Boronic acid derivatives and therapeutic uses thereof
Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs).
1. A compound having the structure of the Formula Ic or IIc, or a pharmaceutically acceptable salt thereof:
wherein
R 2 and R 3 together with the atoms to which they are attached form a fused ring or ring system selected from the group consisting of C 3-7 cycloalkyl and 3-10 membered heterocyclyl, each optionally substituted with one or more R 5 , and
each of R 1 and R 4 is independently selected from the group consisting of H, amino, halogen, cyano, hydroxy, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 haloalkoxy, optionally substituted (C 1-6 alkoxy)C 1-6 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C 3-7 carbocyclyl)C 1-6 alkyl, optionally substituted (3-10 membered heterocyclyl)C 1-6 alkyl, optionally substituted (C 6-10 aryl)C 1-6 alkyl, (C 6-10 aryl)C 1-6 alkoxy, optionally substituted (5-10 membered heteroaryl)C 1-6 alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR c , —C(O)(CH 2 ) 0-3 SR c , —C(O)(CH 2 ) 1-3 R d , —NR f C(O)NR f R g , —NR f S(O) 2 NR f R g , —C(═NR e )R c , —C(═NR e )NR f R g , —NR f CR c (═NR e ), —NR f C(═NR e )NR f R g , —S(O)(CH 2 ) 1-3 R c , and —NR f S(O) 2 NR f OR d ; or
R 5 is —Y 5 —(CH 2 ) t -G;
t is an integer of 0 or 1;
G is selected from the group consisting of H, amino, halogen, cyano, hydroxy, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 haloalkoxy, optionally substituted (C 1-6 alkoxy)C 1-6 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10 aryl optionally substituted 5-10 membered heteroaryl, optionally substituted (C 3-7 carbocyclyl)C 1-6 alkyl, optionally substituted (3-10 membered heterocyclyl)C 1-6 alkyl, optionally substituted (C 6-10 aryl)C 1-6 alkyl, (C 6-10 aryl)C 1-6 alkoxy, optionally substituted (5-10 membered heteroaryl)C 1-6 alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, —SR c , —C(O)(CH 2 ) 0-3 SR c , —C(O)(CH 2 ) 1-3 R d , —NR f C(O)NR f R g , —NR f S(O) 2 NR f R g , —C(═NR e )R c , —C(═NR e )NR f R g , —NR f CR c (═NR e ), —NR f C(═NR e )NR f R g , —S(O)(CH 2 ) 1-3 R c , and —NR f S(O) 2 NR f OR d ;
each J, L, M is independently CR 12 or N (nitrogen);
R 6 is selected from the group consisting of —C(O)OR, and a carboxylic acid isostere;
R is selected from the group consisting of H, C 1-9 alkyl, —CR 10 R 11 OC(O)C 1-9 alkyl, —CR 10 R 11 OC(O)C 3-7 carbocyclyl, —CR 10 R 11 OC(O)(3 to 7 membered heterocyclyl), —CR 10 R 11 OC(O)C 2-8 alkoxyalkyl, —CR 10 R 11 OC(O)OC 1-9 alkyl, —CR 10 R 11 OC(O)OC 3-7 carbocyclyl, —CR 10 R 11 OC(O)O(3 to 7 membered heterocyclyl), —CR 10 R 11 OC(O)OC 2-8 alkoxyalkyl, —CR 10 R 11 OC(O)C 6-10 aryl, —CR 10 R 11 OC(O)OC 6-10 aryl, —CR 10 R 11 C(O)NR 13 R 14 , —CR 10 R 11 OC(O)O(CH 2 ) 1-3 C(O)NR 13 R 14 , —CR 10 R 11 OC(O)O(CH 2 ) 2-3 OC(O)C 1-4 alkyl, —CR 10 R 11 OC(O)O(CH 2 ) 1-3 C(O)OC 1-4 alkyl, —CR 10 R 11 OC(O)O(CH 2 ) 1-3 OC(O)C 1-4 alkyl, and
R 7 is selected from the group consisting of —OH and optionally substituted C 1-6 alkoxy;
