C7-fluoro substituted tetracycline compounds

Abstract

The present invention is directed to a compound represented by Structural Formula (A): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula (A) are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula (A) and its therapeutic use.

1 . A compound represented by Structural Formula (A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from hydrogen, —(C 1 -C 7 )alkyl, carbocyclyl, aryl and heteroaryl; 
 Y is selected from hydrogen, —(C 1 -C 7 )alkyl, carbocyclyl, —(C 1 -C 4 )alkylene-N(R A )(R B ), —(C 1 -C 4 )alkylene-N(R F )—C(O)—[C(R D )(R E )] 0-4 —N(R A )(R B ), —CH═N—OR A , —N(R A )(R B ), —N(R F )—C(O)—[C(R D )(R E )] 0-4 —N(R A )(R B ), —N(R F )—C (O)—N(R A )(R B ), —N(R F )—C(O)—(C 1 -C 6 )alkyl, —N(R F )—C(O)-heterocyclyl, —N(R F )—C(O)-heter oaryl, —N(R F )—C(O)-carbocyclyl, —N(R F )—C(O)-aryl, —N(R F )—S(O) m —(C 1 -C 4 )alkylene-N(R A ) (R B ), —N(R F )—S(O) m —(C 1 -C 4 )alkylene-carbocyclyl, and —N(R F )—S(O) m —(C 1 -C 4 )alkylene-aryl wherein: 
 at least one of X and Y is not hydrogen; 
 each R A  and R B  are independently selected from hydrogen, (C 1 -C 7 )alkyl, —O—(C 1 -C 7 )alkyl, —(C 0 -C 6 )alkylene-carbocyclyl, —(C 0 -C 6 )alkylene-aryl, —(C 0 -C 6 )alkylene-heterocyclyl, —(C 0 -C 6 )alkylene-heteroaryl, —(C 1 -C 6 )alkylene-O-carbocyclyl, —(C 1 -C 6 )alkylene-O-aryl, —(C 1 -C 6 )alkylene-O-heterocyclyl, —(C 1 -C 6 )alkylene-O-heteroaryl, —S(O) m —(C 1 -C 6 )alkyl, —(C 0 -C 4 )alkylene-S(O) m -carbocyclyl, —(C 0 -C 4 )alkylene-S(O) m -aryl, —(C 0 -C 4 )alkylene-S(O) m -heterocyclyl and —(C 0 -C 4 )alkylene-S(O) m -heteroaryl; or 
 R A  and R B  taken together with the nitrogen atom to which they are bound form a heterocyclyl or heteroaryl, wherein the heterocycle or heteroaryl optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O; 
 each R D  and each R E  is independently selected from hydrogen, (C 1 -C 6 )alkyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, or a naturally occurring amino acid side chain moiety, or 
 R D  and R E  taken together with the carbon atom to which they are bound form a 3-7 membered carbocyclyl, or a 4-7 membered heterocyclyl, wherein the heterocyclyl formed by R D  and R E  optionally comprises one to two additional heteroatoms independently selected from N, S and O; 
 R F  is selected from hydrogen, (C 1 -C 7 )alkyl, carbocyclyl, aryl and heteroaryl; and 
 m is 1 or 2, wherein: 
 each carbocyclyl, aryl, heterocyclyl or heteroaryl is optionally and independently substituted with one or more substituents independently selected from halo, —(C 1 -C 4 )alkyl, —OH, ═O, —O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, halo-substituted-(C 1 -C 4 )alkyl, halo-substituted —O—(C 1 -C 4 )alkyl, —C(O)—(C 1 -C 4 )alkyl, —C(O)-(fluoro-substituted-(C 1 -C 4 )alkyl), —S(O) m —(C 1 -C 4 )alkyl, —N(R G )(R G ), and CN; 
 each alkyl in the group represented by R A , R B , R D  and R E  is optionally and independently substituted with one or more substituents independently selected from halo, —(C 1 -C 4 )alkyl, —OH, —O—(C 1 -C 7 )alkyl, —(C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, —S(O) m —(C 1 -C 4 )alkyl, and —N(R G )(R G ), wherein 
 each R G  is hydrogen or (C 1 -C 4 )alkyl, wherein each alkyl in the group represented by R G  is optionally and independently substituted with one or more substituents independently selected from —(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, halo, —OH, —O—(C 1 -C 4 )alkyl, and (C 1 -C 4 )alkyl-O—(C 1 -C 4 )alkyl. 
 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is represented by the following Structural Formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2  are each independently selected from hydrogen, (C 1 -C 7 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 7 )alkoxy(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkoxy(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryloxy(C 1 -C 4 )alkyl, arylthio(C 1 -C 4 )alkyl, arylsufinyl(C 1 -C 4 )alkyl, arylsulfonyl(C 1 -C 4 )alkyl, and —O—(C 1 -C 7 )alkyl, or 
 R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a monocyclic or bicyclic heteroaryl, or a monocyclic, fused bicyclic, bridged bicyclic or spiro bicyclic heterocycle, wherein the heteroaryl or heterocycle optionally contains one or two additional heteroatoms independently selected from N, O and S; and 
 wherein each alkyl, cycloalkyl, alkoxy and cycloalkoxy moiety in the groups represented by R 1  and R 2  and each heterocycle represented by NR 1 R 2  taken together is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, —OH, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, and —N(R 3 )(R 4 ); and 
 each aryl, aryloxy, arylthio, arylsufinyl and arylsulfonyl moiety in the groups represented by R 1  and R 2  and each heteroaryl represented by NR 1 R 2  taken together is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, —OH, (C 1 -C 4 )alkoxy, —S—(C 1 -C 4 )alkyl, —S(O)(C 1 -C 4 )alkyl, —S(O) 2 (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —N(R 3 )(R 4 ); —CN, halo(C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkoxy, and 
 R 3  and R 4  are each independently selected from the group consisting of —H and (C 1 -C 4 )alkyl, wherein the (C 1 -C 4 )alkyl represented by R 3  and R 4  is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, —OH, (C 1 -C 4 )alkoxy, and (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl. 
 
