ExoVII inhibitor and quinolone antibiotic combination useful for treating bacterial infection

1 . A method of treating a bacterial infection in a subject comprising administering a therapeutically effective amount of a combination of a bacterial type IIA topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof and a compound Formula I, or a pharmaceutically acceptable salt thereof, to the subject, where the compound of Formula I is

Y 1 is carbon substituted with oxo and Y 2 is CR 6 ; or

Y 1 is CR 5 and Y 2 is carbon substituted with oxo;

R 1 , R 3 , and R 4 are independently chosen from H, halogen, hydroxyl, amino, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;

R 2 is H, halogen, hydroxyl, amino, nitro, cyano, —COOH, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy; or

R 2 is —C 0 -C 2 alkyl (C 3 -C 2 cycloalkyl), —C 0 -C 2 alkyl (aryl), —C 0 -C 2 alkyl (pyridyl), or —C 0 -C 2 alkyl (furanyl), each of which is optionally substituted with one or more substituents independently chosen from R 10 ,

R 4 is H, halogen, hydroxyl, amino, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 6 alkanoyl, —C 1 -C 6 alkylester, —C 0 -C 4 alkyl (mono- or di-C 1 -C 6 alkylamino), mono- or di-C 1 -C 6 alkylcarboxamide; C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy;

R 5 and R 6 are independently chosen from H, halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, —CONH 3 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 2 -C 6 alkanoyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl (mono- and di-C 1 -C 6 alkylamino), and mono- and di-(C 1 -C 6 alkyl) carboxamide;

R 10 is independently selected at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl, wherein in each C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl, in the definition of R 10 one or more carbon atoms is optionally replaced by O, NR 11 , —C(O)—, —NR 11 C(O)—, —C(O)NR 11 —, —C(O)O—, —OC(O)—, —S(O) n —, —S(O) n NR 11 —, or —NR 11 S(O) n —, where n is 0, 1, or 2, and in which each C 0 -C 4 alkyl, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl is optionally substituted with one or more substituents R 13 ;

R 11 is independently chosen at each occurrence from hydrogen, C 1 -C 6 alkyl, and —C 0 -C 2 alkyl (C 3 -C 2 cycloalkyl); and

R 13 is independently chosen at each occurrence from halogen, hydroxyl, amino, nitro, cyano, —CHO, —COOH, oxo, C 3 -C 7 cycloalkyl, and phenyl.

2 . The method of claim 1 , wherein the type IIA topoisomerase inhibitor is a quinolone antibiotic or a pharmaceutically acceptable salt thereof.

3 . The method of claim 2 , wherein the quinolone antibiotic is cinoxacin, ciprofloxacin, delafloxacin, gatifloxacin, gemifloxacin, lomefloxacin, moxiflaxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, or trovafloxacin.

4 . The method of claim 1 , wherein the compound of Formula I is a compound or pharmaceutically acceptable salt of Formula I-A

5 . The method of claim 4 , wherein

R 1 , R 3 , R 4 , and R 5 are each independently chosen from H and methyl; and

R 2 is phenyl, furanyl, or pyridyl each of which is optionally substituted with one or more substituents independently chosen from R 10 .

6 . The method of claim 4 , wherein

R 1 , R 2 , and R 4 are independently chosen from H and methyl;

R 3 is H, halogen, hydroxyl, or nitro; and

R 5 is H or C 1 -C 6 alkylester; where one of R 3 and R 5 is other than H.

7 . The method of claim 1 , wherein the compound is a compound or pharmaceutically acceptable salt of Formula I-B

8 . The method of claim 7 , wherein

R 1 , R 2 , R 3 , and R 4 are independently chosen from H and methyl; and

R 6 is —CONH 3 , —COOH, C 1 -C 6 alkyl ester, or C 1 -C 6 alkylcarboxaminde.

9 . The method of claim 1 , wherein the compound is a compound of any of the following structures, or a pharmaceutically acceptable salt thereof

10 . The method of claim 1 wherein the therapeutically effective amount of the quinolone antibiotic and the compound of Formula I or pharmaceutically acceptable salt thereof are administered to the subject as a pharmaceutical dosage form comprising the quinolone antibiotic and the compound or pharmaceutically acceptable salt of Formula I.

11 . The method of claim 1 , wherein the subject has a Gram negative bacterial infection.

12 . The method of claim 1 , wherein the subject has a Gram positive bacterial infection.

13 . The method of claim 1 , wherein the bacterial infection comprises E. coli or Staphylococcus aureus.

14 . The method of claim 2 wherein the compound of Formula I is a compound or pharmaceutically acceptable salt of Formula I-A

15 . The method of claim 14 , wherein

R 1 , R 3 , R 4 , and R 5 are each independently chosen from H and methyl; and

R 2 is phenyl, furanyl, or pyridyl each of which is optionally substituted with one or more substituents independently chosen from R 10 .

16 . The method of claim 14 , wherein

R 1 , R 2 , and R 4 are independently chosen from H and methyl;

R 3 is H, halogen, hydroxyl, or nitro; and

R 5 is H or C 1 -C 6 alkylester; where one of R 3 and R 5 is other than H.

17 . The method of claim 2 wherein the compound is a compound or pharmaceutically acceptable salt of Formula I-B

18 . The method of claim 17 , wherein

R 1 , R 2 , R 3 , and R 4 are independently chosen from H and methyl; and

R 6 is —CONH 3 , —COOH, C 1 -C 6 alkyl ester, or C 1 -C 6 alkylcarboxaminde.

19 . The method of claim 3 wherein the compound of Formula I is a compound or pharmaceutically acceptable salt of Formula I-A

20 . The method of claim 3 wherein the compound is a compound or pharmaceutically acceptable salt of Formula I-B

21 . The method of claim 1 wherein the type IIA topoisomerase inhibitor is ciprofloxacin and wherein the compound of Formula I is