each R 10 and R 11 is independently selected from the group consisting of H, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl;
R 12 is selected from the group consisting of hydrogen, amino, halogen, cyano, hydroxy, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 haloalkoxy, optionally substituted (C 1-6 alkoxy)C 1-6 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted (C 3-7 carbocyclyl)C 1-6 alkyl, optionally substituted (3-10 membered heterocyclyl)C 1-6 alkyl, optionally substituted (C 6-10 aryl)C 1-6 alkyl, (C 6-10 aryl)C 1-6 alkoxy, optionally substituted (5-10 membered heteroaryl)C 1-6 alkyl, acyl, C-carboxy, O-carboxy, C-amido, N-amido, S-sulfonamido, N-sulfonamido, sulfhydryl, —C(O)(CH 2 ) 0-3 SR c , —C(O)(CH 2 ) 1-3 R d , —NR f C(O)NR f R g , —NR f S(O) 2 NR f R g , —C(═NR e )R c , —C(═NR e )NR f R g , —NR f CR c (═NR e ), —NR f C(═NR e )NR f R g , —S(O)(CH 2 ) 1-3 R c , —NR f S(O) 2 NR f OR d , and —(CH 2 ) p —Y 6 —(CH 2 ) q K;
each R 13 and R 14 is independently selected from the group consisting of H, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl;
R 15 is optionally substituted C 1-6 alkyl;
Y 2 is —O— or —S—;
Y 3 is —OH or —SH;
Y 4 is selected from the group consisting of —OH, and optionally substituted C 1-6 alkoxy;
Y 5 is absent;
Y 6 is selected from the group consisting of —S—, —S(O)—, —S(O) 2 —, —O—, —CR f R g , and —NR f —;
K is selected from the group consisting of C-amido; N-amido; S-sulfonamido; N-sulfonamido; —NR f C(O)NR f R g ; —NR f S(O) 2 NR f R g ; —C(═NR e )R c ; —C(═NR e )NR f R g ; —NR f CR c (═NR e ); —NR f C(═NR e )NR f R g ; C 1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4 alkoxy, amino, halogen, C-amido, and N-amido; C 6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, amino, halogen, C-amido, and N-amido; C 3-7 carbocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, amino, halogen, C-amido, and N-amido; 5-10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, amino, halogen, C-amido, and N-amido; and 3-10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, amino, halogen, C-amido, and N-amido;
each R c , R d , R e , R f , and R g are independently selected from the group consisting of H, halogen, optionally substituted C 1-4 alkyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl; and
each p and q is independently 0 or 1.
2. The compound of claim 1 , wherein R is selected from the group consisting of H, C 1-9 alkyl, —CR 10 R 11 OC(O)C 1-9 alkyl, —CR 10 R 11 OC(O)OC 1-9 alkyl, —CR 10 R 11 OC(O)C 6-10 aryl, —CR 10 R 11 OC(O)OC 6-10 aryl and
3. The compound of claim 1 , wherein R is —CR 10 R 11 OC(O)C 1-9 alkyl, —CR 10 R 11 OC(O)C 3-7 carbocyclyl, —CR 10 R 11 OC(O)(3 to 7 membered heterocyclyl), or —CR 10 R 11 OC(O)C 2-8 alkoxyalkyl.
4. The compound of claim 3 , wherein the 3 to 7 membered heterocyclyl of R is
5. The compound of claim 1 , wherein R is —CR 10 R 11 OC(O)OC 1-9 alkyl, —CR 10 R 11 OC(O)OC 3-7 carbocyclyl, —CR 10 R 11 OC(O)O(3 to 7 membered heterocyclyl), or —CR 10 R 11 OC(O)OC 2-8 alkoxyalkyl.
