Tricyclic tetrahydroquinoline antibacterial agents

1. A method for the treatment of bacterial infections in mammals comprising administration of an effective amount of a compound of formula I, including enantiomeric, diastereomeric, or tautomeric isomers thereof, or any pharmaceutically acceptable salt thereof to said mammal;

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 , or

(g) —CH 2 CH 2 COR 7 ;

Each R 3 is independently

(a) H,

(b) R 12 ,

(c) C 1-7 alkyl, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by one or more R 11 ,

(d) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which is optionally substituted by one or more R 11 ,

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

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

(g) halo, or

(h) 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, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by one or more R 11 ,

(u) C 3-8 cycloalkyl, C 3-8 cycloalkynyl or C 3-8 cyoloalkynyl each of which 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, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by one or more R 11 ,

(c) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which 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, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by one or more R 11 ,

(u) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which 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, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by one or more oxo, halo, OR 12 , SR 12 , C 1-7 alkyl, or NR 12 R 12 substituents, or

(j) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which 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, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by oxo, halo, C 1-7 alkyl, or C 1-7 alkoxy substituents,

(c) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which 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 by oxo, halo, carboxyl, C 1-7 alkyl, or C 1-7 alkoxy substituents,

(b) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which is optionally substituted by one or more by 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, or

(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, C 1-7 alkenyl or C 1-7 alkynyl each of which 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, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which 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 —O—C(R 15 ) 2 —;

Each R 15 is independently

(a) H,

(b) OR 11 ,

(c) Oxo,

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

(e) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which is optionally substituted 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 17 is

(a) H,

(b) —OH, or

(c) C 1-4 alkyl;

R 20 is

(a) H,

(b) C 1-7 alkyl, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by one or more R 11 ,

(c) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which 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

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—), 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, and ═S; and

each m is independently 0, 1, or 2.

2. The method of claim 1 wherein said compound is administered to the mammal orally, parenterally, transdermally, or topically in a pharmaceutical composition.

3. The method of claim 1 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.

4. The method of claim 1 wherein said compound is administered in an amount of from about 1 to about 50 mg/kg of body weight/day.

5. The method of claim 1 wherein the composition comprises an enantiomerically enriched form of a compound of formula I.

6. The method of claim 5 , wherein the composition comprises at least 50% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound.

7. The method of claim 6 , wherein the composition comprises at least 80% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound.

8. The method of claim 6 , wherein the composition comprises at least 90% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound.

9. The method of claim 1 wherein the compound is selected from the group consisting of:

(2S,4R,4aR)-4-isopropyl-2-methyl-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;

(2R,4S,4aS)-2,4-diethyl-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;

(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;

(2R,4S,4aS)-8-acetyl-9,10-difluoro-2,4-dimethyl-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;

(2R,4S,4aS)-10-fluoro-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;

(2R,4S,4aS)-2,4-dimethyl-8-[5-trifluoromethyl)-1,2,4-oxadiazol-3-yl]-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;

1,2,4,4a-Tetrahydro-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;

(2S,4R,4aR)-2-isopropyl-4-methyl-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;

(2S,4R,4aR)-2-isopropyl-4-methyl-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;

(2R,4S,4aS)-2,4-diisopropyl-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;

(2R,4S,4aS)-2,4-dimethyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3H′)-trione;

(2S,4R,4aR)-8-acetyl-10-fluoro-2,4-dimethyl-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;

8-bromo-2,4-dimethyl-10-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;

(2R,4S,4aS)-2,4-dimethyl-8-(5-methyl-1,2,4-oxadiazol-3-yl)-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;

(2S,4S,4aS)-4-methyl-8-nitro-2-(trifluoromethyl)-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;

4-azido-3-iodobenzyl (2R,4S,4aS)-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-8-carboxylate; and

(2S,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.

10. The method of claim 1 wherein:

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.

11. The method of claim 1 wherein the compound of formula I is administered as a pharmaceutical composition, wherein the pharmaceutical composition additionally comprises a pharmaceutically acceptable carrier.

12. The method of claim 1 , 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, C 1-7 alkenyl or C 1-7 alkynyl each of which is optionally substituted by one or more R 11 , or

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

13. The method of claim 12 , 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 .

14. The method of claim 1 , wherein each R 3 is H.

15. The method of claim 1 , wherein R 1 is —C(O)R 6 .

16. The method of claim 1 , wherein R 2 is —C(O)R 7 .

17. The method of claim 16 , wherein R 1 is —C(O)R 6 .

18. The method of claim 17 , wherein R 6 and R 7 form —N(R 17 )—C(O)—N(R 17 )— or —N(R 17 )—C(S)—N(R 17 )—.

19. The method of claim 1 , wherein each R 15 is independently H, or C 1-7 alkyl optionally substituted by one or more R 11 substituents.

20. The method of claim 19 , wherein X is —C(H)(C 1-4 alkyl)—O—C(H)(C 1-4 alkyl)—.

21. The method of claim 1 , 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 R 11 substituents,

(e) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which is optionally substituted 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 .

