Nargenicin compounds and uses thereof as antibacterial agents
View Patent ↗The present invention relates to novel nargenicin related compounds which can inhibit DnaE and have antibacterial, particularly antimycobacterial activity against Mycobacterium tuberculosis . The present invention also relates to method for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosis by administering an antimycobacterially effective amount of nargenicin or a nargenicin-related compound and/or their pharmaceutically acceptable salts.
1. A compound of formula I
or a pharmaceutically acceptable salt thereof,
wherein
Y is O, —NR B , S or —SO 2 ;
Z is O or —NR 0 ;
R 0 is H, C 1-6 alkyl, C 3-6 cycloalkyl, AryA, or HetA;
R 1a is H; C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, —C(═O)C 1-6 alkyl, AryA, or HetA;
wherein the alkyl is optionally substituted with halogen, —NR B R C ,═NOH, —OR A , -isoindoline-1,3-dione or -1H-indene-1,3(2H)-dione;
R 1b is H, C 1-6 alkyl, or C 2-6 alkenyl;
R A is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, —C(═O)C 1-6 alkyl, —C(═O)C 2-6 alkenyl, —C(═O)NHR g , —C(═O)OR g , —C(═O)C(═O)NHR g , —C(═O)C(═O)OR g , AryA, HetA, —C(═O)-AryA, —C(═O)-HetA, —C(═O)C(═O)-HetA, —SO 2 OH, or tert-butyl dimethylsilyl (TBDMS);
wherein
any alkyl is optionally substituted with 1 or 2 substituents independently selected from halogen, —NR x R y , —N + R x R y R z , —SCH 3 , AryA, and HetA; and
any alkenyl is optionally substituted with AryA;
R g is H, C 1-8 alkyl, C 3-6 cycloalkyl, —C(═O)CCl 3 , —NR x R y , —NHC(═O)NR x R y , —NHC(═O)OCH 3 , AryA or —CH(CH 2 -AryA)C(═O)NHCH(CH 2 CH 2 CH 2 NHC(═NH)NH 2 )C(═O)NH-AryA,
wherein the alkyl or cycloalkyl is optionally substituted by 1 to 3 —NR x R y , —N + R x R y R z , —N + R x R v R w or —OH substituents or 1 substituent selected from C 1-6 alkoxy, —COOH, —C(═O)NR x R y , —NR v R w ,
—S(O) 2 NR x R y , AryA, and HetA;
R x , R y and R z are independently H or C 1-6 alkyl,
R v and R w are C 1-6 alkyl substituted with 1 to 3 —OH substituents;
R B is H, C 1-6 alkyl, C 2-6 alkenyl, —(CH 2 ) 0-3 C 3-6 cycloalkyl, —C(═O)R b , —C(═O)NHR b , —C(═O)OR b ,
C 1-6 alkoxy, —S(═O) 2 R b , —(CH 2 ) 0-3 AryA, or —(CH 2 ) 0-3 HetA;
wherein the alkyl is optionally substituted with —NR x R y or —OH;
R C is H, C 1-6 alkyl, or C 3-6 cycloalkyl;
R b is C 1-6 alkyl, C 3-6 cycloalkyl, AryA, or HetA;
R 2a is halogen, —NR B R C , or —OR 2′ ;
R 2b is H; or
R 2a and R 2b together form ═O, or a 3- to 6-membered ring with 0, 1, or 2 heteroatom ring atoms selected from N, O and S;
R 2′ is H, —C(═O)CH 3 , —C(═O)NR x R y , —C(═O)NHCH 2 CH 2 N(CH 3 ) 2 , —C(═O)NHC(═O)CCl 3 , —C(═O)NH—C 3-6 cycloalkyl, —C(═O)C(═O)OCH 2 CH 2 -HetA, or —C(═O)NHS(O) 2 -AryA;
R 3 is H;
