IP Library Granted Patent US 9,839,641
Granted Patent B2
US 9,839,641 · App. 15/353,325 · Granted Dec 12, 2017

Compounds and methods for treating bacterial infections

Inventors: Gregory Steven Basarab (Sudbury, MA); Madhusudhan Reddy Gowravaram (Acton, MA); Sheila Hauck (Lincoln, MA); Fei Zhou (Jamaica Plain, MA)
Assignee: Entasis Therapeutics Limited
A61K31/5383
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Quick Facts
Patent No.
US 9,839,641
App. No.
15/353,325
Granted
Dec 12, 2017
Kind
B2
Abstract

Compounds of formula (I), pharmaceutically acceptable salts thereof, and uses of the compounds of formula (I) for treating bacterial infections are disclosed.

Claims (113)

1. A method for treating a Gram-positive, Gram-negative, or atypical bacterial infection in a subject comprising administering to the subject an effective amount of a compound having the structural formula (I):

wherein

X is fluorine or chlorine;

R 1 is selected from the group consisting of hydrogen, phenyl, —C≡N, tetrahydropyranyl, N-methyl-1,2,4-triazolyl, pyrimidinyl, pyridinyl, pyrazinyl, cyclopropyl, —C≡CH, —CH═CH 2 , and C 1 -C 3 alkyl, which C 1 -C 3 alkyl is optionally substituted with one or more of: —OR 10 , halogen, —C≡N, —N 3 , —SO 2 CH 3 , —SCH 3 , —CH═CH 2 , —CH═NOR 11 and phenyl;

R 2 is selected from the group consisting of hydrogen, —C≡N, pyridinyl, C 1 -C 3 alkyl, which C 1 -C 3 alkyl is optionally substituted with one or more of: halogen, —OR 20 and —CH═NOR 21 ;

R 3 is hydrogen or C 1 -C 3 alkyl;

R 10 is for each occurrence independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl and (CH 2 ) 2 OCH 3 ; and

R 11 , R 20 and R 21 are for each occurrence independently hydrogen or C 1 -C 4 alkyl.

2. The method of claim 1 , wherein R 10 is hydrogen, methyl, ethyl or —(CH 2 ) 2 OCH 3 .

3. The method of claim 1 , wherein R 11 is hydrogen or methyl.

4. The method of claim 1 , wherein R 20 is hydrogen, methyl or ethyl.

5. The method of claim 1 , wherein R 21 is hydrogen or methyl.

6. The method of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, —CH 2 -phenyl, —CH 2 F, —CH 2 OCH 3 , —CH 2 CH═CH 2 , tetrahydropyranyl, —(CH 2 ) 3 OH, —(CH 2 ) 3 F, —(CH 2 ) 3 OH, —(CH 2 ) 3 F, —CH═CH 2 , —C≡N, —CH═NOCH 3 , —CH 2 SCH 3 , —CH 2 SO 2 CH 3 , —CH 2 N 3 , —CH 2 OCH 2 CH 3 , —CH 2 O(CH 2 ) 2 OCH 3 , cyclopropyl, pyridinyl, —CH(CH 3 )OCH 3 , pyrimidinyl, pyrazinyl, —C≡CH, N-methyl-1,2,4-triazolyl, —CH(OH)CH 3 , —CH═NOH and —CH 2 OH.

7. The method of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, —CH 2 F, —CH 2 OCH 3 , —CH 2 OH, —CH═NOH, —CH 2 N 3 , pyridinyl, —C≡N and —CH═NHOCH 3 .

8. The method of claim 1 , wherein R 3 is hydrogen or methyl.

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

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-(2-oxo-1,3-oxazolidin-3-yl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4R)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(5S)-5-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(5R)-5-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-[(4S)-4-Ethyl-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-[(4R)-4-Ethyl-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione);

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4R)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-[(4R)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-[(4S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-(5,5-Dimethyl-2-oxo-1,3-oxazolidin-3-yl)-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-[(5S)-5-Ethyl-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-[(5R)-5-Ethyl-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(4R)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(4S)-4-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(4S)-4-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(4R)-4-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((S)-5-(fluoromethyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4]oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Chloro-8-[(5S)-4-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Chloro-8-[(5R)-4-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2]oxazolo[4,5-g]quinoline-5,5’-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

((2R,4S,4aS)-11-Chloro-2,4-dimethyl-8-((R)-5-methyl-2-oxooxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((4S,5R)-4,5-Dimethyl-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((4R,5S)-4,5-Dimethyl-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((S)-4-Allyl-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((S)-5-(hydroxymethyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

((2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4R-(tetrahydro-2H-pyran-4-yl)-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-[(4S-(tetrahydro-2H-pyran-4-yl)-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5’-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((S)-4-(3-hydroxypropyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((S)-4-(3-fluoropropyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((S)-4-(2-hydroxyethyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H, 1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Chloro-8-((S)-5-(fluoromethyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H, 1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Choro-8-((S)-4-(3-hydroxpropyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H, 1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Choro-8-((S)-4-(3-fluoropropyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H, 1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(5S)-4-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(5R)-4-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5’-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(5R)-5-(fluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((S)-2-oxo-4-vinyloxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H, 1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-{(5R)-5-[(hydroxyimino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3a] [1,2] oxazolo[4,5-g]quinoline-5,5’-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(4S)-3-[(2R,4S,4aS)-11-Fluoro-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] [1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-2-oxo-1,3-oxazolidine-4-carbonitrile;

