Tetracycline compounds

Abstract

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

1 . A compound of Structural Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from —OCF 3  and —OCH 3 ; 
 Y is selected from hydrogen, —(C 1 -C 7 )alkyl, carbocyclyl, —(C 1 -C 4 )alkylene-N(R 2 )(R 3 ), —(C 1 -C 4 )alkylene-N(R F )—C(O)—[C(R 5a )(R 5b )] 0-4 -N(R 2 )(R 3 ), —CH═N—OR 2 , —C(O)—N(R 2 )(R 4 ), —NO 2 , —COOH, —OH, —N═CH—N(R 2 )(R 3 ), —N(R 2 )(R 3 ), —N(R F )—C(O)—[C(R 5a )(R 5b )] 1-4 —N(R 2 )(R 3 ), —N(R F )—C(O)—N(R 2 )(R 3 ), —N(R F )—C(O)—(C 1 -C 6 )alkyl, —N(R F )—C(O)-heterocyclyl, —N(R F )—C(O)-carbocyclyl, —N(R F )—S(O) m —(C 1 -C 4 ) alkylene-N(R 2 )(R 3 ), —N(R F )—S(O) m —N(R 2 )(R 4 ) and —N(R F )—S(O) m —(C 1 -C 4 )alkylene-carbocyclyl; 
 each R 2  and R 3  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-heterocyclyl, —(C 1 -C 6 )alkylene-O-carbocyclyl, —(C 1 -C 6 )alkylene-O-heterocyclyl, —S(O) m —(C 1 -C 6 )alkyl, —(C 0 -C 4 )alkylene-S(O) m -carbocyclyl, and —(C 0 -C 4 )alkylene-S(O) m -heterocyclyl; or R 2  and R 3 , taken together with the nitrogen atom to which they are bound form a heterocyclyl, wherein the heterocyclyl optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O; 
 each R 4  is independently selected from hydrogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —(C 0 -C 6 ) alkylene-carbocyclyl, and —(C 0 -C 6 )alkylene-heterocyclyl; 
 each R 5a  and each R 5b  is independently selected from hydrogen, (C 1 -C 6 )alkyl, carbocyclyl, heterocyclyl or a naturally occurring amino acid side chain moiety, or 
 R 5a  and R 5b  taken together with the carbon atom to which they are bound form a 3-7 membered non-aromatic carbocyclyl or a 4-7 membered non-aromatic heterocyclyl, wherein the heterocyclyl formed by R 5a  and R 5b  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 or heteroaryl, wherein: 
 each carbocyclyl or heterocyclyl 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 )alkylene-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; 
 the heterocyclyl in —N(R F )—C(O)-heterocyclyl represented by Y is optionally substituted with carbocyclyl or heterocyclyl in addition to the substituents described above, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more substituentts independently selected from halo, (C 1 -C 4 )alkyl, —OH, ═O, —O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-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 is optionally and independently substituted with one or more substituents independently selected from halo, —(C 1 -C 4 )alkyl, —OH, —O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkylene-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 ); 
 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 )alkylene-O—(C 1 -C 4 )alkyl; and 
 each m is 1 or 2. 
 
     
     