R 4a is H, C 1-6 hydroxyalkyl, C 2-6 alkenyl, —CH 2 NO 2 , cyano, —NR x R y , —NR x (CH 2 ) 1-3 AryA, —NR x (CH 2 ) 1-3 HetA, —NR x (CH 2 ) 1-3 NR x R y , —NR x (CH 2 ) 1-3 NR y HetA, —NHC 1-6 alkyl, —NH-AryA, —NH-HetA, —NHC 1-6 alkyl-R z , —NHC(═O)C 1-6 alkyl, —OH, —O—C 1-6 alkyl, —O-AryA, —O-HetA, —OCH 2 -HetA, —OCH 2 -AryA, —OC(═O)CH 3 , —OC(═O)NH 2 , —OC(═O)-AryA, —SO 2 OH, AryA, or HetA;
R 4b is H; or
R 3 and R 4a together form a bond; or
R 4a and R 4b together form ═O;
R z is —NR x R y , disulfanylC 1-6 alkylamine, AryA, or HetA; or
R 5a is H, C 1-6 alkyl, —OH, or AryA;
R 5b is H; or
R 5a and R 5b together form ═O or ═C;
R 6a is H, C 1-6 alkyl, —OH, or AryA;
R 6b is H; or
R 6a and R 6b together form ═O or ═C; or
R 5a and R 6a together form a bond or together with the atoms to which they are attached form an oxirane; a cyclopropyl ring optionally substituted with one or two substituents independently selected from F, Cl, and —C(═O)OC 1-6 alkyl; a cyclopentyl ring optionally substituted with —OR D ; an oxetanyl ring; a pyrrolidinyl ring, wherein the pyrrolidinyl ring is substituted with R B ; or an isoxazolidinyl ring, wherein the isoxazolidinyl ring is substituted with R b ;
R D is H, C 1-6 alkyl, —C(═O)R b , or —C(═O)NHR b ;
R 7 is —OR 8 or —NR B R C ;
R 8 is H or C 1-6 alkyl;
R 9 , R 10 and R 11 are independently H, —CH 3 , or —OH;
R 12a is CH 3 or CH 2 OH;
R 12b and R 13 are H, or together form a bond, or together with the atoms to which they are connected form a cyclopropyl ring;
R 14 is H or C 1-6 alkyl;
AryA is
1) a 4- to 6-membered monocyclic aromatic ring with 0, 1, 2, 3 or 4 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —(CH 2 ) 0-3 NR x R y , —(CH 2 ) 0-3 N + R x R y R z , —OH, —CH═CHC(═O)OC 1-6 alkyl, —C(═O)R b , —(CH 2 ) 0-1 C(═O)NH 2 , C(═O)NHR b , —C(═O)OH, —C(═O)OR b , —NHC(═O)C 1-6 alkyl, —NHC(═O)AryB, —NO 2 , —OC(═O)C 1-6 alkyl,═O, —S(═O) 2 R b , —(CH 2 ) 0-3 AryB, and (CH 2 ) 0-3 HetB; or
2) a 7- to 11-membered bicyclic aromatic ring with 0, 1, 2 or 3 N, or N as a quaternary salt, ring atoms optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl,
C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —(CH 2 ) 0-3 NR x R y , —(CH 2 ) 0-3 N + R x R y R z , —OH, CH═CHC(═O)OC 1-6 alkyl, —C(═O)R b , —(CH 2 ) 0-1 C(═O)NH 2 , —C(═O)NHR b , —C(═O)OH, C(═O)OR b , —NHC(═O)C 1-6 alkyl, —NHC(═O)-AryB, —NO 2 , —OC(═O)C 1-6 alkyl, ═O, —S(═O) 2 R b , —(CH 2 ) 0-3 AryB, and —(CH 2 ) 0-3 HetB;
HetA is
1) a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —(CH 2 ) 0-3 NR x R y , —(CH 2 ) 0-3 N + R x R y R z , —OH, —(CH 2 ) 0-1 C(═O)NH 2 , —(CH 2 ) 0-1 C(═O)NHR b , —(CH 2 ) 0-1 C(═O)NH(CH 2 ) 2 NHC(═O)OCH 2 -AryB, —(CH 2 ) 3 N 3 , —C(═O)R b , —C(═O)OR b , —S(═O) 2 R b , —(CH 2 ) 0-3 AryB, and —(CH 2 ) 0-3 HetB; or