       
     
     
         3 . The compound of  claim 2 , wherein the compound is represented by the following Structural Formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein.
 R 1  and R 2  are each independently selected from hydrogen, (C 1 -C 7 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 7 )alkoxy(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkoxy(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, aryl(C 1 -C 4 )alkyl, aryloxy(C 1 -C 4 )alkyl, arylthio(C 1 -C 4 )alkyl, arylsufinyl(C 1 -C 4 )alkyl, arylsulfonyl(C 1 -C 4 )alkyl; or 
 R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a monocyclic or bicyclic heteroaryl, or a monocyclic, fused bicyclic, bridged bicyclic or spiro bicyclic heterocycle, wherein the heteroaryl or heterocycle optionally contains one or two additional heteroatoms independently selected from N, O and S. 
 
       
     
     
         4 . The compound of  claim 3 , wherein R 1  is hydrogen or a (C 1 -C 4 )alkyl. 
     
     
         5 . The compound of  claim 3 , wherein R 2  is selected from (C 1 -C 7 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 7 )alkoxy(C 1 -C 4 )alkyl, phenyl, phenyl(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl and halo(C 1 -C 4 )alkyl, wherein each alkyl, alkoxy and cycloalkyl moiety in the groups represented by R 2  is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl and halo; and each phenyl moiety in the groups represented by R 2  is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —CN, halo(C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkoxy. 
     
     
         6 . The compound of  claim 3 , wherein R 1  is selected from hydrogen, methyl and ethyl. 
     
     
         7 . The compound of  claim 6 , wherein R 2  is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, phenyl, benzyl, —(CH 2 ) 2 —O—CH 3 , —(CH 2 ) 3 —OCH 3 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 CH(C H 3 ) 2 , —CH 2 —CF 3 , —(CH 2 ) 2 —CH 2 F, and —(CH 2 )—CH 3 ; n is 0, 1, 2, 3, 4, 5 or 6; and wherein the phenyl or benzyl group represented by R 2  is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halogen, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —CN, halo(C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkoxy. 
     
