Tricyclic tetrahydroquinoline antibacterial agents

1. A compound of formula I, or a pharmaceutically acceptable salt thereof;

wherein,

R 1 is

(a) R 12

(b) C(═O)R 6 , or

(c) CN;

R 2 is

(a) R 12

(b) C(═O)R 7 ,

(c) CN,

(d) —CH 2 —R 7 ,

(e) —NR 17 R 7 ,

(f) —CH 2 COR 7 ,

(g) —CH 2 CH 2 COR 7 ;

Each R 3 is independently

(a) H,

(b) R 12 ,

(d) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(e) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(f) aryl optionally substituted by one or more R 8 ,

(g) heteroaryl optionally substituted by one or more R 8 , or

(h) halo; or

both R 3 taken together are oxo;

Each R 4 is independently

(a) H,

(b) halo,

(c) OR 12 ,

(d) OC(═O)NR 9 R 10 ,

(e) SR 12 ,

(f) S(O) m R 13 ,

(g) NR 9 R 10 ,

(h) NR 9 S(O) m R 13 ,

(i) NR 9 C(═O)OR 13 ,

(j) phenyl optionally substituted by one or more R 8 ,

(k) heteroaryl optionally substituted by one or more R 8 ,

(l) cyano,

(m) nitro,

(n) CONR 9 R 10 ,

(o) CO 2 R 12 ,

(p) C(═O)R 13 ,

(q) C(═NOR 12 )R 13 ,

(r) S(O) m NR 9 R 10 ,

(s) NR 9 C(═O)—R 12 ,

(t) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(u) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(v) N 3 ,

(w) het 1 optionally substituted by one or more R 8 , or

(x) C(O)O—C 1-4 alkyl-R 12 ;

Each R 5 is independently,

(a) H,

(b) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(c) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(d) aryl optionally substituted by one or more R 8 , or

(e) heteroaryl optionally substituted by one or more R 8 ;

R 6 and R 7 are independently;

(a) OR 12 ,

(b) NR 9 R 10 ,

(c) R 13 , or

(e) R 6 and R 7 together with the 2 carbons to which they are attached form cyclohexane-1,3-dione optionally substituted by one or more R 13 , cyclopentane-1,3-dione optionally substituted by one or more R 13 , R 6 and R 7 together form —N(R 17 )—S(O) m —N(R 17 )—, —N(R 17 )—C(O)—N(R 17 )—, —N(R 17 )—C(S)—N(R 17 )—, —N(R 17 )—N(R 17 )—, —N(R 17 )—C(O)—, or —N(R 17 )—, or R 6 and R 7 together form a phenyl ring;

R 8 is

(a) H,

(b) halo,

(c) OR 12 ,

(d) OCF 3 ,

(e) SR 12 ,

(f) S(O) m R 13 ,

(g) NR 9 R 10 ,

(h) NR 9 S(O) m R 13 ,

(i) NR 9 C(═O)OR 13 ,

(j) phenyl optionally substituted by halo, cyano, C 1-7 alkyl, or C 1-7 alkoxy, in the alkyl portion of the C 1-7 alkyl and C 1-7 alkoxy is optionally substituted by one or more R 11 ;

(k) heteroaryl optionally substituted by halo, C 1-7 alkyl, or C 1-7 alkoxy,

(l) cyano,

(m) nitro,

(n) CONR 9 R 10 ,

(o) CO 2 R 12 ,

(p) C(═O)R 13 ,

(q) C(═NOR 12 )R 13 ,

(r) S(O) m NR 9 R 10 ,

(s) NR 9 C(═O)—R 12 ,

(t) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(u) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(v) —C(O)H, or

(w) -het 1 ;

R 9 and R 10 are independently

(a) H,

(b) OR 12 ,

(c) aryl optionally substituted by one or more R 14 ,

(d) heteroaryl optionally substituted by one or more R 14 ,

(e) C 1-7 alkyl which is optionally substituted by one or more R 11 ,

(f) C 3-8 cycloalkyl which is optionally substituted by one or more R 11 ,

(g) (C═O)R 13 , or

(h) R 9 and R 10 together with the nitrogen to which they are attached form morpholine, pyrrolidine, piperidine, thiazine, piperazine, each of the morpholine, pyrrolidine, piperidine, thiazine, piperazine being optionally substituted with R 11 ;

R 11 is

(a) oxo,

(b) phenyl optionally substituted by one or more R 14 ,

(c) OR 12 ,

(d) SR 12 ,

(e) NR 12 R 12 ,

(f) halo,

(g) CO 2 R 12 ,

(h) CONR 12 R 12 ,

(i) C 1-7 alkyl which is optionally substituted oxo, halo, OR 12 , SR 12 , C 1-7 alkyl, or NR 12 R 12 substituents, or

(j) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more oxo, halo, OR 12 , SR 12 , C 1-7 alkyl, or NR 12 R 12 substituents;

R 12 is

(a) H,

(b) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, C 1-7 alkyl, or C 1-7 alkoxy substituents,

(c) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more oxo, halo, C 1-7 alkyl, or C 1-7 alkoxy substituents,

