Polycyclic 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 halo, —R, —OR, —SR, —S(O) m R, —N(R) 2 , —N(R)C(O)R, N(R)C(O)OR′, and N(R)S(O) m R′, wherein: 
 each R is independently selected from H, (C 1 -C 6 )alkyl, carbocyclyl, or heterocyclyl; or 
 two R groups taken together with the atom or atoms to which they are bound form a 4-7 membered non-aromatic heterocyclyl; and 
 R′ is (C 1 -C 6 )alkyl, carbocyclyl, or heterocyclyl; 
 ring A is a 5-7 membered non-aromatic heterocyclic ring optionally containing 1-2 heteroatoms independently selected from N, S and O in addition to the indicated nitrogen atom, wherein: 
 R 1  is selected from hydrogen, —(C 1 -C 8 )alkyl, —(C 0 -C 6 )alkylene-carbocyclyl, —(C 0 -C 6 )alkylene-heterocyclyl, —(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkylene-O-carbocyclyl, —(C 2 -C 6 )alkylene-O-heterocyclyl, —S(O) m —(C 1 -C 6 )alkyl, —S(O) m -carbocyclyl, —S(O) m -heterocyclyl, —(C 2 -C 4 )alkylene-S(O) m -carbocyclyl, —(C 2 -C 4 )alkylene-S(O) m -heterocyclyl, —C(O)—[C(R 4 )(R 4 )] 0-4 —N(R 2 )(R 3 ), —C(O)—(C 1 -C 6 )alkyl, —C(O)-heterocyclyl, —C(O)-carbocyclyl, —S(O) m —[C(R 4 )(R 4 )] 0-4 —N(R 2 )(R 3 ), and —S(O) m —(C 1 -C 4 )alkylene-carbocyclyl, —S(O) m —(C 1 -C 4 )alkylene-heterocyclyl, or 
 R 1  taken together with a ring atom adjacent to the nitrogen atom to which R 1  is bound forms a saturated heterocyclic ring fused to ring A; 
 each of R 2  and R 3  is independently selected from hydrogen, (C 1 -C 8 )alkyl, —(C 0 -C 6 ) alkylene-carbocyclyl, —(C 0 -C 6 )alkylene-heterocyclyl, —(C 2 -C 6 )alkylene-O-carbocyclyl, —(C 2 -C 6 )alkylene-O-heterocyclyl, —S(O) m —(C 1 -C 6 )alkyl, —S(O) m -carbocyclyl, —S(O) m -heterocyclyl, —(C 2 -C 4 )alkylene-S(O) m -carbocyclyl, and —(C 2 -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, carbocyclyl, heterocyclyl or a naturally occurring amino acid side chain moiety, or 
 two R 4  taken together with a common 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 two R 4  comprises one to three heteroatoms independently selected from N, S and O; 
 any substitutable carbon atom on ring A is optionally: 
 (i) substituted with one to two substituents independently selected from —(C 1 -C 4 )alkyl, and —(C 0 -C 4 )alkylene-carbocyclyl; or 
 (ii) substituted with ═O; 
 (iii) taken together with an adjacent ring atom to form a 3-7 membered saturated carbocyclyl or a 4-7 membered saturated heterocyclyl ring; or 
 (iv) spyrofused to a 3-7 membered saturated carbocyclyl; 
 any additional N heteroatom on ring A is substituted with hydrogen, C 1 -C 6  alkyl, carbocyclyl, or heterocyclyl; 
 each alkyl or alkylene in Structural Formula I is optionally and independently substituted with one or more substituents independently selected from halo, —OH, ═O, —O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, —S(O) m —(C 1 -C 4 )alkyl and —N(R 5 )(R 5 ); 
 each carbocyclyl or heterocyclyl portion of a substituent of ring A or the saturated heterocyclic ring fused to ring A 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 5 )(R 5 ) and CN; 
 each R 5  is independently selected from hydrogen and (C 1 -C 4 )alkyl, wherein each alkyl in the group represented by R 5  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 independently 1 or 2, 
 
       
       with the proviso that when X is hydrogen, ring A is not an unsubstituted bivalent piperidine radical. 
     
