Non nucleoside reverse transcriptase inhibitors

• US 20050197320A1
• Filed: 04/25/2003
• Published: 09/08/2005
• Est. Priority Date: 04/26/2002
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Xu, Lianhong, Kim, Choung U., Lee, Christopher P., Chen, Xiaowu, Chen, James M., Lee, William A., Nelson, Peter H., Tario, James D.
• Granted Patent: US 7,462,608 B2
• Time in Patent Office: Days
• US Class Current: 514/80
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/85 in position 3
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/20 One oxygen atom attached in position 3 or 5
• CPC Class Codes: C07D 233/42 Sulfur atoms
• CPC Class Codes: C07D 239/49 with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
• CPC Class Codes: C07D 239/80 Oxygen atoms
• CPC Class Codes: C07D 243/04 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07D 265/18 with hetero atoms directly attached in position 2
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/14 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/645 : having two nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07F 9/6506 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/650905 : having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/650947 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/6512 : having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65128 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65335 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65515 : the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 : containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C12N 9/16 : acting on ester bonds (3.1)
• CPC Class Codes: C12Q 1/18 : Testing for antimicrobial activity of a material
• CPC Class Codes: C12Q 1/37 : involving peptidase or proteinase
• CPC Class Codes: C12Q 1/44 : involving esterase
• CPC Class Codes: C40B 40/04 : Libraries containing only organic compounds
• CPC Class Codes: G01N 2333/16 : HIV-1, HIV-2
• CPC Class Codes: G01N 2500/04 : Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/5038 : involving detection of metabolites per se

Abstract

Phosphorus-substituted imidazole compounds with anti-HIV properties having use as therapeutics and for other industrial purposes are disclosed. The compositions inhibit reverse transcriptase activity and are useful therapeutically for the inhibition of such enzymes, as well as in assays for the detection of such enzymes.

Claims

1. A non-nucleoside reverse transcriptase inhibitor compound comprising a phosphonate group.

2. A non-nucleoside reverse transcriptase inhibitor of claim 1 selected from:

Capravirine-like phosphonate NNRTI compounds,

PETT-like phosphonate NNRTI compounds,

Pyrazole-like phosphonate NNRTI compounds,

Urea-PETT-like phosphonate NNRTI compounds,

Nevaripine-like phosphonate NNRTI compounds,

Quinazolinone-like phosphonate NNRTI compounds,

Efavirenz-like phosphonate NNRTI compounds,

Benzophenone-like phosphonate NNRTI compounds,

Pyrimidine-like phosphonate NNRTI compounds,

SJ3366-like phosphonate NNRTI compounds,

Delavirdine-like phosphonate NNRTI compounds,

Emivirine-like phosphonate NNRTI compounds,

Loviride-like phosphonate NNRTI compounds, and

UC781-like phosphonate NNRTI compounds;

and pharmaceutically acceptable salts, hydrates, and formulations thereof.