(d) aryl optionally substituted by one or more halo, C 1-7 alkyl, or C 1-7 alkoxy substituents, or

(e) heteroaryl optionally substituted by one or more halo, C 1-7 alkyl, or C 1-7 alkoxy substituents;

R 13 is

(a) C 1-7 alkyl which is optionally substituted by one or more oxo, halo, carboxyl, C 1-7 alkyl, or C 1-7 alkoxy substituents,

(b) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more oxo, halo, C 1-7 alkyl, or C 1-7 alkoxy substituents,

(c) aryl optionally substituted by one or more halo, C 1-7 alkyl, or C 1-7 alkoxy substituents;

(d) heteroaryl optionally substituted by one or more halo, C 1-7 alkyl, or C 1-7 alkoxy substituents,

(e) —C(O)OH

R 14 is

(a) H,

(b) halo,

(c) C 1-7 alkyl,

(d) OR 12 ,

(e) OCF 3 ,

(f) SR 12 ,

(g) S(O) m R 13 ,

(h) NR 12 R 12 ,

(i) NR 12 S(O) m R 13 ,

(j) NR 12 C(═O)OR 13 ,

(k) phenyl optionally substituted by halo, C 1-7 alkyl, or C 1-7 alkoxy,

(l) heteroaryl optionally substituted by halo, C 1-7 alkyl, or C 1-7 alkoxy,

(m) cyano,

(n) nitro,

(o) CONR 12 R 12 ,

(p) CO 2 R 12 ,

(q) C(═O)R 13 ,

(r) C(═NOR 12 )R 13 ,

(s) S(O) m NR 12 R 12 ,

(t) NR 9 C(═O)—R 12 ,

(u) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, OR 12 , SR 12 , C 1-7 alkyl, or NR 12 R 12 substituents, or

(v) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, OR 12 , SR 12 , C 1-7 alkyl, or NR 12 R 12 substituents;

X is

—(C(R 15 ) 2 )—NR 16 —(C(R 15 ) 2 )—;

Each R 15 is independently

(a) H,

(b) OR 11 ,

(d) C 1-7 alkyl which is optionally substituted by one or more by one or more R 11 substituents,

(e) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by one or more R 11 substituents,

(f) aryl optionally substituted by one or more R 8 , or

(g) heteroaryl optionally substituted by one or more R 8 ;

or both R 15 attached to the same carbon taken together are oxo;

R 16 is

(a) H

(b) OR 12 ,

(c) (C═O)R 13 ,

(d) (C═O)OR 13 ,

(e) (C═O)NR 9 R 10 ,

(f) S(O) m R 13 ,

(g) S(O) m NR 9 R 10 ,

(h) C 1-7 alkyl which is optionally substituted by one or more R 11 substituents,

(i) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 substituents,

(j) aryl optionally substituted by one or more R 8 , or

(k) heteroaryl optionally substituted by one or more R 8 ;

R 17 is

(a) H,

(b) —OH, and

(c) C 1-4 alkyl;

R 19 is

(a) H,

(b) OR 11 ,

(c) Oxo,

(d) C 1-7 alkyl which is optionally substituted by one or more by one or more R 11 substituents,

(e) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by one or more R 11 substituents,

(f) aryl optionally substituted by one or more R 8 , or

(g) heteroaryl optionally substituted by one or more R 8 ;

R 20 is

(a) H,

(b) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(c) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 ,

(d) aryl optionally substituted by one or more R 8 ,

(e) heteroaryl optionally substituted by one or more R 8 , or

(f) R 20 and R 19 , taken together, form —CH 2 —;

wherein, “aryl” denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic;

wherein, “heteroaryl” encompasses a radical attached via a ring carbon or ring nitrogen of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms, selected from oxygen (—O—), sulfur (—S—), oxygenated sulfur such as sulfinyl (S═O) and sulfonyl (S(═O) 2 ), or nitrogen N(Z) wherein Z is absent or is H, O, C 1-4 alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;

het 1 is a C- or N-linked five- (5), six- (6), seven- (7), or eight- (8) membered mono- or bicyclic ring, each mono- or bicyclic ring being fully saturated or partially unsaturated, and having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; het 1 being optionally substituted by 1-2 substituents selected from C 1 -C 4 alkyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 alkyloxy, halogen —CN, ═O, ═S;

each m is independently 0, 1, or 2;

provided that

when each R 4 is H, that R 1 and R 2 are not simultaneously H, CN, or —C(O)—OCH 3 or that R 1 is not CN and R 2 is not —C(O)—OC 1-4 alkyl;

when the compound is 1,2,4,4a-Tetrahydro-cis-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione that the compound is enantiomerically enriched (−) form of (2R,4S,4aS)-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione; and

the compound is not 2,3,4,4a-tetrahydro-1′,3′-dimethylspiro[1H 1-methyl pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′4′6′(1′H, 3′H)-trione.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein each R 4 is independently

(a) H,

(b) halo,

(e) SR 12 ,

(f) S(O) m R 13 ,

(g) NR 9 R 10 ,

(h) NR 9 S(O) m R 13 ,

(i) NR 9 C(═O)OR 13 ,

(j) phenyl optionally substituted by one or more R 8 ,

(k) heteroaryl optionally substituted by one or more R 8 ,

(l) cyano,

(m) nitro,

(n) CONR 9 R 10 ,

(o) CO 2 R 12 ,

(p) C(═O)R 13 ,

(q) C(═NOR 12 )R 13 ,

(s) NR 9 C(═O)—R 12 ,

(t) C 1-7 alkyl which is optionally partially unsaturated and is optionally substituted by one or more R 11 , or

(u) het 1 optionally substituted by one or more R 8 .

