IP Library › Granted Patent US 7,129,259

Granted Patent B2

US 7,129,259 · App. 11/001,446 · Granted Oct 31, 2006

Halogenated biaryl heterocyclic compounds and methods of making and using the same

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Quick Facts

Patent No.: US 7,129,259
App. No.: 11/001,446
Granted: Oct 31, 2006
Kind: B2

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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 at least one halogenated hydrocarbon moiety, a biaryl moiety, and at least one heterocyclic moiety, that are useful as such agents.

Claims (456)

1. A compound having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:

A is phenyl

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) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein

i) any of a)–c) is substituted with one or more moieties selected from the group consisting of F, Cl, Br, and I; and

ii) any of a)–c) optionally is further substituted with one or more R 4 groups;

X is selected from the group consisting of:

a) —O—, b) —NR 5 —, c) —N(O)—, d) —N(OR 5 )—, e) —S(O) p —, f) —NR 5 —N═, g) ═N—NR 5 —, h) —O—N═, i) ═N—O—, j) —N═, k) ═N—, l) —NR 5 —NR 5 —, m) —NR 5 C(O)O—, n) —OC(O)NR 5 —, o) —NR 5 C(O)NR 5 —, p) —NR 5 C(NR 5 )NR 5 —, and

L 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 4 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 7 , g) —CN, h) —NO 2 , i) —NR 7 R 7 , j) —C(O)R 7 , k) —C(O)OR 7 , l) —OC(O)R 7 , m) —C(O)NR 7 R 7 , n) —NR 7 C(O)R 7 , o) —OC(O)NR 7 R 7 , p) —NR 7 C(O)OR 7 , q) —NR 7 C(O)NR 7 R 7 , r) —C(S)R 7 , s) —C(S)OR 7 , t) —OC(S)R 7 , u) —C(S)NR 7 R 7 , v) —NR 7 C(S)R 7 , w) —OC(S)NR 7 R 7 , x) —NR 7 C(S)OR 7 , y) —NR 7 C(S)NR 7 , R 7 , z) —NR 7 C(NR 7 )NR 7 R 7 , aa) —S(O) p R 7 , bb) —SO 2 NR 7 R 7 , and cc) R 7 ;

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 7 , g) —CN, h) —NO 2 , i) —NR 7 R 7 , j) —C(O)R 7 , k) —C(O)OR 7 , l) —OC(O)R 7 , m) —C(O)NR 7 R 7 , n) —NR 7 C(O)R 7 , o) —OC(O)NR 7 R 7 , p) —NR 7 C(O)OR 7 , q) —NR 7 C(O)NR 7 R 7 , r) —C(S)R 7 , s) —C(S)R 7 , t) —OC(S)R 7 , u) —C(S)NR 7 R 7 , v) —NR 7 C(S)R 7 , w) —OC(S)NR 7 R 7 , x) —NR 7 C(S)OR 7 , y) —NR 7 C(S)NR 7 R 7 , z) —NR 7 C(NR 7 )NR 7 R 7 , aa) —S(O) p R 7 , bb) —SO 2 NR 7 R 7 , and cc) R 7 ;

R 3 is selected from the group consisting of:

a) —OR 7 , b) —NR 7 R 7 , c) —C(O)R 7 , d) —C(O)OR 7 , e) —OC(O)R 7 , f) —C(O)NR 7 R 7 , g) —NR 7 C(O)R 7 , h) —OC(O)NR 7 R 7 , i) —NR 7 C(O)OR 7 , j) —NR 7 C(O)NR 7 R 7 , k) —C(S)R 7 , l) —C(S)OR 7 , m) —OC(S)R 7 , n) —C(S)NR 7 R 7 , o) —NR 7 C(S)R 7 , p) —OC(S)NR 7 R 7 , q) —NR 7 C(S)OR 7 , r) —NR 7 C(S)NR 7 R 7 , s) —NR 7 C(NR 7 )NR 7 R 7 , t) —S(O) p R 7 , u) —SO 2 NR 7 R 7 , and v) R 7 ;