3. A compound according to claim 1 selected from the Formulas:

4. A compound of claim 3 having Formula Ia:

5. A compound of claim 3 having Formula Ib:

6. A compound of claim 3 having Formula Ic:

7. A compound of claim 3 having Formula Id:

8. A compound of claim 3 having the formulas:

9. A compound of claim 3 having the formulas:

10. A compound of claim 3 having the formulas:

11. A compound of claim 3 having the formulas:

12. A compound of claim 3 having the formulas:

13. A compound of claim 3 having the formulas:

14. A compound of claim 3 having the formulas:

15. A compound of claim 3 having the formulas:

16. A compound of claim 3 having the formulas:

17. A compound of claim 3 having the formulas:

18. A compound of claim 3 having the formulas:

19. A compound of claim 3 having the formulas:

20. The compound of claim 3 wherein A¹ is of the formula:

21. The compound of claim 20 wherein A¹ is of the formula:

22. The compound of claim 21 wherein A¹ is of the formula:

23. The compound of claim 22 wherein A¹ is of the formula:

24. The compound of claim 23 wherein M12a is 1.

25. The compound of claim 23 wherein A¹ is selected from the formulas:

26. The compound of claim 3 wherein A³ is of the formula:

27. The compound of claim 26 wherein A³ is of the formula:

28. The compound of claim 27 wherein A³ is of the formula:

29. The compound of claim 28 wherein A³ is of the formula:

30. The compound of claim 29 wherein A³ is of the formula:

31. The compound of claim 30 wherein A³ is of the formula:

32. The compound of claim 31 wherein M12d is 1.

33. The compound of claim 3 wherein A³ is of the formula:

34. The compound of claim 33 wherein A³ is of the formula:

35. The compound of claim 34 wherein W⁵ is a carbocycle.

36. The compound of claim 35 wherein A³is of the formula:

37. The compound of claim 36 wherein W⁵ is phenyl.

38. The compound of claim 33 wherein M12b is 1.

39. The compound of claim 38 wherein A³ is of the formula:

40. The compound of claim 39 wherein A³ is of the formula:

41. The compound of claim 40 wherein A³ is of the formula:

42. The compound of claim 41 wherein R¹ is H.

43. The compound of claim 41 wherein M12d is 1.

44. The compound of claim 41 wherein A³ is of the formula:

45. The compound of claim 44 wherein Y^2b is N(R^x).

46. The compound of claim 45 wherein A³ is of the formula:

47. The compound of claim 44 wherein A³ is of the formula:

48. A compound of claim 3 wherein R^x is of the formula:

49. A compound of claim 48 wherein R^x is of the formula:

50. A compound of claim 48 wherein R^x is of the formula:

51. A compound of claim 50 wherein R^x is of the formula:

52. A compound of claim 51 wherein R^x is of the formula:

53. The compound of claim 3 wherein R^x is of the formula:

54. The compound of claim 53 wherein A³ is of the formula:

55. The compound of claim 3 wherein A³ is of the formula:

56. The compound of claim 55 wherein A³ is of the formula:

57. The compound of claim 56 wherein A³ is of the formula:

58. The compound of claim 57 wherein A³ is of the formula:

59. The compound of claim 58 wherein A³ is of the formula:

60. The compound of claim 59 wherein A³ is of the formula:

61. The compound of claim 60 wherein A³ is of the formula:

62. The compound of claim 3 wherein A³ is of the formula:

63. The compound of claim 62 wherein A³ is of the formula:

64. The compound of claim 63 wherein A³ is of the formula:

65. The compound of claim 64 wherein A³ is of the formula:

66. The compound of claim 65 wherein R¹ is H;

and Y^1a and Y^2d are O.

67. The compound of claim 66 wherein M12d is 1.

68. The compound of claim 3 wherein A¹ is of the formula:

69. The compound of claim 68 wherein A¹ is of the formula:

70. The compound of claim 69 wherein A¹ is of the formula:

71. The compound of claim 70 wherein A¹ is of the formula:

72. The compound of claim 71 wherein A¹ is of the formula:

73. The compound of claim 72 wherein A¹ is of the formula:

74. The compound of claim 3 wherein A¹ is of the formula:

75. The compound of claim 74 wherein A¹ is of the formula:

76. The compound of claim 75 wherein A¹ is of the formula:

77. The compound of claim 76 wherein A¹ is of the formula:

78. The compound of claim 77 wherein A³ is of the formula:

79. The compound of claim 75 wherein A¹ is of the formula:

80. The compound of claim 79 wherein A¹ is of the formula:

81. The compound of claim 3 wherein A² is of the formula:

82. The compound of claim 81 wherein A² is of the formula:

83. The compound of claim 82 wherein M12b is 1.

84. The compound of claim 82 where M12b is 0, Y² is a bond and W⁵ is a carbocycle or heterocycle where W⁵ is optionally and independently substituted with 1, 2, or 3 R² groups.

85. The compound of claim 82 wherein A² is of the formula:

86. The compound of claim 85 wherein M12a is 1.

87. The compound of claim 86 wherein A² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.

88. The compound of claim 3 wherein A is of the formula:

89. The compound of claim 88 wherein A² is of the formula:

90. The compound of claim 89 wherein M12b is 1.

91. The compound of claim 6 having the formula:

92. The compound of claim 91 wherein A² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.

93. The compound of claim 92 wherein substituted phenyl, substituted benzyl, and substituted pyridyl are independently substituted with 1, 2 or 3 R² groups.