     
         2 . A compound of Structural Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from halo, —R′, —OR, —SR, —S(O) m R, —N(R) 2 , —N(R)C(O)R, N(R)C(O)OR′, and N(R)S(O) m R′, wherein: 
 each R is independently selected from H, (C 1 -C 6 )alkyl, carbocyclyl, or heterocyclyl; or 
 two R groups taken together with the atom or atoms to which they are bound form a 4-7 membered non-aromatic heterocyclyl; and 
 R′ is (C 1 -C 6 )alkyl, carbocyclyl, or heterocyclyl; 
 ring A is a 5-7 membered non-aromatic heterocyclic ring optionally containing 1-2 heteroatoms independently selected from N, S and O in addition to the indicated nitrogen atom, wherein: 
 R 1  is selected from hydrogen, —(C 1 -C 8 )alkyl, —(C 0 -C 6 )alkylene-carbocyclyl, —(C 0 -C 6 )alkylene-heterocyclyl, —(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkylene-O-carbocyclyl, —(C 2 -C 6 )alkylene-O-heterocyclyl, —S(O) m —(C 1 -C 6 )alkyl, —S(O) m -carbocyclyl, —S(O) m -heterocyclyl, —(C 2 -C 4 )alkylene-S(O) m -carbocyclyl, —(C 2 -C 4 )alkylene-S(O) m -heterocyclyl, —C(O)—[C(R 4 )(R 4 )] 0-4 —N(R 2 )(R 3 ), —C(O)—(C 1 -C 6 )alkyl, —C(O)-heterocyclyl, —C(O)-carbocyclyl, —S(O) m —[C(R 4 )(R 4 )] 0-4 —N(R 2 )(R 3 ), and —S(O) m —(C 1 -C 4 )alkylene-carbocyclyl, —S(O) m —(C 1 -C 4 )alkylene-heterocyclyl; or 
 R 1  taken together with a ring atom adjacent to the nitrogen atom to which R 1  is bound forms a saturated heterocyclic ring fused to ring A; 
 each of R 2  and R 3  is independently selected from hydrogen, (C 1 -C 8 )alkyl, —(C 0 -C 6 ) alkylene-carbocyclyl, —(C 0 -C 6 )alkylene-heterocyclyl, —(C 2 -C 6 )alkylene-O-carbocyclyl, —(C 2 -C 6 )alkylene-O-heterocyclyl, —S(O) m —(C 1 -C 6 )alkyl, —S(O) m -carbocyclyl, —S(O) m -heterocyclyl, —(C 2 -C 4 )alkylene-S(O) m -carbocyclyl, and —(C 2 -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, carbocyclyl, heterocyclyl or a naturally occurring amino acid side chain moiety, or 
 two R 4  taken together with a common 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 two R 4  comprises one to three heteroatoms independently selected from N, S and O; 
 any substitutable carbon atom on ring A is optionally: 
 (i) substituted with one to two substituents independently selected from —(C 1 -C 4 )alkyl, and —(C 0 -C 4 )alkylene-carbocyclyl; or 
 (ii) substituted with ═O; 
 (iii) taken together with an adjacent ring atom to form a 3-7 membered saturated carbocyclyl or a 4-7 membered saturated heterocyclyl ring; or 
 (iv) spyrofused to a 3-7 membered saturated carbocyclyl; 
 any additional N heteroatom on ring A is substituted with hydrogen, C 1 -C 6  alkyl, carbocyclyl, or heterocyclyl; 
 each alkyl or alkylene in Structural Formula I is optionally and independently substituted with one or more substituents independently selected from halo, —OH, ═O, —O—(C 1 -C 4 )alkyl, fluoro-substituted-(C 1 -C 4 )alkyl, —S(O) m —(C 1 -C 4 )alkyl and —N(R 5 )(R 5 ); 
 each carbocyclyl or heterocyclyl portion of a substituent of ring A or the saturated heterocyclic ring fused to ring A 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 5 )(R 5 ) and CN; 
 each R 5  is independently selected from hydrogen and (C 1 -C 4 )alkyl, wherein each alkyl in the group represented by R 5  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 independently 1 or 2. 
       
     
     
         3 . The compound of  claim 1 , wherein X is selected from fluoro, chloro, hydrogen, methoxy, methyl, trifluoromethyl, trifluoromethoxy and dimethylamino. 
     
     
         4 . The compound of  claim 2 , wherein X is selected from fluoro, chloro, methoxy, methyl, trifluoromethyl, trifluoromethoxy and dimethylamino. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is selected from hydrogen, —(C 1 -C 8 )alkyl, —(C 2 -C 4 )alkylene-O—(C 1 -C 4 )alkyl, —(C 0 -C 3 )alkylene-(saturated heterocycle), —(C 0 -C 3 )alkylene-(C 3 -C 7 )cycloalkyl, —C(O)—(C 1 -C 3 )alkylene-N(R 2 )(R 3 ), or R 1  taken together with a ring atom adjacent to the nitrogen atom to which R 1  is bound forms a saturated heterocyclic ring fused to ring A; wherein:
 any alkyl or alkylene portion of R 1  or the saturated heterocyclic ring fused to ring A is optionally substituted with fluoro or hydroxy; 
 R 2  is selected from hydrogen and (C 1 -C 3 )alkyl; 
 R 3  is selected from (C 1 -C 3 )alkyl and (C 3 -C 7 )cycloalkyl, or 
 R 2  and R 3 , taken together with the nitrogen atom to which they are bound form a 4-7 membered saturated heterocyclyl, wherein the heterocyclyl is optionally substituted with fluoro. 
 
