Compositions and methods comprising 2-(acylamino)imidazoles

1. A composition for therapeutic use, the composition comprising: a pharmaceutically acceptable excipient and

a 2-(acylamino)imidazole compound selected from the group consisting of

and salts thereof

wherein:

R 1 is a member selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;

X is a member selected from the group consisting of a bond, O, and NR 5a ;

Y is a member selected from the group consisting of O, S, or NR 5b ; wherein when X is O or a bond, Y is O;

R 2 is a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, arylalkyl, acyl, and carbamoyl;

R 3 is alkyl;

R 4a and R 4b are each a member independently selected from the group consisting of hydrogen, alkyl, fluoro, fluoroalkyl, alkenyl, aryl, and heteroaryl; or, alternatively, the two R 4 join to form a spirocycloalkyl ring;

R 5a and R 5b are each a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl;

A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 are each independently selected from the group consisting of N and CR 6n ;

each of the R 6n members is independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, aminoalkoxy, alkylamino, alkylaminoalkoxy, alkenyl, alkynyl, aryl, aryloxy, arylamino, cycloalkyl, cycloalkylalkyl, cycloalkoxy, cycloalkylalkoxy, cycloalkylamino, cycloalkylalkylamino, heterocyclyl, heterocycyloxy, heterocycylamino, halo, haloalkyl, fluoroalkyloxy, heteroaryl, heteroaryloxy, heteroarylamino, arylalkyl, arylalkyloxy, arylalkylamino, heteroarylalkyl, heteroarylalkyloxy, and heteroarylalkylamino; or, alternatively, a pair of adjacent R 6n members join to form an additional fused ring that is selected from the group consisting of cycloalkyl, aryl, heterocyclyl, and heterocycloaryl; and

R 7 is a member independently selected from the group consisting of alkyl, aminoalkyl, alkenyl, arylalkyl, and heteroarylalkyl;

wherein the 2-(acylamino)imidazole has <2% (w/w) of N 2 ,N 2 -diacylation; and

wherein the 2-(acylamino)imidazole has <2% (w/w) of acyl regioisomers.

2. The composition of claim 1 , wherein the 2-(acylamino)imidazole compound is

or a salt thereof.

3. The composition of claim 2 , wherein the 2-(acylamino)imidazole compound is substantially free from a regioisomeric compound

or a salt thereof.

4. The composition of claim 1 , wherein the 2-(acylamino)imidazole compound is

or a salt thereof.

5. The composition of claim 1 , wherein the 2-(acylamino)imidazole compound is

or a salt thereof.

6. The composition of claim 4 , wherein the 2-(acylamino)imidazole compound is substantially free from a regioisomeric compound

or a salt thereof.

7. The composition of claim 1 , wherein the 2-(acylamino)imidazole compound is

or a salt thereof.

8. The composition of claim 7 , wherein the 2-(acylamino)imidazole compound is substantially free from a regioisomeric compound

or a salt thereof.

9. The composition of claim 1 , wherein R 1 is a member selected from the group consisting of alkyl, aryl, arylalkyl, and heteroaryl.

10. The composition of claim 9 , wherein R 1 is a member selected from the group consisting of isopropyl, sec-butyl, phenyl, 2-fluorophenyl, 2,4-dichlorophenyl, and 2-thiazolyl.

11. The composition of claim 1 , wherein X is a bond.

12. The composition of claim 1 , wherein Y is O.

13. The composition of claim 1 , wherein X is NR 5a ; and wherein Y is NR 5b .

14. The composition of claim 1 , wherein X is O; and wherein Y is O.

15. The composition of claim 1 , wherein R 2 is a member independently selected from the group consisting of hydrogen, alkyl, acyl, and carbamoyl.

16. The composition of claim 15 , wherein R 2 is a member independently selected from the group consisting of hydrogen and carbamoyl.

17. The composition of claim 16 , wherein R 2 is a member independently selected from the group consisting of hydrogen, tert-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

18. The composition of claim 1 , wherein R 3 is methyl.

19. The composition of claim 1 , wherein R 4a and R 4b are each a member independently selected from the group consisting of hydrogen, alkyl, fluoro, and fluoroalkyl.

20. The composition of claim 19 , wherein R 4a and R 4b are hydrogen.

21. The composition of claim 1 , wherein R 5a and R 5b are each a member independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl.

