Antibacterial agents: O-alkyl-deuterated pyronins

1. A compound of formula Ia, Ib, Ic, or Id:

or a salt thereof, wherein:

W is sulfur, oxygen, or nitrogen;

X, Y, and Z are individually carbon, sulfur, oxygen, or nitrogen, wherein at least two of X, Y, and Z are carbon;

one of R 1 and R 2 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, or heteroaryl, wherein any C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, and heteroaryl is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy; or one of R 1 and R 2 is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1 and R 2 is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

V′, W′, X′, Y′, and Z′ are individually carbon or nitrogen; wherein at least three of V′, W′, X′, Y′, and Z′ are carbon;

one of R 1′ and R 2′ is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, or heteroaryl, wherein any C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, and heteroaryl is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy; or one of R 1′ and R 2′ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1′ and R 2′ is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3′ , R 4′ , and R 5′ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

W″ is sulfur, oxygen, or nitrogen;

U″, V″, X″, Y″, and Z″ are individually carbon, sulfur, oxygen, or nitrogen, wherein at least three of U″, V″, X″, Y″, and Z″ are carbon;

one of R 1″ and R 2″ is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, or heteroaryl, wherein any C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, and heteroaryl is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy; or one of R 1″ and R 2″ is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1″ and R 2″ is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3″ is absent or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4″ , R 5″ , and R 6″ are each independently absent, H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 5 is H or M + , where M + is a pharmaceutically acceptable cation;

R 6 is H, halogen, or methyl that is optionally substituted with halogen;

R 9 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, wherein any C 1 -C 10 alkyl or C 2 -C 10 alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NR a R b ;

R 10 is methyl that is substituted with 1, 2, or 3 deuterium atoms;

one of R 12 and R 13 s hydrogen or C 1 -C 4 straight alkyl, and the other of R 12 and R 13 is C 1 -C 10 straight or branched alkyl, C 2 -C 12 straight or branched hydroxyalkyl, C 2 -C 12 straight or branched alkenyl, C 2 -C 12 straight or branched hydroxyalkenyl, phenyl, C 7 -C 12 aralkyl, C 7 -C 12 (aryl)hydroxyalkyl, C 6 -C 12 heteroaralkyl, C 6 -C 12 (heteroaryl)hydroxyalkyl, or R 12 and R 13 are taken together with their intervening atom to form a 4-6 membered ring having 0-1 ring heteroatoms selected from nitrogen, oxygen or sulfur, said ring optionally substituted by one or two C 1 -C 6 alkyl, C 2 -C 6 alkenyl or hydroxyalkyl groups, wherein an alkyl, aryl or heteroaryl moiety of R 12 and R 13 optionally is substituted with 1-3 groups independently selected from halo, —C 1 -C 6 hydroxyalkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 trifluoroalkoxy, —CN, —C 1 -C 4 alkoxycarbonyl, —C 1 -C 4 alkylcarbonyl, —S(C 1 -C 4 alkyl), and —SO 2 (C 1 -C 4 alkyl);

each R a is C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; and

each R b is H or C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy.

2. The compound of claim 1 , wherein the compound of formula Ia is a compound of Ia″ and the compound of formula Id is a compound of formula Id″

wherein:

W is sulfur, oxygen, or nitrogen;

X, Y, and Z are individually carbon, or nitrogen, wherein at least two of X, Y, and Z are carbon;

one of R 1 and R 2 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 1 -C 10 alkoxy, aryloxy, heteroaryloxy, or NR a R b , wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkoxy, tetrahydrofuranyl, or furanyl, and wherein any aryloxy or heteroaryloxy is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy, aryl, or heteroaryl, wherein any C 1 -C 5 alkyl, C 1 -C 5 alkoxy, aryl, and heteroaryl is optionally substituted by at least one of halogen, hydroxy, C 1 -C 5 alkyl, or C 1 -C 5 alkoxy; or one of R 1 and R 2 is a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle that is optionally substituted by at least one of halogen, hydroxy, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy; and the other of R 1 and R 2 is absent or is one of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy, wherein any C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 1 -C 10 alkoxy is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy;

