Biaryl heterocyclic compounds and methods of making and using the same

1. A compound having the formula:

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

A is phenyl;

B is 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 heteroatoms;

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 —, and 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, and d) ;

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

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

R 3 is —NR 4 C(O)R 4 ;

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

a) H, and 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)OR 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, and 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, and 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.

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 phenyl;

B is phenyl;

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 R 3 is —NHC(O)R 4 .

10. The compound according to claim 9 , wherein R 4 is —CH 3 .

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

12. 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 , and m are defined as described in claim 1 .

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

or a pharmaceutically acceptable salt, ester or prodrug thereof,

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

15. The compound according to claim 14 , wherein R 3 is —NHC(O)CH 3- .

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

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

or a pharmaceutically acceptable salt, ester or prodrug thereof,

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

19. The compound according to claim 18 , wherein R 3 is —NHC(O)CH 3 .

20. The compound according to claim 1 , wherein

M—L is M—L 1 —X—L 2 , and

X is —NR 4 —.

21. The compound according to claim 20 , wherein X is —NH—.

22. The compound according to claim 20 , wherein X is:

23. The compound according to claim 20 , wherein

L 1 is C 1-6 alkyl, and

L 2 is C 1-6 alkyl.

24. The compound according to claim 23 , wherein

L 1 is —CH 2 —, and

L 2 is —CH 2 —.

25. The compound according to claim 20 , wherein M—L is:

M—CH 2 —NH—CH 2 —.

26. The compound according to claim 20 , wherein M—L is:

27. The compound according to claim 1 , wherein M is selected from the group consisting of:

a) pytrolyl, b) imidazolyl, c) pyrazolyl, d) triazolyl, e) tetrazolyl,

wherein any of a)-e) optionally is substituted with one or more R 5 groups.

28. The compound according to claim 27 , wherein M is [1, 2, 3]triazol-l-yl.

29. The compound according to claim 27 , wherein M is 3H-[1, 2, 3]triazol-4-yl.

30. The compound according to claim 27 , wherein M is 1H-tetrazol-5-yl.

31. A compound having the structure corresponding to any one of the structures listed below,

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

32. A pharmaceutical composition comprising one or more compounds according to claim 1 or claim 31 and a pharmaceutically acceptable carrier.

33. A method of treating a microbial infection in a mammal comprising the step of administering to the mammal an effective amount of one or more compounds according to claim 1 or claim 31 .

34. 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 or claim 31 thereby to ameliorate a symptom of the disorder, wherein the disorder is selected from the group consisting of:

a skin infection, nosocomial pheumonia, post-viral pneumonia, an abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meniagitis, surgical prophyfaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aurens infection, a vancomycin-resistant Exterococci infection, a linezolid-resistant organism infection, and tuberculosis.

35. The method according to claim 33 , wherein the compound is administered orally, parentally, or topically.

36. 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 C(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 OSO 3 —; and

A, B, L, M, R 1 , R 2 , R 3 , R 4 , m, and n are defined as described in claim 1 .

37. The process according to claim 36 , wherein Z is 1.

38. The process according to claim 36 , wherein Q is —BF 2 —KF.

39. The process according to claim 36 , wherein Q is:

40. The process according to claim 36 , wherein the base is selected from the group consisting of an alkali metal hydroxide, an alkali metal carbonate, an alkali metal fluoride, a trialkyl amine, and mixtures thereof.

41. The process according to claim 40 , wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium fluoride, triethylamine, diisopropylethylamine, and mixtures thereof.

42. The process according to claim 40 , wherein the ratio of equivalents of base to equivalents of compound of formula (I) is about 3:1.

43. The process according to claim 36 , wherein the palladium catalyxt is a ligand coordinated palladium (O) catalyst.

44. The process according to claim 43 , wherein the palladium catalyst is a tetrakis (trialkylphosphine) palladium (O) or a tetrakis (triarylphosphine) palladium (O) catalyst.

45. The process according to claim 44 , wherein the palladium catalyst is tetrakis (triphenylphosphine) palladium (O).

46. The process according to claim 43 , wherein the ratio of the equivalents of palladium catalyst to the equivalents of compound (I) is about 1:20.

47. The process according to claim 36 , wherein the solvent comprises an aqueous solvent.

48. The process according to claim 36 , wherein the solvent comprises a mixture of water and an organic solvent, wherein the organic solvent is selected from the group consisting of:

methanol, ethanol, propanol, isopropanol, butanol, isobutanol, secondary butanol, tertiary butanol, benzene, toluene, tetrahydrofuran, dimethylformamide, 1, 2-diethyl ether, dimethoxyethane, diisopropyl ether, methyltertiarybutyl ether, methoxymethyl ether, 2-methoxyethyl ether, 1, 4-dioxane, 1, 3-dioxolane, and mixtures thereof.

49. The process according to claim 48 , wherein the solvent comprises a mixture of water, toluene, and ethanol.

50. The process according to claim 49 wherein the solvent comprises a mixture of water, toluene, and ethanol in a ratio of about 1:3:1 by volume.

51. The process according to claim 36 , wherein the process is carried out at a temperature between about 20° C. and about 100° C.

52. The process according to claim 36 , wherein the process is carried out at the reflux temperature of the solvent.

53. A compound having the structure

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

54. A compound having the structure

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

55. A compound having the structure

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

56. A compound having the structure

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

57. A compound having the structure

or pharmaceutically acceptable salt, ester, or prodrug thereof.

58. A compound having the structure

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

59. A compound having the structure

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

60. A compound having the structure

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

61. A compound having the structure

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

62. A compound having the structure

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

63. A compound having the structure

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

64. A compound having the structure

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

65. A compound having the structure

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

66. A compound having the structure

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

67. A compound having the structure

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

68. A compound having the structure

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

69. A compound having the structure

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

70. A compound having the structure

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

71. A compound having the structure

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

72. A compound having the structure

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

73. A compound having the structure

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

74. A compound having the structure

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

75. A compound having the structure

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

76. A compound having the structure

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

77. A compound having the structure

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

78. A compound having the structure

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

79. A compound having the structure

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

80. A compound having the structure

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

81. A compound having the structure

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

82. A compound having the structure

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

83. A compound having the structure

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

84. A compound having the structure

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

85. A compound having the structure

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

86. A compound having the structure

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

87. A compound having the structure

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

88. A compound having the structure

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

89. A compound having the structure

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

90. A compound having the structure

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

91. A compound having the structure

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

92. A compound having the structure

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

93. A compound having the structure

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

94. A compound having the structure

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

95. A compound having the structure

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

96. A compound having the structure

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

97. A compound having the structure

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

98. A compound having the structure

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

99. A compound having the structure

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

100. A compound having the structure

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

101. A compound having the structure

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

102. A compound having the structure

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

103. A compound having the structure

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

104. A compound having the structure

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