22. The composition of claim 1 , wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 is each an independently selected CR 6n .

23. The composition of claim 1 , wherein only one of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 is N.

24. The composition of claim 1 , wherein each of the R 6n members is independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkoxy, cycloalkylalkoxy, heterocyclyl, heterocycyloxy, halo, fluoroalkyl, fluoroalkyloxy, heteroaryl, heteroaryloxy, arylalkyl, arylalkyloxy, arylalkylamino, and heteroarylalkyloxy.

25. The composition of claim 1 , wherein each of the R 6n members is independently selected from the group consisting of hydrogen, alkyl, hydroxy, alkoxy, cycloalkylalkoxy, halo, fluoroalkyl, fluoroalkyloxy, and arylalkyloxy.

26. The composition of claim 1 , wherein each of the R 6n members is independently selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy.

27. The composition of claim 1 , wherein A 8 is C(OH) or C(OMe).

28. The composition of claim 1 , wherein at least six of the R 6n members are hydrogen.

29. The composition of claim 1 , wherein

has from one to three hydroxyl substituents.

30. The composition of claim 1 , wherein A 3 is C(OH) or C(OMe).

31. The pharmaceutical formulation of claim 1 , wherein

has from one to three hydroxyl substituents.

32. The composition of claim 1 , wherein A 8 is C(OH) or C(OMe).

33. The composition of claim 1 , wherein R 7 is alkyl or heteroarylalkyl.

34. The composition of claim 1 , the composition comprising a 2-(acylamino)imidazole compound

and a salt thereof;

wherein R 1 and Z are each selected from the group consisting of phenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2-thiazolyl, isopropyl, and sec-butyl; and

wherein A 8 is selected from the group consisting of CH and C(OMe).

35. The composition of claim 1 , the composition comprising a 2-(acylamino)imidazole compound

and a salt thereof;

wherein R 1 is selected from the group consisting of phenyl, 2-fluorophenyl, 2,4-dichlorophenyl, 2-thiazolyl, isopropyl, and sec-butyl.

36. The composition of claim 1 , the composition comprising a 2-(acylamino)imidazole compound

and a salt thereof;

wherein R 1 and Z are each selected from the group including phenyl, 2-fluorophenyl, 3-trifluoromethylphenyl, 4-chlorophenyl, 4-methoxyphenyl, and cyclopropyl; and

wherein A 8 is CCl.

37. The composition of claim 1 , the composition comprising a 2-(acylamino)imidazole compound selected from the group consisting of

and salts thereof.

38. The composition of claim 1 , the composition comprising a 2-(acylamino)imidazole compound selected from the group consisting of

and salts thereof.

39. The composition of claim 38 , wherein the 2-(acylamino)imidazole compound is

40. A method of treating cancer, the method comprising administering the composition of claim 1 to a patient with cancer, thereby treating the patient.

41. A method of selectively preparing a 2-acylamino imidazole, the method comprising the steps:

cyclizing an N-monoprotected α-guanidinyl alkyne reactant to form an 3-N-protected imidazolidin-2-imine product with a 4-exocyclic olefin; and

selectively acylating at the 2-amino position to form a 2-acylamino product;

wherein the 2-acylamino product is substantially free from 1-acyl and 3-acyl regioisomers.

42. The method of claim 41 , the method further comprising the step of deprotecting the 3-N-protected 2-acyl imidazolidin-2-imine to produce a 2-acyl imidazolidin-2-imine.

43. The method of claim 42 , the method further comprising the step of isomerizing the 2-acyl imidazolidin-2-imine to produce a 2-acylamino imidazole.

44. The method of claim 41 , the method further comprising the step of isomerizing the 3-N-protected imidazolidin-2-imine to produce a 3-N-protected 2-aminoimidazole.

45. The method of claim 44 , the method further comprising the step of deprotecting the 3-N-protected 2-acylamino imidazole to produce a 2-acylamino imidazole.

46. The method of claim 41 , wherein the 3-N-protecting group is a carbamate protecting group.

47. The method of claim 46 , wherein the 3-N-protecting group is a Cbz group.

48. The method of claim 41 , wherein the 2-acylamino imidazole is a compound of claim 1 .