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

a) H, b) F, c) Cl, d) Br, e) I, f) ═O, g) ═S, h) ═NR 5 , i) ═NOR 5 , j) ═N—NR 5 R 5 , k) —CF 3 , l) —OR 5 , m) —CN, n) —NO 2 , o) —NR 5 R 5 , p) —C(O)R 5 , q) —C(O)OR 5 , r) —OC(O)R 5 , s) —C(O)NR 5 R 5 , t) —NR 5 C(O)R 5 , u) —OC(O)NR 5 R 5 , v) —NR 5 C(O)OR 5 , w) —NR 5 C(O)NR 5 R 5 , x) —C(S)R 5 , y) —C(S)OR 5 , z) —OC(S)R 5 , aa) —C(S)NR 5 R 5 , bb) —NR 5 C(S)R 5 , cc) —OC(S)NR 5 R 5 , dd) —NR 5 C(S)OR 5 , ee) —NR 5 C(S)NR 5 R 5 , ff) —NR 5 C(NR 5 )NR 5 , R 5 , gg) —S(O) p R 5 , and hh) R 5 ;

R 5 , 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(O)—C 1-6 alkyl, f) —C(O)—C 2-6 alkenyl, g) —C(O)—C 2-6 alkynyl, h) —C(O)O—C 1-6 alkyl, i) —C(O)O—C 2-6 alkenyl, and j) —C(O)O—C 2-6 alkynyl,

wherein any of b)–j) optionally is substituted with one or more R 6 groups;

R 6 , at each occurrence, independently is selected from the group consisting of:

a) F, b) Cl, c) Br, d) I, e) —CF 3 , f) —OH, g) —OC 1-6 alkyl, h) —SH, i) —SC 1-6 alkyl, j) —CN, k) —NO 2 , l) —NH 2 , m) —NHC 1-6 alkyl, n) —N(C 1-6 alkyl) 2 , o) —C(O)C 1-6 alkyl, p) —C(O)OC 1-6 alkyl, q) —C(O)NH 2 , r) —C(O)NHC 1-6 alkyl, s) —C(O)N(C 1-6 alkyl) 2 , t) —NHC(O)C 1-6 alkyl, and u) —S(O) p C 1-6 alkyl;

R 7 , 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 consisting 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 consisting 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 consisting 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 8 groups;

R 8 , 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 9 , h) ═NOR 9 , i) ═N—NR 9 R 9 , j) —CF 3 , k) —OR 9 , l) —CN, m) —NO 2 , n) —NR 9 R 9 , o) —C(O)R 9 , p) —C(O)OR 9 , q) —OC(O)R 9 , r) —C(O)NR 9 R 9 , s) —NR 9 C(O)R 9 , t) —OC(O)NR 9 R 9 , u) —NR 9 C(O)OR 9 , v) —NR 9 C(O)NR 9 R 9 , w) —C(S)R 9 , x) —C(S)OR 9 , y) —OC(S)R 9 , z) —C(S)NR 9 R 9 , aa) —NR 9 C(S)R 9 , bb) —OC(S)NR 9 R 9 , cc) —NR 9 C(S)OR 9 , dd) —NR 9 C(S)NR 9 R 9 , ee) —NR 9 C(NR 9 )NR 9 R 9 , ff) —S(O) p R 9 , gg) —SO 2 NR 9 R 9 , and hh) R 9 ;

R 9 , 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 consisting 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)—C3–14 membered saturated, unsaturated, or aromatic heterocycle consisting 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 consisting 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:

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 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 , X, m, and n are defined as described in claim 1 .

3. 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 , X, m, and n are defined as described in claim 1 .

4. The compound according to claim 1 , wherein

A is phenyl

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 R 2 is selected from the group consisting of H and F, and n is 0, 1, or 2.

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 5 , wherein A-B is:

wherein A 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 —NR 7 C(O)R 7 .

11. The compound according to claim 1 , wherein R 3 is —NHC(O)R 7 .

12. The compound according to claim 10 , wherein R 7 is C 1-6 alkyl, optionally substituted with one or more substituents independently selected from F or Cl.

13. The compound according to claim 10 wherein R 7 is selected from the group consisting of —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CHFCl, —CF 2 Cl, and —CFCl 2 .

14. The compound according to claim 13 , wherein R 7 is —CH 3 .

15. The compound according to claim 1 , wherein R 3 is:

16. 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 , X, m, and n are defined as described in claim 1 .

17. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , R 3 , X, and m are defined as described in claim 1 , A is selected from the group consisting of H and F, and n is 0, 1, or 2.

18. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , R 3 , X, and m are defined as described in claim 1 .

19. The compound according to claim 18 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , X, and m are defined as described in claim 1 .

20. The compound according to claim 18 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, R 3 , and X are defined as described in claim 1 .

21. The compound according to claim 20 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, and X are defined as described in claim 1 .

