compound is of formula IX-a or IX-b:

or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or methyl.

12. The compound of claim 11 , where L is selected from:

13. A compound selected from the compounds

3,4-Difluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate

4-Fluorobenzyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-3-methylbutanoate

(tetrahydro-2H-pyran-4-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate

((S)-tetrahydrofuran-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate, or

a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , wherein the compound is:

(Tetrahydro-2H-pyran-4-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate; or, a pharmaceutically acceptable salt thereof.

15. The compound of claim 13 , wherein the compound is:

3,4-Difluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate; or, a pharmaceutically acceptable salt thereof.

16. The compound of claim 13 , wherein the compound is: 4-Fluorobenzyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-3-methylbutanoate; or, a pharmaceutically acceptable salt thereof.

17. The compound of claim 13 , wherein the compound is:

((S)-tetrahydrofuran-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate; or, a pharmaceutically acceptable salt thereof.

18. A method of treating Chagas disease in a subject comprising administering to a subject a compound selected from the group consisting of:

(Tetrahydro-2H-pyran-4-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate;

3,4-Difluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate;

4-Fluorobenzyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-3-methylbutanoate; and,

((S)-tetrahydrofuran-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate; or, a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the disease.

19. The method of claim 18 , wherein the compound is:

(Tetrahydro-2H-pyran-4-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate; or, a pharmaceutically acceptable salt thereof.

20. The method of claim 18 , wherein the compound is:

3,4-Difluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate; or, a pharmaceutically acceptable salt thereof.

21. The method of claim 18 , wherein the compound is: 4-Fluorobenzyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamido)-3-methylbutanoate; or, a pharmaceutically acceptable salt thereof.

22. The method of claim 18 , wherein the compound is: ((S)-tetrahydrofuran-3-yl)methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate; or, a pharmaceutically acceptable salt thereof.