         2 . The compound of  claim 1 , wherein:
 Y is selected from hydrogen, —(C 1 -C 4 )alkylene-N(R 2 )(R 3 ), —CH═N—OR 2 , —C(O)—N(R 2 )(R 4 ), —NO 2 , —COOH, —OH, —N═CH—N(R 2 )(R 3 ), —N(R 2 )(R 3 ), —N(R F )—C(O)—[C(R 5a )(R 5b )] 1-4 —N(R 2 )(R 3 ), —N(R F )—C(O)—(C 1 -C 6 )alkyl, —N(R F )—C(O)-heterocyclyl, —N(R F )—C(O)-carbocyclyl, —N(R F )—S(O) m —(C 1 -C 4 )alkylene-N(R 2 )(R 3 ), —N(R F )—S(O) m —N(R 2 )(R 4 ), and —N(R F )—S(O) m —(C 1 -C 4 ) alkylene-carbocyclyl, wherein:   each R 2  is independently selected from hydrogen, and (C 1 -C 3 )alkyl;   each R 3  is independently selected from hydrogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —(C 0 -C 6 ) alkylene-carbocyclyl, —(C 0 -C 6 )alkylene-heterocyclyl, —S(O) m- —(C 1 -C 6 )alkyl, —S(O) m -carbocyclyl, and —S(O) m -heterocyclyl; and   each R 4  is independently selected from hydrogen, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, —(C 0 -C 6 ) alkylene-carbocyclyl, and —(C 0 -C 6 )alkylene-heterocyclyl; or   R 2  and R 3 , taken together with the nitrogen atom to which they are bound form a heterocyclyl, wherein the heterocylyl optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O;   each R 5a  and each R 5b  is independently selected from hydrogen, (C 1 -C 6 )alkyl, carbocyclyl, heterocyclyl, or a naturally occurring amino acid side chain moiety, or   R 5a  and R 5b  taken together with the carbon atom to which they are bound form a 3-7 membered saturated carbocyclyl or a 4-7 membered saturated heterocyclyl, wherein the saturated heterocyclyl formed by R 5a  and R 5b  optionally comprises one to two additional heteroatoms independently selected from N, S and O,   R F  is hydrogen or (C 1 -C 3 )alkyl; and   each m is 1 or 2, wherein:   each carbocyclyl or heterocyclyl is optionally and independently substituted with one or more substituents independently selected from chloro, fluoro, (C 1 -C 4 )alkyl, —OH, —O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, —C(O)—(C 1 -C 4 )alkyl, —C(O)-(fluoro-substituted-(C 1 -C 4 )alkyl, and —N(R G )(R G ); and   each alkyl is optionally and independently substituted with one or more substituents independently selected from fluoro, chloro, —O—(C 1 -C 4 )alkyl, and fluoro-substituted-(C 1 -C 4 )alkyl.   
     
     
         3 . The compound of  claim 2 , wherein:
 Y is selected from hydrogen, —N(R 2 )(R 3 ), —NH—C(O)—(CH 2 ) 1-4 —N(R 2 )(R 3 ), —NH—C(O)-heterocyclyl, —NH—C(O)-carbocyclyl, and —NH—S(O) 2 —(C 1 -C 6 )alkyl, wherein:   each R 2  is independently selected from hydrogen, and (C 1 -C 3 )alkyl; and   each R 3  is independently selected from hydrogen, (C 1 -C 6 )alkyl, and —(C 0 -C 6 )alkylene-carbocyclyl; or   R 2  and R 3  taken together with the nitrogen atom to which they are bound form a heterocyclyl, wherein the heterocylyl optionally comprises 1 to 4 additional heteroatoms independently selected from N, S and O; wherein   each carbocyclyl or heterocyclyl is optionally and independently substituted with one or more substituents independently selected from fluoro, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, and —N(R G )(R G ); and   each alkyl is optionally and independently substituted with one or more substituents independently selected from fluoro, —O—(C 1 -C 4 )alkyl, and fluoro-substituted-(C 1 -C 4 )alkyl.   
     
     
         4 . The compound of  claim 3 , wherein:
 Y is selected from hydrogen, —NH 2 , —NH—C(O)—CH 2 —N(R 2 )(R 3 ),   
       
         
           
           
               
               
           
         
       
       —NH—C(O)-phenyl, —NH—C(O)-thienyl and —NH—S(O) 2 —(C 1 -C 6 )alkyl, wherein:
 each R 2  is independently selected from hydrogen, and (C 1 -C 2 )alkyl; and 
 each R 3  is independently selected from hydrogen, (C 1 -C 6 )alkyl, and —(C 0 -C 1 )alkylene-cycloalkyl; or 
 R 2  and R 3  taken together with the nitrogen atom to which they are bound form a saturated heterocyclyl; 
 ring A represents a 4-7 membered saturated heterocyclyl; 
 R 3′  is hydrogen or methyl; 
 each cycloalkyl, phenyl or heterocyclyl is optionally and independently substituted with one or more substituents independently selected from fluoro, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, and —N(R 2 )(R 2 ); and 
 each alkyl is optionally and independently substituted with one or more substituents independently selected from fluoro, —O—(C 1 -C 4 )alkyl, and fluoro-substituted-(C 1 -C 4 )alkyl. 
 
