Aminothiazoles and their uses

Abstract

The present application describes organic compounds of Formula (I) and pharmaceutical compositions thereof, and their use for the treatment, prevention and/or amelioration of diseases, particularly bacterial infections.

What is claimed is: 
     
         1 . A compound of the formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, including the pyridine N-oxide thereof, 
         wherein: 
         R 1  is —Z—CO 2 H and -A-Z—CO 2 H; 
         R 1a  is hydrogen, —Z—CO 2 H, and -A-Z—CO 2 H, wherein if R 1a  is hydrogen, then the Z residue of R 1  is substituted by at least two CO 2 H groups; 
         A is independently selected at each occurrence from the group consisting of a —C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —C(H)═N—, —S(O) 2 N(R 8a )—, and —S(O)N(R 8a )—; 
         Z is C 1 -C 10 alkylene, C 3 -C 8 cycloalkylene, C 3 -C 8 heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, each of which is optionally substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, amino, mono- and di-C 1 -C 6 alkylamino, C(O)OH, or halogen; 
         R 2a  is selected from the group consisting of H, substituted or unsubstituted alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2  and N(R 8a ) 2 ; 
         R 2b  is selected from the group consisting of absent, H and alkyl, or R 2a  and R 2b  may together form ═O or ═NH; 
         R 3  an R 12  are each, independently, selected from the group consisting of H, halogen, OR 4b , -A-J, and N(R 8a ) 2 ; 
         R 4a  is selected from the group consisting of H, and alkyl; 
         R 4b  is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000; 
         R 5  is selected from the group consisting of H, alkyl, and R 4b ; 
         J is selected from the group consisting of H, F, O-alkyl, N(R 8a ) 2 , N+(R 8a ) 3 , N(R 8a )C(O)alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CO 2 -alkyl, P(O)(OH) 2 , P(O)(O-alkyl) 2 , and a substituted nitrogen-containing heterocycle; 
         R 8a  is absent, or selected from the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl) 2 -J, —R 4b , wherein R 8a  can also cyclize with the atom to which R 8a  is bonded to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times with substitutents that are the same or different; and 
         R 9  is selected from the group consisting of H, alkyl and CH 2 CO 2 H. 
       
     
     
         2 . The compound of  claim 1 , wherein R 2b , R 4b  and R 5  are H, and R 4a  is CH 3 . 
     
     
         3 . The compound of  claim 1 , wherein R 2b , R 4b  and R 5  are H, R 4a  is CH 3 , and R 12  is CH 2 —O—CH 3 . 
     
     
         4 . The compound of  claim 1 , wherein formula I is represented by a compound of formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 1 , wherein formula I is represented by a compound of formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The compound of  claim 5 , wherein R 2b , R 4b  and R 5  are H, and R 4a  is CH 3 . 
     
     
         7 . The compound of  claim 5 , wherein R 2b , R 4b  and R 5  are H, R 4a  is CH 3 , and R 12  is CH 2 —O—CH 3 . 
     
     
         8 . The compound of  claim 5 , wherein formula III is represented by a compound of formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The compound of  claim 8 , wherein
 A is selected from the group consisting of —C(O)O—, C(O)—NH—, —C(O)—, —S(O) 2 —, and —S(O) 2 NH—; and   Z is independently selected at each occurrence from the group consisting of C 1 -C 10 alkylene,   
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein R 2a  is OH or OAc. 
     
     
         11 . The compound of  claim 1 , wherein the core pyridine functionality is of the following N-oxide formula: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A compound of formula VII: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, including the pyridine N-oxide thereof; 
         wherein 
         R 1  is —Z—CO 2 H and -A-Z—CO 2 H; 
         R 1a  is hydrogen, —Z—CO 2 H, and -A-Z—CO 2 H, wherein if R 1a  is hydrogen, then the Z residue of R 1  is substituted by at least two CO 2 H groups; 
         A is independently selected at each occurrence from the group consisting of a —C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —C(H)═N—, —S(O) 2 N(R 8a )—, and —S(O)N(R 8a )—; 
         Z is C 1 -C 10 alkylene, C 3 -C 8 cycloalkylene, C 3 -C 8 heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, each of which is optionally substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, amino, mono- and di-C 1 -C 6 alkylamino, C(O)OH, or halogen; 
         R 2  is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 0-6 alkyl, C 3-7 cycloalkylC 0-4 alkyl, arylC 0-4 alkyl, or a residue of the formula: 
       
       
         
           
           
               
               
           
         
         R 2a  is selected from the group consisting of H, substituted or unsubstituted alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2  and N(R 8a ) 2 ; 
         R 2b  is selected from the group consisting of absent, H and alkyl, or R 2a  and R 2b  may together form ═O or ═NH; 
         R 3  an R 12  are each, independently, selected from the group consisting of H, halogen, OR 4b , -A-J, and N(R 8a ) 2 ; 
         R 4a  is selected from the group consisting of H, and alkyl; 
         R 4b  is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000; 
         R 5  is selected from the group consisting of H, alkyl, and R 4b ; 
         J is selected from the group consisting of H, F, O-alkyl, N(R 8a ) 2 , N+(R 8a ) 3 , N(R 8a )C(O)alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CO 2 -alkyl, P(O)(OH) 2 , P(O)(O-alkyl) 2 , and a substituted nitrogen-containing heterocycle; 
         R 8a  is absent, or selected from the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl) 2 -J, —R 4b , wherein R 8a  can also cyclize with the atom to which R 8a  is bonded to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times with substitutents that are the same or different; and 
         R 9  is selected from the group consisting of H, alkyl and CH 2 CO 2 H. 
       
     
     
         14 . The compound of  claim 1 , or a salt thereof, which is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A pharmaceutical composition comprising a compound of  claim 1 , and at least one pharmaceutically acceptable carrier or diluent. 
     
     
         16 . A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of  claim 1 , such that the bacterial infection is treated.