1,2,5-OXADIAZOLES AS INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE

• US 20100015178A1
• Filed: 07/07/2009
• Published: 01/21/2010
• Est. Priority Date: 07/08/2008
• Status: Active Grant

• Current Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation), Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Zhou, Jiacheng, Lin, Qiyan, Liu, Pingli, Yue, Tai-Yuen, Weng, Lingkai, Combs, Andrew P., Sparks, Richard B., Yue, Eddy W., Zhu, Wenyu
• Granted Patent: US 8,088,803 B2
• Time in Patent Office: Days
• US Class Current: 424/204.100
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 271/08 : 1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links

Abstract

The present invention is directed to 1,2,5-oxadiazole derivatives, and compositions of the same, which are inhibitors of indoleamine 2,3-dioxygenase and are useful in the treatment of cancer and other disorders, and to the processes and intermediates for making such 1,2,5-oxadiazole derivatives.

Claims

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein;

R¹ is NH₂ or CH₃;

R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R¹ is NH₂.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein, R¹ is CH₃.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is Cl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is Br.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is CF₃.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is CH₃.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R² is CN.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is H.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is F.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2.

13. A compound of claim 1 selected from:

4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide;

N-(3-Bromo-4-fluorophenyl)-N′

-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;

4-({3-[(Aminosulfonyl)amino]propyl}amino)-N-(3-bromo-4-fluorophenyl)-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide;

N-(3-Bromo-4-fluorophenyl)-N′

-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide;

4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-(3-chloro-4-fluorophenyl)-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide;

N-(3-Chloro-4-fluorophenyl)-N′

-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;

4-({3-[(Aminosulfonyl)amino]propyl}amino)-N-(3-chloro-4-fluorophenyl)-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide;

N-(3-Chloro-4-fluorophenyl)-N′

-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-1,2,5-oxadiazole-3-carboximidamide;

4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide;

N-[4-Fluoro-3-(trifluoromethyl)phenyl]-N′

-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}-amino)-1,2,5-oxadiazole-3-carboximidamide;

4-({3-[(Aminosulfonyl)amino]propyl}amino)-N-[4-fluoro-3-(trifluoromethyl)phenyl]-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide;

N-[4-Fluoro-3-(trifluoromethyl)phenyl]-N′

-hydroxy-4-({3-[(methylsulfonyl)amino]propyl}-amino)-1,2,5-oxadiazole-3-carboximidamide;

4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N′

-hydroxy-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;

N′

-Hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;

4-({3-[(Aminosulfonyl)amino]propyl}amino)-N′

-hydroxy-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;

N′

-Hydroxy-4-({3-[(methylsulfonyl)amino]propyl}amino)-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide;

N-(4-Fluoro-3-methylphenyl)-N′

-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;

4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-(3-cyano-4-fluorophenyl)-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide; and

N-(3-Cyano-4-fluorophenyl)-N′

-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide;

or a pharmaceutically acceptable salt thereof.

24. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

27. A method of inhibiting activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound of any one of claims 1, 25, or 26, or a pharmaceutically acceptable salt thereof.

28. A method of inhibiting immunosuppression in a patient comprising administering to said patient an effective amount of a compound of any one of claims 1, 25, or 26, or a pharmaceutically acceptable salt thereof.

29. A method of treating cancer, viral infection, depression, a neurodegenerative disorder, trauma, age-related cataracts, organ transplant rejection, or an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1, 25, or 26, or a pharmaceutically acceptable salt thereof.

30. The method of claim 29 further comprising administering to said patient an anti-viral agent, a chemotherapeutic, an immunosuppressant, radiation, an anti-tumor vaccine, an anti-viral vaccine, cytokine therapy, or a tyrosine kinase inhibitor.

31. A method of treating melanoma in a patient comprising administering to said patient a therapeutically effective amount of a compound of any one of claims 1, 25, or 26, or a pharmaceutically acceptable salt thereof.

32. The method of claim 31 further comprising administering to said patient a chemotherapeutic, radiation, an anti-tumor vaccine, or cytokine therapy.

14. A compound which is 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof.

15. A compound which is 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-(3-bromo-4-fluorophenyl)-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide.

