Antibacterial agents

1. A compound of formula I:

or a salt, solvate, or a hydrate thereof,

wherein:

R 1 is pyrazine,

 indicates a point of attachment;

R 7 is H, halo, C 1-6 alkyl, C 3 -C 8 cycloalkyl, heterocyclyl, ether, —CN, —NR 8 R 9 , —OR 10 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 , —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, —(CH 2 ) m CO 2 (CH 2 ) m CH 3 , —(CH 2 ) m CO 2 (CH 2 ) m CO 2 R 6 , —(CH 2 ) m CO 2 (CH 2 ) m NR 8 R 9 , —(CH 2 ) m CO 2 E, —(CH 2 ) m C(═O)NR 6 (CH 2 ) m CO 2 R 6 , —(CH 2 ) m C(═O)NR 8 R 9 , —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m PO 3 (R 11 ) 2 , —(CH 2 ) m OR 10 , which is optionally substituted with —OR 11 , —(CH 2 ) m C(═O)OR 11 , —(CH 2 ) m NR 11 SO n R 12 , —(CH 2 ) m SO n R 12 , —(CH 2 ) m SO n NR 8 R 9 , aryl, or heteroaryl;

each n is independently is 0, 1 or 2;

R 10 is H, C 1-6 alkyl, —PO 3 H 2 , C(═O)R 13 , C(═O)OR 13 or C(═O)NR 8 R 9 and

R 11 , R 12 and R 13 are independently H, C 1-6 alkyl, aminoalkyl, benzyl, phenyl, an amino acid residue or a peptide residue;

R 2 and R 3 are independently H or C 1-6 alkyl;

R 4 and R 5 are independently H, C 1-6 alkyl which is optionally substituted with halo, ether, —(CH 2 ) m aryl, benzyl, —O(CH 2 ) m aryl, —Obenzyl, —(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OR 6 , —(CH 2 ) m OPO 3 (R p ) 2 , —(CH 2 ) m OC(═O)(CH 2 ) m CH 3 , —(CH 2 ) m OC(═O)(CH 2 ) m CO 2 R 6 , —(CH 2 ) m OC(═O)(CH 2 ) m NR 8 R 9 , —(CH 2 ) m OC(═O)E, or R 4 and R 5 together with the atoms to which they are attached form a heterocyclic ring;

each m is independently 0, 1, 2 or 3;

E is an ether;

each R p is independently H, C 1-6 alkyl, benzyl, phenyl, or (R p ) 2 together with the atoms to which they are attached form a heterocyclic ring;

each R 6 is independently H, C 1-6 alkyl, C 1-6 acyl or benzyl;

R 8 and R 9 are independently H, C 1-6 alkyl or R 8 and R 9 together with the atom to which they are attached form a heterocyclic ring which is optionally substituted with C 1-6 alkyl; and

X and Y are independently H, halo, C 1-6 alkyl, —OR 6 , —CN, a ether which is optionally substituted with halo, a heterocyclyl, or a amine.

2. The compound of claim 1 or a salt, solvate, or a hydrate thereof, wherein X is H or F, Y is H or F or both X and Y are H or F.

3. The compound of claim 2 or a salt, solvate, or a hydrate thereof, wherein R 2 and R 3 are methyl.

4. The compound of claim 3 or a salt, solvate, or a hydrate thereof, wherein R 1 is

5. The compound of claim 4 or a salt, solvate, or a hydrate thereof, wherein R 7 is H or methyl.

6. The compound of claim 5 having formula Ib:

or a salt, solvate, or a hydrate thereof.

7. The compound of claim 1 or a salt, solvate, or a hydrate thereof, wherein each E or ether independently has the formula —[(CV 2 ) p O(CV 2 ) p ] q CH 3 wherein each p is independently 0, 1, 2, 3, 4, 5 or 6, each q is independently 1, 2, 3, 4, 5 or 6, each V is independently H or another —[(CV 2) p O(CV 2 ) p ] q CH 3 .

8. The compound of claim 7 or a salt, solvate, or a hydrate thereof, wherein each E or ether independently has the formula —[(CH 2) p O(CH 2 ) p ] q CH 3 where each p is independently 0, 1, 2, 3 or 4 and each q is independently 1, 2, 3 or 4.

