Antibacterial compounds
Disclosed are compounds of formulae (I) and (II) and pharmaceutically acceptable salts thereof, wherein the variables, R, R 1 , R 2 , R 3 , Y, Z, X, R 12 , R 17 , R 18 , R 19 , Y 1 , Z 1 , X 1 , and X 2 are defined herein. These compounds are useful for treating Gram-negative bacteria infections, such as Neisseria gonorrhoeae bacterial infections.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
X 1 represents —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH═CH—, —CH═CHCH 2 —, —CH 2 CH═CH—, —C(O)NH—, or —C(O)NH—CH 2 —;
X 2 represents CH 2 or NR 13 ;
Y 1 represents phenyl optionally substituted with R 14 , or thiophenyl optionally substituted with R 14 ;
Z 1 represents phenyl optionally substituted with R 15 , or thiophenyl optionally substituted with R 15 ;
R 12 is hydrogen, C 1 -C 6 alkyl optionally substituted with R 16 , or thiophenyl optionally substituted with R 16 ;
and
moiety is of formula:
wherein
R 13 is hydrogen or C 1 -C 6 alkyl;
each R 14 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;
each R 15 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy;
each R 16 is independently selected from the group consisting of halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aryl, aryl(C 1 -C 6 alkyl), heteroaryl, heteroaryl(C 1 -C 6 alkyl), heterocyclyl, and heterocyclyl(C 1 -C 6 alkyl), wherein each alkyl, aryl, heteroaryl, or heterocyclyl moiety is optionally substituted with one or more R 11 ;
R 18 is independently selected from the group consisting of —CONH 2 , —CON(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CONH—OH, —CONH—NH 2 , —CO 2 H, and —CO 2 (C 1 -C 6 alkyl);
R 19 is hydrogen or C 1 -C 6 alkyl;
R 27 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), —OCO(C 1 -C 6 alkyl), and —NHCO(C 1 -C 6 alkoxy);
R 28 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), and amino(C 1 -C 6 alkyl);
R 29 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; and
each R 11 is independently selected from the group consisting of halogen, —NO 2 ,—CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy.
2. A compound according to claim 1 , wherein R 28 is methyl.
3. A compound according to claim 1 , wherein
R 27 is selected from the group consisting of —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —S(C 1 -C 6 alkyl), —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), —OCO (C 1 -C 6 alkyl), and —NHCO(C 1 -C 6 alkoxy).
4. A compound that is:
or pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition comprising a compound according claim 1 and a pharmaceutically acceptable carrier, solvent, adjuvant or diluent.
6. A compound according to claim 1 , wherein R 29 is methyl, —CH 2 F, —CHF 2 , or —CF 3 .
7. A compound according to claim 1 , where R 28 is hydrogen.
8. A compound according to claim 1 , wherein R 27 is —NH 2 , —NHCO(C 1 -C 6 alkyl), —NHCONH 2 , —NHCONH(C 1 -C 6 alkyl), or —NHCO(C 1 -C 6 alkoxy).
9. A compound according to claim 1 , wherein R 27 is —OH or C 1 -C 6 alkoxy.
10. A compound according to claim 1 , wherein R 18 is —CONH—OH, —CONH—NH 2 , or —CO 2 H.
11. A compound according to claim 1 , wherein R 19 is hydrogen or methyl.
12. A compound according to claim 1 , where
is of formula:
13. A compound according to claim 1 , wherein —X 1 —CH 2 —X 2 —moiety is: —(CH 2 ) 3 —, —(CH 2 ) 4 —, or —(CH 2 ) 5 —.
14. A compound according to claim 1 , wherein —X 1 —CH 2 —X 2 — moiety is: —(CH 2 ) 2 NH—, —(CH 2 ) 3 NH—, or —(CH 2 ) 4 NH—.
15. A compound according to claim 1 , wherein —X 1 —CH 2 —X 2 — moiety is: —C(O)NH 2 —(CH 2 ) 2 —,—C(O)NH 2 —CH 2 —NH—, or —C(O)NH 2 —(CH 2 ) 2 —NH—.
16. A compound according to claim 1 , wherein the compound is of formula:
17. A compound according to claim 1 , wherein the compound is of formula:
18. A compound according to claim 1 , wherein the compound is of formula:
19. A compound of claim 1 , that is:
or a pharmaceutically acceptable salt thereof.