6. The compound of claim 5 , wherein the 3 to 7 membered heterocyclyl of R is
7. The compound of claim 1 , wherein R is —CR 10 R 11 C(O)NR 13 R 14 .
8. The compound of claim 1 , wherein R is —CR 10 R 11 OC(O)O(CH 2 ) 1-3 C(O)NR 11 R 14 , —CR 10 R 11 OC(O)O(CH 2 ) 2-3 OC(O)C 1-4 alkyl, —CR 10 R 11 OC(O)(CH 2 ) 1-3 OC(O)C 1-4 alkyl, or —CR 10 OR 11 OC(O)O(CH 2 ) 1-3 C(O)OC 1-4 alkyl.
9. The compound of claim 1 , wherein each J, L and M is CR 12 .
10. The compound of claim 9 , wherein each R 12 is independently hydrogen, halogen, C 1-6 alkoxy, or C 1-6 haloalkoxy.
11. The compound of claim 1 , wherein at least one of J, L and M is N.
12. The compound of claim 1 , wherein M is N.
13. The compound of claim 1 , wherein R 2 and R 3 together with the atoms to which they are attached form C 3-7 cycloalkyl optionally substituted with one or more R 5 .
14. The compound of claim 13 , having the structure of Formula Id or IId, or a pharmaceutically acceptable salt thereof:
wherein the cyclopropyl moiety
is optionally substituted with one or more R 5 .
15. The compound of claim 14 , having the structure of Formula Id-1, Id-2, IId-1 or IId-2, or a pharmaceutically acceptable salt thereof:
16. The compound of claim 1 , wherein R 1 is hydrogen or C 1-6 hydroxyalkyl.
17. The compound of claim 1 , wherein R 4 is hydrogen.
18. The compound of claim 1 , wherein R 6 is —C(O)OR.
19. The compound of claim 18 , wherein R is H.
20. The compound of claim 1 , wherein R 7 is —OH.
21. The compound of claim 1 , wherein Y 2 is —O—.
22. The compound of claim 1 , wherein Y 3 is —OH.
23. The compound of claim 1 , wherein Y 4 is —OH.
24. The compound of claim 1 , wherein t is 0, and R 5 is selected from the group consisting of amino, halogen, cyano, hydroxy, optionally substituted C 1-6 alkoxy, acyl, C-carboxy, C-amido, N-amido, N-sulfonamido, —SR c , —C(O)(CH 2 ) 0-3 SR c , —C(O)(CH 2 ) 1-3 R d , —NR f C(O)NR f R g , —NR f S(O) 2 NR f R g , —C(═NR e )R c , —C(═NR e )NR f R g , —NR f CR c (═NR e ), —NR f C(═NR e )NR f R g , —S(O)(CH 2 ) 1-3 R c , and —NR f S(O) 2 NR f OR d .
25. The compound of claim 1 , selected from the group consisting of
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 pharmaceutical composition of claim 26 , further comprising an additional medicament.
28. A method of treating a bacterial infection caused by β-lactam antibacterial agent-resistant enterobacteriaceae, comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof to a subject in need thereof.
29. The method of claim 28 , further comprising administering to the subject an additional medicament selected from β-lactam antibacterial agents.
30. The compound of claim 15 , wherein each J, L and M is CR 12 .
31. The compound of claim 30 , wherein each R 12 is independently hydrogen, halogen, C 1-6 alkoxy, or C 1-6 haloalkoxy.
32. The compound of claim 31 , wherein R 6 is —C(O)OR.
33. The compound of claim 25 , wherein the pharmaceutically acceptable salt is a sodium salt.
34. A compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 34 , wherein the pharmaceutically acceptable salt is a sodium salt.
36. A compound selected from the group consisting
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 36 , wherein the pharmaceutically acceptable salt is a sodium salt.
38. The method of claim 28 , wherein the pharmaceutically acceptable salt is a sodium salt.