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

rel-(2S,4R,4aR)-9,10-difluoro-2,4-dimethyl-8-pyrazin-2-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;

(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-pyrazin-2-yl-1,2,4,4a-tetrahydro-2′H,6-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2S,4R,4aR)-9,10-difluoro-2,4-dimethyl-8-pyrazin-2-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;

(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-1′,3′-bis(morpholin-4-ylmethyl)-8-pyrazin-2-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;

(2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-1′,3′-bis[(4-methylpiperazin-1-yl)methyl]-8-pyrazin-2-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;

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

rel-(2S,4R,4aR)-9,10-difluoro-2,4-dimethyl-2′,4′,6′-trioxo-8-pyrazin-2-yl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-1′,3′(4′H,6′H)-diyl]bis(methylene)diacetate;

(2S,4R,4aR)-9,10-difluoro-2,4-dimethyl-2′,4′,6′-trioxo-8-pyrazin-2-yl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-1′,3′(4′H,6′H)-diyl]bis(methylene)diacetate;

rel-(2S,4R,4aR)-9,10-difluoro-1′,3′-bis(hydroxymethyl)-2,4-dimethyl-8-pyrazin-2-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)-9,10-difluoro-1′,3′-bis(hydroxymethyl)-2,4-dimethyl-8-pyrazin-2-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;

rel-(2S,4R,4aR)-1′,3′-bis(chloromethyl)-9,10-difluoro-2,4-dimethyl-8-pyrazin-2-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;

rel-tetrabenzyl [(2S,4R,4aR)-9,10-difluoro-2,4-dimethyl-2′,4′,6′-trioxo-8-pyrazin-2-yl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-1′,3′(4′H,6′H)-diyl]bis(methylene)bis(phosphate);

(2S,4R,4aR)-1′,3′-bis(bromomethyl)-9,10-difluoro-2,4-dimethyl-8-pyrazin-2-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;

tetra-tert-butyl [(2S,4R,4aR)-9,10-difluoro-2,4-dimethyl-2′,4′,6′-trioxo-8-pyrazin-2-yl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-1′,3′(4′H,6′H)-diyl]bis(methylene)bis(phosphate);

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

rel-(2S,4R,4aR)-10-fluoro-2,4-dimethyl-9-morpholin-4-yl-8-pyrazin-2-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;

rel-(2S,4R,4aR)-10-fluoro-9-(2-methoxyethoxy)-2,4-dimethyl-8-pyrazin-2-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;

rel-(2S,4R,4aR)-10-fluoro-9-(2-fluoroethoxy)-2,4-dimethyl-8-pyrazin-2-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;

rel-(2S,4R,4aR)-9-fluoro-2,4-dimethyl-8-pyrazin-2-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;

rel-(2S,4R,4aR)-2,4-dimethyl-8-pyrazin-2-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;

rel-(2S,4R,4aR)-8-(3-methoxypyrazin-2-yl)-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)-8-(5-aminopyrazin-2-yl)-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)-9,10-difluoro-2,4-dimethyl-8-(5-methylpyrazin-2-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;

(2R,4S,4aS)-8-(5-bromopyrazin-2-yl)-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)-9,10-difluoro-8-(5-methoxypyrazin-2-yl)-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; and

(2R,4S,4aS)-8-(5-ethoxypyrazin-2-yl)-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;

or an enantiomer or diastereomer thereof or a salt, solvate, or hydrate thereof.

10. The compound of claim 1 wherein said compound is (2R,4S,4aS)-9,10-difluoro-2, 4-dimethyl-8-(5-methylpyrazin-2-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, or an enantiomer or diastereomer thereof or a salt, solvate, or hydrate thereof.

11. The compound of claim 1 wherein said compound is (2R,4S,4aS)-9,10-difluoro-2,4-dimethyl-8-(5-methylpyrazin-2-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, or a salt, solvate, or a hydrate thereof.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

13. A method of making a compound of claim 1 having formula Ia comprising:

(a) reacting a compound of formula IIIa with a compound of formula IV at a temperature sufficient to produce a compound of formula Ia:

14. The method of claim 13 wherein (a) occurs in an aqueous or organic solvent.

15. The method of claim 14 wherein temperature of (a) is about 60 to about 180° C.

16. The method of claim 15 wherein (a) is performed for about 30 minutes to about 24 hours.