16. A solid form of the compound of claim 15 which is crystalline.

17. A solid form of the compound of claim 15 which is substantially anhydrous.

18. A solid form of the compound of claim 15 having a melting point of about 162 to about 166°

C.

19. A solid form of the compound of claim 15 having a DSC thermogram substantially as shown in FIG. 2.

20. A solid form of the compound of claim 15 having at least one XRPD peak, in terms of 2-theta, selected from about 18.4°

, about 18.9°

, about 21.8°

, about 23.9°

, about 29.2°

, and about 38.7°

.

21. A solid form of the compound of claim 15 having at least two XRPD peaks, in terms of 2-theta, selected from about 18.4°

, about 18.9°

, about 21.8°

, about 23.9°

, about 29.2°

, and about 38.7°

.

22. A solid form of the compound of claim 15 having at least three XRPD peaks, in terms of 2-theta, selected from about 18.4°

, about 18.9°

, about 21.8°

, about 23.9°

, about 29.2°

, and about 38.7°

.

23. A solid form of the compound of claim 15 having an XRPD pattern substantially as shown in FIG. 1.

25. A compound which is 4-({2-[(aminosulfonyl)amino]ethyl}amino)-N-[(4-bromo-2-furyl)methyl]-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof.

26. A compound which is 4-({2-[(Aminosulfonyl)amino]ethyl}amino)-N-[(4-chloro-2-furyl)methyl]-N′

-hydroxy-1,2,5-oxadiazole-3-carboximidamide, or a pharmaceutically acceptable salt thereof.

33. A process for preparing a compound of Formula F15:

or a salt thereof, wherein R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2, comprising;

a) reacting a compound of Formula F13;

or a salt thereof, wherein Pg¹ is an amino protecting group, with an amino deprotecting agent to afford a compound of Formula F14;

or a salt thereof, and

b) reacting said compound of Formula F14 with a base to afford said compound of Formula F15.

34. The process of claim 33 wherein R² is Br, R³ is F, and n is 1.

35. The process of claim 33 wherein R² is Br, R³ is F, and n is 2.

36. The process of claim 33 wherein R² is Cl, R³ is F, and n is 1.

37. The process of claim 33 wherein R² is Cl, R³ is F, and n is 2.

38. The process of claim 33 wherein R² is CF₃, R³ is F, and n is 1.

39. The process of claim 33 wherein R² is CF₃, R³ is F, and n is 2.

40. The process of claim 33 wherein R² is CF₃, R³ is H, and n is 1.

41. The process of claim 33 wherein R² is CF₃, R³ is H, and n is 2.

42. The process of claim 33 wherein R² is CN, R³ is F, and n is 1.

43. The process of claim 33 wherein said Pg¹ is alkoxycarbonyl.

44. The process of claim 43 wherein said alkoxycarbonyl is tert-butoxycarbonyl.

45. The process of claim 33 wherein said amino deprotecting agent is trifluoroacetic acid.

46. The process of claim 33 wherein said amino deprotecting agent is hydrochloric acid.

47. The process of claim 46 wherein said reacting is performed in a solvent comprising dioxane.

48. The process of claim 46 wherein said reacting is performed in isopropanol.

49. The process of claim 33 wherein said base comprises an alkali metal hydroxide.

50. The process of claim 33 wherein said base is sodium hydroxide.

51. The process of claim 33 wherein said compound of Formula F13 is obtained by treating a compound of Formula F12:

or a salt thereof, with Pg¹-NH-sulfonyl chloride followed by treatment with an organic base to afford said compound of Formula F13.

52. The process of claim 51 wherein said Pg¹ comprises alkoxycarbonyl.

53. The process of claim 52 wherein said alkoxycarbonyl is tert-butoxycarbonyl.

54. The process of claim 51 wherein said treating is performed in a solvent.

55. The process of claim 51 wherein said treating is performed in a halogenated solvent.

56. The process of claim 55 wherein said halogenated solvent is dichloromethane.

57. The process of claim 51 wherein said organic base comprises a tri(C_1-6)alkylamine.

58. The process of claim 51 wherein said organic base is triethylamine.

59. The process of claim 51 wherein said compound of Formula F12 is obtained by reducing a compound of Formula F11:

or a salt thereof.

