1. A compound of formula (I): or a pharmaceutically acceptable salt and/or prodrug thereof, wherein X is O, NR7 or CR7R8; Y is O or S; Z is NR19, O or S; Het is heterocyclyl or heteroaryl; R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1- 6alkyl, amino-C1-6alkyl, -O-C(O)-O-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl; and R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; or R1a and R1b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl; R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1- 6alkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl; R2b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; or R2a and R2b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl; R3 is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and -(CH2)-C(O)OR9; R4 is selected from heteroaryl, alkyl, -C(O)OR9, -C(O)NR11R12, -S(O)2R10, -P(O)(OR11)(OR12), and -P(O)(OR11)(NR13R15); R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9; R6 is selected from -C(O)OR9 and -P(O)(OR11)(OR12); each R7 and R8 is H R9 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and -(CHR13)m-Z-C(O)-R14; each R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and each R11 and R12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and -(CHR13)m-Z-C(O)-R14; or R11 and R12, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl; and each R13 is independently H or alkyl; each R14 is independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl; R15 is selected from alkyl, aralkyl,–C(R16)(R17)-C(O)O-R18; each R16 and R17 are selected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and -(CH2)C(O)OR9; R18 is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; R19 is H or alkyl, preferably H; and m is 1 or 2; provided that either R4 is tetrazolyl, or R5 is aralkyl or heteroaralkyl, or both.

2. The compound of claim 1, wherein R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2- 6alkenyl, and C2-6alkynyl.

3. The compound of claim 1, wherein R1a is fluoro.

4. The compound of claim 1, wherein R1a is chloro.

5. The compound of claim 1, wherein R1a is bromo.

6. The compound of claim 1, wherein R1a is C1-6alkoxy.

7. The compound of claim 1, wherein R1a is C1-6alkyl.

8. The compound of claim 1, wherein R1a is hydroxy.

9. The compound of claim 1, wherein R1a is cyano.

10. The compound of claim 1, wherein R1a is azido.

11. The compound of claim 1, wherein R1a is amino.

12. The compound of claim 1, wherein R1a is vinyl.

13. The compound of claim 1, wherein R1a is ethynyl.

14. The compound of claim 1, wherein R1a is hydrogen.

15. The compound of claim 1, wherein R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2- 6alkenyl, and C2-6alkynyl.

16. The compound of any preceding claim, wherein R2a is fluoro.

17. The compound of any one of claims 1-14, wherein R2a is chloro.

18. The compound of any one of claims 1-14, wherein R2a is bromo.

19. The compound of any one of claims 1-14, wherein R2a is C1-6alkoxy. 20. The compound of any one of claims 1-14, wherein R2a is C1-6alkyl. 21. The compound of any one of claims 1-14, wherein R2a is hydroxy. 22. The compound of any one of claims 1-14, wherein R2a is cyano. 23. The compound of any one of claims 1-14, wherein R2a is azido.

24. The compound of any one of claims 1-14, wherein R2a is amino. 25. The compound of any one of claims 1-14, wherein R2a is vinyl.

26. The compound of any one of claims 1-14, wherein R2a is ethynyl. 27. The compound of any one of claims 1-14, wherein R2a is C1-6acyloxy. 28. The compound of any preceding claim, wherein R1b is H.

29. The compound of any one of claims 1-28, wherein R1b is fluoro. 30. The compound of any one of claims 1-28, wherein R1b is C1-6alkyl. 31. The compound of any preceding claim, wherein R2b is H.

32. The compound of any one of claims 1-30, wherein R2b is fluoro. 33. The compound of any one of claims 1-30, wherein R2b is C1-6alkyl. 34. The compound of claim 1, wherein R1a is fluoro and R1b is H.

35. The compound of claim 1, wherein R2a is fluoro and R2b is H.

36. The compound of claim 1, wherein R1a and R1b are each fluoro.

37. The compound of claim 1, wherein R2a and R2b are each fluoro.

38. The compound of claim 1, wherein R1a is fluoro and R2a is C1-6alkoxy.

39. The compound of claim 1, wherein R1a is fluoro and R2a is C1-6alkyl.

40. The compound of claim 1, wherein R1a is fluoro and R2a is methyl or ethyl.

41. The compound of claim 1, wherein R1a is hydroxy and R2b is methyl.

42. The compound of claim 1, wherein R1a is fluoro and R2a is hydroxy.

43. The compound of claim 1, wherein R1a is chloro and R2a is hydroxy.

44. The compound of claim 1, wherein R1a is hydroxy and R2a is hydrogen.

45. The compound of claim 1, wherein R1a is fluoro and R2a is hydrogen.

46. The compound of claim 1, wherein R1a is hydroxy and R2a is C1-6alkoxy.

47. The compound of claim 1, wherein R1a is hydroxy and R2a is fluoro.

48. The compound of claim 1, wherein R1a is hydroxy and R2a and R2b, together with the carbon atom to which they are attached, form an ethynyl.

49. The compound of claim 1, wherein R1a is hydroxy and R2a is C1-6alkyl.

50. The compound of claim 1, wherein R1a is fluoro, R2a is fluoro and R2a is hydroxy.

51. The compound of claim 1, wherein R1a is hydroxy and R2a is hydroxyl and R2b is C1-6alkynyl.

52. The compound of claim 1, wherein R1a is hydroxy and R2a is C1-6alkynyl.

53. The compound of claim 1, wherein R1a is hydroxy and R2a is C2-6alkenyl.

54. The compound of claim 1, wherein R1a is hydroxy and R2a is amino.

55. The compound of claim 1, wherein R1a is hydroxy and R2a is azido.

56. The compound of claim 1, wherein R1a is azido and R2a is hydroxy.

57. The compound of claim 1, wherein R1a is C1-6alkyl and R2a is hydroxyl.

58. The compound of any preceding claim, having the structure: .

59. The compound of any preceding claim, wherein R1a is in the α-configuration.

60. The compound of claim 59, wherein the compound of Formula (I) has the structure (IA): . (IA)

61. The compound of any one of claims 1-58, wherein R1a is in the β-configuration.

62. The compound of claim 61, wherein the compound of Formula (I) has the structure (IB): .

63. The compound of any preceding claim, wherein R2a is in the α-configuration.

64. The compound of claim 63, wherein the compound of Formula (I) has the structure (IC): . (IC)

65. The compound of any one of claims 1-62, wherein R2a is in the β-configuration.

66. The compound of claim 65, wherein the compound of Formula (I) has the structure (ID): . (ID)

67. The compound of claim 68, wherein the compound of Formula (I) has the structure (IE): . (IE)

68. The compound of any preceding claim, wherein R3 is H.

69. The compound of any one of claims 1-67, wherein R3 is unsubstituted C1-6alkyl.

70. The compound of any one of claims 1-67, wherein R3 is alkyl, and the alkyl is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.

71. The compound of claim 70, wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

72. The compound of any preceding claim, wherein R3 is in the R-configuration.

73. The compound of any one of claims 1-69, wherein R3 is in the S-configuration.

74. The compound of any preceding claim, wherein R4 is heteroaryl.

75. The compound of any preceding claim, wherein R4 is tetrazolyl.

76. The compound of any preceding claim, wherein R4 is selected from -C(O)OR9, -C(O)NR11R12, -S(O)2R10, and -P(O)(OR11)(OR12).

77. The compound of any preceding claim, wherein R4 is -C(O)OR9.

78. The compound of any one of claims 1-73, wherein R4 is alkyl.

79. The compound of any one of claims 1-74, wherein R4 is -C(O)NR11R12.

80. The compound of any preceding claim, wherein R5 is selected from alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, and each is unsubstituted or substituted with one or more substituents, selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl, heterocyclyl, arylalkyl and heteroarylalkyl.

81. The compound of claim 80, wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

82. The compound of any preceding claim, wherein R5 is selected from H, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl.

83. The compound of any preceding claim, wherein R5 is H, aralkyl, or heteroaralkyl.

84. The compound of any preceding claim, wherein R5 is H or aralkyl.

85. The compound of any one of claims 1-83, wherein R5 is aralkyl or heteroaralkyl.

86. The compound of claim 85, wherein R5 is heteroaralkyl, wherein the heteroaryl ring is selected from benzofuranyl, benzothienyl, benzothiazolyl, pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl, and oxazolyl, and oxadiazolyl, each of which may be substituted or unsubstituted.

87. The compound of any one of claims 85-86, wherein R5 is unsubstituted or substituted with one or more substituents selected from halo, CN, OH, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl.

88. The compound of claim 87, wherein the substituents are selected from halo, CN, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, and aryl.

89. The compound of claim 87, wherein the substituents are selected from tetrazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.

90. The compound of any one of claims 1-83, wherein R5 is CH2-pyridinyl.

91. The compound of any one of claims 1-83, wherein R5 is -CH2-thiophenyl.

92. The compound of any one of claims 1-83, wherein R5 is benzyl or β-naphthyl.

93. The compound of claim 87, wherein R5 is unsubstituted or substituted with one or more substituents, selected from chloro, trifluoromethyl, trifluoromethoxy, phenyloxy, dimethylamido, methylsulfonyl, CN, and carboxylic acid.

94. The compound of any preceding claim, wherein R6 is -C(O)OR9.

95. The compound of any one of claims 1-93, wherein R6 is -P(O)(OR11)(OR12), and R11 and R12 are each H.

96. The compound of any preceding claim, wherein R7 is H or C1-6alkyl.

97. The compound of any preceding claim, wherein R8 is H.

98. The compound of any preceding claim, wherein R9 is H, C1-6alkyl or amido.

99. The compound of any preceding claim, wherein R9 is H, methyl or ethyl.

100. The compound of any preceding claim, wherein R11 and R12 are each H.

101. The compound of any one of claims 1-99, wherein R11 and R12 are each alkyl.

102. The compound of any one of claims 1-95, wherein each R7, R8, R9, R10, R11 and R12 is independently selected from alkyl, alkenyl, alkynyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and each is unsubstituted or substituted, with one or more selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.

103. The compound of claim 102, wherein the substituents on each R7, R8, R9, R10, R11 and R12 are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

104. The compound of any preceding claim, wherein X is O.

105. The compound of any preceding claim, wherein Y is O.

106. The compound of any preceding claim, wherein the Y-bearing substituent is in the R-configuration.

107. The compound of any one of claims 1-105, wherein the Y-bearing substituent is in the S-configuration.

108. The compound of any preceding claim, wherein Z is O.

109. The compound of any preceding claim, wherein Het is a nitrogen-containing heterocyclyl or heteroaryl.

110. The compound of any preceding claim, wherein Het is attached via a nitrogen atom.

111. The compound of any one of claims 1-107, wherein Het is attached via a carbon atom.

112. The compound of any preceding claim, wherein Het is a 5- to 8-membered monocyclic or 5- to 10-membered bicyclic heteroaryl and is unsubstituted or substituted, with one or more substituents selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.

113. The compound of claim 112, wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.

114. The compound of any preceding claim, wherein Het is selected from purinyl, imidazopyrimidinyl, and pyrrolopyrimidinyl.

115. The compound of any preceding claim, wherein Het is substituted with one halo and one amino substituent.

116. The compound of any one of claims 1-110, wherein Het is .

117. The com ound of claim 1 wherein Het is selected from .

118. The compound of claim 1, wherein Het is substituted with one or two substituents selected from halo, aralkyl, amino, azido and hydroxy.

119. The compound of claim 118, wherein Het is selected from

120. The compound of claim 1, wherein

121. The compound of claim 1, wherein , , ,

122. The compound of claim 1, wherein represents where each RA is independently selected from H, halo, CN, OH, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl; and k is 1, 2, or 3.

123. The compound of claim 122, wherein RA is selected from pyridyl, pyrazolyl, pyrrolidinonyl, azapanonyl, morpholinonyl, piperazonyl, tetrahydropyrimidinonyl, phenyl, and benzyloxy.

