Tricyclic tetrahydroquinoline antibacterial agents

Abstract

The invention includes tetrahydroquinoline and related compounds of formula I, and pharmaceutical compositions thereof, that exhibit useful antibacterial activity against a wide range of human and veterinary pathogens.

1 . A compound of formula I, including enantiomeric, diastereomeric, or tautomeric isomers thereof, or any 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 , 
 (c) Oxo, 
 (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; 
 
 Each R 4  is independently
 (a) H, 
 (b) halo, 
 (c) OR 12 , 
 (d) OC(═O)NR 9 R 10 , 
 (e) SR 12 , 
 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) COR 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-1,3dione 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 by 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 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, 
 (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
 (a) —(C(R 15 ) 2 ) n —, 
 (b) —(C(R 15 ) 2 ) m —O—(C(R 15 ) 2 ) k —, 
 (c) —(C(R 15 ) 2 ) m —S(O) m —(C(R 15 ) 2 ) k —, or 
 (d) —(C(R 15 ) 2 ) m —NR 16 —(C(R 15 ) 2 ) k —; 
 
 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 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 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), 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 k is independently 0, 1, or 2; 
 each m is independently 0, 1, or 2; 
 each n is independently 1, 2, or 3; and
 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 —(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 , 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 , 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 , wherein each R 3  is H. 
   
   
       5 . The compound of  claim 1 , wherein R 1  is —C(O)R 6 . 
   
   
       6 . The compound of  claim 1 , wherein R 2  is —C(O)R 7 . 
   
   
       7 . The compound of  claim 6 , wherein R 1  is —C(O)R 6    
   
   
       8 . The compound of  claim 7 , 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 , wherein X is —(C(R 15 ) 2 ) m —O—(C(R 15 ) 2 ) m — or —(C(R 15 ) 2 ) m —NR 16 —(C(R 15 ) 2 ) k —. 
   
   
       10 . The compound of  claim 9 , wherein X is —C(R 15 ) 2 —O—C(R 15 ) or —C(R 15 ) 2 —NR 16 —C(R 15)   2 —. 
   
   
       11 . The compound of  claim 10 , wherein each R 15  is independently H, C 1-7 alkyl optionally substituted by one or more R 11  substituents. 
   
   
       12 . The compound of  claim 11 , wherein X is —C(H)(C 1-4  alkyl)-O—C(H)(C 1-4 alkyl)- or —C(H)(C 1-4  alkyl)-NR 16 —C(H)(C 1-4 alkyl)-. 
   
   
       13 . The compound of  claim 10 , wherein the compound has the formula of 
     
       
         
         
             
             
         
       
     
     and each R 15  is independently (b), (c), (d), (e), (f), or (g) 
   
   
       14 . The compound of  claim 10 , wherein the compound has the formula of 
     
       
         
         
             
             
         
       
     
     and each R 15  is independently (b), (c), (d), (e), (f), or (g). 
   
   
       15 . The compound of  claim 10 , wherein R 16  is (C═O)OR 13  or C 1-7  alkyl. 
   
   
       16 . The compound of  claim 1 , wherein each R 5  is independently H or C 1-7 alkyl. 
   
   
       17 . A compound selected from
 (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-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-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;   8-Bromo-1,2,4,4a-tetrahydro-2,4-methylspiro[[1,4]piperazino[4,3-a]quinoline-5(6H), 5′(2′ H)-pyrimidine]-2′,4′,6′ (1′ H,3′ H)-trione;   1,2,4,4a-Tetrahydro-2,4a-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]qui noline-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′(2H)-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;   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;   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-a]quinoline]-8′-carbonitrile;   1,2,4,4a-Tetrahydro-2,4-dimethyl[1,4]oxazino[4,3-a]quinoline-5,5,8(6H)-tricarbonitrile;   8-Bromo-1,2,4-4-a-tetrhydro-2,4-dimethyl[1,4]oxazino[4,3-a]quinoline-5,5(6H)-dicarbonitrile;   2,3,4,4a-Tetrhydro-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);   9-(4-Chlorophenyl) 1,2,4,4a-tetryhydro-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-Tetrhydro-2,4-dimethyl-9-[4-(trifluoromethyoxy)phenyl]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-9-(methoxyphenyl)-2,4-dimethylspiro[[1,4]oxazino[4,3-a]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-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-(3-nitrophenyl)spiro[[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′-Octahydro-2-4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]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-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-(4-pyridinyl)spiro[[1,4]oxazino[4,3a]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-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-9-carboxylate;   Methyl-1,1′-2,3′,4,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-8-carboxylate;   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.   
   
   
       18 . A compound selected from 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       19 . A method of synthesizing compounds of formula I, comprising reacting an amine of the formula III with a fluoroaldehyde of the formula II in a polar, aprotic solvent, followed by methylenation with a compound of the formula IV, and thermal rearrangement in a polar, protic solvent, an aprotic solvent, or a nonpolar solvent system including ZnCl 2 . 
     
       
         
         
             
             
         
       
     
     wherein, X, R 1 , R 2 , R 3 , R 4 , R 5 , and R 20  are as defined above. 
   
   
       20 . A method for the treatment of microbial infections in mammals comprising administration of an effective amount of compound of  claim 1  to said mammal. 
   
   
       21 . The method of  claim 20  wherein said compound of  claim 1  is administered to the mammal orally, parenterally, transdermally, or topically in a pharmaceutical composition. 
   
   
       22 . The method of  claim 20  wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day. 
   
   
       23 . The method of  claim 20  wherein said compound is administered in an amount of from about 1 to about 50 mg/kg of body weight/day. 
   
   
       24 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       25 . A pharmaceutical composition comprising one or more compounds of  claim 1 . 
   
   
       26 . The composition of  claim 25  wherein the composition comprises an enantiomerically enriched form of a compound of formula I. 
   
   
       27 . The composition of  claim 26 , wherein the composition comprises at least 50% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound. 
   
   
       28 . The compositions of  claim 27 , wherein the composition comprises at least 80% of one enantiomer of a compound of formula I relative to the other enantiomcr of the compound. 
   
   
       29 . The compositions of  claim 27 , wherein the composition comprises at least to 90% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound. 
   
   
       30 . A compound selected from
 (2S,4R,4aR)-4-isopropyl-2-methyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1H,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,3H)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,3H)-trione;   (2S,4R,4aR)-2-isopropylmethyl-8-nitro-1,2,4,4a-tetrahydro-2H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;   (2R,4S,4aS)-2,4diisopropyl-8-nitro-1,2,4,4a-tetrahydro-2H,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-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,3′H)-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;   (2′R,4′S,4a′S)-2′,4′-dimethyl-8′-nitro-1′,2′,4′,4a′-tetrahydro-2H,6′H-spiro[pyrimidine-5,5′-[1,4]thiazino[4,3-a]quinoline]-2,4,6(1H,3H)-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′(1H,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′(11′,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′(1H,3H)-trione;   4-azido-3-iodobenzyl (2R,4S,4aS)-2,411-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-8-carboxylate;   or   (2S,4S,4aS-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3H)-trione.