60. The process of claim 59 wherein said reducing is carried out in the presence of sodium iodide, chlorotrimethylsilane, and methanol.

61. The process of claim 59 further comprising purifying said compound of Formula F12 by:

a) reacting said compound of Formula F12 with an amino protecting agent to afford a compound of Formula F12′

;

or a salt thereof, wherein Pg²N is a protected amine;

b) purifying said compound of Formula F12′

to provide a purified compound of Formula F12′

; and

c) reacting said purified compound of Formula F12′

with an amino deprotecting agent to provide a purified compound of Formula F12.

62. The process of claim 61 wherein said amino protecting agent is di-t-butyl dicarbonate.

63. The process of claim 61 wherein said purifying is performed by chromatography on silica gel.

64. The process of claim 62 wherein said amino deprotecting agent is hydrochloric acid.

65. The process of claim 64 wherein said reacting is performed in a solvent comprising dioxane.

66. The process of claim 64 wherein said reacting is performed in isopropanol.

67. The process of claim 59 wherein said compound of Formula F11 is obtained by treating a compound of Formula F10:

or a salt thereof, wherein L¹ is selected from alkylsulfonyl, haloalkylsulfonyl, and arylsulfonyl;

with an azide reagent to afford said compound of Formula F11.

68. The process of claim 67 wherein L¹ is alkylsulfonyl.

69. The process of claim 68 wherein said alkylsulfonyl is methanesulfonyl.

70. The process of claim 67 wherein said azide reagent is sodium azide.

71. The process of claim 51 wherein said compound of Formula F12 is obtained by reacting a compound of Formula F24:

or a salt thereof, wherein Pg³N is a protected amine;

with an amino deprotecting agent to afford said compound of Formula F12.

72. The process of claim 71 wherein said protected amine is (C₆H₅)₃C—

NH.

73. The process of claim 71 wherein said protected amine is (C₆H₅)₂C═

N.

74. The process of claim 71 wherein said deprotecting agent comprises an organic acid.

75. The process of claim 71 wherein said deprotecting agent comprises an organic acid and an organosilane.

76. The process of claim 75 wherein said organic acid is trifluoroacetic acid and said organosilane comprises trialkylsilane.

77. The process of claim 76 wherein said trialkylsilane is tri(isopropyl)silane.

78. The process of claim 74 wherein said organic acid is trifluoroacetic acid.

79. The process of claim 71 wherein said compound of Formula F24 is obtained by treating a compound of Formula F22:

or a salt thereof, with a compound of Formula F25;

or a salt thereof, wherein Pg³N is a protected amine; and

a coupling reagent to provide said compound of Formula F24.

80. The process of claim 79 wherein said protected amine is (C₆H₅)₃C—

NH.

81. The process of claim 79 wherein said protected amine is (C₆H₅)₂C═

N.

83. The process of claim 79 wherein said coupling reagent comprises a tertiary phosphine and a dialkyl azodicarboxylate.

84. The process of claim 83 wherein said tertiary phosphine is a triarylphosphine.

85. The process of claim 84 wherein said triarylphosphine is triphenylphosphine.

86. The process of claim 83 wherein said dialkyl azodicarboxylate is diisopropyl azodicarboxylate.

82. A process for preparing a compound of Formula F8:

or a salt thereof, wherein, R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2;

comprising reacting a compound of Formula F22;

or a salt thereof, with a compound of Formula F25′

;

or a salt thereof, and a coupling reagent to provide said compound of Formula F8.

87. The process of claim 82 wherein said compound of Formula F22 is obtained by

a) treating a compound of Formula F21:

or a salt thereof, with carbonyl diimidazole to afford a compound of Formula F26;

or a salt thereof; and

b) treating said compound of Formula F26 with trifluoroacetic anhydride to afford said compound of Formula F22.

88. A process for preparing a compound of Formula F15:

or a salt thereof, wherein R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2, comprising;

a) reacting a compound of Formula F12;

or a salt thereof, with sulfamide and an organic base to afford a compound of Formula F14;

or a salt thereof, and

b) reacting said compound of Formula F14, or a salt thereof, with a base to afford said compound of Formula F15.