124. The compound of claim 1, having the structure: wherein: R5 is: (i) phenylC1-6alkyl or naphthylC1-6alkyl wherein phenyl and naphthyl are optionally substituted with one, two, or three substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,– COOC1-6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1- 6alkylene-CO2C1-6alkyl, or -C1-6alkylene- substituted with one or two substituents independently selected from hydroxy, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1- 6alkylene-heterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,– COheterocyclyl,–CONRmRi,–CONRmC1-6alkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and–CONHSO2Rz; or (ii) 5-10 membered heteroarylC1-6alkyl having one to three heteroatoms independently selected from N, O, or S and 5-10 membered heteroaryl in 5-10 membered heteroarylC1-6alkyl is optionally substituted with one or two substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,–COOC1-6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two hydroxyl, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1- 6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,– COheterocyclyl,–CONRmRi,–CONRmalkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and–CONHSO2Rz; and the R55-10 membered heteroaryl ring is additionally optionally substituted with an additional substituent selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy; wherein: each Rm is hydrogen or -C1-6alkyl; Ro, Rp, and Ry are each independently hydrogen or -C1-6alkyl; Rz is -C1-6alkyl, -NHC1-6alkyl, or–N(C1-6alkyl)2; phenyl by itself or as part of -C1-6alkylenephenyl, phenoxy, or -OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1- 6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2; each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, and -C1-6alkylene-CO2C1-6alky, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, - SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2l; heterocyclyl by itself or as part of -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, - NRmCOC1-6alkylene-heterocyclyl,–COheterocyclyl, or -NRmCOheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, or -C1-6alkyl (substituted with hydroxy or -OC1- 6alkyl); and Het is a group selected from a group of formula (i) through (xvi) below: wherein: Ru is hydrogen, halo, cyano, -NH2, -NHR20, -NHCOR20, -NR20R21, -R20, -SR20, -OH, and -OR20; Rw is hydrogen, halo, -NHR22, -NR22R23, -R22, -OH, and -OR22; Rv and Rx are independently hydrogen, halo, haloC1-6alkyl, -NH2, -NHR24, -NR24R25, -R24, -SR24, cyano, -OH, -OR24, -SO2R24, -C1-6alkyleneNH2, -C1-6alkyleneNHR24, -C1-6alkyleneNR24R25, -R24, -C1-6alkyleneSR24, -C1-6alkyleneOH, -C1-6alkyleneOR24, -C1- 6alkyleneSO2R24, Rs and Rt are independently hydrogen, halo, or C1-6alkyl; and wherein: R20, R21, R22, R23, R24 and R25 are independently optionally substituted C1-6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21, R22 and R23, and R24 and R25 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl; and further wherein, unless otherwise specified: C1-6alkyl is unsubstituted; C1-6alkyl of C1-6alkyloxy is unsubstituted; haloC1-6alkyl is C1-6alkyl substituted with one to five halo atoms; haloC1-6alkyloxy is C1-6alkyloxy substituted with one to five halo atoms; C2-6alkenyl is unsubstituted; C2-6alkynyl is unsubstituted; C1-6alkylene is unsubstituted; C2-6alkenylene is unsubstituted; optionally substituted C1-6alkyl is optionally substituted with one or two substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; carbocyclyl is an unsubstituted saturated or partially unsaturated mono or bicyclic ring containing 3 to 10 carbon atoms; optionally substituted carbocyclyl is optionally substituted with one, two, or three substituents independently selected from C1-6alkyl, halo, hydroxy, or C1-6alkoxy; optionally substituted aryl is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH( C1-6alkyl), -N(C1-6alkyl)2; aryl is phenyl or naphthyl; optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(unsubstitued C1-6alkyl)2]; heteroaryl is an unsubstituted five to ten membered or five to six membered aromatic ring containing one to four or one to three heteroatoms independently selected from N, O, and S; the remaining ring atoms being carbon; optionally substituted heteroaryl is a five to ten membered aromatic ring containing one to four heteroatoms independently selected from N, O, and S; the remaining ring atoms being carbon, that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, unsubstituted C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2]; heterocyclyl is an unsubstituted monocyclic, saturated or partially unsaturated 4 to 8 membered ring containing one to three heteroatoms independently selected from N, O, S, SO, and SO2 and optionally contains one or two CO, the remaining atoms in the ring being carbon that is optionally fused to phenyl or 5 to 6 membered carbocyclyl or 5 or 6 heteroaryl ring; nitrogen-containing heterocyclyl is a heterocyclyl ring that has at least a nitrogen atom; optionally substituted heterocyclyl is heterocyclyl that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2]; optionally substituted carbocyclyl C1-6alkyl is optionally substituted carbocyclyl attached via C1-6alkyl; optionally substituted heterocyclylC1-6alkyl is optionally substituted heterocyclyl attached via C1-6alkyl; optionally substituted arylC1-6alkyl is optionally substituted aryl attached via C1-6alkyl; and optionally substituted heteroarylC1-6alkyl is optionally substituted heteroaryl attached via C1- 6alkyl;

125. The compound of claim 124 having the structure: .

126. The compound of claim 124 or 125 wherein: R5 is phenylC1-6alkyl wherein phenyl is optionally substituted with one or two substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1- 6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two– OC1-6alkyl), -CO2H,–COOC1-6alkyl, halo, hydroxy, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, - C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1- 6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, phenoxy, benzyl, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1- 6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1- 6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1- 6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkylene-heterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCO-heterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi,–CONRmalkylene-Ri, and– CONHSO2Rz ; and additionally the R5 phenyl is optionally substituted with an additional substituent selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxyl; wherein: phenyl by itself or as part of phenoxy, benzyl, or -OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2.

127. The compound of claim 124 or 125 wherein: R5 is benzyl wherein phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached -CH2- group of the benzyl ring and which one substituent is selected from–C1-6alkyl,–OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1- 6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -CO2H,–COOC1-6alkyl, halo, hydroxy, cyano, nitro, -PO3H2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1- 6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxy, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1- 6alkyl), phenyl, phenoxy, benzyl, benzyloxy, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1- 6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkylene-heterocyclyl, -SC1-6alkylene-heterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi, and –CONRmalkylene-Ri; and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy; wherein phenyl by itself or as part of benzyl, phenoxy, or benzyloxy is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H, –COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1- 6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2.

128. The compound of claim 124 or 125 wherein: R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached to the -CH2- group of the benzyl ring, which one substituent is selected from -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkyl substituted with hydroxy, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1- 6alkylene-CO2C1-6alkyl, -CO2H, nitro,–COOC1-6alkyl, halo, hydroxy, cyano, -CONReRf (where Re is hydrogen or -C1-6alkyl and Rf is -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, -NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg is hydrogen or -C1-6alkyl and Rh is hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl or isoxazolyl (wherein each of the aforementioned heteroaryl ring is optionally substituted with one or two substituents independently selected from C1-6alkyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2; and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

129. The compound of claim 124 or 125 wherein: R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached to -CH2- group of the benzyl ring, with phenyl, benzyl, benzyloxy, or phenoxy [wherein the phenyl ring in each of aforementioned group is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1- 6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1- 6alkyl)2]; and R5 phenyl is further optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

130. The compound of claim 124 or 125 wherein: R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached to -CH2- group of the benzyl ring, with haloC1-6alkoxy or haloC1-6alkyl, and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

131. The compound of claim 124 or 125 wherein: R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the benzyl ring that is attached to the -CH2- group of the benzyl ring with -CO2H and the benzyl ring and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

132. The compound of claim 124 or 125 wherein: R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the benzyl ring that is attached to the -CH2- group of the benzyl ring with -CO2Me or -CO2ethyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

133. The compound of claim 124 or 125 wherein: R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the benzyl ring that is attached to the -CH2- group of the benzyl ring with tetrazolyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

134. The compound of claim 124 or 125 wherein: R5 is–CH2- or–(CH2)2-5-10 membered heteroaryl having one to three heteroatoms independently selected from N, O, or S and the heteroaryl ring is optionally substituted with one substituent, independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,–COOC1- 6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1- 6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1- 6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi,– CONRmalkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and–CONHSO2Rz; and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxyl.

135. The compound of claim 124 or 125 wherein: R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with phenyl [wherein the phenyl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2]; and the R5 heteroaryl ring is further optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

136. The compound of claim 124 or 125 wherein: R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with haloC1-6alkoxy or haloC1-6alkyl and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

137. The compound of claim 124 or 125 wherein: R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with -CO2H and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

138. The compound of claim 124 or 125 wherein: R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with -CO2C1-6alkyl and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

139. The compound of claim 124 or 125 wherein: R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with tetrazolyl and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.

140. The compound of any one of claims 124-139 wherein: the R55-10 membered heteroaryl ring is selected from thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolylo, isoxazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, indolyl, quinolinyl, or isoquinolinyl, and benzothienyl.

141. The compound of any one of claims 124-139 wherein Het is a group of formula (iii).

142. The compound of any one of claims 124 to 141 wherein Rs is hydrogen.

143. The compound of any one of claims 124 to 142 and wherein Rw and Rd are hydrogen.

144. The compound of any one of claims 124 to 143 wherein Ru is hydrogen, halo, cyano, -NH2, -NHR20, -NHCOR20, -NR20R21, -R20, -SR20, or -OR20 wherein R20 and R21 are independently optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl; Rv is hydrogen, halo, haloC1-6alkyl, cyano, -R24, -SR24, -OR24, or -SO2R24; wherein: R24 is optionally substituted C1-6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl.

145. The compound of any one of claims 124 to 144 wherein: Ru is -NH2, -NHR20, or -NR20R21 wherein R20 and R21 are independently optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl.

146. The compound of any one of claims 124 to 145 wherein Ru is NH2 and Rv is chloro.

147. A compound selected from: or a pharmaceutically acceptable salt thereof.

148. A compound selected from: , , , , and , or a pharmaceutically acceptable salt thereof.

149. A pharmaceutical composition comprising a compound according to any one of claims 1-148, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

150. A method of inhibiting CD73 in a cell, comprising contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-148.

151. The method of claim 150, wherein contacting the cell occurs in a subject in need thereof, thereby treating a disease or disorder selected from cancer, cerebral and cardiac ischemic diseases, fibrosis, immune and inflammatory disorders, inflammatory gut motility disorder, neurological, neurodegenerative and CNS disorders and diseases, depression, Parkinson’s disease, and sleep disorders.

152. The method of claim 151, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head & neck cancer, Kaposi’s sarcoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, myeloma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germcell cancer, thymoma and thymic carcinoma.

153. The method of claim 151 or 152, wherein the cancer is selected from breast cancer, brain cancer, colon cancer, fibrosarcoma, kidney cancer, lung cancer, melanoma, ovarian cancer, and prostate cancer.

154. The method of any one of claims 151-153, wherein the cancer is breast cancer.

155. The method of any one of claims 151-154, further comprising conjointly administering one or more additional chemotherapeutic agents.

156. The method of claim 155, wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette–Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA).

157. The method of claim 155, wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.

158. The method of claim 155, wherein the additional chemotherapeutic agent is an immuno-oncology agent.

(EXTRACTED FROM WIPO PAGE)
Ectonucleotidase Inhibitors and Methods of Use Thereof
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 62/437,915 filed 22 December 2016, 62/437,935 filed 22 December 2016 and 62/555,791 filed 08 September 2017, each of which are hereby incorporated by reference in its entirety.
BACKGROUND CD73, also referred to as 5’-nucleotidase (5’-NT) or ecto-5’-nucleotidase (Ecto 5’NTase), is a membrane-bound cell surface enzyme whose primary role is to catalyze the conversion of extracellular nucleotides (e.g., AMP) to their corresponding nucleosides (e.g., adenosine). CD73 is found in most tissues and expressed on lymphocytes, endothelial cells, and epithelial cells. It is also widely expressed in many tumor cell lines and, notably, is upregulated in cancerous tissues (Antonioli et al., Nat. Rev. Cancer, 13: 842-857, 2013).
In tandem with CD39 (ecto-ATPase), CD73 generates adenosine from ATP/AMP, which is often released from damaged or inflamed cells into the extracellular environment. Extracellular adenosine produced by CD73 interacts with G-protein coupled receptors on target cells. An important downstream effect of this signaling is increased
immunosuppression via a number of pathways. For example, CD73 is a co-signaling molecule on T lymphocytes. Under normal circumstances, extracellular adenosine levels promote a self-limiting immune response that prevents excessive inflammation and tissue damage. For tumors, an advantage of abnormally increased CD73 is that the resulting increased CD73-catalyzed adenosine levels yield inhibition of anti-tumor immune system responses.
Even though CD73 plays a role in cancer immunosuppression, higher expression of CD73 is associated with a variety of stages of tumor progression, including tumor vascularization, invasiveness, and metastasis, and with shorter breast cancer patient survival time. Some of these observations result from CD73’s enzyme-independent function as an adhesion molecule required for lymphocyte binding to the endothelium.
Overall, CD73 has become an important target for developing new cancer therapies, either as single agents or in combination with other cancer therapies. Indeed, combining CD73 monoclonal antibodies with antibodies for other chemotherapy targets enhances
response and survival in animal cancer models (Allard et al., Clin. Cancer Res., 19:5626-35, 2013).
Many of the current cancer treatments and chemotherapeutic agents fail to successfully treat all patients or all symptoms in treated patients, and many of these therapies are associated with undesirable side effects. As certain cancers develop resistance to various chemotherapeutic agents, alternate cancer therapies are needed. Thus, there is a need for additional compounds and methods for treating cancer and other diseases.
SUMMARY
Disclosed herein are compounds of Formula (I):