     
         8 . The compound of  claim 7 , wherein R 2  is selected from cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, —(CH 2 ) 2 —O—CH 3 , —C(CH 3 ) 3 , —CH(CH 3 ) 2 , —CH 2 —CF 3 , —CH 2 CH(CH 3 ) 2 , —CH 3  and —CH 2 CH 3 . 
     
     
         9 . The compound of  claim 3 , wherein R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a monocyclic or bicyclic heteroaryl, or a monocyclic, fused bicyclic, bridged bicyclic or spiro bicyclic heterocycle, wherein the heteroaryl or heterocycle optionally contains one additional heteroatom selected from N, O and S; and the heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, —OH, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, and —N(R 3 )(R 4 ); and the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, —OH, (C 1 -C 4 )alkoxy, —S—(C 1 -C 4 )alkyl, —S(O)(C 1 -C 4 )alkyl, —S(O) 2 (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —N(R 3 )(R 4 ), —CN, halo(C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkoxy. 
     
     
         10 . The compound of  claim 9 , wherein R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a heterocycle selected from the group consisting of azetidine, pyrrolidine, morpholine, piperidine, octahydrocyclopenta[c]pyrrol, isoindoline, and azabicyclo[3.1.0]hexane, wherein the heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halogen, —OH, (C 1 -C 4 )alkoxy, —S—(C 1 -C 4 )alkyl, —S(O)(C 1 -C 4 )alkyl, —S(O) 2 (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, and —N(R 3 )(R 4 ). 
     
     
         11 . The compound of  claim 10 , wherein the heterocycle is optionally substituted with halogen, methoxy, hydroxy, methoxymethyl or dimethylamino group. 
     
     
         12 . The compound of  claim 3 , wherein:
 a) R 1  is methyl, and R 2  is cyclopropyl;   b) R 1  is hydrogen, and R 2  is cyclopropyl;   c) R 1  is hydrogen, and R 2  is cyclobutyl;   d) R 1  is methyl, and R 2  is cyclobutyl;   e) R 1  is hydrogen, and R 2  is cyclopropylmethyl;   f) R 1  is hydrogen, and R 2  is cyclobutylmethyl;   g) R 1  is hydrogen, and R 2  is benzyl;   h) R 1  is hydrogen, and R 2  is methoxypropyl;   i) R 1  is hydrogen, and R 2  is methoxyethyl;   j) R 1  is hydrogen, and R 2  is phenyl;   k) R 1  is methyl, and R 2  is t-butyl;   l) R 1  is hydrogen, and R 2  is t-butyl;   m) R 1  is hydrogen, and R 2  is methyl;   n) R 1  is hydrogen, and R 2  is ethyl;   o) R 1  is hydrogen, and R 2  is propyl;   p) R 1  is hydrogen, and R 2  is butyl;   q) R 1  is hydrogen, and R 2  is pentyl;   r) R 1  is hydrogen, and R 2  is hexyl;   s) R 1  is hydrogen, and R 2  is heptyl;   t) R 1  is methyl, and R 2  is methyl;   u) R 1  is hydrogen, and R 2  is isopropyl;   v) R 1  is hydrogen, and R 2  is 2,2-dimethylpropyl;   w) R 1  is hydrogen, and R 2  is trifluoroethyl;   x) R 1  is hydrogen, and R 2  is 2-methylpropyl;   y) R 1  is hydrogen, and R 2  is 3-fluoropropyl;   z) R 1  is ethyl, and R 2  is ethyl;   a1) R 1  is methyl, and R 2  is methyl;   b1) R 1  is hydrogen, and R 2  is hydrogen;   c1) R 1  is hydrogen, and R 2  is cyclopentyl;   d1) R 1  is methyl, and R 2  is cyclopentyl; or   e1) R 1  is methyl, and R 2  is propyl,   
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         13 . The compound of  claim 3 , wherein R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a group selected from:
 a) azetidin-1-yl;   b) 3-fluoroazetidin-1-yl;   c) 3-methylazetidin-1-yl;   d) 3-methoxyazetidin-1-yl;   e) pyrrolidin-1-yl;   f) morpholin-4-yl;   g) 3-fluoropyrrolidin-1-yl;   h) 3-hydroxypyrrolidin-1-yl;   i) 3-N,N-dimethylaminopyrrolidin-1-yl;   j) 2-methoxymethylpyrrolidin-1-yl;   k) piperidin-1-yl;   l) octahydrocyclopenta[c]pyrrol-2-yl;   m) isoindolin-2-yl; and   n) 3-azabicyclo[3.1.0]hexan-3-yl,   
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         14 . The compound of  claim 3 , wherein
 R 1  is hydrogen or a (C 1 -C 4 )alkyl; and   R 2  is selected from (C 1 -C 7 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 7 )alkoxy(C 1 -C 4 )alkyl, phenyl, phenyl(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl and halo(C 1 -C 4 )alkyl, wherein each alkyl, alkoxy and cycloalkyl moiety in the groups represented by R 2  is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl and halo; and each phenyl moiety in the groups represented by R 2  is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —CN, halo(C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkoxy; or   R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a monocyclic or bicyclic heteroaryl, or a monocyclic, fused bicyclic, bridged bicyclic or spiro bicyclic heterocycle, wherein the heteroaryl or heterocycle optionally contains one additional heteroatom selected from N, O and S; and the heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, —OH, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, and —N(R 3 )(R 4 ); and the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, halo, —OH, (C 1 -C 4 )alkoxy, —S—(C 1 -C 4 )alkyl, —S(O)(C 1 -C 4 )alkyl, —S(O) 2 (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —N(R 3 )(R 4 ), —CN, halo(C 1 -C 4 )alkyl, and halo(C 1 -C 4 )alkoxy.   
     