89. The process of claim 88 wherein said organic base comprises a heterocyclic base.

90. The process of claim 88 wherein said organic base is pyridine.

91. The process of claim 88 wherein reacting a compound of Formula F12 further comprises heating the reaction.

92. The process of claim 91 wherein said heating is performed using microwave irradiation.

93. The process of claim 88 wherein said base comprises an alkali metal hydroxide.

94. The process of claim 88 wherein said base is sodium hydroxide.

95. A compound of Formula F9:

or a salt thereof, wherein R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2.

96. The compound of claim 95 wherein R² is Br, R³ is F, and n is 1.

97. The compound of claim 95 wherein R² is Br, R³ is F, and n is 2.

98. The compound of claim 95 wherein R² is Cl, R³ is F, and n is 1.

99. The compound of claim 95 wherein R² is Cl, R³ is F, and n is 2.

100. The compound of claim 95 wherein R² is CF₃, R³ is F, and n is 1.

101. The compound of claim 95 wherein R² is CF₃, R³ is F, and n is 2.

102. The compound of claim 95 wherein R² is CF₃, R³ is H, and n is 1.

103. The compound of claim 95 wherein R² is CF₃, R³ is H, and n is 2.

104. The compound of claim 95 wherein R² is CH₃, R³ is F, and n is 1.

105. The compound of claim 95 wherein R² is CN, R³ is F, and n is 1.

106. A compound of Formula F12:

or a salt thereof, wherein R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2.

107. The compound of claim 106 wherein R² is Br, R³ is F, and n is 1.

108. The compound of claim 106 wherein R² is Br, R³ is F, and n is 2.

109. The compound of claim 106 wherein R² is Cl, R³ is F, and n is 1.

110. The compound of claim 106 wherein R² is Cl, R³ is F, and n is 2.

111. The compound of claim 106 wherein R² is CF₃, R³ is F, and n is 1.

112. The compound of claim 106 wherein R² is CF₃, R³ is F, and n is 2.

113. The compound of claim 106 wherein R² is CF₃, R³ is H, and n is 1.

114. The compound of claim 106 wherein R² is CF₃, R³ is H, and n is 2.

115. The compound of claim 106 wherein R² is CH₃, R³ is F, and n is 1.

116. The compound of claim 106 wherein R² is CN, R³ is F, and n is 1.

117. A compound of Formula F14:

or a salt thereof, wherein R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2.

118. The compound of claim 117 wherein R² is Br, R³ is F, and n is 1.

119. The compound of claim 117 wherein R² is Br, R³ is F, and n is 2.

120. The compound of claim 117 wherein R² is Cl, R³ is F, and n is 1.

121. The compound of claim 117 wherein R² is Cl, R³ is F, and n is 2.

122. The compound of claim 117 wherein R² is CF₃, R³ is F, and n is 1.

123. The compound of claim 117 wherein R² is CF₃, R³ is F, and n is 2.

124. The compound of claim 117 wherein R² is CF₃, R³ is H, and n is 1.

125. The compound of claim 117 wherein R² is CF₃, R³ is H, and n is 2.

126. The compound of claim 117 wherein R² is CH₃, R³ is F, and n is 1.

127. The compound of claim 117 wherein R² is CN, R³ is F, and n is 1.

128. A process for preparing a compound of Formula F19:

or a salt thereof, wherein R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2;

comprising;

a) reacting a compound of Formula F12;

or a salt thereof, with methanesulfonyl chloride in the presence of an organic base to afford a compound of Formula F20;

b) reacting said compound of Formula F20, or a salt thereof, with a base to afford said compound of Formula F19.

129. The process of claim 128 wherein said reacting a compound of Formula F12 further comprises a halogenated solvent.

130. The process of claim 129 wherein said halogenated solvent is dichloromethane.

131. The process of claim 128 wherein said organic base comprises a tri(C_1-6)alkylamine.

132. The process of claim 128 wherein said organic base is triethylamine.

133. The process of claim 128 wherein said base comprises an aqueous base.

134. The process of claim 128 wherein said base comprises an alkali metal hydroxide.

135. The process of claim 128 wherein said base comprises sodium hydroxide.

136. A process for preparing a compound of Formula F19:

or a salt thereof, wherein R² is Cl, Br, CF₃, CH₃, or CN;

R³ is H or F; and

n is 1 or 2;

comprising;

a) reacting a compound of Formula F17;

or a salt thereof, with hydrochloric acid followed by treatment with a nitrite reagent to afford a compound of Formula F18;

or a salt thereof; and

b) reacting said compound of Formula F18 with a compound of Formula F27;

or a salt thereof, to afford said compound of Formula F19.