(2R,4S,4aS)-11-Fluoro-8-{(4S)-4-[(methoxyimino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-{(5R)-5-(methoxyimino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g]quinoline-5,5’-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-[(5R)-5-(Azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-Spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5’-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-4-((methylthio)methyl)-2-oxooxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-4-((methylsulfonyl)methyl)-2-oxooxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H, 1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((R)-4-(Azidomethyl)-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((S)-4-(azidomethyl)-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a] quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-[(4S)-4-(Ethoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-Spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5’-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-{(4S)-4-[(2-methoxyethoxy)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a] [1,2] oxazolo[4,5-g] quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-8-((R)-4-(Difluoromethyl)-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((S)-4-Cyclopropyl-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-2-oxo-5-(pyridin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-((S)-2-oxo-5-(pyridin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-2-oxo-4-(pyridin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-((S)-2-oxo-4-(pyridin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-2-oxo-4-(pyridin-4-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-((S)-2-oxo-4-(pyridin-4-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((R)-4-((R)-1-methoxyethyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g] [1,4] oxazino[4,3-a]quinoline-5,5’-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((R)-4-((S)-1-methoxyethyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-2-oxo-4-(pyrazin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-((S)-2-oxo-4-(pyrazin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-2-oxo-4-(pyrimidin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-((S)-2-oxo-4-(pyrimidin-2-yl)oxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((S)-4-Ethynyl-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Chloro-2,4-dimethyl-8-((S)-4-methyl-2-oxooxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-[(4S)-4-(methoxymethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((S)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-oxooxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-((R)-4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-oxooxazolidin-3-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-Fluoro-8-((R)-4-((S)-1-hydroxyethyl)-2-oxooxazolidin-3-yl)-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

{(4S)-3-[(2R,4S,4aS)-11-Fluoro-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][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-2-oxo-1,3-oxazolidin-4-yl}acetonitrile;

(2R,4S,4aS)-8-((R)-4-((R)-1,2-Dihydroxyethyl)-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-8-((R)-4-((S)-1,2-Dihydroxyethyl)-2-oxooxazolidin-3-yl)-11-fluoro-2,4-dimethyl-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione;

(2R,4S,4aS)-11-fluoro-8-{(4S)-4-[(hydroxyimino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;

(5R)-3-[(2R,4S,4aS)-11-Fluoro-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][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-2-oxo-1,3-oxazolidine-5-carbonitrile; and

(5S)-3-[(2R,4S,4aS)-11-fluoro-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][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidin]-8-yl]-2-oxo-1,3-oxazolidine-5-carbonitrile,

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein the Gram-positive bacterial infection is a Staphylococcus or Streptococcus infection.

11. The method of claim 10 , wherein the Staphylococcus infection is caused by S. aureus, S. haemolyticus or S. epidermis.

12. The method of claim 10 , wherein the Staphylococcus infection is caused by S. aureus.

13. The method of claim 12 , wherein the S. aureus is resistant to vancomycin or methicillin.

14. The method of claim 10 , wherein the Streptococcus infection is caused by S. pneumoniae, S. pyogenes , or S. agalactiae.

15. The method of claim 1 , wherein the Gram-negative bacterial infection is a Haemophilus infection.

16. The method of claim 15 , wherein the Haemophilus infection is caused by H. influenza.

17. The method of claim 1 , wherein the atypical bacterial infection is a Legionella infection.

18. The method of claim 17 , wherein the Legionella infection is caused by H. influenza.

19. A method for treating a Gram-positive, Gram-negative, or atypical bacterial infection in a subject comprising administering to the subject an effective amount of a compound having the structure:

or a pharmaceutically acceptable salt thereof.

20. The method of claim 19 , wherein the Gram-positive bacterial infection is a Staphylococcus or Streptococcus infection.

21. The method of claim 20 , wherein the Staphylococcus infection is caused by S. aureus, S. haemolyticus or S. epidermis.

22. The method of claim 20 , wherein the Staphylococcus infection is caused by S. aureus.

23. The method of claim 22 , wherein the S. aureus is resistant to vancomycin or methicillin.

24. The method of claim 20 , wherein the Streptococcus infection is caused by S. pneumoniae, S. pyogenes , or S. agalactiae.

25. The method of claim 19 , wherein the Gram-negative bacterial infection is a Haemophilus infection.

26. The method of claim 25 , wherein the Haemophilus infection is caused by H. influenza.

27. The method of claim 19 , wherein the atypical bacterial infection is a Legionella infection.

28. The method of claim 27 , wherein the Legionella infection is caused by H. influenza.

Assignments (5)
NUNC PRO TUNC ASSIGNMENT Recorded Feb 20, 2025
From: ENTASIS THERAPEUTICS LIMITED
To: ENTASIS THERAPEUTICS INC.
Reel/Frame 070271/0396 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 6, 2017
From: BASARAB, GREGORY STEVEN; ZHOU, FEI; GOWRAVARAM, MADHUSUDHAN REDDY; HAUCK, SHEILA
To: ASTRAZENECA PHARMACEUTICALS LP
Reel/Frame 041474/0911 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 6, 2017
From: ASTRAZENECA PHARMACEUTICALS LP
To: ASTRAZENECA UK LIMITED
Reel/Frame 041474/0984 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 6, 2017
From: ASTRAZENECA UK LIMITED
To: ASTRAZENECA AB
Reel/Frame 041475/0238 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 6, 2017
From: ASTRAZENECA AB
To: ENTASIS THERAPEUTICS LIMITED
Reel/Frame 041475/0336 →
Continuity (6)
Continuation 14881595 · Oct 13, 2015
Continuation 14515684 · Oct 16, 2014
Continuation 14159773 · Jan 21, 2014
Provisional Application 61859910 · Jul 30, 2013
Provisional Application 61755537 · Jan 23, 2013
Related Publication 20170128458A1 · May 11, 2017