22. The method of claim 1 , 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 R 11 substituents,

(e) C 3-8 cycloalkyl, C 3-8 cycloalkenyl or C 3-8 cycloalkynyl each of which is optionally substituted 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 .

23. The method of claim 1 , wherein each R 5 is independently H or C 1-7 alkyl.

24. The method of claim 1 wherein the compound is selected from the group consisting 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;

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

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

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

1,2,4,4a-Tetrahydro-2,4-dimethyl-8-trifluoromethylspiro[[1,4]oxazino]4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,1′,2,3′4,4′,4a,6′-Octrahydro-2,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinoline-5(6H,5′(2′H)-pyrimidine]-8-carbonitrile;

1,2,4,4a-Tetrahydro-2,4-dimethyl-8-carboxamidespiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

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

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

1,2,4,4a-Tetrahydro-1,4a-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

8-Bromo-1,2,4,4a-tetrahydro-cis-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-4′-thioxo-2′,6′(1′H,3′H)-dione;

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

N-[1,1′,2,3′,4,4′,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinolone-5(6H),5′(2′H)-pyrimidin]-8-yl]acetamide;

tert-butyl 1,1′,2,3′,4,4′,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinolone-5(6H),5′(2′H)-pyrimidin]-8-ylcarbamate;

8-Amino-1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinolone-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione monohydrochloride;

9-Bromo-1,2,4,4a-tetrahydro-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;

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

8-Ethanone-O-methyloxime-1,1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2H)-pyrimidine)-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-8-(methylsulfonyl)spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-8-(methylsulfinyl)spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-8-(methylthio)spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-9-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′methyl,3′methyl)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′methyl)-trione;

1,2,4,4a-Tetrahydro-4-methyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2-methyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′s)-trione;

1,1′,2′3′4′4′a-Hexahydro-2′,4′-dimethyl-1,3-dioxospiro[2H-indene-2,5′(6′H)-[1,4]oxazino[4,3-α]quinoline]-8′-carbonitrile;

1,2,4,4a-Tetrahydro-2,4-dimethyl[1,4]oxazino[4,3-α]quinoline-5,5,8(6H)-tricarbonitrile;

8-Bromo-1,2,4-4a-tetrahydro-2,4-dimethyl[1,4]oxazino[4,3-α]quinoline-5,5(6H)-dicarbonitrile;

9-(4-Chlorophenyl)-1,2,4,4a-tetryhydro-2,4-dimethylspiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-9-[4-(trifluoromethyoxy)phenyl]spiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)pyrimidine]-2′4′6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-9-(methoxyphenyl)-2,4-dimethylspiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

9-(3-Chloro-4-fluorophenyl)-1,2,4,4a,-tetrahydro-2,4-dimethylsprio[[1,4]oxazino[4,3-α]quinoline-5(6H,5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-9-(3-nitrophenyl)spiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)trione;

1,1′,2,3′,4,4′,4a,6′-Octahydro-2-4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5(2′H)-pyrimidin]-9-yl]benzonitrile;

1,2,4,4a-Tetrahydro-2,4-dimethyl-9-[4-(methylsulfonyl)phenyl]spiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

1,2,4,4a-Tetrahydro-2,4-dimethyl-9-(4-pyridinyl)spiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(‘H,3′H)-trione;

Methyl-1,1′-2,3′,4,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)-pyrimidine]-9-carboxylate; and

Methyl-1,1′-2,3′,4,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-α]quinoline-5(6H),5′(2′H)-pyrimidine]-8-carboxylate.

25. The method of claim 1 wherein the compound is selected from the group consisting of:

26. The method of claim 14 wherein:

R 1 is —C(O)R 6 ;

R 2 is —C(O)R 7 ;

each R 4 is independently selected from H, F and heteroaryl optionally substituted by one or more R 8 ;

each R 5 is H;

R 6 and R 7 form —N(R 17 )—C(O)—N(R 17 )—;

each R 17 is H;

R 20 is H; and

X is —C(H)(C 1-4 alkyl)-O—C(H)(C 1-4 alkyl)-.

27. The method of claim 26 wherein R 8 is C 1-7 alkyl.

28. The method of claim 21 wherein:

R 1 is —C(O)R 6 ;

R 2 is —C(O)R 7 ;

each R 3 is H;

each R 4 is independently selected from H, F and heteroaryl optionally substituted by one or more R 8 ;

each R 5 is H;

R 6 and R 7 form —N(R 17 )—C(O)—N(R 17 )—;

each R 15 is C 1-7 alkyl;

each R 17 is H; and

R 20 is H.

29. The method of claim 28 wherein R 8 is C 1-7 alkyl.

30. The method of claim 21 wherein:

R 1 is —C(O)R 6;

R 2 is —C(O)R 7 ;

each R 3 is H;

each R 4 is independently selected from H, halo, and heteroaryl optionally substituted by one or more R 8 ;

each R 5 is H;

R 6 R 7 form —N(R 17 )—C(O)—N(R 17 )—;

each R 15 is C 1-7 alkyl;

each R 17 is H; and

R 20 is H.