137. The process of claim 136 wherein R² is Br, R³ is F, and n is 1.

138. The process of claim 136 wherein R² is Br, R³ is F, and n is 2.

139. The process of claim 136 wherein R² is Cl, R³ is F, and n is 1.

140. The process of claim 136 wherein R² is Cl, R³ is F, and n is 2.

141. The process of claim 136 wherein R² is CF₃, R³ is F, and n is 1.

142. The process of claim 136 wherein R² is CF₃, R³ is F, and n is 2.

143. The process of claim 136 wherein R² is CF₃, R³ is H, and n is 1.

144. The process of claim 136 wherein R² is CF₃, R³ is H, and n is 2.

145. The process of claim 136 wherein R² is CH₃, R³ is F, and n is 1.

146. The process of claim 136 wherein R² is CN, R³ is F, and n is 1.

147. The process of claim 136 wherein the nitrite reagent is aqueous sodium nitrite.

148. A compound of Formula F18:

or a salt thereof, wherein n is 1 or 2.

149. The compound of claim 148 wherein n is 1.

150. The compound of claim 148 wherein n is 2.

151. A process for preparing a compound of Formula F28:

or a salt thereof, wherein R⁴ is F, Cl, Br, or I; and

n is 1 or 2;

comprising;

a) reacting a compound of Formula F29;

or a salt thereof, with sulfamide and an organic base to afford a compound of Formula F30;

or a salt thereof, and

b) reacting said compound of Formula F30 with a base to afford said compound of Formula F28.

152. The process of claim 151 wherein R⁴ is Cl and n is 1.

153. The process of claim 151 wherein R⁴ is Br and n is 1.

154. The process of claim 151 wherein said organic base comprises a heterocyclic base.

155. The process of claim 151 wherein said organic base comprises pyridine.

156. The process of claim 151 wherein reacting a compound of Formula F29 further comprises heating the reaction.

158. The process of claim 151 wherein said base comprises an aqueous base.

159. The process of claim 151 wherein said base comprises an alkali metal hydroxide.

160. The process of claim 151 wherein said base comprises sodium hydroxide.

161. The process of claim 151 wherein said compound of Formula F29 is obtained by reducing a compound of Formula F31:

or a salt thereof.

162. The process of claim 161 wherein said reducing is carried out in the presence of sodium iodide, chlorotrimethylsilane, and methanol.

163. The process of claim 161 wherein said compound of Formula F31 is obtained by treating a compound of Formula F32:

or a salt thereof, wherein L¹ is selected from alkylsulfonyl, haloalkylsulfonyl, and arylsulfonyl;

with an azide reagent to afford said compound of Formula F31.

164. The process of claim 163 wherein L¹ is alkylsulfonyl.

165. The process of claim 164 wherein said alkylsulfonyl comprises methanesulfonyl.

166. The process of claim 163 wherein said azide reagent comprises sodium azide.

157. The process of claim 157 wherein said heating is performed using microwave irradiation.

167. A compound which is 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-chloro-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one, or a salt thereof.

168. A compound which is 3-{4-[(2-azidoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-chloro-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one, or a salt thereof.

169. A compound which is 4-[(4-chloro-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one, or a salt thereof.

170. A compound which is N-[(4-chloro-2-furyl)methyl]-N′

-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide, or a salt thereof.

171. A compound which is 3-{4-[(2-aminoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one, or a salt thereof.

172. A compound which is 3-{4-[(2-azidoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[(4-bromo-2-furyl)methyl]-1,2,4-oxadiazol-5(4H)-one, or a salt thereof.

173. A compound which is 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one, or a salt thereof.

174. A compound which is N-[(4-bromo-2-furyl)methyl]-N′

-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide, or a salt thereof.