2) a 7- to 11-membered saturated or monounsaturated bicyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —(CH 2 ) 0-3 NR x R y , —(CH 2 ) 0-3 N + R x R y R z , —OH, —(CH 2 ) 0-1 C(═O)NH 2 , —(CH 2 ) 0-1 C(═O)NHR b , —(CH 2 ) 0-1 C(═O)NH(CH 2 ) 2 NHC(═O)OCH 2 -AryB, —(CH 2 ) 3 N 3 , —C(═O)R b , —C(═O)OR b , —S(═O) 2 R b , —(CH 2 ) 0-3 AryB, and —(CH 2 ) 0-3 HetB;
AryB is
1) a 4- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , —OH, —(CH 2 ) 0-3 C(═O)NR x R y , —(CH 2 ) 1-3 SO 2 NR x R y , —CH═CHC(═O)OC 1-6 alkyl, —NHC(═O)C 1-6 alkyl, —NO 2 , —N + (O)OH, —OC(═O)C 1-6 alkyl, or —C(═O)OC 1-6 alkyl; or
2) a 7- to 11-membered bicyclic aromatic ring with 1, 2 or 3 N, or N as a quaternary salt, ring atoms optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , —OH, —(CH 2 ) 0-3 C(═O)NR x R y , —(CH 2 ) 1-3 SO 2 NR x R y , —CH═CHC(═O)OC 1-6 alkyl, —NHC(═O)C 1-6 alkyl, —NO 2 , —OC(═O)C 1-6 alkyl, and —C(═O)OC 1-6 alkyl;
HetB is
1) a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, —(CH 2 ) 0-3 C(═O)NR x R y , cyano, —NH 2 , —OH, and —(CH 2 ) 0-3 HetC; or
2) a 7- to 11-membered saturated or monounsaturated bicyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, —(CH 2 ) 0-3 C(═O)NR x R y , cyano, —NH 2 , —OH, and —(CH 2 ) 0-3 HetC; and
HetC is
1) a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S; or
2) a 7- to 11-membered saturated or monounsaturated bicyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S;
with the proviso
that the compound is not nodusmicin, and
that when
Y and Z are O;
R 1b , R 2b , R 9 , R 10 , R 11 and R 14 are H;
R 2a is —OH;
R 4a is —OC(═O)-pyrrolyl;
R 5a and R 6a together form a bond;
R 12b and R 13 together form a bond;
R 7 is —OH or —OCH 3 ;
R 12a is —CH 3 ;
then R 1a is not ethyl optionally substituted with: —OH; C 1-6 alkoxy; hydroxyl and methoxy; amine or amine substituted with C 1-3 alkyl; or ═NOH.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is O.
3. The compound of claim 1 , which has the formula
or a pharmaceutically acceptable salt thereof, wherein Z is O is —NH.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1a is H, C 1-6 alkyl, C 2-6 alkenyl, —CH(CH 3 )NH-cyclopropyl, —CH(CH 3 )═NOH, —CH(CH 3 )OR A , —CH(CH 3 )-1H-indene-1,3(2H)-dione, —CH(CH 3 )-isoindoline-1,3-dione, —C(═O)C 1-6 alkyl, or AryA;
R 1b is H;
R A is H, C 1-6 alkyl, —C(═O)C 1-6 alkyl, C(═O)NHR g , —C(═O)OR g , —C(═O)C(═O)NHR g , —C(═O)C(═O)OR g , —C(═O)-AryA, —C(═O)-HetA, —C(═O)C(═O)-HetA, —SO 2 OH, or tert-butyl dimethylsilyl;
wherein the alkyl is optionally substituted with one or two substituents independently selected from halogen, —SCH 3 , AryA, and HetA; and
R g is H, C 1-8 alkyl, C 3-6 cycloalkyl, —C(═O)CCl 3 , —NR x R y , —NHC(═O)NR x R y , —NHC(═O)OCH 3 ; and
AryA or —CH(CH 2 -AryA)C(═O)NHCH(CH 2 CH 2 CH 2 NHC(═NH)NH 2 )C(═O)NH-AryA,
wherein the alkyl is optionally substituted by 1 to 3 —NR x R y or —OH substituents or 1 sub stituent selected from C 1-6 alkoxy, —COOH, —C(═O)NR x R y , AryA, and HetA.