     
         15 . The compound of  claim 2 , wherein
 R 1  is hydrogen, methyl, ethyl, methoxy or tert-butoxy;   R 2  is selected from (C 1 -C 7 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl, (C 1 -C 7 )alkoxy(C 1 -C 4 )alkyl, phenyl, (C 3 -C 6 )cycloalkyl, and fluoro(C 1 -C 4 )alkyl; or   R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a ring selected from pyrrolidinyl, morpholinyl, azetidinyl, piperidinyl, octahydrocyclopenta[c]pyrrolyl, isoindolinyl, indazolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl, wherein the ring formed by R 1  and R 2  taken together with the nitrogen atom to which they are bonded is optionally substituted with fluoro, —OH, —OCH 3 , or N(CH 3 ) 2 .   
     
     
         16 . The compound of  claim 3 , wherein:
 R 1  hydrogen, methyl, or ethyl   R 2  is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 2,2-dimethylpropyl, t-butyl, isobutyl, n-pentyl, (C 4 -C 6 )cycloalkyl, (C 3 -C 5 )cycloalkylmethyl, methoxyethyl, and 2-fluoroethyl; or   R 1  and R 2  taken together with the nitrogen atom to which they are bonded form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, tetrazolyl, or octahydrocyclopenta[c]pyrrolyl, and wherein the ring formed by R 1  and R 2  taken together with the nitrogen atom to which they are bonded is optionally substituted with fluoro.   
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of  claim 1  or a salt thereof. 
     
     
         18 . A method for treating or preventing an infection or colonization in a subject comprising administering to the subject an effective amount of a compound of  claim 1  or a salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the infection is caused by a Gram-positive organism. 
     
     
         20 . The method of  claim 19 , wherein the Gram-positive organism is selected from the group consisting of  Staphylococcus  spp.,  Streptococcus  spp.,  Propionibacterium  spp.,  Enterococcus  spp.,  Bacillus  spp.,  Corynebacterium  spp.,  Nocardia  spp.,  Clostridium  spp.,  Actinobacteria  spp., and  Listeria  spp. 
     
     
         21 . The method of  claim 18 , wherein the infection is caused by a Gram-negative organism. 
     
     
         22 . The method of  claim 21 , wherein the Gram-negative organism is selected form the group consisting of Enterobactericeae, Bacteroidaceae, Vibrionaceae, Pasteurellae, Pseudomonadaceae, Neisseriaceae, Rickettsiae, Moraxellaceae, any species of  Proteeae, Acinetobacter  spp.,  Helicobacter  spp., and  Campylobacter  spp. 
     
     
         23 - 30 . (canceled)