Tricyclic tetrahydroquinoline antibacterial agents
View Patent ↗The invention includes tetrahydroquinoline and related compounds of formula I and pharmaceutical compositions thereof, that exhibit useful antibacterial activity again 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) both R 3 taken together are oxo,
(d) 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 ,
(e) C 3-8 cycloalkyl; C 3-8 cycloalkenyl; or C 1-7 cycloalkynyl each of which 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 ,
(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 )—;
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
(C(R 15 ) 2[m] —O—C(R 15 ) 2[k] ,
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 ;
R 17 is
(a) H,
(b) —OH, and
(c) C 1-4 alkyl;
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 ,
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; and
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.
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 3 ,
(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 .
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 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 , wherein X is —C(H)(C 1-4 alkyl)—O—C(H)(C 1-4 alkyly)—or —C(H)(C 1-4 alkyl)—NR 16 —C(H)(C 1-4 alkyl)—.
11. The compound of claim 1 , wherein the compound has the formula of
and each R 15 is independently (b), (c), (d), (e), (f), or (g).
12. The compound of claim 1 , wherein the compound has the formula of
and each R 15 is independently (b), (c), (d), (e), (f), or (g).
13. The compound of claim 1 , wherein R 5 is H or C 1-7 alkyl.
14. A compound selected from
(2R,4S,4aS)-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3a]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] 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′(2TH)-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;
1,1′,2′3′4′4′a-Hexahydro-2′,4′-dimethyl-1,3-dioxospiro[2H-indene-2,5′(6H)-[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-1,2,4-4a-tetrhydro-2,4-dimethyl[1,4]oxazino[4,3-a]quinoline-5,5(6H) -dicarbonitrile;
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-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[4,3-a]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]oxzaino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-8-carboxylate.
15. A compound selected from
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.
18. The composition of claim 17 wherein the composition comprises an enantiomerically enriched form of a compound of formula I.
19. The composition of claim 18 , wherein the composition comprises at least 50% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound.
20. The compositions of claim 19 , wherein the composition comprises at least 80% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound.
21. The compositions of claim 19 , wherein the composition comprises at least 90% of one enantiomer of a compound of formula I relative to the other enantiomer of the compound.
22. A compound selected from
(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,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;
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,3H)-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; or
(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.