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 )] 1-4 —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)-heteroaryl, —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 any one 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 ) n 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 . (canceled) 
     
     
         21 . The method of  claim 18 , wherein the infection is caused by a Gram-negative organism. 
     
     
         22 - 30 . (canceled)