R 3 is absent, or is one of H, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 4 is absent, or is one of H, halogen, C 1 -C 2 alkyl, or halogen-substituted C 1 -C 2 alkyl;

R 5 is H or M + , where M + is a pharmaceutically acceptable cation;

R 6 is H, halogen, or methyl that is optionally substituted with halogen;

R 9 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, wherein any C 1 -C 10 alkyl or C 2 -C 10 alkenyl is optionally substituted by at least one of halogen, hydroxy, alkoxy, or NR a R b ;

R 10 is methyl that is substituted with 1, 2, or 3 deuterium atoms;

one of R 12 and R 13 is hydrogen or C 1 -C 4 straight alkyl, and the other of R 12 and R 13 is C 1 -C 10 straight or branched alkyl, C 2 -C 12 straight or branched hydroxyalkyl, C 2 -C 12 straight or branched alkenyl, C 2 -C 12 straight or branched hydroxyalkenyl, phenyl, C 7 -C 12 aralkyl, C 7 -C 12 (aryl)hydroxyalkyl, C 6 -C 12 heteroaralkyl, C 6 -C 12 (heteroaryl)hydroxyalkyl, or R 12 and R 13 are taken together with their intervening atom to form a 4-6 membered ring having 0-1 ring heteroatoms selected from nitrogen, oxygen or sulfur, said ring optionally substituted by one or two C 1 -C 6 alkyl, C 2 -C 6 alkenyl or hydroxyalkyl groups, wherein an alkyl, aryl or heteroaryl moiety of R 12 and R 13 optionally is substituted with 1-3 groups independently selected from halo, —C 1 -C 6 hydroxyalkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 trifluoroalkoxy, —CN, —C 1 -C 4 alkoxycarbonyl, —C 1 -C 4 alkylcarbonyl, —S(C 1 —C 4 alkyl), and —SO 2 (C 1 -C 4 alkyl);

each R a is C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy; and

each R b is H or C 1 -C 10 alkyl that is optionally substituted by at least one of halogen, hydroxy, or C 1 -C 5 alkoxy.

3. The compound of claim 1 , which is a compound of formula Ia, or a salt thereof.

4. The compound of claim 1 , which is a compound of formula Ib, or a salt thereof.

5. The compound of claim 1 , which is a compound of formula Ic, or a salt thereof.

6. The compound of claim 1 , which is a compound of formula Id, or a salt thereof.

7. The compound or salt of claim 1 , wherein R 6 is H.

8. The compound or salt of claim 1 , wherein R 6 is methyl.

9. The compound or salt of claim 8 , wherein R 6 is methyl and where the compound is a mixture of the R and S stereoisomers.

10. The compound or salt of claim 8 , wherein R 6 is methyl and wherein the compound, or a salt thereof, is at least 90% of the R isomer.

11. The salt of claim 1 , that has formula Ia′, Ib′, Ic′, or Id′:

wherein Y is a pharmaceutically acceptable counter ion.

12. The compound or salt of claim 1 wherin R 10 is methyl that is enriched in deuterium by at least 10-times the natural abundance of deuterium.

13. A compound or salt selected from the group consisting of

14. The salt:

15. A composition comprising the compound or salt of claim 1 and water, that is suitable for intravenous administration.

16. The composition of claim 15 , which is free of co-solvents and surfactants.

17. A method of inhibiting a bacterial RNA polymerase, comprising contacting a bacterial RNA polymerase with a compound or salt of claim 1 .

18. A method of treating a bacterial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or salt of claim 1 .

19. An antibacterial composition comprising the compound or salt of claim 1 .

20. The antibacterial composition of claim 19 , that 1) comprises water, 2) is suitable for intravenous administration, 3) is free of co-solvents, and 4) is free of surfactants.