Biaryl Heterocyclic Compounds And Methods Of Making And Using The Same

Abstract

The present invention relates generally to the field of anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of compounds having both a biaryl moiety and at least one heterocylic moiety that are useful as such agents.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:
 A is selected from the group consisting of:
 phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 
 
 B is selected from the group consisting of:
 phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 
 
 Het-CH 2 —R 3  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         M is selected from the group consisting of:
 a) saturated, unsaturated, or aromatic C 3-14  carbocycle, and b) saturated, unsaturated, or aromatic 3-14 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
 wherein a) or b) optionally is substituted with one or more R 5  groups; 
 
 
         M-L is selected from the group consisting of:
 a) M-X, b) M-L 1 , c) M-L 1 -X, d) M-X-L 2 , e) M-L 1 -X-L 2 , f) M-X-L 1 -X-L 2 , g) M-L 1 -X-L 2 -X, h) M-X-X-, i) M-L 1 -X-X-, j) M-X-X-L 2 , and k) M-L 1 -X-X-L 2 , wherein 
 X, at each occurrence, independently is selected from the group consisting of:
 a) —O—, b) —NR 4 —, c) —N(O)—, d) —N(OR 4 )—, e) —S(O) p —, f) —SO 2 NR 4 —, g) —NR 4 SO 2 —, h) —NR 4 —N═, i) ═N—NR 4 —, j) —O—N═, k) ═N—O—, l) —N═, m) ═N—, n) —NR 4 —NR 4 —, o) —NR 4 C(O)O—, p) —OC(O)NR 4 —, q) —NR 4 C(O)NR 4 — r) —NR 4 C(NR 4 )NR 4 —, and s) 
 
 
       
       
         
           
           
               
               
           
         
         
           L 1  is selected from the group consisting of:
 a) C 1-6  alkyl, b) C 2-6  alkenyl, and c) C 2-6  alkynyl,
 wherein any of a)-c) optionally is substituted with one or more R 5  groups; and 
 
 
           L 2  is selected from the group consisting of:
 a) C 1-6  alkyl, b) C 2-6  alkenyl, and c) C 2-6  alkynyl,
 wherein any of a)-c) optionally is substituted with one or more R 5  groups; 
 
 
         
         R 1 , at each occurrence, independently is selected from the group consisting of:
 a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OR 4 , g) —CN, h) —NO 2 , i) —NR 4 R 4 , j) —C(O)R 4 , k) —C(O)OR 4 , l) —OC(O)R 4 , m) —C(O)NR 4 R 4 , n) —NR 4 C(O)R 4 , o) —OC(O)NR 4 R 4 , p) —NR 4 C(O)OR 4 , q) —NR 4 C(O)NR 4 R 4 , r) —C(S)R 4 , s) —C(S)OR 4 , t) —OC(S)R 4 , u) —C(S)NR 4 R 4 , v) —NR 4 C(S)R 4 , w) —OC(S)NR 4 R 4 , x) —NR 4 C(S)OR 4 , y) —NR 4 C(S)NR 4 R 4 , z) —NR 4 C(NR 4 )NR 4 R 4 , aa) —S(O) p R 4 , bb) —SO 2 NR 4 R 4 , and cc) R 4 ; 
 
         R 2 , at each occurrence, independently is selected from the group consisting of:
 a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OR 4 , g) —CN, h) —NO 2 , i) —NR 4 R 4 , j) —C(O)R 4 , k) —C(O)OR 4 , l) —OC(O)R 4 , m) —C(O)NR 4 R 4 , n) —NR 4 C(O)R 4 , o) —OC(O)NR 4 R 4 , p) —NR 4 C(O)OR 4 , q) —NR 4 C(O)NR 4 R 4 , r) —C(S)R 4 , s) —C(S)OR 4 , t) —OC(S)R 4 , u) —C(S)NR 4 R 4 , v) —NR 4 C(S)R 4 , w) —OC(S)NR 4 R 4 , x) —NR 4 C(S)OR 4 , y) —NR 4 C(S)NR 4 R 4 , z) —NR 4 C(NR 4 )NR 4 R 4 , aa) —S(O) p R 4 , bb) —SO 2 NR 4 R 4 , and cc) R 4 ; 
 
