2-amino-N-(arylsulfinyl)-acetamide compounds as inhibitors of bacterial aminoacyl-tRNA synthetase

1. A compound selected from compounds of the following formula pharmaceutically acceptable salts thereof:

wherein:

-A is independently -A C or -A H ;

-A C is independently phenyl or naphthyl, and is optionally substituted with one or more substituents —R X ;

-A H is independently C 5-12 heteroaryl, and is optionally substituted with one or more substituents —R X ;

each —R X is independently selected from:

—R XX , —R XXU , —R XXV , —R XXH ,

—F, —Cl, —Br, —I,

—OH, —OR XX ,

-L XX -OH, -L XX -OR XX ,

—CF 3 , —OCF 3 ,

—NH 2 , —NHR XX , —NR XX 2 , —R XM ,

-L XX -NH 2 , -L XX -NHR XX , -L XX -NR XX 2 , -L XX -R XM ,

—C(═O)OH, —C(═O)OR XX , —OC(═O)R XX ,

—C(═O)NH 2 , —C(═O)NHR XX , —C(═O)NR XX 2 , —C(═O)R XM ,

—NHC(═O)R XX , —NR XN C(═O)R XX ,

—NHC(═O)NH 2 , —NHC(═O)NHR XX , —NHC(═O)NR XX 2 , —NHC(═O)R XM ,

—NR XN C(═O)NH 2 , —NR XN C(═O)NHR XX , —NR XN C(═O)NR XX 2 , —NR XN C(═O)R XM ,

—NHC(═O)OR XX , —NR XN C(═O)OR XX ,

—OC(═O)NH 2 , —OC(═O)NHR XX , —OC(═O)NR XX 2 , —OC(═O)R XM ,

—NHC(═NH)NH 2 ,

—C(═O)R XX ,

—S(═O)NH 2 , —S(═O)NHR XX , —S(═O)NR XX 2 , —S(═O)R XM ,

—S(═O) 2 NH 2 , —S(═O) 2 NHR XX , —S(═O) 2 NR XX 2 , —S(═O) 2 R XM ,

—NHS(═O)R XX , —NR XN S(═O)R XX ,

—NHS(═O) 2 R XX , —NR XN S(═O) 2 R XX ,

—S(═O)R XX , —S(═O) 2 R XX ,

—SH, —SR XX , —CN, and —NO 2 ;

and additionally, two adjacent groups —R X , if present, may together form:

—O—CH 2 —O— or —O—CH 2 CH 2 —O—;

wherein:

each -L XX - is linear or branched saturated C 1-4 alkylene;

each —R XX is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl;

each —R XXU is independently linear or branched C 2-4 alkenyl;

each —R XXV is independently linear or branched C 2-4 alkynyl;

each —R XXH is C 5-10 heteroaryl, and is optionally substituted with one or more groups —R XMM ;

each —R XN is linear or branched saturated C 1-4 alkyl;

each —R XM is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is:

optionally substituted with one or more groups selected from:

—R XMM , —C(═O)R XMM , —C(═O)OR XMM , and —S(═O) 2 R XMM ;

wherein each —R XMM is independently linear or branched saturated C 1-4 alkyl, phenyl, or benzyl;

—R 1 is iBu; and

—R is H.

2. A compound according to claim 1 , wherein -A is -A C .

3. A compound according to claim 1 , wherein -A is -A H .

4. A compound according to claim 1 , wherein -A C , if present, is phenyl, and is optionally substituted with one or more substituents —R X .

5. A compound according to claim 1 , wherein -A C , if present, is independently selected from:

wherein each —R X1 , —R X2 , —R X3 , —R X4 , —R X5 , and —R X6 is independently as defined for —R X .

6. A compound according to claim 1 , wherein -A C , if present, is independently selected from:

wherein each —R X1 , —R X2 , and —R X3 is independently as defined for —R X .

7. A compound according to claim 1 , wherein -A C , if present, is:

wherein —R X2 is independently as defined for —R X .

8. A compound according to claim 1 , wherein -A C , if present, is independently selected from:

wherein each —R X1 and —R X2 is independently as defined for —R X .

9. A compound according to claim 1 , wherein -A C , if present, is:

wherein each —R X1 and —R X2 is independently as defined for —R X .