5. The compound of claim 4 , which has the formula
or a pharmaceutically acceptable salt thereof, wherein
R 2a is halogen or —OR 2′ ;
R 2b is H; or
R 2a and R 2b together form ═O;
R 2′ is H, —C(═O)CH 3 , —C(═O)NR x R y , —C(═O)NHCH 2 CH 2 N(CH 3 ) 2 , —C(═O)NHC(═O)CCl 3 , —C(═O)NHC 3-6 cycloalkyl, —C(═O)C(═O)OCH 2 CH 2 -HetA, or —C(═O)NHS(O) 2 -AryA;
R 5a is H or —OH;
R 5b is H; or
R 5a and R 5b together form ═O or ═C;
R 6a is H or —OH;
R 6b is H; or
R 6a and R 6b together form ═O or ═C; or
R 5a and R 6a together form a bond or together with the atoms to which they are attached form an oxirane;
R 7 is —OR 8 ;
R 8 is H or C 1-6 alkyl;
AryA is
1) a 5- to 6-membered monocyclic aromatic ring with 0, 1, or 2 ring atoms independently selected from N, N as a quaternary salt, O and S, or 4 N ring atoms, optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —(CH 2 ) 0-1 NR x R y , —OH, —CH═CHC(═O)OC 1-6 alkyl, —C(═O)C 1-6 alkyl, —C(═O)NH 2 , —C(═O)OH, —NHC(═O)C 1-6 alkyl, —NHC(═O)-AryB, —OC(═O)C 1-6 alkyl, ═O, —(CH 2 ) 0-1 AryB, and —CH 2 HetB; or
2) a 10-membered bicyclic aromatic ring with 0 N ring atoms;
HetA is
1) a 5- to 6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, and O, optionally substituted with 1 substituent selected from C 1 -C 6 alkyl,—OH, and ═O; or
2) a 8-membered saturated bicyclic ring with 2 N, or N as a quaternary salt, ring atoms, optionally substituted with 1 substituent selected from C 1 -C 6 alkyl, —CH 2 C(═O)NH 2 , —(CH 2 )C(═O)NH(CH 2 ) 2 NHC(═O)OCH 2 -AryB, —(CH 2 ) 3 N 3 , and —(CH 2 ) 3 HetB;
AryB is
a 5- to 6-membered monocyclic aromatic ring with 0 or 1 ring atoms selected from N, N as a quaternary salt, and S, optionally substituted with 1 substituent selected from C 1 -C 6 alkyl, —C(═O)NH 2 ,—NO 2 , —N + (O)OH, —OC(═O)C 1-6 alkyl, and —C(═O)OC 1-6 alkyl;
HetB is
a 8-membered saturated bicyclic ring with 2 N, or N as quaternary salt, ring atoms, optionally substituted with 1 substituent selected from C 1 -C 6 alkyl, —CH 2 C(═O)NH 2 , and —(CH 2 ) 3 HetC; and
HetC is
a 8-membered saturated bicyclic ring with 2 N, or N as quaternary salt, ring atoms.
6. The compound of claim 5 , wherein
AryA is
1) a monocyclic ring selected from furanyl, imidazolyl, pyrazolyl, pyrrolyl, phenyl, pyridinyl, tetrazolyl, thiazolyl, or thiophenyl, wherein any N ring atom in the monocyclic ring is optionally in the form of a quaternary salt, and wherein the monocyclic ring is optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —(CH 2 ) 0-1 NR x R y , —OH, —CH═CHC(═O)OC 1-6 alkyl, C(═O)C 1-6 alkyl, —C(═O)NH 2 , —C(═O)OH, —NHC(═O)C 1-6 alkyl, —NHC(═O)-AryB, —OC(═O)C 1-6 alkyl, ═O, —(CH 2 ) 0-1 AryB, and —CH 2 HetB, or
2) naphthalenyl,
HetA is
1) a monocyclic ring selected from morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, wherein any N ring atom in the monocyclic ring is optionally in the form of a quaternary salt, and wherein the monocyclic ring is optionally substituted with 1 substituent selected from C 1 -C 6 alkyl, —OH, and ═O; or
2) 1,4-diazabicyclo[2.2.2]octane, optionally substituted with 1 substituent selected from C 1 -C 6 alkyl, —CH 2 C(═O)NH 2 ,
—(CH 2 )C(═O)NH(CH 2 ) 2 NHC(═O)OCH 2 -AryB, —(CH 2 ) 3 N 3 , and —(CH 2 ) 3 HetB;
AryB is a monocyclic ring selected from imidazolyl, phenyl, pyridinyl, pyrrolyl, thiophenyl, wherein any N ring atom in the monocyclic ring is optionally in the form of a quaternary salt, and wherein the monocyclic ring is optionally substituted with 1 substituent selected from C 1 -C 6 alkyl, C(═O)NH 2 ,—NO 2 , —N + (O)OH, or —C(═O)OC 1-6 alkyl;
HetB is 1,4-diazabicyclo[2.2.2]octane, optionally substituted with 1 substituent selected from C 1 -C 6 alkyl, —CH 2 C(═O)NH 2 , and —(CH 2 ) 3 HetC; and
HetC is 1,4-diazabicyclo[2.2.2]octane.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 4a is H, —NH 2 , —OH, cyano,
R 4b is H; or
R 4a and R 4b together form ═O.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2a is —OH, F,
R 2b is H; or
R 2a and R 2b together form ═O.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1a is H, methyl, ethyl, phenyl,
R 1b is H.