94. The compound of claim 91 wherein A¹ is of the formula:

95. The compound of claim 94 wherein A³ is of the formula:

96. The compound of claim 94 wherein R^x is of the formula:

97. The compound of claim 96 wherein A³ is of the formula:

98. The compound of claim 95 wherein R^x is of the formula:

99. The compound of claim 98 wherein A³ is of the formula:

100. The compound of claim 91 having the formula:

101. The compound of claim 100 wherein R⁴ is isopropyl.

102. The compound of claim 100 having the formula:

103. The compound of claim 100 wherein A¹ is of the formula:

104. The compound of claim 103 wherein A³ is of the formula:

105. The compound of claim 104 wherein A³ is of the formula:

106. The compound of claim 105 wherein A³ is of the formula:

107. The compound of claim 106 wherein A¹ is of the formula:

108. The compound of claim 106 wherein A¹ is of the formula:

109. The compound of claim 102 wherein W⁵ is selected from the structures:

110. The compound of claim 91 wherein A¹ is of the formula:

111. The compound of claim 110 wherein R¹ is H and n is 1.

112. The compound of claim 5 having the formula:

113. The compound of claim 112 wherein A¹ is of the formula:

114. The compound of claim 113 wherein A³ is of the formula:

115. The compound of claim 113 wherein R^x is of the formula:

116. The compound of claim 115 wherein A³ is of the formula:

117. The compound of claim 113 wherein R^x is of the formula:

118. The compound of claim 117 wherein A³ is of the formula:

119. The compound of claim 112 wherein A² is selected from:

120. The compound of claim 112 having the formula:

121. The compound of claim 120 wherein A¹ is of the formula:

122. The compound of claim 120 wherein A³ is of the formula:

123. The compound of claim 112 wherein A³ is of the formula:

124. The compound of claim 112 wherein A¹ is of the formula:

125. The compound of claim 124 wherein A¹ is of the formula:

126. The compound of claim 125 wherein A¹ is of the formula:

127. The compound of claim 126 wherein A¹ is of the formula:

128. The compound of claim 112 wherein A² is a phenyl substituted with 0 to 3 R² groups.

129. The compound of claim 120 wherein W⁴ is of the formula:

130. The compound of claim 129 having the formula:

131. A compound of claim 130 selected from the formulas:

132. A compound of claim 6 selected from the structures:

133. A compound of claim 4 selected from the structures:

134. A compound of claim 6 selected from the structures:

135. A compound of claim 5 selected from the structures:

136. A compound of claim 5 selected from the structures:

137. A compound of claim 5 selected from the structures:

138. A compound of claim 5 selected from the structures:

139. A compound of claim 3 selected from the structures:

161. A method of inhibiting the activity of HIV RT comprising the step of contacting a sample suspected of containing HIV RT with a composition of claim 1.

162. The method of claim 161 wherein the HIV RT is in vivo.

163. A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal a formulation comprising a therapeutically effective amount of a compound according to claim 1.

164. The method of claim 163 wherein the compound is formulated with a pharmaceutically acceptable carrier.

165. A method of targetting white blood cells comprising administering to an HIV infected animal a formulation comprising a therapeutically effective amount of a compound according to claim 1 whereby the compound or metabolites derived from the compound accumulate in the white blood cells of the HIV infected animal.

166. The use of a compound of claim 1 to prepare a medicament for treatment of HIV infection.

167. The method of claim 163 wherein the formulation further comprises a second active ingredient selected from a protease inhibitor (Prt), a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and an integrase inhibitor.

168. A process for preparing a compound of claim 1 wherein a compound comprising A³ or a precursor to A³ is reacted with an imidazole compound whereby a compound of claim 1 is formed.

140. A compound of the formula:

141. The compound of claim 140 wherein:

A¹ is —

(C(R²)(R²))_m1—

W₃, wherein W₃ is substituted with 1 A₃ group;

A₂ is —

(C(R²)(R²))_m1—

W₃; and

A₃ is —

(C(R²)(R²))_m1—

P(Y₁)(Y₁R^6a)(Y₁R^6a).

142. The compound of claim 141 having the formula:

143. The compound of claim 142 having the formula:

144. The compound of claim 143 having the formula:

145. The compound of claim 144 having the formula:

146. The compound of claim 145 wherein W⁵ is selected from:

147. A compound of claim 140 having the formula:

148. A compound of the formula:

149. The compound of claim 148 wherein:

A¹ is —

(C(R²)(R²))_m1—

W₃, wherein W₃ is substituted with 1 A₃ group;

A₂ is —

(C(R²)(R²))_m1—

W₃; and

A₃ is —

(C(R²)(R²))_m1—

P(Y₁)(Y₁R^6a)(Y₁R^6a).

150. The compound of claim 148 having the formula:

151. The compound of claim 148 having the formula:

152. The compound of claim 151 having the formula:

153. The compound of claim 152 wherein W₃ is —

OC(O)NH₂.

154. The compound of claim 152 having the formula:

155. The compound of claim 151 having the formula:

156. The compound of claim 155 wherein W₅ is a pyridine heterocycle bonded to —

C(R₂)₂—

at the 2, 3, 4, 5 or 6 position.