10. A compound according to claim 1 , wherein -A H , if present, is C 5-6 heteroaryl or C 9-10 heteroaryl, and is optionally substituted with one or more substituents —R X .

11. A compound according to claim 1 , wherein -A H , if present, is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, indazolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, or benzopyranyl, and is optionally substituted with one or more substituents —R X .

12. A compound according to claim 1 , wherein -A H , if present, is pyridyl, furanyl, thienyl, or quinolinyl, and is optionally substituted with one or more substituents —R X .

13. A compound according to claim 1 , wherein each —R X , if present, is independently selected from:

—R XX , —R XXU , —R XXV , —R XXH ,

—F, —Cl, —Br, —I,

—OH, —OR XX ,

—CF 3 , —OCF 3 ,

—NH 2 , —NHR XX , —NR XX 2 , —R XM ,

—C(═O)OH, —C(═O)OR XX , —OC(═O)R XX ,

—C(═O)NH 2 , —C(═O)NHR XX , —C(═O)NR XX 2 , —C(═O)R XM ,

—NHC(═O)R XX , —NR XN C(═O)R XX ,

—C(═O)R XX ,

—S(═O)NH 2 , —S(═O)NHR XX , —S(═O)NR XX 2 , —S(═O)R XM ,

—S(═O) 2 NH 2 , —S(═O) 2 NHR XX , —S(═O) 2 NR XX 2 , —S(═O) 2 R XM ,

—NHS(═O)R XX , —NR XN S(═O)R XX ,

—NHS(═O) 2 R XX , —NR XN S(═O) 2 R XX ,

—S(═O)R XX , —S(═O) 2 R XX ,

—SR XX , —CN, and —NO 2 .

14. A compound according to claim 1 , wherein each —R X , if present, is independently selected from:

—R XX , —R XXU , —R XXV ,

—F, —Cl, —Br, —I,

—OH, —OR XX ,

—CF 3 , —OCF 3 ,

—NH 2 , —NHR XX , —NR XX 2 , —R XM ,

—C(═O)OH, —C(═O)OR XX , —OC(═O)R XX ,

—SR XX , —CN, and —NO 2 .

15. A compound according to claim 1 , wherein each —R X , if present, is independently selected from:

—R XX ,

—F, —Cl, —Br, —I,

—OH, —OR XX ,

—CF 3 , —OCF 3 .

16. A compound according to claim 1 , which is selected from compounds of the following formulae, and pharmaceutically acceptable salts thereof:

17. A compound according to claim 1 , wherein the sulfur atom which forms part of the sulfoxide group is in the (R) configuration.

18. A compound according to claim 1 , wherein the sulfur atom which forms part of the sulfoxide group is in the (S) configuration.

19. A compound according to claim 1 , wherein the carbon atom to which —R 1 and —R 2 are attached is in the (R) configuration.

20. A compound according to claim 1 , wherein the carbon atom to which —R 1 and —R 2 are attached is in the (S) configuration.

21. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.

22. A method of preparing a pharmaceutical composition comprising the step of mixing a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.

23. A method of inhibiting bacterial aminoacyl-tRNA synthetase, in vitro or in vivo, comprising contacting the synthetase with an effective amount of a compound according to claim 1 .

24. A method of inhibiting bacterial aminoacyl-tRNA synthetase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to claim 1 .

25. A method of treatment of a bacterial infection of the human or animal body, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to claim 1 .

26. A method according to claim 25 , wherein the bacteria are Gram-positive bacteria.

27. A method according to claim 25 , wherein the bacteria are Gram-negative bacteria.

28. A method according to claim 25 , wherein the infection is:

a central nervous system infection;

an external ear infection;

an infection of the middle ear, including acute otitis media;

an infection of the cranial sinuses;

an eye infection;

an infection of the oral cavity, including an infection of the teeth, gums, or mucosa;

an upper respiratory tract infection;

a lower respiratory tract infection;

a genitourinary infection;

a urinary tract infection;

an intra-abdominal infection;

a gastrointestinal infection;

a gynecological infection;

septicemia;

a bone or joint infection;

a skin or skin structure infection;

bacterial endocarditis; or

a burn infection.