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof wherein each R 4 is independently selected from NO 2 , H, Br, F, CF 3 , CN, NH 2 , —C(O)—OCH 3 , —S—CH 3 , —S(O) 2 —CH 3 , —N(OCH 3 )—CH 3 , —NH—C(O)—O-tbutyl, —NH—C(O)—CH 3 , heteroaryl optionally substituted by one or more R 8 , het 1 optionally substituted by one or more R 8 , —S(O) 2 —CH 3 , or phenyl optionally substituted by one or more of NO 2 , Cl, F, —OCH 3 , and —OCF 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein each R 3 is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is —C(O)R 6 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 2 is —C(O)R 7 .

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof wherein R 1 is —C(O)R 6 .

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof wherein R 6 and R 7 form —N(R 17 )—C(O)—N(R 17 )— or —N(R 17 )—C(S)—N(R 17 )—.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein each R 15 is independently H, C 1-7 alkyl optionally substituted by one or more R 11 substituents.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof wherein X is —C(H)(C 1-4 alkyl)-NR 16 —C(H)(C 1-4 alkyl)-.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the compound has the formula of

and each R 15 is independently

(b) OR 11 ,

(d) C 1-7 alkyl which is optionally substituted by one or more by one or more R 11 substituents,

(e) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by one or more R 11 substituents,

(f) aryl optionally substituted by one or more R 8 , or

(g) heteroaryl optionally substituted by one or more R 8 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein the compound has the formula of

and each R 15 is independently

(b) OR 11 ,

(d) C 1-7 alkyl which is optionally substituted by one or more by one or more R 11 substituents,

(e) C 3-8 cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by one or more R 11 substituents,

(f) aryl optionally substituted by one or more R 8 , or

(g) heteroaryl optionally substituted by one or more R 8 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 16 is (C═O)OR 13 or C 1-7 alkyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein each R 5 is independently H or C 1-7 alkyl.

15. A compound selected from

8-Bromo-1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]piperazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

2,3,4,4a-Tetrahydro-1′,3,3′-trimethylspiro[1H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′4′,6′(1′H,3′H)-trione;

2,3,4,4a-Tetrahydro-3-methylspiro[1H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′6′(1′H,3,H)-trione;

1,1-Dimethylethyl 1,1′2,3′,4′,4a,6′-octahydro-8-nitro-2′,4′,6′-trioxospiro[3H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-3-carboxylate;

1,1-Dimethylethyl-8-cyano-1,1′,2,3′,4,4′,4a,6′-octahydro-2′,4′,6′-trioxospiro[3H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-3-carboxylate;

2,3,4,4a-Tetrahydro-3-methyl-8-nitro-2′-thioxospiro[1H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-4′,6′(1′H,3′H)-dione);

1,2,3,3′,4,4′,4a,6′-Octahydro-2′,4′,6′-trioxospiro[1H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine-8-carbonitrile monohydrochloride; and

2,3,4,4a-Tetrahydro-8-nitrospiro[1H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione monohydrochloride.

16. The compound

or a pharmaceutically acceptable salt thereof.

17. A method of treating a bacterial infection in a mammal, the method comprising administration of an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to said mammal in need of treatment thereof.

18. The method of claim 17 wherein said compound of claim 1 or a pharmaceutically acceptable salt thereof is administered to the mammal orally, parenterally, transdermally, or topically in a pharmaceutical composition.

19. The method of claim 17 wherein said compound of claim 1 or a pharmaceutically acceptable salt thereof is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.

20. The method of claim 17 wherein said compound of claim 1 or a pharmaceutically acceptable salt thereof is administered in an amount of from about 1 to about 50 mg/kg of body weight/day.

21. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising one or more compounds of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

23. The composition of claim 22 wherein the composition comprises an enantiomerically enriched form of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

24. The composition of claim 23 , wherein the composition comprises at least 50% more of one enantiomer of a compound of formula I according to claim 1 relative to the other enantiomer of the compound.

25. The compositions of claim 24 , wherein the composition comprises at least 80% more of one enantiomer of a compound of formula I according to claim 1 relative to the other enantiomer of the compound.

26. The compositions of claim 24 , wherein the composition comprises at least 90% more of one enantiomer of a compound of formula I according to claim 1 relative to the other enantiomer of the compound.

27. The compound 2,3,4,4a-Tetrahydro-1′,3,3′-trimethylspiro[1H-pyrazino[1,2-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′4′,6′(1′H,3′H)-trione; or a pharmaceutically acceptable salt thereof.