         R 3  is selected from the group consisting of:
 a) —OR 4 , b) —NR 4 R 4 , c) —C(O)R 4 , d) —C(O)OR 4 , e) —OC(O)R 4 , f) —C(O)NR 4 R 4 , g) —NR 4 C(O)R 4 , h) —OC(O)NR 4 R 4 , i) —NR 4 C(O)OR 4 , j) —NR 4 C(O)NR 4 R 4 , k) —C(S)R 4 , l) —C(S)OR 4 , m) —OC(S)R 4 , n) —C(S)NR 4 R 4 , o) —NR 4 C(S)R 4 , p) —OC(S)NR 4 R 4 , q) —NR 4 C(S)OR 4 , r) —NR 4 C(S)NR 4 R 4 , s) —NR 4 C(NR 4 )NR 4 R 4 , t) —S(O) p R 4 , u) —SO 2 NR 4 R 4 , and v) R 4 ; 
 
         R 4 , at each occurrence, independently is selected from the group consisting of:
 a) H, b) C 1-6  alkyl, c) C 2-6  alkenyl, d) C 2-6  alkynyl, e) C 3-14  saturated, unsaturated, or aromatic carbocycle, f) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, g) —C(O)—C 1-6  alkyl, h) —C(O)—C 2-6  alkenyl, i) —C(O)—C 2-6  alkynyl, j) —C(O)—C 3-14  saturated, unsaturated, or aromatic carbocycle, k) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, l) —C(O)O—C 1-6  alkyl, m) —C(O)O—C 2-6  alkenyl, n) —C(O)O—C 2-6  alkynyl, o) —C(O)O—C 3-14  saturated, unsaturated, or aromatic carbocycle, and p) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
 wherein any of b)-p) optionally is substituted with one or more R 5  groups; 
 
 
         R 5 , at each occurrence, is independently selected from the group consisting of:
 a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 6 , h) ═NOR 6 , i) ═N—NR 6 R 6 , j) —CF 3 , k) —OR 6 , l) —CN, m) —NO 2 , n) —NR 6 R 6 , o) —C(O)R 6 , p) —C(O)OR 6 , q) —OC(O)R 6 , r) —C(O)NR 6 R 6 , s) —NR 6 C(O)R 6 , t) —OC(O)NR 6 R 6 , u) —NR 6 C(O)OR 6 , v) —NR 6 C(O)NR 6 R 6 , w) —C(S)R 6 , x) —C(S)OR 6 , y) —OC(S)R 6 , z) —C(S)NR 6 R 6 , aa) —NR 6 C(S)R 6 , bb) —OC(S)NR 6 R 6 , cc) —NR 6 C(S)OR 6 , dd) —NR 6 C(S)NR 6 R 6 , ee) —NR 6 C(NR 6 )NR 6 R 6 , ff) —S(O) p R 6 , gg) —SO 2 NR 6 R 6 , and hh) R 6 ; 
 
         R 6 , at each occurrence, independently is selected from the group consisting of:
 a) H, b) C 1-6  alkyl, c) C 2-6  alkenyl, d) C 2-6  alkynyl, e) C 3-14  saturated, unsaturated, or aromatic carbocycle, f) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, g) —C(O)—C 1-6  alkyl, h) —C(O)—C 2-6  alkenyl, i) —C(O)—C 2-6  alkynyl, j) —C(O)—C 3-14  saturated, unsaturated, or aromatic carbocycle, k) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, l) —C(O)O—C 1-6  alkyl, m) —C(O)O—C 2-6  alkenyl, n) —C(O)O—C 2-6  alkynyl, o) —C(O)O—C 3-14  saturated, unsaturated, or aromatic carbocycle, and p) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
 wherein any of b)-p) optionally is substituted with one or more R 7  groups; 
 
