Biaryl heterocyclic compounds and methods of making and using the same

1. A topical formulation comprising one or more dermatologically acceptable carriers and one or more compounds having the formula:

or a pharmaceutically acceptable salt, ester, tautomer 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 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

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, 1) —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.

2. The formulation according to claim 1 , wherein:

A is a phenyl;

B is a phenyl;

Het-CH 2 —R 3 is:

M is a 5-membered unsaturated heterocycle containing one or more nitrogen heteroatoms optionally substituted with one or more R 5 groups, wherein the heterocycle contains only nitrogen atoms;

M-L is M-L 1 -X-L 2 , wherein

X, at each occurrence, independently is selected from the group consisting of:

a) —NR 4 —, b) —SO 2 NR 4 —

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;

R 2 , at each occurrence, independently is selected from the group consisting of:

a) F, b) Cl, c) Br, d) I;

R 3 is —NR 4 C(O)R 4 ;

R 4 , at each occurrence, independently is selected from the group consisting of:

a) H, b) C 1-6 alkyl;

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) —CF 3 , h) —CN, i) —NO 2 , j) —NR 6 R 6 , k) —C(O)R 6 , l) —C(O)NR 6 R 6 , m) —S(O) p R 6 , and n) 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,

wherein any of b)-d) 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) ═NR 8 , f) —CF 3 , g) —OR 8 , h) —CN, i) —NO 2 , j) —NR 8 R 8 , k) —C(O)R 8 , and l) —C(O)OR 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,

wherein any of b)-d) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, —CF 3 , and —OH;

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.

3. The formulation according to claim 2 , wherein said compound has the formula:

or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.

4. A method of treating, preventing, or reducing the risk of a skin infection in a patient comprising administering an effective amount of the topical formulation of claim 1 .

5. The method according to claim 4 , wherein said compound has the formula:

or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.

6. The method according to claim 5 , wherein said compound has the formula:

or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.

7. The method according to claim 4 , 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.

8. The method according to claim 4 , wherein A-B is:

9. The method according to claim 8 , wherein A-B is:

10. The method according to claim 4 , wherein A-B is:

11. The method according to claim 4 , wherein R 3 is —NHC(O)R 4 .

12. The method according to claim 11 , wherein R 4 is —CH 3 .

13. The method according to claim 1 , wherein R 3 is:

14. The method according to claim 4 , wherein said compound has the formula:

or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.

15. The method according to claim 4 , wherein said compound has the formula:

or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.

16. The method of claim 4 , wherein:

A is a phenyl;

B is a phenyl;

Het-CH 2 —R 3 is:

M is a 5-membered unsaturated heterocycle containing one or more nitrogen heteroatoms optionally substituted with one or more R 5 groups, wherein the heterocycle contains only nitrogen atoms;

M-L is M-L 1 -X-L 2 , wherein

X, at each occurrence, independently is selected from the group consisting of:

a) —NR 4 —, b) —SO 2 NR 4 —

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;

R 2 , at each occurrence, independently is selected from the group consisting of:

a) F, b) Cl, c) Br, d) I;

R 3 is —NR 4 C(O)R 4 ;

R 4 , at each occurrence, independently is selected from the group consisting of:

a) H, b) C 1-6 alkyl;

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) —CF 3 , h) —CN, i) —NO 2 , j) —NR 6 R 6 , k) —C(O)R 6 , l) —C(O)NR 6 R 6 , m) —S(O) p R 6 , and n) 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,

wherein any of b)-d) 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) ═NR 8 , f) —CF 3 , g) —OR 8 , h) —CN, i) —NO 2 , j) —NR 8 R 8 , k) —C(O)R 8 , and l) —C(O)OR 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,

wherein any of b)-d) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, —CF 3 , and —OH;

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.

17. A method of treating, preventing, or reducing the risk of a skin infection in a patient comprising administering an effective amount of the topical formulation of claim 1 , wherein the compound has the formula:

or a pharmaceutically acceptable salt, ester, tautomer or prodrug thereof.