(I)
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
X is O, NR7 or CR7R8;
Y is O or S;
Z is NR19, O or S;
Het is heterocyclyl or heteroaryl;
R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl; and
R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl,
C2-6alkenyl, and C2-6alkynyl; or
R1a and R1b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl;
R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2- 6alkynyl;
R2b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl,
C2-6alkenyl, and C2-6alkynyl; or
R2a and R2b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl;
R3 is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and -(CH2)-C(O)OR9;
R4 is selected from heteroaryl, alkyl, -C(O)OR9, -C(O)NR11R12, -S(O)2R10,
-P(O)(OR11)(OR12), and -P(O)(OR11)(NR13R15);
R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9;
R6 is selected from -C(O)OR9 and -P(O)(OR11)(OR12);
each R7 and R8 is H
R9 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and -(CHR13)m-Z-C(O)-R14;
each R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and each R11 and R12 is independently selected from H, alkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and -(CHR13)m-Z-C(O)-R14; or
R11 and R12, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl; and
each R13 is independently H or alkyl;
each R14 is independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;
R15 is selected from alkyl, aralkyl,–C(R16)(R17)-C(O)O-R18;
each R16 and R17 are selected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and -(CH2)C(O)OR9;
R18 is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
R19 is H or alkyl, preferably H; and
m is 1 or 2;
provided that either R4 is tetrazolyl, or R5 is aralkyl or heteroaralkyl, or both.
In certain embodiments, the present invention provides a pharmaceutical composition suitable for use in a subject in the treatment or prevention of cancer comprising an effective amount of any of the compounds described herein (e.g., a compound of the invention, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein.
Disclosed herein are methods of treating diseases and conditions that benefit from the inhibition of CD73, comprising administering to a subject in need thereof an effective amount of a compound as disclosed herein (e.g., a compound of Formula (I) or any of the
embodiments thereof disclosed herein). In certain embodiments, the human subject is in need of such treatment. These diseases include, but are not limited to cancers, such as lung cancer, kidney cancer, skin cancer, breast cancer, and ovarian cancer. Other diseases and conditions that can be treated using the methods described herein include, but are not limited to, neurological, neurodegenerative and CNS disorders and diseases such as depression and Parkinson’s disease, cerebral and cardiac ischemic diseases, sleep disorders, fibrosis, immune and inflammatory disorders.
Provided herein are combination therapies of compounds of formula (I) with monoclonal antibodies and other chemotherapeutic agents that can enhance the therapeutic benefit beyond the ability of the adjuvant therapy alone.
DETAILED DESCRIPTION
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The
Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.
In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.
In this disclosure, "comprises," "comprising," "containing" and "having" and the like can have the meaning ascribed to them in U.S. Patent law and can mean " includes,"
"including," and the like; "consisting essentially of" or "consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms "a", "an", and "the" are understood to be singular or plural.
The term“acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
The term“acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.
The term“acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
The term“alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
The term“alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
The term“alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
An“alkyl” group or“alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
The term“Cx-y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term“Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as
trifluoromethyl and 2,2,2-tirfluoroethyl, etc. C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms“C2-yalkenyl” and“C2-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term“alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.
The term“alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
The term“alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
The term“amide”, as used herein, refers to a group
wherein each R30 independently represents a hydrogen or hydrocarbyl group, or two R30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
The terms“amine” and“amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

wherein each R31 independently represents a hydrogen or a hydrocarbyl group, or two R31 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term“aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.
The term“aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.
The term“aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
The term“carbamate” is art-recognized and refers to a group

wherein R32 and R33 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R32 and R33 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The terms“carbocycle”, and“carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
The term“carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term“fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary“carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene,
bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene.“Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
A“cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
“Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term“fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A“cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
The term“carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.
The term“carbonate” is art-recognized and refers to a group -OCO2-R34, wherein R34 represents a hydrocarbyl group.
The term“carboxy”, as used herein, refers to a group represented by the
formula -CO2H.
The term“ester”, as used herein, refers to a group -C(O)OR35 wherein R35 represents a hydrocarbyl group.
The term“ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.
Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include“alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
The terms“halo” and“halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
The terms“hetaralkyl” and“heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
The terms“heteroaryl” and“hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and“hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is
heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
The term“heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
The terms“heterocyclyl”,“heterocycle”, and“heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and“heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
The term“heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.
The term“hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not
carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
The term“hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.
The term“lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A“lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other
substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
The terms“polycyclyl”,“polycycle”, and“polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are“fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
The term“silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
The term“substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that“substitution” or“substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by
rearrangement, cyclization, elimination, etc. As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may
have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an“aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
The term“sulfate” is art-recognized and refers to the group -OSO3H, or a
pharmaceutically acceptable salt thereof.
The term“sulfonamide” is art-recognized and refers to the group represented by the general formulae

wherein R36 and R37 independently represent hydrogen or hydrocarbyl, such as alkyl, or R36 and R37 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term“sulfoxide” is art-recognized and refers to the group -S(O)-R38, wherein R38 represents a hydrocarbyl.
The term“sulfonate” is art-recognized and refers to the group SO3H, or a
pharmaceutically acceptable salt thereof.
The term“sulfone” is art-recognized and refers to the group -S(O)2-R39, wherein R39 represents a hydrocarbyl.
The term“thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.
The term“thioester”, as used herein, refers to a group -C(O)SR40 or -SC(O)R40 wherein R10 represents a hydrocarbyl.
The term“thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
The term“urea” is art-recognized and may be represented by the general formula

wherein R41 and R42 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R41 taken together with R42 and the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term“protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
In the pictorial representation of the compounds given through this application, a thickened tapered line ( ) indicates a substituent which is above the plane of the ring to which the asymmetric carbon belongs and a dotted line ( ) indicates a substituent which is below the plane of the ring to which the asymmetric carbon belongs.
In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or greater ee. In certain embodiments, compounds of the invention may have more than one
stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula (I)). An enantiomerically enriched mixture may comprise, for example, at least about 60 mol percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mol percent of the first enantiomer and only about 2% of the second enantiomer.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (I)). A diastereomerically enriched mixture may comprise, for example, at least about 60 mol percent of one diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent.
The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. Preferred subjects are humans.
As used herein, a therapeutic that“prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
The term“treating” includes prophylactic and/or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the subject of one or more of the disclosed compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
The term“prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of Formula (I)). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of Formula (I) in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid.
An“effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A“therapeutically effective amount”, as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a
therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cancer.
A“response” to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, partial or complete remedy of disease, among others.
The present invention provides compounds of Formula (I):

(I)
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
X is O, NR7 or CR7R8;
Y is O or S;
Z is NR19, O or S;
Het is heterocyclyl or heteroaryl;
R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1- 6alkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl; and
R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl,
C2-6alkenyl, and C2-6alkynyl; or
R1a and R1b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl;
R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1- 6alkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R2b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl,
C2-6alkenyl, and C2-6alkynyl; or
R2a and R2b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl;
R3 is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and -(CH2)-C(O)OR9;
R4 is selected from heteroaryl, alkyl, -C(O)OR9, -C(O)NR11R12, -S(O)2R10,
-P(O)(OR11)(OR12), and -P(O)(OR11)(NR13R15);
R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9;
R6 is selected from -C(O)OR9 and -P(O)(OR11)(OR12);
each R7 and R8 is H
R9 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and -(CHR13)m-Z-C(O)-R14;
each R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and
each R11 and R12 is independently selected from H, alkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and -(CHR13)m-Z-C(O)-R14; or
R11 and R12, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl; and
each R13 is independently H or alkyl;
each R14 is independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;
R15 is selected from alkyl, aralkyl,–C(R16)(R17)-C(O)O-R18;
each R16 and R17 are selected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and -(CH2)C(O)OR9;
R18 is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
R19 is H or alkyl, preferably H; and
m is 1 or 2;
provided that either R4 is tetrazolyl, or R5 is aralkyl or heteroaralkyl, or both.
In certain embodiments, R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2- 6alkynyl. In certain embodiments, R1a is fluoro, chloro or bromo, preferably fluoro. In certain embodiments, R1a is C1-6alkoxy. In certain embodiments, R1a is C1-6alkyl. In certain embodiments, R1a is hydroxy. In certain embodiments, R1a is ethynyl or vinyl. In certain embodiments, R1a is cyano. In certain embodiments, R1a is azido. In certain embodiments, R1a is amino. In certain embodiments, R1a is hydrogen.
In certain embodiments, R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2- 6alkynyl. In other embodiments, R2a is fluoro, chloro, or bromo, preferably fluoro. In certain embodiments, R2a is C1-6alkoxy. In certain embodiments, R2a is C1-6alkyl. In certain embodiments, R2a is hydroxy. In certain embodiments, R2a is cyano. In certain embodiments, R2a is azido. In certain embodiments, R2a is amino. In certain embodiments, R2a is C1-6acyloxy.
In certain embodiments, R1b is H. In other embodiments, R1b is fluoro. In other embodiments, R1b is C1-6alkyl. In certain embodiments, R2b is H. In other embodiments, R2b is fluoro. In other embodiments, R2b is C1-6alkyl.
In certain embodiments, R1a is fluoro and R1b is H. In other embodiments, R2a is fluoro and R2b is H. In certain embodiments, R1a and R1b are each fluoro. In other embodiments, R2a and R2b are each fluoro. In some embodiments, R1a is fluoro and R2a is C1-6alkoxy. In some embodiments, R1a is fluoro and R2a is C1-6alkyl, such as methyl or ethyl. In certain embodiments, R2a is hydroxy and R2b is methyl.
In certain embodiments, R1a is fluoro and R2a is hydroxy. In certain embodiments, R1a is chloro and R2a is hydroxy. In certain embodiments, R1a is hydroxy and R2a is hydrogen. In certain embodiments, R1a is fluoro and R2a is hydrogen. In certain embodiments, R1a is hydroxy and R2a is C1-6alkoxy, such as methoxy. In certain embodiments, R1a is hydroxy and R2a is fluoro. In certain embodiments, R1a is hydroxy and R2a and R2b, together with the carbon atom to which they are attached, form an ethynyl. In certain embodiments, R1a is hydroxy and R2a is C1-6alkyl, such as methyl. In certain embodiments, R1a is fluoro, R2a is fluoro and R2a is hydroxy. In certain embodiments, R1a is hydroxy and R2a is hydroxyl and R2b is C1-6alkynyl, such as ethynyl. In certain embodiments, R1a is hydroxy and R2a is C1- 6alkynyl, such as ethynyl. In certain embodiments, R1a is hydroxy and R2a is C2-6alkenyl. In certain embodiments, R1a is hydroxy and R2a is amino. In certain embodiments, R1a is hydroxy and R2a is azido. In certain embodiments, R1a is azido and R2a is hydroxy. In certain embodiments, R1a is C1-6alkyl, such as methyl, and R2a is hydroxy.
In certain embodiments, the compound of Formula (I) has the following structure:

.
In certain embodiments, R1a is in the α-configuration. In some such embodiments, the compound of Formula (I) has the structure (IA):

.
(IA)
In other embodiments, R1a is in the β-configuration. In some such embodiments, the compound of Formula (I) has the structure (IB):

.
(IB)
In certain embodiments, R2a is in the α-configuration. In some such embodiments, the compound of Formula (I) has the structure (IC):

.
(IC)
In other embodiments, R2a is in the β-configuration. In some embodiments, the compound of Formula (I) has the structure (ID):

.
(ID)
In certain embodiments, the compound of Formula (I) has the structure (IE):

.
(IE)
In certain embodiments, R3 is alkyl, and the alkyl is unsubstituted or substituted, e.g., with one or more substituents selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate. In certain embodiments, the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. In certain preferred embodiments, R3 is H. In other preferred embodiments, R3 is unsubstituted C1-6alkyl.
In certain embodiments, R4 is heteroaryl. In certain preferred embodiments, R4 is tetrazolyl.
In certain embodiments, R4 is selected from -C(O)OR9, -C(O)NR11R12, -S(O)2R10, and -P(O)(OR11)(OR12). In some preferred embodiments, R4 is -C(O)OR9. In certain
embodiments, R9 is H or C1-6alkyl. In some embodiments, R4 is -C(O)NR11R12. In certain such embodiments, R11 and R12 are each alkyl, such as methyl. In alternative such
embodiments, R11 is alkyl and R12 is hydrogen. In other embodiments, R4 is alkyl substituted with carboxyl or ester (e.g., alkoxycarbonyl).
In certain embodiments, R5 is selected from H, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl. In certain embodiments, R5 is H, aralkyl, or heteroaralkyl. For example, R5 can be -CH2-pyridinyl, -CH2-thiophenyl, benzyl or β-naphthyl. In certain embodiments, R4 is heteroaryl, such as tetrazolyl, R5 is unsubstituted or substituted benzyl and R6 is–COOH.
In certain embodiments, R5 is selected from H, alkyl, cycloalkylalkyl,
heterocyclylalkyl, aralkyl, and heteroaralkyl. In certain embodiments, R5 is selected from alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, and each is unsubstituted or substituted with one or more substituents, e.g., selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl and heteroarylalkyl. In certain embodiments, the substituents are selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl, heterocyclyl, arylalkyl and heteroarylalkyl. In certain embodiments, the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. In other embodiments, the substitutents are selected from chloro, trifluoromethyl, trifluoromethoxy, phenyloxy, dimethylamido, methylsulfonyl, CN, and carboxylic acid. In some preferred embodiments, R5 is H or aralkyl.
In some embodiments, R5 is aralkyl, e.g., wherein the aryl ring is substituted or unsubstituted phenyl or naphthyl. In other embodiments, R5 is heteroaralkyl, e.g., wherein the heteroaryl ring is selected from substituted or unsubstituted benzofuranyl, benzothienyl, benzothiazolyl, pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl, oxazolyl, and oxadiazolyl.
In some embodiments, R5 is aralkyl or heteroaralkyl, wherein the aryl or heteroaryl ring, respectively, is unsubstituted or substituted with one or more substituents, e.g., selected from halo, CN, OH, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, carboxyl, ester (e.g., lower alkyl ester), heterocyclyl, heteroaryl, aryl, aralkyl, and heteroaralkyl. In certain embodiments, the substituents are selected from halo, CN, OH, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, carboxyl, ester (e.g., lower alkyl ester), heteroaryl, aryl, aralkyl, and heteroaralkyl. In certain such
embodiments, the substituents on the aryl or heteroaryl ring of the aralkyl or heteroaralkyl, respectively, are selected from halo, CN, haloalkyl, haloalkoxy, carboxy, ester (e.g., lower alkyl ester), and aryl. In other such embodiments, the substituents on the aryl or heteroaryl ring of the aralkyl or heteroaralkyl, respectively, are selected from tetrazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.
In certain embodiments, R6 is -C(O)OR9. In some embodiments, R9 is H or C1-6alkyl. In other embodiments, R6 is -P(O)(OR11)(OR12), and R11 and R12 are each H. In certain embodiments, R7 is H or C1-6alkyl. In certain embodiments, R8 is H. In certain embodiments, R9 is H or C1-6alkyl, such as methyl or ethyl. In certain embodiments, R11 and R12 are each H.
In certain embodiments, each R7, R8, R9, R10, R11 and R12 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and each is unsubstituted or substituted, e.g., with one or more selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate. In some embodiments, the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.
In certain embodiments, X is O. In certain embodiments, Y is O. In certain embodiments, the Y-bearing substituent is in the R-configuration. In other embodiments, the Y-bearing substituent is in the S-configuration. In certain embodiments, Z is O. In other embodiments, Z is NH.
In certain embodiments, Het is a nitrogen-containing heterocyclyl or heteroaryl. In certain embodiments, Het is attached via a nitrogen atom. In other, embodiments, Het is attached via a carbon atom. In some embodiments, Het is a 5- to 8-membered monocyclic or 5- to 10-membered bicyclic heteroaryl and is unsubstituted or substituted, e.g., with one or more substituents selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, cyclothioalkyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate. In certain embodiments, the substituents are selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate,
phosphonate, and phosphinate. In certain embodiments, the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl. In certain preferred embodiments, Het is selected from purinyl, imidazopyrimidinyl, and pyrrolopyrimidinyl. In other embodiments, Het is substituted with one or two substituents independently selected from halo, aralkyl, amino, azido and hydroxy. In some embodiments, Het is substituted with one halo and one amino substituent. In certain preferred embodiments, Het is