 
         R 7 , at each occurrence, independently is selected from the group consisting of:
 a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR 8 , h) ═NOR 8 , i) ═N—NR 8 R 8 , j) —CF 3 , k) —OR 8 , l)—CN, m) —NO 2 , n) —NR 8 R 8 , o) —C(O)R 8 , p) —C(O)OR 8 , q) —OC(O)R 8 , r) —C(O)NR 8 R 8 , s) —NR 8 C(O)R 8 , t) —OC(O)NR 8 R 8 , u) —NR 8 C(O)OR 8 , v) —NR 8 C(O)NR 8 R 8 , w) —C(S)R 8 , x) —C(S)OR 8 , y) —OC(S)R 8 , z) —C(S)NR 8 R 8 , aa) —NR 8 C(S)R 8 , bb) —OC(S)NR 8 R 8 , cc) —NR 8 C(S)OR 8 , dd) —NR 8 C(S)NR 8 R 8 , ee) —NR 8 C(NR 8 )NR 8 R 8 , ff) —S(O) p R 8 , gg) —SO 2 NR 8 R 8 , hh) C 1-6  alkyl, ii) C 2-6  alkenyl, jj) C 2-6  alkynyl, kk) C 3-14  saturated, unsaturated, or aromatic carbocycle, and ll) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
 wherein any of hh)-ll) optionally is substituted with one or more moieties selected from the group consisting of R 8 , F, Cl, Br, I, —CF 3 , —OR 8 , —SR 8 , —CN, —NO 2 , —NR 8 R 8 , —C(O)R 8 , —C(O)OR 8 , —OC(O)R 8 , —C(O)NR 8 R 8 , —NR 8 C(O)R 8 , —OC(O)NR 8 R 8 , —NR 8 C(O)OR 8 , —NR 8 C(O)NR 8 R 8 , —C(S)R 8 , —C(S)OR 8 , —OC(S)R 8 , —C(S)NR 8 R 8 , —NR 8 C(S)R 8 , —OC(S)NR 8 R 8 , —NR 8 C(S)OR 8 , —NR 8 C(S)NR 8 R 8 , —NR 8 C(NR 8 )NR 8 R 8 , —SO 2 NR 8 R 8 , and —S(O) p R 8 ; 
 
 
         R 8 , at each occurrence, independently is selected from the group consisting of:
 a) H, b) C 1-6  alkyl, c) C 2-6  alkenyl, d) C 2-6  alkynyl, e) C 3-14  saturated, unsaturated, or aromatic carbocycle, f) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, g) —C(O)—C 1-6  alkyl, h) —C(O)—C 2-6  alkenyl, i) —C(O)—C 2-6  alkynyl, j) —C(O)—C 3-14  saturated, unsaturated, or aromatic carbocycle, k) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, l) —C(O)O—C 1-6  alkyl, m) —C(O)O—C 2-6  alkenyl, n) —C(O)O—C 2-6  alkynyl, o) —C(O)O—C 3-14  saturated, unsaturated, or aromatic carbocycle, and p) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
 wherein any of b)-p) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, —CF 3 , —OH, —OCH 3 , —SH, —SCH 3 , —CN, —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(O)CH 3 , —C(O)OCH 3 , —C(O)NH 2 , —NHC(O)CH 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 N(CH 3 ) 2 , and —S(O) p CH 3 ; 
 
 
         m is 0, 1, 2, 3, or 4; 
         n is 0, 1, 2, 3, or 4; and 
         p, at each occurrence, independently is 0, 1, or 2, 
         and wherein the compound does not have the formula corresponding to any of the structures listed in Table 1. 
       
     
     
         2 . The compound according to  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or prodrug thereof,
 wherein A, B, L, M, R 1 , R 2 , R 3 , m, and n are defined as described in  claim 1 . 
 
