Granted Patent B2

US 11,414,435 · App. 16/864,634 · Granted Aug 16, 2022

Inventors: Christopher J. Burns (Malvern, PA); Denis Daigle (Street, MD); Bin Liu (Plainsboro, NJ); Daniel McGarry (Malvern, PA); Daniel C. Pevear (Downingtown, PA); Robert E. Lee Trout (Collegeville, PA); Randy W. Jackson (Livingston, MT)

Assignee: VENATORX PHARMACEUTICALS, INC.

C07F5/025A61K31/407A61K31/496A61K31/546A61K31/69A61K45/06Y02A50/30

Abstract

Claims (46)

1. A compound of Formula (I) or Formula (Ia), a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof:

wherein:

M is a bond;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

p is 3;

X 1 and X 2 are independently selected from —OH, —OR 8 , or F;

Z is >C═O, >C═S, or >SO 2 ;

ArA is an optionally substituted aromatic or 6-membered heteroaromatic ring system;

each Y is selected from the group consisting of

fluoro, chloro, —CN, optionally substituted C 1 -C 6 alkyl, —OH, —OR 10 ,—NR 4 R 5 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —O(CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —C(O)NR 4 (CR 6 R 7 ) v NR 4R 5 , —S(O) 0,1,2 NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —OC(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 ) R 6 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 ) NR 4 R 5 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C (═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 C(O)R 6 , —NR 4 S 02 R 6 , —NR 4 C(O)R 6 , —NR 4 C(═O)OR 6 , —C(O) NR 4 R 5 , —(CR 6 R 7 ) v C(O)NR 4 R 5 , -Heteroaryl-NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , -Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , -Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —N(R 4 )—Heteroaryl-NR 4 R 5 , —N(R 4 )-Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl, —(CR 6 R 7 ) v Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl, —NR 4 (CR 6 R 7 ) v Heteroaryl, —NR 4 (CR 6 R 7 ) v Heterocyclyl, —O(CR 6 R 7 ) v Heteroaryl, —O(CR 6 R 7 ) v Heterocyclyl, and —O(CR 6 R 7 ) v O- Heterocyclyl;

v is 1-4;

R a , R b , and R C are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 10 , —NR 4 R 5 , and —SR 10 ;

R 1 and R 2 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , and —NR 4 R 5 ,

or R 1 and R 2 taken together form an oxo, oxime, or an optionally substituted carbocycle or optionally substituted heterocycle with the carbon to which they are attached;

R 3 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a pharmaceutically acceptable prodrug;

R d , R 4 and R 5 are independently selected from the group consisting of hydrogen, —OH, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an optionally substituted saccharide;

or R 4 and R 5 taken together form an optionally substituted heterocycle with the nitrogen to which they are attached;

R 6 and R 7 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , —NR 4 R 5 , —NR 4 C(O)R 5 , —C(O)NR 4 R 5 , —NR 4 SO 2 R 5 , optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

or R 6 and R 7 taken together form an oxo, oxime, or an optionally substituted carbocycle or an optionally substituted heterocycle with the carbon to which they are attached;

R 8 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, or a pharmaceutically acceptable boronate ester group; and

R 10 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl.

2. The compound of claim 1 , wherein R a , R b , and R C are independently hydrogen, fluoro, or chloro.

3. The compound of claim 2 , wherein R a , R b , and R c are hydrogen.

4. The compound of claim 1 , wherein R 3 is hydrogen.

5. The compound of claim 1 , wherein X 1 and X 2 are —OH.

6. The compound of claim 1 , wherein R d is hydrogen or C 1 -C 4 -alkyl.

7. The compound of claim 1 , wherein Z is >C═0.

8. The compound of claim 1 , wherein:

M is a bond; and

m and n are 0.

9. The compound of claim 1 , wherein:

M is a bond; and

m or n are 1.

10. The compound of claim 1 , wherein each R 1 and R 2 are independently selected from the group consisting of fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , and —NR 4 R 5 ,

or R 1 and R 2 taken together form an oxo, oxime, or an optionally substituted carbocycle or optionally substituted heterocycle with the carbon to which they are attached.

11. The compound of claim 1 , wherein ArA is benzene.

12. The compound of claim 1 , wherein ArA is selected from the group consisting of benzene, pyridine, or pyrimidine.

13. The compound of claim 1 , wherein at least one Y is selected from the group consisting of fluoro, chloro, —CN, optionally substituted C 1 -C 6 alkyl, —OH, —OR 10 ,—NR 4 R 5 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —O(CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —OC(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 ) NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 C(O)R 6 , —NR 4 SO 2 R 6 , —NR 4 C(O)R 6 , —NR 4 C(═O)OR 6 , —C(O)NR 4 R 5 , and —(CR 6 R 7 ) v C(O)NR 4 R 5 .

14. The compound of claim 1 , wherein at least one Y is selected from the group consisting of fluoro, chloro, —CN, optionally substituted C 1 -C 6 alkyl, —OH, —OR 10 ,—NR 4 R 5 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —O(CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —OC(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , and —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 .

15. The compound of claim 1 , wherein R 4 and R 5 are independently hydrogen or optionally substituted C 1 -C 6 alkyl and each R 6 and R 7 are independently hydrogen, fluoro, or optionally substituted C 1 -C 6 alkyl.

16. The compound of claim 15 wherein each R 4 and R 5 is hydrogen and each R 6 and R 7 are hydrogen.

17. The compound of claim 1 , wherein v is 1.

18. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof, and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition of claim 18 , further comprising a beta-lactam antibiotic.

20. A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 18 , optionally in combination with a beta-lactam antibiotic.

Assignments (2)

Continuity (9)