.
In certain embodiments, Het is selected from

In certain embodiments, Het is selected from

.
In certain embodiments, Het is a group of formula (i) through (xiv) below:

wherein:
Ru is hydrogen, halo, cyano, -NH2, -NHR20, -NHCOR20, -NR20R21, -R20, -SR20, -OH, and
-OR20;
Rw is hydrogen, halo, -NHR22, -NR22R23, -R22, -OH, and -OR22;
Rv and Rx are independently hydrogen, halo, haloC1-6alkyl, -NH2, -NHR24,
-NR24R25, -R24, -SR24, cyano, -OH, -OR24, -SO2R24, -C1-6alkyleneNH2, -C1-6alkyleneNHR24, -C1-6alkyleneNR24R25, -R24, -C1-6alkyleneSR24, -C1-6alkyleneOH, -C1-6alkyleneOR24, -C1-6alkyleneSO2R24,
Rs and Rt are independently hydrogen, halo, or C1-6alkyl; and wherein:
R20, R21, R22, R23, R24 and R25 are independently optionally substituted C1-6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylC1-6alkyl, optionally substituted heterocyclyl, optionally substituted
heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21, R22 and R23, and R24 and R25 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl.
In certain embodiments, represents



wherein
each RA is independently selected from halo, CN, OH, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy (e.g., substituted or unsubstituted benzyloxy), alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heterocyclyl, heteroaryl, aryl, aralkyl, and heteroaralkyl; and
k is 1, 2, or 3.
In certain embodiments, RA is selected from halo, CN, OH, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy (e.g., substituted or unsubstituted benzyloxy), alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl. In certain embodiments, RA is selected from pyridyl, pyrazolyl, pyrrolidinonyl, azapanonyl, morpholinonyl, piperazonyl,
tetrahydropyrimidinonyl, phenyl, and benzyloxy.
Further Embodiments:
In the following numbered embodiments, unless otherwise specified:
C1-6alkyl is unsubstituted;
C1-6alkyl of C1-6alkyloxy is unsubstituted;
haloC1-6alkyl is C1-6alkyl substituted with one to five halo atoms;
haloC1-6alkyloxy is C1-6alkyloxy substituted with one to five halo atoms;
C2-6alkenyl is unsubstituted;
C2-6alkynyl is unsubstituted;
C1-6alkylene group is unsubstituted;
C2-6alkenylene group is unsubstituted;
optionally substituted C1-6alkyl is optionally substituted with one or two substituents
independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
carbocyclyl is an unsubstituted saturated or partially unsaturated mono or bicyclic ring
containing 3 to 10 carbon atoms;
optionally substituted carbocyclyl is optionally substituted with one, two, or three
substituents independently selected from C1-6alkyl, halo, hydroxy, or C1-6alkoxy; aryl is phenyl or naphthyl;
optionally substituted aryl is optionally substituted with one, two, or three substituents
independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), - N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(unsubstitued C1-6alkyl)2];
heteroaryl is an unsubstituted five to ten membered or five to six membered aromatic ring containing one to four or one to three heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon;
optionally substituted heteroaryl is a five to ten membered aromatic ring containing one to four heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-
6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, unsubstituted C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2];
heterocyclyl is an unsubstituted monocyclic, saturated or partially unsaturated 4 to 8
membered ring containing one to three heteroatoms independently selected from N, O, S, SO, and SO2 and optionally contains one or two CO, the remaining atoms in the ring being carbon that is optionally fused to phenyl or 5 to 6 membered carbocyclyl or 5 or 6 heteroaryl ring;
nitrogen-containing heterocyclyl is a heterocyclyl ring that has at least a nitrogen atom;
optionally substituted heterocyclyl is heterocyclyl that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three
substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl
[optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2];
optionally substituted carbocyclyl C1-6alkyl is optionally substituted carbocyclyl attached via C1-6alkyl;
optionally substituted heterocyclylC1-6alkyl is optionally substituted heterocyclyl attached via C1-6alkyl;
optionally substituted arylC1-6alkyl is optionally substituted aryl attached via C1-6alkyl; and optionally substituted heteroarylC1-6alkyl is optionally substituted heteroaryl attached via C1- 6alkyl.
Embodiment 1:
In embodiment 1, the compound of Formula (I) is as defined in the Summary.
In a subembodiment of embodiment 1, the compounds of Formula (I) are those wherein when R5 is hydrogen, R1a and R1b are independently hydrogen, hydroxy, halo, C1-C3alkyl, C1-C3alkoxy, C2-C3alkenyl, or C2-C3alkynyl, R2a, R2b and R3 are hydrogen, then Het is not 2,4-dioxo-3,4-dihydropyrimidinyl, 2,4-dioxo-3,4,5,6-tetrahydropyrimidinyl, 6-oxopurinyl, 6-amino-9H-purin-9-yl, or oxopyrimidinyl wherein each ring of the
aforementioned ring is optionally substituted with C1-6alkyl.
Embodiment 2:
In embodiment 2, the compounds of embodiment 1 and subembodiments contained therein are those wherein R5 is phenylC1-6alkyl or naphthylC1-6alkyl, preferably benzyl, wherein phenyl and naphthyl are optionally substituted with one, two, or three substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,–COOC1-6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkylene- substituted with one or two substituents independently selected from hydroxy, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1- 6alkylenephenyl, phenoxy, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1- 6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-
heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1- 6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-
6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi,–CONRmC1-6alkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and– CONHSO2Rz; wherein:
each Rm is hydrogen or -C1-6alkyl;
Ro, Rp, and Ry are independently hydrogen or -C1-6alkyl;
Rz is -C1-6alkyl, -NHC1-6alkyl, or–N(C1-6alkyl)2;
phenyl by itself or as part of -C1-6alkylenephenyl, phenoxy, or -OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1- 6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, and -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
heterocyclyl by itself or as part of -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl, or -NRmCOheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, or -C1-6alkyl (substituted with hydroxy or -OC1- 6alkyl).
Embodiment 3:
In embodiment 3, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is phenylC1-6alkyl or naphthylC1-6alkyl, preferably benzyl, wherein phenyl and naphthyl (also referred to below as R5 phenyl and naphthyl rings respectivelyl) are optionally substituted, preferably substituted, with one or two substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two substituents independently selected from–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,–COOC1-6alkyl, halo, hydroxy, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NHC1-6alkyl, or -N(C1- 6alkyl)2), phenyl, phenoxy, benzyl, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S
[wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1- 6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2],
heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCO-heterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi,– CONRmalkylene-Ri, and–CONHSO2Rz ; and
additionally the R5 phenyl and naphthyl rings are optionally substituted with a third substituent selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy; wherein:
each Rm is hydrogen or -C1-6alkyl;
Ro and Rp are independently hydrogen or -C1-6alkyl;
Rz is -C1-6alkyl, -NHC1-6alkyl, or–N(C1-6alkyl)2;
phenyl by itself or as part of phenoxy, benzyl, or -OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, and -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
heterocyclyl by itself or as part of -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkylene-heterocyclyl, -NRmCOheterocyclyl,–COheterocyclyl, or -NRmCOC1-6alkyleneheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, or -C1-6alkyl (substituted with hydroxy or -OC1- 6alkyl).
Embodiment 4:
In embodiment 4, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is phenylC1-6alkyl, preferably benzyl, wherein phenyl is substituted with one substituent at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–C1-6alkyl in–C1-6alkylphenyl or–CH2- in benzyl respectively, which one substituent is selected from–C1-6alkyl,–OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1- 6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1- 6alkyl, -CO2H,–COOC1-6alkyl, halo, hydroxy, cyano, nitro, -PO3H2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxy, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), phenyl, phenoxy, benzyl, benzyloxy, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the
heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi, and– CONRmalkylene-Ri; and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy; wherein
each Rm is hydrogen or -C1-6alkyl;
Ro and Rp are independently hydrogen or -C1-6alkyl;
phenyl by itself or as part of benzyl, phenoxy, or benzyloxy is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H, –COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1- 6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, and -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
heterocyclyl by itself or as part of -C1-6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOheterocyclyl,–COheterocyclyl, or -NRmCOC1-6alkyleneheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, or -C1-6alkyl (substituted with hydroxy or -OC1-6alkyl).
Embodiment 5:
In embodiment 5, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2phenyl or–(CH2)2phenyl, preferably– CH2phenyl (benzyl) wherein phenyl is optionally substituted, preferably substituted, with one substituent at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–C1-6alkyl in–C1-6alkylphenyl and–CH2- in–CH2phenyl (benzyl) respectively, which one substituent is selected from -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkyl substituted with hydroxy, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1- 6alkylene-CO2C1-6alkyl, -CO2H, nitro,–COOC1-6alkyl, halo, hydroxy, cyano, -CONReRf (where Re is hydrogen or -C1-6alkyl and Rf is -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two hydroxyl, -NH2, -NHC1-6alkyl or– N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg is hydrogen or -C1-6alkyl and Rh is hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl or isoxazolyl (wherein each of the aforementioned heteroaryl rings is optionally substituted with one or two substituents independently selected from C1-6alkyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2), and
the R5 phenyl ring is additionally optionally substituted with one or twosubstituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 6:
In embodiment 6, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is phenylC1-6alkyl, preferably benzyl, wherein phenyl ring in phenylC1-6alkyl and benzyl is substituted at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–C1-6alkyl in–C1-6alkylphenyl and– CH2- in benzyl respectively, with phenyl, benzyl, benzyloxy, or phenoxy [wherein the phenyl ring either by itself or as part of benzyl, benzyloxy, and phenoxy is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, CN, -CO2H,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2]; and
R5 phenyl is further optionally substituted with one or twosubstituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 7:
In embodiment 7, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl,–CH2-naphthyl,–(CH2)2-phenyl, or– (CH2)2-naphthyl, preferably–CH2-phenyl, wherein the phenyl and naphthyl rings are optionally substituted with one, two, or three substituents independently selected from methyl, ethyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CH2CO2H, -CH2CH2CO2H, -OCH2CO2H, -OCH2CH2CO2H, -CH2CO2CH3, -CH2CH2CO2CH3, -CH2CO2ethyl, -CH2CH2CO2ethyl, -CH2OH, -CH2CH2OH, -OCH2OCH3, -OCH2CH2OCH3, -CO2H,–COOmethyl,–CO2ethyl, hydroxy, nitro, PO3H2, methylthio, ethylthio, methylsulfoxide, ethylsulfoxide, methylcarbonylaminosulfonyl, ethylcarbonylaminosulfonyl, fluoro, chloro, cyano, -NH2, -NHCH3, -NHethyl, -N(methyl)2, -N(ethyl)2, -CONReRf (where Re is hydrogen, methyl, ethyl, or propyl and Rf is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, -(CH2)3-CO2ethyl, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)2-NHMe, -(CH2)3-NHMe, -(CH2)2-N(CH3)2, or -(CH2)3-N(CH3)2), -SO2Me, -SO2NRgRh (where Rg is hydrogen, methyl, ethyl, or propyl and Rh is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, or -(CH2)3-CO2ethyl), phenyl, phenoxy, -CH2-phenyl, -CH2-CH2-phenyl, -OCH2-phenyl or -OCH2-CH2-phenyl [wherein the phenyl ring, by itself or as part of phenoxy, -CH2-phenyl, -CH2-CH2-phenyl, -OCH2-phenyl, and -OCH2-CH2-phenyl, is optionally substituted with one, two, or three substituents
independently selected from hydroxyl, chloro, fluoro, -CO2H, CN,–CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, -CH2-CO2ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONH2, -CONHCH3, and -CON(CH3)2], 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from from hydroxyl, chloro, fluoro, CN, -CO2H,– CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, and -CH2-CO2ethyl], -ORi, -SRi, -OCH2Ri, -O(CH2)2-Ri, -CH2Ri and -(CH2)2-Ri [where each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from from hydroxyl, chloro, fluoro, CN, -CO2H,– CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, -CH2-CO2ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONH2, -CONHCH3, and -CON(CH3)2].
Embodiment 8:
In embodiment 8, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl,–CH2-naphthyl,–(CH2)2-phenyl, or– (CH2)2-naphthyl, preferably–CH2-phenyl, wherein phenyl and naphthyl rings are substituted with one or two substituents independently selected from difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CH2CO2H, -CH2CH2CO2H, -OCH2CO2H, -OCH2CH2CO2H, -CH2CO2CH3, -CH2CH2CO2CH3, -CH2CO2ethyl, -CH2CH2CO2ethyl, -CH2OH, -CH2CH2OH, -OCH2OCH3, -OCH2CH2OCH3, -CO2H,–COOmethyl,–CO2ethyl, hydroxy, nitro, PO3H2, methylthio, ethylthio, methylsulfoxide, ethylsulfoxide,
methylcarbonylaminosulfonyl, ethylcarbonylaminosulfonyl, fluoro, chloro, cyano, -NH2, -NHCH3, -NHethyl, -N(methyl)2, -N(ethyl)2, -CONReRf (where Re is hydrogen, methyl, ethyl, or propyl and Rf is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, -(CH2)3-CO2ethyl, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)2-NHMe, -(CH2)3-NHMe, -(CH2)2-N(CH3)2, or -(CH2)3-N(CH3)2), -SO2Me, -SO2NRgRh (where Rg is hydrogen, methyl, ethyl, or propyl and Rh is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, or -
(CH2)3-CO2ethyl), phenyl, phenoxy, -CH2-phenyl, -CH2-CH2-phenyl, -OCH2-phenyl or -OCH2-CH2-phenyl [wherein the phenyl ring by itself or as part of phenoxy, -CH2-phenyl, -CH2-CH2-phenyl, -OCH2-phenyl, and -OCH2-CH2-phenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, chloro, fluoro, -CO2H, CN, –CO2Me,-CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, -CH2-CO2ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONH2, -CONHCH3, and -CON(CH3)2], 5-or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from from hydroxyl, chloro, fluoro, CN, -CO2H, –CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, -CH2-CO2ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONH2, -CONHCH3, and -CON(CH3)2], -ORi, -SRi, -OCH2Ri, -O(CH2)2-Ri,