157. The compound of claim 155 wherein W₅-A₃ has a formula selected from:

158. The compound of claim 155 wherein A₃ has a formula selected from:

159. The compound of claim 158 wherein A₃ has a formula selected from:

160. The compound of claim 159 wherein A₃ has a formula selected from:

169. A compound of the formula MBF.

170. In a non-nucleotide reverse transcriptase inhibitor, the improvement comprising a substituent having a phosphonate or phosphonate prodrug.

171. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 170 selected from:

Capravirine-like phosphonate NNRTI compounds,

PETT-like phosphonate NNRTI compounds,

Pyrazole-like phosphonate NNRTI compounds,

Urea-PETT-like phosphonate NNRTI compounds,

Nevaripine-like phosphonate NNRTI compounds,

Quinazolinone-like phosphonate NNRTI compounds,

Efavirenz-like phosphonate NNRTI compounds,

Benzophenone-like phosphonate NNRTI compounds,

Pyrimidine-like phosphonate NNRTI compounds,

SJ3366-like phosphonate NNRTI compounds,

Delavirdine-like phosphonate NNRTI compounds,

Emivirine-like phosphonate NNRTI compounds,

Loviride-like phosphonate NNRTI compounds, and

UC781-like phosphonate NNRTI compounds;

and pharmaceutically acceptable salts, hydrates, and formulations thereof.

172. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 170 of the Formulas:

173. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

174. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

175. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

176. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

177. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

178. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

179. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

180. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

181. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

182. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

183. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

184. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

185. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 172 of the Formulas:

186. In a non-nucleotide reverse transcriptase inhibitor not containing a phosphonate or phosphonate prodrug, the improvement comprising a substituent having a phosphonate or phosphonate prodrug.

187. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 186 selected from:

Capravirine-like phosphonate NNRTI compounds,

PETT-like phosphonate NNRTI compounds,

Pyrazole-like phosphonate NNRTI compounds,

Urea-PETT-like phosphonate NNRTI compounds,

Nevaripine-like phosphonate NNRTI compounds,

Quinazolinone-like phosphonate NNRTI compounds,

Efavirenz-like phosphonate NNRTI compounds,

Benzophenone-like phosphonate NNRTI compounds,

Pyrimidine-like phosphonate NNRTI compounds,

SJ3366-like phosphonate NNRTI compounds,

Delavirdine-like phosphonate NNRTI compounds,

Emivirine-like phosphonate NNRTI compounds,

Loviride-like phosphonate NNRTI compounds, and

UC781-like phosphonate NNRTI compounds;

and pharmaceutically acceptable salts, hydrates, and formulations thereof.

188. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 186 of the Formulas:

189. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

190. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

191. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

192. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

193. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

194. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

195. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

196. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

197. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

198. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

199. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

200. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

201. The improved non-nucleotide reverse transcriptase inhibitor compound of claim 188 of the Formulas:

202. An MBF compound of Table 100.

203. A compound described herein.

204. A compound of claim 203 described in the schemes or examples.

205. A method of making a compound described herein.

206. A method of claim 205 described in the schemes or examples.

207. The use of a compound described here for treatment of HIV in humans.

208. The method of claim 207 wherein the compound is described in the schemes or examples.

209. The use of a compound described here in the manufacture of a medicament.

210. The use of claim 209 wherein the compound is described in the schemes or examples.

211. An non-nucleotide reverse transcriptase inhibitor compound capable of accumulating in human PBMCs.

212. The compound of claim 211 further comprising a phosphonate or phosphonate prodrug.

213. The compound of claim 212 wherein the phosphonate or phosphonate prodrug are of the formula A³:

A³ is;

Y¹ is independently O, S, N(R^x), N(O)(R^x), N(OR^x), N(O)(OR^x), or N(N(R^x)(R^x));

Y² is independently a bond, O, N(R^x), N(O)(R^x), N(OR^x), N(O)(OR^x), N(N(R^x)(R^x)), —

S(O)_M2—

, or —

S(O)_M2—

S(O)_M2—

;

R^x is independently H, R¹, W³, a protecting group, or the formula;

R^y is independently H, W₃, R² or a protecting group;

R¹ is independently H or an alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³ groups;

R³ is R^3a, R^3b, R^3c or R^3d, provided that when R³ is bound to a heteroatom, then R³ is R^3c or R^3d;

R^3a is F, Cl, Br, I, —

CN, N₃ or —

NO₂;

R^3b is Y¹;