     
     
         3 . The compound according to  claim 2 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or prodrug thereof,
 wherein A, B, L, M, R 1 , R 2 , R 3 , m, and n are defined as described in  claim 1 . 
 
     
     
         4 . The compound according to  claim 1 , wherein
 A is selected from the group consisting of phenyl and pyridyl;   B is selected from the group consisting of phenyl and pyridyl;   m is 0, 1, or 2; and   n is 0, 1, or 2.   
     
     
         5 . The compound according to  claim 1 , wherein A-B is: 
       
         
           
           
               
               
           
         
         wherein A, R 2 , and n are defined as described in  claim 1 . 
       
     
     
         6 . The compound according to  claim 5 , wherein A-B is: 
       
         
           
           
               
               
           
         
         wherein A is defined as described in  claim 1 . 
       
     
     
         7 . The compound according to  claim 5 , wherein A-B is: 
       
         
           
           
               
               
           
         
         wherein A is defined as described in  claim 1 . 
       
     
     
         8 . The compound according to  claim 1 , wherein A-B is: 
       
         
           
           
               
               
           
         
         wherein B is defined as described in  claim 1 . 
       
     
     
         9 . The compound according to  claim 1 , wherein A-B is: 
       
         
           
           
               
               
           
         
         wherein B is defined as described in  claim 1 . 
       
     
     
         10 . The compound according to  claim 1 , wherein R 3  is —NHC(O)R 4 . 
     
     
         11 . The compound according to  claim 10 , wherein R 4  is —CH 3 . 
     
     
         12 . The compound according to  claim 1 , wherein R 3  is: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or prodrug thereof,
 wherein A, B, L, M, R 2 , m, and n are defined as described in  claim 1 . 
 
     
     
         14 . The compound according to  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester or prodrug thereof,
 wherein A, L, M, R 3 , and m are defined as described in  claim 1 . 
 
     
     
         15 . A pharmaceutical composition comprising one or more compounds according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         16 . A method of treating an infection, disease, or disorder in a mammal comprising the step of administering to the mammal an effective amount of one or more compounds according to  claim 1 , wherein the infection, disease, or disorder is selected from microbial infection, fungal infection, parasitic infection, proliferative disease, viral infection, inflammatory disease and gastrointestinal motility disorder. 
     
     
         17 . A method of treating a disorder in a mammal comprising the step of administering to the mammal an effective amount of one or more compounds according to  claim 1  thereby to ameliorate a symptom of the disorder, wherein the disorder is selected from the group consisting of:
 a skin infection, nosocomial pneumonia, post-viral pneumonia, an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant  Staphylococcus aureus  infection, a vancomycin-resistant Enterococci infection, a linezolid-resistant organism infection, and tuberculosis. 
 
     
     
         18 . A medical devise containing one or more compounds according to  claim 1 . 
     
     
         19 . A process for preparing a compound according to  claim 1 , comprising the step of reacting a compound of formula (I): 
       
         
           
           
               
               
           
         
         with a compound of formula (II): 
       
       
         
           
           
               
               
           
         
       
       in a solvent in the presence of a base and a palladium catalyst, wherein
 Q is a boronate having the formula —BY 2 , wherein 
 Y, at each occurrence, independently is selected from the group consisting of:
 a) —OH, and b) —O—C 1-4 alkyl, 
 
 alternatively, two Y groups taken together are selected from the group consisting of:
 a) —OC(R 4 )(R 4 )C(R 4 )(R 4 )O—, and b) —OC(R 4 )(R 4 )CH 2 (R 4 )(R 4 )O—, 
 
 alternatively, two Y groups taken together with the boron to which they are bound comprise a BF 3  alkali metal salt; 
 Z is selected from the group consisting of:
 a) I, b) Br, c) Cl, and d) R 4 OSO3-; and 
 
 A, B, L, M, R 1 , R 2 , R 3 , R 4 , m, and n are defined as described in  claim 1 .