10. The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , which has the formula
or a pharmaceutically acceptable salt thereof,
wherein
R A is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, —C(═O)C 1-6 alkyl, —C(═O)NHR g , —C(═O)OR g , —C(═O)C(═O)NHR g , —C(═O)C(═O)OR g , AryA, HetA, —C(═O)-AryA, or —C(═O)C(═O)-HetA;
wherein
any alkyl is optionally substituted with one or two substituents independently selected from halogen, —NR x R y , N + R x R y R z , —SCH 3 , AryA, and HetA; and
the alkenyl is optionally substituted with AryA;
R b is C 1-6 alkyl, C 3-6 cycloalkyl, AryA, or HetA;
R g is H, C 1-8 alkyl, C 3-6 cycloalkyl, —C(═O)CCl 3 , —NR x R y , —NHC(═O)NR x R y , —NHC(═O)OCH 3 , or AryA, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 3 —NR x R y or —OH substituents or 1 substituent selected from C 1-6 alkoxy, —COOH, —C(═O)NR x R y , —NR v R w , —S(O) 2 NR x R y , AryA, and HetA;
R k is H, —CH 3 , —C(═O)C 1-6 alkyl, —CH═CHC(═O)OCH 3 or —OH;
R x , R y and R z are independently H or C 1-6 alkyl;
R v and R w are C 1-6 alkyl substituted with 1 to 3 —OH substituents;
AryA is
1) a 4- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , —OH, —CH═CHC(═O)O C 1-6 alkyl, —C(═O)R b , —C(═O)NHR b , —C(═O)OR b , —NHC(═O)C 1-6 alkyl, —NHC(═O)-AryB, —NO 2 , —OC(═O)C 1-6 alkyl, —S(═O) 2 R b , —(CH2) 0-3 AryB, and —(CH2) 0-3 HetB; or
2) a 7- to 11-membered bicyclic aromatic ring with 1, 2 or 3 N, or N as a quaternary salt, ring atoms optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , —OH, —C(═O)R b , —C(═O)NHR b , —C(═O)OR b , —S(═O) 2 R b , —(CH2) 0-3 AryB, and —(CH 2 ) 0-3 HetB;
HetA is
1) a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , —OH, —(CH 2 ) 0-1 C(═O)NR b —C(═O)R b , —C(═O)OR b , —S(═O) 2 R b , —(CH 2 ) 0-3 AryB, and —(CH 2 ) 0-3 HetB; or
2) a 7- to 11-membered saturated or monounsaturated bicyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , —OH, —(CH 2 ) 0-1 —C(═O)NR b , —C(═O)R b , —C(═O)OR b , —S(═O) 2 R b , —(CH2) 0-3 AryB, and —(CH2) 0-3 HetB;
AryB is
1) a 4- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 to 3 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , —OH, —(CH 2 ) 1-3 —C(═O)NR x R y , —(CH 2 ) 1-3 SO 2 NR x R y , —CH═CHC(═O)OC 1-6 alkyl, —NHC(═O)C 1-6 alkyl, —NO 2 , —N + (O)OH, and —OC(═O)C 1-6 alkyl; or
2) a 7- to 11-membered bicyclic aromatic ring with 1, 2 or 3 N, or N as a quaternary salt, ring atoms optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , and —OH;
HetB is
1) a 4- to 6-membered saturated or monounsaturated monocyclic ring with 1 or 2 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , and —OH; or
2) a 7- to 11-membered saturated or monounsaturated bicyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, optionally substituted with 1 or 2 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 alkoxy, cyano, —NH 2 , and —OH.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R k is H or —C(═O)C 1-6 alkyl.
13. A pharmaceutical composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. A method for inhibiting bacterial DnaE in a subject having a bacterial infection which comprises administering to the subject (i) an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition according to claim 13 .
15. A method for treating a bacterial infection which comprises administering to a subject in need of such treatment (i) a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition according to claim 13 .