R^3c is —

R^x, —

N(R^x)(R^x), —

SR^x, —

S(O)R^x, —

S(O)₂R^x, —

S(O)(OR^x), —

S(O)₂(OR^x), —

OC(Y¹)R^x, —

OC(Y¹)OR^x, —

OC(Y¹)(N(R^x)(R^x)), —

SC(Y¹)R^x, —

SC(Y¹)OR^x, —

SC(Y¹)(N(R^x)(R^x)), —

N(R^x)C(Y¹)R^x, —

N(R^x)C(Y¹)OR^x, or —

N(R^x)C(Y¹)(N(R^x)(R^x));

R^3d is —

C(Y¹)R^x, —

C(Y¹)OR^x or —

C(Y¹)(N(R^x)(R^x));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —

C(Y¹)R⁵, —

C(Y¹)W⁵, —

SO₂R⁵, or —

SO₂W⁵;

W₅ is carbocycle or heterocycle wherein W₅ is independently substituted with 0 to 3 R² groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

214. The compound of claim 213 wherein the intracellular half-life of the compound or an intracellular metabolite of the compound in human PBMCs is improved when compared to an analog of the compound not having the phosphonate or phosphonate prodrug.

215. The compound of claim 214 wherein the half-life is improved by at least about 50%.

216. The compound of claim 214 wherein the half-life is improved by at least about 100%.

217. The compound of claim 214 wherein the intracellular half-life of a metabolite of the compound in human PBMCs is improved when compared to an analog of the compound not having the phosphonate or phosphonate prodrug.

218. The compound of claim 217 wherein the half-life is improved by at least about 50%.

219. The compound of claim 217 wherein the half-life is improved by at least about 100%.

220. The compound of claim 217 wherein the half-life is improved by greater than 100%.

221. Use of a compound of the invention for the treatment of HIV infection.

222. Use of a compound of the invention in the manufacture of a medicament.

223. Use of a compound of the invention in the manufacture of a medicament for the treatment of disorders affecting white blood cells.

224. Method of treating a disorder affecting white blood cells, comprising:

administering a compound of the invention to a patient in need of white-blood-cell targeting.

225. Method of targeting a compound to white blood cells, comprising:

selecting a compound having a desired pharmaceutical activity and having a first structure;

modifying said first structure by replacing one or more atom of said first structure with an organic substituent comprising a phosphonate group or incipient phosphonate group to provide a compound having a second structure.

226. A method of manufacturing a non-nucleoside compound having both selectivity for white blood cells and a desired pharmaceutical activity, comprising:

chemically synthesizing a first molecule having a first structure containing a phosphonate or precursor phosphonate group, wherein said first structure differs from a second structure of a compound known to have said desired pharmaceutical activity by having at least one hydrogen atom of said second structure replaced by an organic substituent comprising a phosphonate group or incipient phosphonate group.

227. The method of claim 226, wherein said first molecule is synthesized by a series of chemical reactions in which a hydrogen of said second structure is replaced by said organic substituent.

228. The method of claim 226, wherein said first molecule is synthesized by a series of chemical reactions that never includes a molecule of said second structure.

229. Method of accumulating an non-nucleotide reverse transcriptase inhibitor inside a white blood cell, comprising:

administering to a sample a composition comprising a compound of the invention.

230. The method of claim 229 wherein said sample is a patient.

231. The method of claim 229, wherein said compound of the invention has a chemical structure A-B, wherein (a) a compound having structure A-H has non-nucleotide reverse transcriptase inhibitor activity and (b) substructure B comprises a phosphonate group or a precursor phosphonate group.

232. Method of increasing half-life of a non-nucleoside compound having anti-retroviral activity, comprising:

replacing at least one hydrogen atom or organic radical of said compound by an organic substituent comprising a phosphonate group or incipient phosphonate.

233. Method of designing a drug having specificity for white blood cells for synthesis, comprising:

obtaining a first list of first compounds having a desired activity;

creating a second list of second compounds, each of said second compounds having a structure in which at least one hydrogen atom or organic radical of a compound of said first list has been replaced by an organic substituent comprising a phosphonate group or incipient phosphonate group; and

selecting a synthetic pathway capable of producing some or all of said second compounds from available starting materials, thereby providing a third list of compounds and associated synthetic techniques.

234. Method of manufacturing a pharmaceutical composition having said specificity of claim 233, comprising:

synthesizing a compound selected from said third list using said associated synthetic technique; and

admixing said synthesized compound with a pharmaceutically acceptable carrier.

235. A composition produced by the method of claim 234.

236. Method for producing a pharmaceutical composition having specificity for white blood cells, comprising:

admixing a therapeutically effective amount of a compound of the invention with a pharmaceutically acceptable carrier.