-CH2Ri and -(CH2)2-Ri [where each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from from hydroxyl, chloro, fluoro, CN, -CO2H,–CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, and -CH2-CO2ethyl]; and
the R5 phenyl and naphthyl rings are additionally optionally substituted with a third substituent independently selected from methyl, ethyl, fluoro, chloro, methoxy, ethoxy, hydroxy, -NH2, and cyano.
Embodiment 9:
In embodiment 9, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein phenyl is substituted with one substituent at a meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in –CH2-phenyl or–(CH2)2-phenyl respectively, and is selected from trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CH2CO2H, -CH2CH2CO2H, -OCH2CO2H, -OCH2CH2CO2H, -CH2CO2CH3, -CH2CH2CO2CH3, -CH2CO2ethyl, -CH2CH2CO2ethyl, -CH2OH, -CH2CH2OH, -OCH2CH2OH, -OCH2OCH3, -OCH2CH2OCH3, -CO2H, -
COOmethyl, -COOethyl, hydroxy, fluoro, chloro, cyano, -CONReRf (where Re is hydrogen, methyl, ethyl, or propyl and Rf is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, -(CH2)3-CO2ethyl, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)2-NHMe, -(CH2)3-NHMe, -(CH2)2-NHCH3, -(CH2)3-N(CH3)2), -SO2Me, or -SO2NRgRh (where Rg is hydrogen, methyl, ethyl, or propyl and Rh is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, or -(CH2)3-CO2ethyl), tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl or isoxazolyl, wherein each of the aforementioned heteroaryl rings is optionally substituted with one or two substituents independently selected from C1-6alkyl, halo, CN, -CO2H,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, or -OC1-6alkyl (substituted with one to five fluoro); and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from methyl, ethyl, fluoro, chloro, methoxy, ethoxy, hydroxy, -NH2, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.
Embodiment 10:
In embodiment 10, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein the phenyl ring in–CH2-phenyl and–(CH2)2-phenyl is substituted at the meta or para position to the carbon atom of the phenyl ring that is attached to the -CH2- group of the–CH2-phenyl and–(CH2)2-phenyl ring with haloC1-6alkoxy or haloC1-6alkyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy .
Embodiment 11:
In embodiment 11, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein phenyl is substituted with a substituent at the meta or para position, preferably para position, to the carbon atom of the phenyl ring that is attached to–CH2- or– (CH2)2- in–CH2-phenyl or–(CH2)2-phenyl, which substituent is selected from -CONReRf
(where Re is hydrogen or -C1-6alkyl and Rf is -C1-6alkylene- substituted with one or two substituents independently selected from hydroxyl, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri,–CONRmRi,–CONRmC1- 6alkylene-Ri [where each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), or -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOheterocyclyl,–COheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl [wherein each Rm is hydrogen or -C1-6alkyl and the heterocyclyl ring by itself or as part of -C1- 6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1- 6alkyleneheterocyclyl,
–COheterocyclyl, -NRmCOheterocyclyl, and -NRmCOC1-6alkyleneheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, or -C1-6alkyl (wherein alkyl is substituted with hydroxy or -OC1-6alkyl)], and -NRmCOC1-6alkyleneNRoRp (where Rm, Ro and Rp are independently hydrogen or C1-6alkyl); and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 12:
In embodiment 12, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein phenyl is substituted with -CH=CHCO2H, -CH2CO2H or CH2CH2CO2 at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in–CH2-phenyl or–(CH2)2-phenyl; and
the phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 13:
In embodiment 13, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein phenyl is substituted -CH2CO2CH3, -CH2CH2CO2CH3, -CH2CO2ethyl, or -CH2CH2CO2ethyl at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in–CH2-phenyl or–(CH2)2-phenyl; and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy .
Embodiment 14:
In embodiment 14, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl (benzyl), wherein phenyl is substituted with CO2H at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in –CH2-phenyl (benzyl) or–(CH2)2-phenyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 15:
In embodiment 15, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl (benzyl) or–(CH2)2-phenyl, preferably–CH2-phenyl (benzyl), wherein phenyl is substituted with -COOmethyl or -COOethyl at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in–CH2-phenyl (benzyl) or–(CH2)2-phenyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy .
Embodiment 16:
In embodiment 16, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein phenyl is substituted with fluoro, chloro, or cyano at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or– (CH2)2- in–CH2-phenyl or–(CH2)2-phenyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy
Embodiment 17:
In embodiment 17, the compounds of embodiment 1or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein phenyl is substituted with -CONReRf (where Re is hydrogen, methyl, ethyl, or propyl and Rf is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, -(CH2)3-CO2ethyl, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)2-NHMe, -(CH2)3-NHMe, -(CH2)2-NHCH3, -(CH2)3-N(CH3)2) or–CONHSO2Rz where Rz is -C1-6alkyl, -NHC1-6alkyl, or–N(C1-6alkyl)2 at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in–CH2-phenyl or –(CH2)2-phenyl; and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 18:
In embodiment 18, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-
phenyl, wherein phenyl is substituted -SO2NRgRh (where Rg is hydrogen, methyl, ethyl, or propyl and Rh is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, or -(CH2)3-CO2ethyl) or–SO2NHCORj (where Rj is -C1-6alkyl, -NHC1-6alkyl, or–N(C1-6alkyl)2) at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in–CH2-phenyl or –(CH2)2-phenyl; and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 19:
In embodiment 19, the compounds of embodiment 1 or 2 and subembodiments contained therein are those wherein R5 is–CH2-phenyl or–(CH2)2-phenyl, preferably–CH2-phenyl, wherein phenyl is substituted with tetrazol-5-yl at the meta or para position, preferably para, to the carbon atom of the phenyl ring that is attached to–CH2- or–(CH2)2- in –CH2-phenyl or–(CH2)2-phenyl; and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 20:
In embodiment 20, the compounds of embodiment 1 and subembodiments contained therein are those wherein R5 is 5-10 membered heteroarylC1-6alkyl (also referred to below as R5 heteroaryl), preferably–CH2- or–(CH2)2-5-10 membered heteroaryl, having one to three heteroatoms independently selected from N, O, or S and is optionally substituted, preferably substituted, with one or two substituents, more preferably one substituent, independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -C1-6alkyl substituted with one or two substituents independently
selected from hydroxy, -OC1-6alkyl substituted with hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,–COOC1- 6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1- 6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi,– CONRmalkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and–CONHSO2Rz; and
the R5 heteroaryl ring is additionally optionally substituted with an additional substituent selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy; wherein:
each Rm is hydrogen or -C1-6alkyl;
Ro, Rp, and Ry are independently hydrogen or -C1-6alkyl;
Rz is -C1-6alkyl, -NHC1-6alkyl, or–N(C1-6alkyl)2;
phenyl by itself or as part of -C1-6alkylenephenyl, phenoxy, or -OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, and -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2;
heterocyclyl by itself or as part of -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOheterocyclyl,–COheterocyclyl, and -NRmCOC1-6alkyleneheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, or -C1-6alkyl (substituted with hydroxy or -OC1-6alkyl).
Embodiment 21:
In embodiment 21, the compounds of embodiment 1 or 20 and subembodiments contained therein are those wherein R5 is–CH2- or–(CH2)2-(5-9 membered heteroaryl ring) which heteroaryl ring is optionally substituted with one or two substituents, preferably one substituent, independently selected from difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, -CH2CO2H, -CH2CH2CO2H, -CH2CO2CH3, -CH2CH2CO2CH3, -CH2CO2ethyl, -CH2CH2CO2ethyl, -CH2OH, -CH2CH2OH, -OCH2CH2OH, -OCH2OCH3, -OCH2CH2OCH3, -CO2H,–COOmethyl,–CO2ethyl, hydroxy, nitro, PO3H2, methylthio, ethylthio, methylsulfoxide, ethylsulfoxide, methylcarbonylaminosulfonyl,
ethylcarbonylaminosulfonyl, fluoro, chloro, cyano, -NH2, -NHCH3, -NHethyl, -N(methyl)2, -N(ethyl)2, -CONReRf (where Re is hydrogen, methyl, ethyl, or propyl and Rf is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, -(CH2)3-CO2ethyl, -(CH2)2-NH2, -(CH2)3-NH2, -(CH2)2-NHMe, -(CH2)3-NHMe, -(CH2)2-N(CH3)2, or -(CH2)3-N(CH3)2), -SO2Me, -SO2NRgRh (where Rg is hydrogen, methyl, ethyl, or propyl and Rh is hydrogen, methyl, ethyl, propyl, -(CH2)2-CO2H, -(CH2)3-CO2H, -(CH2)2-CO2Me, -(CH2)3-CO2Me, -(CH2)2-CO2ethyl, or -(CH2)3-CO2ethyl), phenyl, phenoxy, -CH2-phenyl, -CH2-CH2-phenyl, -OCH2-phenyl or -OCH2-CH2-phenyl [wherein the
phenyl ring by itself or as part of phenoxy, -CH2-phenyl, -CH2-CH2-phenyl, -OCH2-phenyl, and -OCH2-CH2-phenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, chloro, fluoro, -CO2H, CN,–CO2Me,-CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, -CH2-CO2ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONH2, -CONHCH3, and -CON(CH3)2], 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from from hydroxyl, chloro, fluoro, CN, -CO2H,– CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, -CH2-CO2ethyl, tetrazolyl, -SO2CH3, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, -CONH2, -CONHCH3, and -CON(CH3)2], -ORi, -SRi, -OCH2Ri, -O(CH2)2-Ri, -CH2Ri and -(CH2)2-Ri [where each Ri, is independently 5-or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from from hydroxyl, chloro, fluoro, CN, -CO2H,–CO2Me, -CO2ethyl, methyl, ethyl, methoxy, ethoxy, difluoromethoxy,
trifluoromethoxy, difluoromethyl, trifluoromethyl, -CH2-CO2H, -CH2-CO2methyl, and -CH2-CO2ethyl]; and
the R5 heteroaryl ring is optionally additionally substituted with a substituent selected from methyl, ethyl, fluoro, chloro, methoxy, ethoxy, hydroxy, -NH2, and cyano.
Embodiment 22:
In embodiment 22, the compounds of embodiment 1 or 20 and subembodiments contained therein are those wherein R5 is–(CH2)1-2-(5-10 membered heteroaryl ring) having one to three heteroatoms independently selected from N, O, or S, preferably–CH2-(5-9 membered heteroaryl ring) having one to 3 heteroatoms independently selected from N, O, or S, wherein the heteroaryl ring is substituted with one or two substituents independently selected from -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -CO2H, nitro,–COOC1-6alkyl, halo, hydroxy, cyano, -CONReRf (where Re is hydrogen or-C1-6alkyl and Rf is -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SO2(C1- 6alkyl), -SO2NRgRh (where Rg is hydrogen or -C1-6alkyl and Rh is hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl or isoxazolyl, (wherein each of the aforementioned heteroaryl rings is optionally substituted with one or two substituents independently selected from C1-6alkyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2); and
the R5 heteroaryl ring is additionally optionally substituted with one or two substituents, independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 23:
In embodiment 23, the compounds of embodiment 1 or 20 and subembodiments contained therein are those wherein R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein the heteroaryl ring is substituted with phenyl [wherein the phenyl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1- 6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1- 6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2]; and
the R5 heteroaryl ring is further optionally substituted with two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
Embodiment 24:
In embodiment 24, the compounds of embodiment 1, 20, 21, 22, or 23 and
subembodiments contained therein are those wherein the heteroaryl ring in the–CH2-(5-10 membered heteroaryl ring) of R5 is selected from thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, indolyl, and
benzothienyl. In one subembodiment of embodiment 24, the heteroaryl ring is a 9- or 10-membered heteroaryl ring selected from benzimidazol-5-yl, benzoxazol-5-yl, indol-5-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzofuran-5-yl, indol-2-yl, quinolinyl, or isoquinolinyl. In one subembodiment of embodiment 24, the heteroaryl ring is 5-membered heteroaryl ring that is preferably substituted at the 3-position to the ring atom of the 5-membered ring that is attached to -CH2-, and the 6-membered heteroaryl ring is substituted at a meta or para position to the ring atom that is attached to the -CH2- and furthermore, the above rings are optionally substituted, preferably substituted, with one or more substituent(s) as indicated in embodiments 20, 21, 22, or 23 above.
Embodiment 25:
In embodiment 25, the compounds of any one of embodiments 1-24 and
subembodiments contained therein are those wherein R3 is hydrogen, X is O, and Y is O.
Embodiment 26:
In embodiment 26, the compounds of any one of embodiments 1-24 and
subembodiments contained therein are those are wherein R3 is hydrogen, C1-6alkyl, or benzyl, X is CH2, and Y is O. In one group of compounds within embodiment 26, R3 is hydrogen, X is CH2, and Y is O.
Embodiment 27:
In embodiment 27, the compounds of any one of embodiments 1-24 and
subembodiments contained therein are those wherein R3 is hydrogen, X is N. Within embodiment 27, in one group of compounds Y is O. Within embodiment 27, in another group of compounds Y is S.
Embodiment 28:
In embodiment 28, the compounds of any one of embodiments 1-24 and
subembodiments contained therein are those wherein R3 is hydrogen, X is O, and Y is S.
Embodiment 29:
In embodiment 29, the compounds of any one of embodiments 1-24 and
subembodiments contained therein and groups contained therein are those wherein R3 is hydrogen, X is CH2, and Y is S.
Embodiment 30:
In embodiment 30, the compounds of any one of embodiments 1-29 and
subembodiments contained therein and groups contained therein are those wherein:
R1a is hydroxy, halo, C1-6alkyl, cyano, azido, NH2, C1-6alkylcarbonyloxy, ethynyl, or vinyl; preferably hydroxy, fluoro, chloro, cyano, azido, NH2, or methyl;
R1b is hydrogen;
R2a is hydrogen, hydroxy, halo, C1-6alkyl, NH2, cyano, azido, ethynyl, or vinyl; and R2b is hydrogen.
Embodiment 31:
In embodiment 31, the compounds of embodiment 30 are those wherein:
R1a is hydroxy, fluoro, or methyl;
R1b is hydrogen;
R2a is hydroxy, fluoro, or methyl; and
R2b is hydrogen.
Embodiment 32:
In embodiment 32, the compounds of embodiment 30 are those wherein:
R1a is fluoro;
R1b is hydrogen;
R2a is hydroxy, hydrogen, methyl or NH2; and
R2b is hydrogen.
Within embodiment 32, in one group of compounds R2a is hydrogen.
Within embodiment 32, in another group of compounds R2a is hydroxy. Within embodiment 32, in yet another group of compounds R2a is methyl. Within embodiment 32, in yet another group of compounds R2a is NH2.
Embodiment 33:
In embodiment 33, the compounds of embodiment 30, 31 and 32 and groups contained therein are those wherein:

.
Embodiment 34:
In embodiment 34, the compounds of embodiment 30, 31 and 32 and groups
contained therein are those wherein:
.
Embodiment 35:
In embodiment 35, the compounds of embodiment 30 31 and 32 and groups
contained therein are those wherein:
Embodiment 36:
In embodiment 36, the compounds of embodiment 30 31 and 32 and groups
contained therein are those wherein:
Embodiment 37:
In embodiment 37, the compounds of embodiment 30 31 and 32 and groups
contained therein are those wherein:
Embodiment 38:
In embodiment 38, the compounds of embodiment 30 31 and 32 and groups
contained therein are those wherein:
Embodiment 39:
In embodiment 39, the compounds of any one of embodiments 1-29 are those wherein:
R1a is halo, C1-6alkyl, cyano, azido, NH2, C1-6alkylcarbonyloxy, ethynyl, or vinyl; R1b is hydroxy or fluoro;
R2a is hydrogen, halo, hydroxy, C1-6alkyl, C1-6alkyloxy, NH2, ethynyl, or vinyl; and R2b is hydrogen.
Embodiment 40:
In embodiment 40, the compounds of embodiment 39 are those wherein:
R1a is fluoro or methyl;
R1b is fluoro or hydroxy;
R2a is hydrogen, hydroxy, NH2, methyl, methoxy, ethoxy, or propoxy; and
R2b is hydrogen.
Embodiment 41:
In embodiment 41, the compounds of embodiments any one of embodiments 1-29 are those wherein:
R1a is hydroxy, halo, C1-6alkyl, or cyano;
R1b is hydrogen;
R2a is hydroxy, halo, C1-6alkyl, cyano, ethynyl, or vinyl; and
R2b is halo, hydroxy, or C1-6alkyl.
Embodiment 42:
In embodiment 42, the compound of embodiment 42 are those wherein:
R1a is hydroxy, fluoro, or methyl;
R1b is hydrogen;
R2a is methyl, fluoro, cyano, or hydroxy; and
R2b is fluoro, hydroxyl, or methyl.
Embodiment 43:
In embodiment 43, the compound of embodiment 42 are those wherein:
R1a is fluoro or methyl;
R1b is hydrogen;
R2a is methyl; and
R2b is fluoro, hydroxy, or methyl.
Embodiment 44:
In embodiment 44, the compound of any one of embodiments 1-29 and
subembodiments and groups of compounds contained therein are those wherein:
R1a is halo, C1-6alkyl, cyano, azido, NH2, C1-6alkylcarbonyloxy, ethynyl, or vinyl; R1b is hydroxy or fluoro;
R2a is hydroxy, halo, C1-6alkyl, or cyano; and
R2b is halo, hydroxy, or C1-6alkyl.
Embodiment 45:
In embodiment 45, the the compounds of any one of embodiments 1 to 45 and subembodiments and groups of compounds contained therein are those wherein:
R4 is selected from -C(O)OR9, -C(O)NR11R12, -S(O)2R10,
-P(O)(OR11)(OR12), and -P(O)(OR11)(NR13R15); and
R6 is selected from -C(O)OR9 and -P(O)(OR11)(OR12); wherein:
R9, R10, R11, R12, R13 and R15 are independently hydrogen or C1-6 alkyl.
Within the groups of compounds in embodiment 46, in one group of compounds, R4 and R6 are -C(O)OR9 where R9 is as defined above, preferably R9 is hydrogen or C1-6 alkyl.
Within the groups of compounds in embodiment 46, in another group of compounds, R4 and R6 are -C(O)OH.
Within the groups of compounds in embodiment 46, in yet another group of compounds, R4 is selected from -C(O)NR11R12 or -S(O)2R11; and
R6 is selected from -C(O)OR9 and -P(O)(OR11)(OR12); wherein:
R9, R11, and R12 are independently hydrogen or C1-6 alkyl. In one subembodiment, the compounds are those wherein R9, R11, and R12 are independently hydrogen, methyl, or ethyl.
Within the groups of compounds in embodiment 46, in yet another group of compounds, R4 is P(O)(OR11)(OR12); and
R6 is -P(O)(OR11)(OR12); wherein:
R11 and R12 are independently hydrogen or C1-6 alkyl,
preferably R11 and R12 are independently hydrogen, methyl, or ethyl.
Embodiment 46:
In embodiment 46, the the compounds of embodiments 1 to 46 and subembodiments and groups of compounds contained therein are those wherein:
Het is a group selected from a group of formula (i) through (xiv) below:

wherein:
Ru is hydrogen, halo, cyano, -NH2, -NHR20, -NHCOR20, -NR20R21, -R20, -SR20, -OH, and
-OR20;
Rw is hydrogen, halo, -NHR22, -NR22R23, -R22, -OH, and -OR22;
Rv and Rx are independently hydrogen, halo, haloC1-6alkyl, -NH2, -NHR24,
-NR24R25, -R24, -SR24, cyano, -OH, -OR24, -SO2R24, -C1-6alkyleneNH2, -C1-6alkyleneNHR24, -C1-6alkyleneNR24R25, -R24, -C1-6alkyleneSR24, -C1-6alkyleneOH, -C1-6alkyleneOR24, -C1- 6alkyleneSO2R24,
Rs and Rt are independently hydrogen, halo, or C1-6alkyl; and wherein:
R20, R21, R22, R23, R24 and R25 are independently optionally substituted C1-6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, optionally substituted cycloalkyl, optionally substituted
cycloalkylC1-6alkyl, optionally substituted heterocyclyl, optionally substituted
heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21, R22 and R23, and R24 and R25 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl.
Claims:
1. A compound of formula (I):

or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
X is O, NR7 or CR7R8;
Y is O or S;
Z is NR19, O or S;
Het is heterocyclyl or heteroaryl;
R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1- 6alkyl, amino-C1-6alkyl, -O-C(O)-O-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl; and
R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl,
C2-6alkenyl, and C2-6alkynyl; or
R1a and R1b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl;
R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxy-C1- 6alkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl;
R2b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl,
C2-6alkenyl, and C2-6alkynyl; or
R2a and R2b, together with the carbon atom to which they are attached, form a C=CH2 or C=C(H)C1-6alkyl;
R3 is selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, and -(CH2)-C(O)OR9;
R4 is selected from heteroaryl, alkyl, -C(O)OR9, -C(O)NR11R12, -S(O)2R10,
-P(O)(OR11)(OR12), and -P(O)(OR11)(NR13R15);
R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9;
R6 is selected from -C(O)OR9 and -P(O)(OR11)(OR12);
each R7 and R8 is H
R9 is independently selected from H, alkyl, acyloxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and -(CHR13)m-Z-C(O)-R14;
each R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and each R11 and R12 is independently selected from H, alkyl,
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl and -(CHR13)m-Z-C(O)-R14; or
R11 and R12, together with the atoms to which they are attached, form a 5- to 7-membered heterocyclyl; and
each R13 is independently H or alkyl;
each R14 is independently selected from alkyl, aminoalkyl, heterocyclyl, and heterocyclylalkyl;
R15 is selected from alkyl, aralkyl,–C(R16)(R17)-C(O)O-R18;
each R16 and R17 are selected from H, alkyl, amino-alkyl, hydroxy-alkyl, mercapto-alkyl, sulfonyl-alkyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaralkyl, and -(CH2)C(O)OR9;
R18 is selected from H, alkyl, alkoxyalkyl, aminoalkyl, haloalkyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
R19 is H or alkyl, preferably H; and
m is 1 or 2;
provided that either R4 is tetrazolyl, or R5 is aralkyl or heteroaralkyl, or both.
2. The compound of claim 1, wherein R1a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2- 6alkenyl, and C2-6alkynyl.
3. The compound of claim 1, wherein R1a is fluoro.
4. The compound of claim 1, wherein R1a is chloro.
5. The compound of claim 1, wherein R1a is bromo.
6. The compound of claim 1, wherein R1a is C1-6alkoxy.
7. The compound of claim 1, wherein R1a is C1-6alkyl.
8. The compound of claim 1, wherein R1a is hydroxy.
9. The compound of claim 1, wherein R1a is cyano.
10. The compound of claim 1, wherein R1a is azido.
11. The compound of claim 1, wherein R1a is amino.
12. The compound of claim 1, wherein R1a is vinyl.
13. The compound of claim 1, wherein R1a is ethynyl.
14. The compound of claim 1, wherein R1a is hydrogen.
15. The compound of claim 1, wherein R2a is selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyC1-6alkyl, amino-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2- 6alkenyl, and C2-6alkynyl.
16. The compound of any preceding claim, wherein R2a is fluoro.
17. The compound of any one of claims 1-14, wherein R2a is chloro.
18. The compound of any one of claims 1-14, wherein R2a is bromo.
19. The compound of any one of claims 1-14, wherein R2a is C1-6alkoxy. 20. The compound of any one of claims 1-14, wherein R2a is C1-6alkyl. 21. The compound of any one of claims 1-14, wherein R2a is hydroxy. 22. The compound of any one of claims 1-14, wherein R2a is cyano. 23. The compound of any one of claims 1-14, wherein R2a is azido.
24. The compound of any one of claims 1-14, wherein R2a is amino. 25. The compound of any one of claims 1-14, wherein R2a is vinyl.
26. The compound of any one of claims 1-14, wherein R2a is ethynyl. 27. The compound of any one of claims 1-14, wherein R2a is C1-6acyloxy. 28. The compound of any preceding claim, wherein R1b is H.
29. The compound of any one of claims 1-28, wherein R1b is fluoro. 30. The compound of any one of claims 1-28, wherein R1b is C1-6alkyl. 31. The compound of any preceding claim, wherein R2b is H.
32. The compound of any one of claims 1-30, wherein R2b is fluoro. 33. The compound of any one of claims 1-30, wherein R2b is C1-6alkyl. 34. The compound of claim 1, wherein R1a is fluoro and R1b is H.
35. The compound of claim 1, wherein R2a is fluoro and R2b is H.
36. The compound of claim 1, wherein R1a and R1b are each fluoro.
37. The compound of claim 1, wherein R2a and R2b are each fluoro.
38. The compound of claim 1, wherein R1a is fluoro and R2a is C1-6alkoxy.
39. The compound of claim 1, wherein R1a is fluoro and R2a is C1-6alkyl.
40. The compound of claim 1, wherein R1a is fluoro and R2a is methyl or ethyl.
41. The compound of claim 1, wherein R1a is hydroxy and R2b is methyl.
42. The compound of claim 1, wherein R1a is fluoro and R2a is hydroxy.
43. The compound of claim 1, wherein R1a is chloro and R2a is hydroxy.
44. The compound of claim 1, wherein R1a is hydroxy and R2a is hydrogen.
45. The compound of claim 1, wherein R1a is fluoro and R2a is hydrogen.
46. The compound of claim 1, wherein R1a is hydroxy and R2a is C1-6alkoxy.
47. The compound of claim 1, wherein R1a is hydroxy and R2a is fluoro.
48. The compound of claim 1, wherein R1a is hydroxy and R2a and R2b, together with the carbon atom to which they are attached, form an ethynyl.
49. The compound of claim 1, wherein R1a is hydroxy and R2a is C1-6alkyl.
50. The compound of claim 1, wherein R1a is fluoro, R2a is fluoro and R2a is hydroxy.
51. The compound of claim 1, wherein R1a is hydroxy and R2a is hydroxyl and R2b is C1-6alkynyl.
52. The compound of claim 1, wherein R1a is hydroxy and R2a is C1-6alkynyl.
53. The compound of claim 1, wherein R1a is hydroxy and R2a is C2-6alkenyl.
54. The compound of claim 1, wherein R1a is hydroxy and R2a is amino.
55. The compound of claim 1, wherein R1a is hydroxy and R2a is azido.
56. The compound of claim 1, wherein R1a is azido and R2a is hydroxy.
57. The compound of claim 1, wherein R1a is C1-6alkyl and R2a is hydroxyl.
58. The compound of any preceding claim, having the structure:

.
59. The compound of any preceding claim, wherein R1a is in the α-configuration.
60. The compound of claim 59, wherein the compound of Formula (I) has the structure (IA):

.
(IA)
61. The compound of any one of claims 1-58, wherein R1a is in the β-configuration.
62. The compound of claim 61, wherein the compound of Formula (I) has the structure (IB):
.

63. The compound of any preceding claim, wherein R2a is in the α-configuration.
64. The compound of claim 63, wherein the compound of Formula (I) has the structure (IC):

.
(IC)
65. The compound of any one of claims 1-62, wherein R2a is in the β-configuration.
66. The compound of claim 65, wherein the compound of Formula (I) has the structure (ID):

.
(ID)
67. The compound of claim 68, wherein the compound of Formula (I) has the structure (IE):

.
(IE)
68. The compound of any preceding claim, wherein R3 is H.
69. The compound of any one of claims 1-67, wherein R3 is unsubstituted C1-6alkyl.
70. The compound of any one of claims 1-67, wherein R3 is alkyl, and the alkyl is unsubstituted or substituted with one or more substituents selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.
71. The compound of claim 70, wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.
72. The compound of any preceding claim, wherein R3 is in the R-configuration.
73. The compound of any one of claims 1-69, wherein R3 is in the S-configuration.
74. The compound of any preceding claim, wherein R4 is heteroaryl.
75. The compound of any preceding claim, wherein R4 is tetrazolyl.
76. The compound of any preceding claim, wherein R4 is selected from -C(O)OR9, -C(O)NR11R12, -S(O)2R10, and -P(O)(OR11)(OR12).
77. The compound of any preceding claim, wherein R4 is -C(O)OR9.
78. The compound of any one of claims 1-73, wherein R4 is alkyl.
79. The compound of any one of claims 1-74, wherein R4 is -C(O)NR11R12.
80. The compound of any preceding claim, wherein R5 is selected from alkyl,
cycloalkylalkyl, heterocyclylalkyl, aralkyl and heteroaralkyl, and each is unsubstituted or substituted with one or more substituents, selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, phosphinate, cycloalkyl, heterocyclyl, arylalkyl and heteroarylalkyl.
81. The compound of claim 80, wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.
82. The compound of any preceding claim, wherein R5 is selected from H, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, and heteroaralkyl.
83. The compound of any preceding claim, wherein R5 is H, aralkyl, or heteroaralkyl.
84. The compound of any preceding claim, wherein R5 is H or aralkyl.
85. The compound of any one of claims 1-83, wherein R5 is aralkyl or heteroaralkyl.
86. The compound of claim 85, wherein R5 is heteroaralkyl, wherein the heteroaryl ring is selected from benzofuranyl, benzothienyl, benzothiazolyl, pyridyl, thienyl, furanyl, pyrazolyl, thiazolyl, and oxazolyl, and oxadiazolyl, each of which may be substituted or unsubstituted.
87. The compound of any one of claims 85-86, wherein R5 is unsubstituted or substituted with one or more substituents selected from halo, CN, OH, alkyl, alkenyl, haloalkyl,
hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl.
88. The compound of claim 87, wherein the substituents are selected from halo, CN, haloalkyl, haloalkoxy, carboxy, alkoxycarbonyl, and aryl.
89. The compound of claim 87, wherein the substituents are selected from tetrazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl.
90. The compound of any one of claims 1-83, wherein R5 is CH2-pyridinyl.
91. The compound of any one of claims 1-83, wherein R5 is -CH2-thiophenyl.
92. The compound of any one of claims 1-83, wherein R5 is benzyl or β-naphthyl.
93. The compound of claim 87, wherein R5 is unsubstituted or substituted with one or more substituents, selected from chloro, trifluoromethyl, trifluoromethoxy, phenyloxy, dimethylamido, methylsulfonyl, CN, and carboxylic acid.
94. The compound of any preceding claim, wherein R6 is -C(O)OR9.
95. The compound of any one of claims 1-93, wherein R6 is -P(O)(OR11)(OR12), and R11 and R12 are each H.
96. The compound of any preceding claim, wherein R7 is H or C1-6alkyl.
97. The compound of any preceding claim, wherein R8 is H.
98. The compound of any preceding claim, wherein R9 is H, C1-6alkyl or amido.
99. The compound of any preceding claim, wherein R9 is H, methyl or ethyl.
100. The compound of any preceding claim, wherein R11 and R12 are each H.
101. The compound of any one of claims 1-99, wherein R11 and R12 are each alkyl.
102. The compound of any one of claims 1-95, wherein each R7, R8, R9, R10, R11 and R12 is independently selected from alkyl, alkenyl, alkynyl, amido, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, and each is unsubstituted or substituted, with one or more selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.
103. The compound of claim 102, wherein the substituents on each R7, R8, R9, R10, R11 and R12 are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.
104. The compound of any preceding claim, wherein X is O.
105. The compound of any preceding claim, wherein Y is O.
106. The compound of any preceding claim, wherein the Y-bearing substituent is in the R-configuration.
107. The compound of any one of claims 1-105, wherein the Y-bearing substituent is in the S-configuration.
108. The compound of any preceding claim, wherein Z is O.
109. The compound of any preceding claim, wherein Het is a nitrogen-containing heterocyclyl or heteroaryl.
110. The compound of any preceding claim, wherein Het is attached via a nitrogen atom.
111. The compound of any one of claims 1-107, wherein Het is attached via a carbon atom.
112. The compound of any preceding claim, wherein Het is a 5- to 8-membered monocyclic or 5- to 10-membered bicyclic heteroaryl and is unsubstituted or substituted, with one or more substituents selected from halo, CN, NO2, azido, hydroxy, alkoxy, alkylthio, thioalkoxy, carbonyl, thiocarbonyl, amidino, imino, amino, amido, alkoxycarbonyl, carbamate, urea, sulfinamido, sulfonamido, sulfinyl, sulfinamido, sulfonyl, phosphoryl, phosphate, phosphonate, and phosphinate.
113. The compound of claim 112, wherein the substituents are selected from halo, CN, azido, alkoxy, carbonyl, amino, amido, and alkoxycarbonyl.
114. The compound of any preceding claim, wherein Het is selected from purinyl, imidazopyrimidinyl, and pyrrolopyrimidinyl.
115. The compound of any preceding claim, wherein Het is substituted with one halo and one amino substituent.
116. The compound of any one of claims 1-110, wherein Het is

.
117. The com ound of claim 1 wherein Het is selected from

.
118. The compound of claim 1, wherein Het is substituted with one or two substituents selected from halo, aralkyl, amino, azido and hydroxy.
119. The compound of claim 118, wherein Het is selected from

120. The compound of claim 1, wherein


121. The compound of claim 1, wherein
,

,

,

122. The compound of claim 1, wherein represents


where each RA is independently selected from H, halo, CN, OH, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylsulfonyl, sulfonamido, amido, amino, hydroxycarbonyl, alkoxycarbonyl, heteroaryl, aryl, aralkyl, and heteroaralkyl; and
k is 1, 2, or 3.
123. The compound of claim 122, wherein RA is selected from pyridyl, pyrazolyl, pyrrolidinonyl, azapanonyl, morpholinonyl, piperazonyl, tetrahydropyrimidinonyl, phenyl, and benzyloxy.
124. The compound of claim 1, having the structure:

wherein:
R5 is:
(i) phenylC1-6alkyl or naphthylC1-6alkyl wherein phenyl and naphthyl are optionally substituted with one, two, or three substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,– COOC1-6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1- 6alkylene-CO2C1-6alkyl, or -C1-6alkylene- substituted with one or two substituents
independently selected from hydroxy, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four
heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1- 6alkylene-heterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,– COheterocyclyl,–CONRmRi,–CONRmC1-6alkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and–CONHSO2Rz; or
(ii) 5-10 membered heteroarylC1-6alkyl having one to three heteroatoms independently selected from N, O, or S and 5-10 membered heteroaryl in 5-10 membered heteroarylC1-6alkyl is optionally substituted with one or two substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,–COOC1-6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two hydroxyl, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1- 6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four
heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,– COheterocyclyl,–CONRmRi,–CONRmalkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and–CONHSO2Rz; and
the R55-10 membered heteroaryl ring is additionally optionally substituted with an additional substituent selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy; wherein:
each Rm is hydrogen or -C1-6alkyl;
Ro, Rp, and Ry are each independently hydrogen or -C1-6alkyl;
Rz is -C1-6alkyl, -NHC1-6alkyl, or–N(C1-6alkyl)2;
phenyl by itself or as part of -C1-6alkylenephenyl, phenoxy, or -OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1- 6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2;
each Ri is independently 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S and wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, and -C1-6alkylene-CO2C1-6alky, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, - SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2l;
heterocyclyl by itself or as part of -C1-6alkyleneheterocyclyl, -OC1- 6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, - NRmCOC1-6alkylene-heterocyclyl,–COheterocyclyl, or -NRmCOheterocyclyl is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo,– COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, or -C1-6alkyl (substituted with hydroxy or -OC1- 6alkyl); and
Het is a group selected from a group of formula (i) through (xvi) below:

wherein:
Ru is hydrogen, halo, cyano, -NH2, -NHR20, -NHCOR20, -NR20R21, -R20, -SR20, -OH, and
-OR20;
Rw is hydrogen, halo, -NHR22, -NR22R23, -R22, -OH, and -OR22;
Rv and Rx are independently hydrogen, halo, haloC1-6alkyl, -NH2, -NHR24,
-NR24R25, -R24, -SR24, cyano, -OH, -OR24, -SO2R24, -C1-6alkyleneNH2, -C1-6alkyleneNHR24, -C1-6alkyleneNR24R25, -R24, -C1-6alkyleneSR24, -C1-6alkyleneOH, -C1-6alkyleneOR24, -C1- 6alkyleneSO2R24,
Rs and Rt are independently hydrogen, halo, or C1-6alkyl; and wherein:
R20, R21, R22, R23, R24 and R25 are independently optionally substituted C1-6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted
heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21, R22 and R23, and R24 and R25 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl;
and further wherein, unless otherwise specified:
C1-6alkyl is unsubstituted;
C1-6alkyl of C1-6alkyloxy is unsubstituted;
haloC1-6alkyl is C1-6alkyl substituted with one to five halo atoms;
haloC1-6alkyloxy is C1-6alkyloxy substituted with one to five halo atoms;
C2-6alkenyl is unsubstituted;
C2-6alkynyl is unsubstituted;
C1-6alkylene is unsubstituted;
C2-6alkenylene is unsubstituted;
optionally substituted C1-6alkyl is optionally substituted with one or two substituents
independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
carbocyclyl is an unsubstituted saturated or partially unsaturated mono or bicyclic ring
containing 3 to 10 carbon atoms;
optionally substituted carbocyclyl is optionally substituted with one, two, or three
substituents independently selected from C1-6alkyl, halo, hydroxy, or C1-6alkoxy; optionally substituted aryl is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH( C1-6alkyl), -N(C1-6alkyl)2;
aryl is phenyl or naphthyl;
optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl
[optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(unsubstitued C1-6alkyl)2]; heteroaryl is an unsubstituted five to ten membered or five to six membered aromatic ring containing one to four or one to three heteroatoms independently selected from N, O, and S; the remaining ring atoms being carbon;
optionally substituted heteroaryl is a five to ten membered aromatic ring containing one to four heteroatoms independently selected from N, O, and S; the remaining ring atoms being carbon, that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally substituted carbocyclyl, aryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1- 6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl [optionally substituted with one, two, or three substituents independently selected from hydroxy, unsubstituted C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl [optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2];
heterocyclyl is an unsubstituted monocyclic, saturated or partially unsaturated 4 to 8 membered ring containing one to three heteroatoms independently selected from N, O, S, SO, and SO2 and optionally contains one or two CO, the remaining atoms in the ring being carbon that is optionally fused to phenyl or 5 to 6 membered carbocyclyl or 5 or 6 heteroaryl ring;
nitrogen-containing heterocyclyl is a heterocyclyl ring that has at least a nitrogen atom;
optionally substituted heterocyclyl is heterocyclyl that is optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, optionally
substituted carbocyclyl, aryl [optionally substituted with one, two, or three
substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), and -N(C1-6alkyl)2], heteroaryl
[optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1-6alkyl, haloC1-6alkyloxy, cyano, -NH2, - NH(C1-6alkyl), -N(C1-6alkyl)2], and heterocyclyl optionally substituted with one, two, or three substituents independently selected from hydroxy, C1-6alkyloxy, halo, haloC1- 6alkyl, haloC1-6alkyloxy, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2];
optionally substituted carbocyclyl C1-6alkyl is optionally substituted carbocyclyl attached via C1-6alkyl;
optionally substituted heterocyclylC1-6alkyl is optionally substituted heterocyclyl attached via C1-6alkyl;
optionally substituted arylC1-6alkyl is optionally substituted aryl attached via C1-6alkyl; and optionally substituted heteroarylC1-6alkyl is optionally substituted heteroaryl attached via C1- 6alkyl;
125. The compound of claim 124 having the structure:

.
126. The compound of claim 124 or 125 wherein:
R5 is phenylC1-6alkyl wherein phenyl is optionally substituted with one or two substituents independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1- 6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two– OC1-6alkyl), -CO2H,–COOC1-6alkyl, halo, hydroxy, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, - C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1- 6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, phenoxy, benzyl, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four
heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1- 6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1- 6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1- 6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkylene-heterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCO-heterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi,–CONRmalkylene-Ri, and–
CONHSO2Rz ; and
additionally the R5 phenyl is optionally substituted with an additional substituent selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxyl; wherein:
phenyl by itself or as part of phenoxy, benzyl, or -OC1-6alkylenephenyl is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, or -CON(C1-6alkyl)2.
127. The compound of claim 124 or 125 wherein:
R5 is benzyl wherein phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached -CH2- group of the benzyl ring and which one substituent is selected from–C1-6alkyl,–OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1- 6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1-6alkylene-CO2C1-6alkyl, -CO2H,–COOC1-6alkyl, halo, hydroxy, cyano, nitro, -PO3H2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1- 6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxy, NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1- 6alkyl), phenyl, phenoxy, benzyl, benzyloxy, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1- 6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkylene-heterocyclyl, -SC1-6alkylene-heterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi, and –CONRmalkylene-Ri; and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy; wherein
phenyl by itself or as part of benzyl, phenoxy, or benzyloxy is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H, –COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1- 6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2.
128. The compound of claim 124 or 125 wherein:
R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached to the -CH2- group of the benzyl ring, which one substituent is selected from -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkyl substituted with hydroxy, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -OC1-6alkylene-CO2H, -OC1- 6alkylene-CO2C1-6alkyl, -CO2H, nitro,–COOC1-6alkyl, halo, hydroxy, cyano, -CONReRf (where Re is hydrogen or -C1-6alkyl and Rf is -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, -NH2, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg is hydrogen or -C1-6alkyl and Rh is hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, furanyl, thienyl, pyrrolyl or isoxazolyl (wherein each of the aforementioned heteroaryl ring is optionally substituted with one or two substituents independently selected from C1-6alkyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl (substituted with one to five fluoro), tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2; and
the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
129. The compound of claim 124 or 125 wherein:
R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached to -CH2- group of the benzyl ring, with phenyl, benzyl, benzyloxy, or phenoxy [wherein the phenyl ring in each of aforementioned group is optionally substituted with one, two, or three substituents independently selected from hydroxy, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1- 6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1- 6alkyl)2]; and
R5 phenyl is further optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
130. The compound of claim 124 or 125 wherein:
R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the phenyl ring that is attached to -CH2- group of the benzyl ring, with haloC1-6alkoxy or haloC1-6alkyl, and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
131. The compound of claim 124 or 125 wherein:
R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the benzyl ring that is attached to the -CH2- group of the benzyl ring with -CO2H and the benzyl ring and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
132. The compound of claim 124 or 125 wherein:
R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the benzyl ring that is attached to the -CH2- group of the benzyl ring with -CO2Me or -CO2ethyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
133. The compound of claim 124 or 125 wherein:
R5 is benzyl wherein the phenyl ring is substituted with one substituent that is at the meta or para position to the carbon atom of the benzyl ring that is attached to the -CH2- group of the benzyl ring with tetrazolyl and the R5 phenyl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
134. The compound of claim 124 or 125 wherein:
R5 is–CH2- or–(CH2)2-5-10 membered heteroaryl having one to three heteroatoms independently selected from N, O, or S and the heteroaryl ring is optionally substituted with one substituent, independently selected from -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl substituted with one to five fluoro, -OC1-6alkyl substituted with one to five fluoro, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, -C2-6alkenylene-CO2H, -C1-6alkyl substituted with one or two hydroxy, -OC1-6alkyl substituted with one or two hydroxy, -C1-6alkyl substituted with one or two–OC1-6alkyl, -OC1-6alkyl (substituted with one or two–OC1-6alkyl), -CO2H,–COOC1- 6alkyl, hydroxy, halo, nitro, -PO3H2, cyano, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, -CONReRf (where Re and Rf are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, or -C1-6alkyl substituted with one or two substituents independently selected from hydroxyl, -NHC1-6alkyl or–N(C1-6alkyl)2), -SO2(C1-6alkyl), -SO2NRgRh (where Rg and Rh are independently hydrogen, -C1-6alkyl, -C1-6alkylene-CO2H, or -C1-6alkylene-CO2C1-6alkyl), -SC1-6alkyl, -SOC1-6alkyl, -SO2NHCORj (where Rj is -C1-6alkyl, -NH2, -NHC1-6alkyl, or -N(C1-6alkyl)2), phenyl, -C1-6alkylenephenyl, phenoxy, -OC1-6alkylenephenyl, 5- or 6-membered monocyclic heteroaryl containing one to four heteroatoms independently selected from O, N, and S [wherein the heteroaryl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-
6alkyl, -OC1-6alkyl, -C1-6alkyl (substituted with one to five fluoro), -OC1-6alkyl (substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1- 6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2], -ORi, -C1-6alkylene-Ri, -OC1-6alkylene-Ri, -SRi, -SC1-6alkylene-Ri, heterocyclyl, -C1-6alkyleneheterocyclyl, -OC1-6alkyleneheterocyclyl, -SC1-6alkyleneheterocyclyl, -CONRmC1-6alkyleneheterocyclyl, -NRmCOC1-6alkyleneNRoRp, -NRmCOheterocyclyl, -NRmCOC1-6alkyleneheterocyclyl,–COheterocyclyl,–CONRmRi,– CONRmalkylene-Ri, -OCONRmRm, -NRm-CORy, -NRm-CO-NRmRy, -NRm-SO2-Ry, -NRm-SO2-NRmRy, and–CONHSO2Rz; and
the R5 heteroaryl ring is additionally optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxyl.
135. The compound of claim 124 or 125 wherein:
R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with phenyl [wherein the phenyl ring is optionally substituted with one, two, or three substituents independently selected from hydroxyl, halo, CN, -CO2H,–COOC1-6alkyl, -C1-6alkyl, -OC1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), -C1-6alkylene-CO2H, -C1-6alkylene-CO2C1-6alkyl, tetrazolyl, -SO2C1-6alkyl, -SO2NH2, -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, and -CON(C1-6alkyl)2]; and
the R5 heteroaryl ring is further optionally substituted with one or two substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
136. The compound of claim 124 or 125 wherein:
R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with haloC1-6alkoxy or haloC1-6alkyl and the R5 heteroaryl ring is additionally optionally substituted with one or two
substituents independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
137. The compound of claim 124 or 125 wherein:
R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with -CO2H and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents
independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
138. The compound of claim 124 or 125 wherein:
R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with -CO2C1-6alkyl and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents
independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
139. The compound of claim 124 or 125 wherein:
R5 is 5-10 membered heteroarylC1-6alkyl having one to 3 heteroatoms independently selected from N, O, or S wherein heteroaryl ring is substituted with tetrazolyl and the R5 heteroaryl ring is additionally optionally substituted with one or two substituents
independently selected from -C1-6alkyl, -C1-6alkyl (wherein alkyl is substituted with one to five fluoro), -O-C1-6alkyl, -OC1-6alkyl (wherein alkyl is substituted with one to five fluoro), halo, CN, -NH2, and hydroxy.
140. The compound of any one of claims 124-139 wherein:
the R55-10 membered heteroaryl ring is selected from thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, oxazolyl, oxadiazolylo, isoxazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, indolyl, quinolinyl, or isoquinolinyl, and benzothienyl.
141. The compound of any one of claims 124-139 wherein Het is a group of formula (iii).
142. The compound of any one of claims 124 to 141 wherein Rs is hydrogen.
143. The compound of any one of claims 124 to 142 and wherein Rw and Rd are hydrogen.
144. The compound of any one of claims 124 to 143 wherein Ru is hydrogen, halo, cyano, -NH2, -NHR20, -NHCOR20, -NR20R21, -R20, -SR20, or -OR20 wherein R20 and R21 are independently optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl;
Rv is hydrogen, halo, haloC1-6alkyl, cyano, -R24, -SR24, -OR24, or -SO2R24; wherein: R24 is optionally substituted C1-6alkyl, -C2-C6alkenyl, -C2-C6alkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl.
145. The compound of any one of claims 124 to 144 wherein:
Ru is -NH2, -NHR20, or -NR20R21 wherein R20 and R21 are independently optionally substituted C1-6alkyl, optionally substituted carbocyclyl, optionally substituted carbocyclyl C1-6alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-6alkyl, optionally substituted aryl, optionally substituted arylC1-6alkyl, optionally substituted heteroaryl, or optionally substituted heteroarylC1-6alkyl; or R20 and R21 together with the nitrogen to which they are attached form an optionally substituted nitrogen-containing heterocyclyl.
146. The compound of any one of claims 124 to 145 wherein Ru is NH2 and Rv is chloro.
147. A compound selected from:




or a pharmaceutically acceptable salt thereof.
148. A compound selected from:
,
,
,

, and

, or a pharmaceutically acceptable salt thereof.
149. A pharmaceutical composition comprising a compound according to any one of claims 1-148, or a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients.
150. A method of inhibiting CD73 in a cell, comprising contacting the cell with a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1-148.
151. The method of claim 150, wherein contacting the cell occurs in a subject in need thereof, thereby treating a disease or disorder selected from cancer, cerebral and cardiac ischemic diseases, fibrosis, immune and inflammatory disorders, inflammatory gut motility disorder, neurological, neurodegenerative and CNS disorders and diseases, depression, Parkinson’s disease, and sleep disorders.
152. The method of claim 151, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head & neck cancer, Kaposi’s sarcoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, myeloma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germcell cancer, thymoma and thymic carcinoma.
153. The method of claim 151 or 152, wherein the cancer is selected from breast cancer, brain cancer, colon cancer, fibrosarcoma, kidney cancer, lung cancer, melanoma, ovarian cancer, and prostate cancer.
154. The method of any one of claims 151-153, wherein the cancer is breast cancer.
155. The method of any one of claims 151-154, further comprising conjointly
administering one or more additional chemotherapeutic agents.
156. The method of claim 155, wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette–Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine,
lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib,
pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other
embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA).
157. The method of claim 155, wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.
158. The method of claim 155, wherein the additional chemotherapeutic agent is an immuno-oncology agent.