     
     
         5 . The compound of  claim 2 , wherein:
 X is —OCH 3 ;   Y is selected from —NH—C(O)—CH 2 —N(R 2 )(R 3 ),   
       
         
           
           
               
               
           
         
       
       and —NH—S(O) 2- —(C 1 -C 6 )alkyl, wherein the alkyl group in —NH—S(O) 2 —(C 1 -C 6 )alkyl is optionally substituted with fluoro;
 each R 2  is independently selected from hydrogen and —CH 3 ; 
 each R 3  is independently selected from (C 1 -C 6 )alkyl, and —(C 0 -C 1 )alkylene-carbocyclyl; or R 2  and R 3 , taken together with the nitrogen atom to which they are bound form a saturated heterocyclyl optionally substituted with fluoro; 
 ring A represents a 4-7 membered saturated heterocyclyl; 
 R 3′  is hydrogen or methyl; 
 each carbocyclyl or heterocyclyl is optionally and independently substituted with one or more substituents independently selected from fluoro, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, and —N(R 2 )(R 2 ); and 
 each alkyl is optionally and independently substituted with one or more substituents independently selected from fluoro, —O—(C 1 -C 4 )alkyl, and fluoro-substituted-(C 1 -C 4 )alkyl. 
 
     
     
         6 . The compound of  claim 2 , wherein:
 X is —OCF 3 ;   Y is selected from —NH 2 , —NH—C(O)—CH 2 —N(R 2 )(R 3 ),   
       
         
           
           
               
               
           
         
       
       —NH—C(O)-phenyl, and —NH—C(O)-thienyl, wherein:
 the phenyl in the group represented by Y is optionally substituted with —OCH 3  or —N(CH 3 ) 2 ; 
 each R 2  is independently selected from hydrogen and —CH 3 ; 
 each R 3  is independently selected from (C 1 -C 6 )alkyl and —(C 0 -C 1 )alkylene-carbocyclyl, wherein the (C 1 -C 6 )alkyl is optionally substituted with fluoro or —OCH 3 ; or 
 R 2  and R 3 , taken together with the nitrogen atom to which they are bound form a saturated heterocyclyl optionally substituted with fluoro or —OCH 3 ; 
 ring A represents a 4-7 membered saturated heterocyclyl; 
 R 3′  is hydrogen or methyl; 
 each carbocyclyl or heterocyclyl is optionally and independently substituted with one or more substituents independently selected from fluoro, (C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, and —N(R G )(R G ); and 
 each alkyl is optionally and independently substituted with one or more substituents independently selected from fluoro, —O—(C 1 -C 4 )alkyl, and fluoro-substituted-(C 1 -C 4 )alkyl. 
 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 2 , wherein the compound is selected from any one of compound numbers 101, 102, 103, 104, 105, 106, 107, 109, 112, 114, 115, 120, 123, 125, 126, 127, 128, 130, 131, 132, 133, 135, 136, 142, 144, 145, 146, 147, 148, 152, 154, 169, 170, 173, 209, 210, 212, 213, 214, 217, 218, 220, 221, 222, 224, 226, 230, 234, 239, 243, 244, 245, 246, 247, 248, 250, 251, 252, 257, 258, 259, 260, 261, and 263, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of  claim 1 . 
     
     
         10 . 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 . 
     
     
         11 . The method of  claim 10 , wherein the infection is caused by a Gram-positive organism. 
     
     
         12 . The method of  claim 11 , 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. 
     
     
         13 . The method of  claim 10 , wherein the infection is caused by a Gram-negative organism. 
     
     
         14 . The method of  claim 13 , 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. 
     
     
         15 . The method of  claim 10 , wherein the infection is caused by an organism selected from the group consisting of rickettsiae, chlamydiae,  Legionella  spp.  Mycoplasma  spp., and any other intracellular pathogens. 
     
     
         16 - 22 . (canceled)