22. The compound according to claim 1 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , R 3 , X, and m are defined as described in claim 1 .

23. The compound according to claim 22 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein A, L, M, R 1 , X, and m are defined as described in claim 1 .

24. The compound according to claim 22 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M, R 3 , and X are defined as described in claim 1 .

25. The compound according to claim 24 , having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein L, M and X are defined as described in claim 1 .

26. The compound according to claim 1 , wherein L is C 1-6 alkyl.

27. The compound according to claim 26 , wherein L is —CH 2 —.

28. The compound according to claim 1 , wherein X is selected from the group consisting of-NR 5 —, —N(O)—, and —N(OR 5 )—, and R 5 is selected from the group consisting of H and C 1-6 alkyl.

29. The compound according to claim 1 , wherein X is —NR 5 —, and R 5 is selected from the group consisting of H and C 1-6 alkyl.

30. The compound according to claim 29 , wherein X is —NH—.

31. The compound according to claim 29 , wherein X is —NC 1-6 alkyl, wherein the C 1-6 alkyl group is substituted with one or more moieties selected from the group consisting of F, Cl, Br, and I.

32. The compound according to claim 1 , wherein M is C 1-6 alkyl substituted with one or more moieties selected from the group consisting of F, Cl, Br, and I.

33. The compound according to claim 32 , wherein M is C 1-6 alkyl substituted with one or more F atoms.

34. The compound according to claim 33 , wherein M is —CH 2 CH 2 CH 2 F.

35. The compound according to claim 1 , wherein M is —CH 2 CH(OH)CH 2 F.

36. A compound having a structure corresponding to any one of the compounds listed below:

Compound Number

Structure

or a pharmaceutically acceptable salt, ester or prodrug thereof.

37. A pharmaceutically acceptable salt of a compound corresponding to any one of the compounds according to claim 36 .

38. A pharmaceutically acceptable salt according to claim 37 wherein the compound corresponds to any one of compounds 1–12, 20–22, 24–42, 44–49, and 53–81 listed below:

Compound

Number

Structure

39. A pharmaceutically acceptable salt according to claim 38 , wherein said salt is a monohydrochloride salt.

40. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier.

41. A compound having the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:

A is phenyl

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) C 1-6 alkyl, b) C 2-6 alkenyl, and c) C 2-6 alkynyl,

wherein

i) any of a)–c) is substituted with one or more moieties selected from the group consisting of F, Cl, Br, and I; and

ii) any of a)–c) optionally is further substituted with one or more R 4 groups;

X is selected from the group consisting of:

L 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 4 groups;

R 1 , at each occurrence, independently is selected from the group consisting of:

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 7 , g) —CN, h) —NO 2 , i) —NR 7 R 7 , j) —C(O)R 7 , k) —C(O)OR 7 , l) —OC(O)R 7 , m) —C(O)NR 7 R 7 , n) —NR 7 C(O)R 7 , o) —OC(O)NR 7 R 7 , p) —NR 7 C(O)OR 7 , q) NR 7 C(O)NR 7 R 7 , r) —C(S)R 7 , s) —C(S)R 7 , t) —OC(S)R 7 , u) —C(S)NR 7 R 7 , v) —NR 7 C(S)R 7 , w) —OC(S)NR 7 R 7 , x) —NR 7 C(S)OR 7 , y) —NR 7 C(S)NR 7 R 7 , z) —NR 7 C(NR 7 )NR 7 R 7 , aa) —S(O) p R 7 , bb) —SO 2 NR 7 R 7 , and cc) R 7 ;

R 3 is selected from the group consisting of:

a) —NR 7 R 7 , b) —C(O)R 7 , c) —C(O)OR 7 , d) —OC(O)R 7 , e) —C(O)NR 7 R 7 , f) —NR 7 C(O)R 7 , g) —OC(O)NR 7 R 7 , h) —NR 7 C(O)OR 7 , i) —NR 7 C(O)NR 7 R 7 , j) —C(S)R 7 , k) —C(S)OR 7 , l) —OC(S)R 7 , m) —(S)NR 7 R 7 , n) —NR 7 C(S)R 7 , o) —OC(S)NR 7 R 7 , p) —NR 7 C(S)OR 7 , q) —NR 7 C(S)NR 7 R 7 , r) —NR 7 C(NR 7 )NR 7 R 7 , s) —SOR 7 , t) SO 2 R 7 , u)—SO 2 NR 7 R 7 , and v) R 7 ;