     
     
         6 . The compound of  claim 5 , wherein R 1  is selected from hydrogen; (C 1 -C 3 )straight alkyl optionally substituted with one or more of: 1 to 5 methyl groups, a single hydroxy group, a single methoxy group, 1 to 3 fluoro groups, a single saturated heterocycle, and a single (C 3 -C 7 )cycloalkyl group; (C 3 -C 7 )cycloalkyl; tetrahydrofuranyl; and —C(O)—CH 2 —N(R 2 )(R 3 ), wherein R 2  and R 3  are simultaneously methyl; R 2  is hydrogen and R 3  is C 3 -C 7  cycloalkyl; or R 2  and R 3 , taken together with the nitrogen atom to which they are bound form a pyrrolidinyl ring optionally substituted with fluoro, or
 R 1  taken together with a ring atom adjacent to the nitrogen atom to which R 1  is bound forms a pyrrolidinyl or piperidinyl ring fused to ring A, wherein the pyrrolidinyl or piperidinyl ring fused to ring A is optionally substituted with hydroxy or fluorine. 
 
     
     
         7 . The compound of  claim 1 , wherein:
 ring A is selected from   
       
         
           
           
               
               
           
         
         R 6a  is selected from hydrogen and methyl; and 
         R 6  is selected from hydrogen, (C 1 -C 4 )alkyl optionally substituted with hydroxy or phenyl; or 
         R 6  taken together with R 1  and the nitrogen atom and the carbon atom to which they are respectively bound form a pyrrolidinyl or piperidinyl ring fused to ring A, wherein the pyrrolidinyl or piperidinyl ring is optionally substituted with —OH or —F; or 
         R 6  and R 6a  are taken together with the carbon atom to which they are both bound to form a cyclopropyl ring; and 
         R 7a  and R 7b  are each hydrogen or are taken together to form ═O. 
       
     
     
         8 . The compound of  claim 1 , wherein:
 ring A is   
       
         
           
           
               
               
           
         
         X is selected from fluoro, chloro, methoxy, trifluoromethyl, and dimethylamino; and 
         R 1  is selected from ethyl, propyl, (C 3 -C 5 )branched alkyl, (C 3 -C 5 )cycloalkyl, (C 1 -C 3 )alkylene-cyclopropyl, —C(O)CH 2 NH-cyclopentyl, and —C(O)CH 2 -pyrrolidin-1-yl, wherein R 1  is optionally substituted with fluoro. 
       
     
     
         9 . The compound of  claim 8 , wherein:
 X is selected from fluoro, chloro, methoxy, trifluoromethyl, and dimethylamino; and   R 1  is selected from 3-fluoroethyl, propyl, isopropyl, sec-butyl, tert-butyl, (C 3 -C 5 )cycloalkyl, —C(CH 3 ) 2 -cyclopropyl, —C(O)CH 2 NH-cyclopentyl, —C(O)CH 2 -(3-fluoropyrrolidin-1-yl); and when X is methoxy or dimethylamino, R 1  is further selected from tert-pentyl.   
     
     
         10 . The compound of  claim 1 , wherein:
 ring A is   
       
         
           
           
               
               
           
         
         X is fluoro; and 
         R 1  is selected from hydrogen, (C 1 -C 4 )alkyl. 
       
     
     
         11 . The compound of  claim 10 , wherein R 1  is selected from isopropyl, propyl or ethyl. 
     
     
         12 . The compound of  claim 1 , wherein:
 ring A is   
       
         
           
           
               
               
           
         
         X is fluoro; 
         R 1  is selected from hydrogen, (C 1 -C 4 )alkyl; 
         R 6  is selected from hydrogen, (R)-(C 1 -C 4 )alkyl, or —CH 2 -phenyl, or 
         R 1  and R 6  taken together with the nitrogen atom and the carbon atom to which they are respectively bound form a pyrrolidinyl ring fused to ring A; 
         R 7a  and R 7b  are each hydrogen or are taken together to form ═O; 
         wherein at least one of R 1 , and R 6  is other than hydrogen. 
       
     
     
         13 . The compound of  claim 12 , wherein:
 R 1  is selected from hydrogen, methyl, isobutyl, and tert-butyl; and   R 6  is selected from hydrogen, (R)-methyl, (R)-isobutyl, (R)-sec-butyl, (R)-isopropyl, and —CH 2 -phenyl, or   R 1  and R 6  taken together with the nitrogen atom and the carbon atom to which they are respectively bound form a pyrrolidinyl ring fused to ring A.   
     
     
         14 . A compound of  claim 1  selected from any one of Compounds 100, 103, 110, 112, 113, 114, 115, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 129, 130, 132, 135, 138, 141, 142, 143, 144, 145, 148, and 149 or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A compound of  claim 1  selected from any one of Compounds 300, 304, and 307 or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A compound of  claim 1  selected from any one of Compounds 400, 404, 405, 406, 407, 408, 409, 410, 412, 413, 416, 417, 419, 421, 422, 423, 424, 427, 428, and 429 or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of  claim 1 . 
     
     
         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 pharmaceutically acceptable salt thereof. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 18 , wherein the infection is caused by a Gram-positive organism. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 18 , wherein the infection is caused by a Gram-negative organism. 
     
     
         26 - 47 . (canceled) 
     
     
         48 . A method for treating or preventing a respiratory infection in a subject comprising administering to the subject an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         49 - 50 . (canceled) 
     
     
         51 . A method for treating or preventing a skin infection in a subject comprising administering to the subject an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         52 - 53 . (canceled)