Naphthofuran derivatives, preparation, and methods of use thereof

1. A method of making a compound having formula (I):

or a prodrug, a pharmaceutically acceptable salt, or a solvate thereof;

comprising reacting a compound having formula (i):

or a salt or solvate thereof, with an acid;

wherein R 1 and R 2 each independently is a leaving group.

2. The method of claim 1 , wherein

R 1 is chosen from halides, OR a , and NR b R c ; where R a is chosen from hydrogen, alkyl groups, substituted alkyl groups, cycloalkyl groups, substituted cycloalkyl groups, alkenyl groups, substituted alkenyl groups, cycloalkenyl groups, substituted cycloalkenyl groups, alkynyl groups, substituted alkynyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and

R b and R c each is independently chosen from hydrogen, alkyl groups, substituted alkyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups, or

R b and R c together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group.

3. The method of claim 1 , wherein R 1 is NR b H, where R b is phenyl or substituted phenyl.

4. The method of claim 1 , wherein R 2 is chosen from halides, carboxylates, alkoxycarboxylates, and aryloxycarboxylates.

5. The method of claim 1 , wherein R 2 is chosen from Cl, Br, —COOH, —COO—, methoxycarboxylate, ethoxycarboxylate, isopropoxycarboxylate, and tert-butoxycarboxylate.

6. The method of claim 1 , wherein R 2 is tert-butoxycarboxylate.

7. The method of claim 1 , wherein the compound having formula (i) has formula (i-a):

or a salt or solvate thereof.

8. The method of claim 1 , further comprising reacting a compound having formula (ii):

or a salt or solvate thereof;

wherein

X is O or N—R 4 , and

R 3 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups;

R 4 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, substituted aryl groups, C(═O)R g , S(═O) 2 R e , P(═O) 2 R e , C(═O)OR e , C(═O)NR b R c , S(═O) 2 NR b R c , and P(═O) 2 NR b R c ;

wherein R b and R c each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups,

or R b and R c together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group;

R c is chosen from alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and

R g is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups;

with a compound having formula (iii):

wherein R 2 and R 5 each independently is a leaving group.

9. The method of claim 8 , wherein the compound having formula (ii) has the formula (ii-b)

wherein R 4 is chosen from methyl, ethyl, isopropyl, tert- butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, pyridyl, and pyrrolyl.

10. The method of claim 8 , wherein R 4 is phenyl.

11. The method of claim 8 , wherein the compound having formula (ii) has formula (ii-c):

or a salt or solvate thereof.

12. The method of claim 11 , wherein the compound having formula (iii) has the formula (iii-a):

13. The method of claim 8 , further comprising converting a 2-hydroxynaphthalene-1,4-dione having formula (iv):

or a salt or solvate thereof, to the compound having formula (ii).

14. The method of claim 1 , wherein the acid comprises an acid chosen from sulfuric acid (H 2 SO 4 ), phosphoric acid (H 3 PO 4 ), nitric acid (HNO 3 ), perchloric acid (HClO 4 ), hydrofluoric acid (HF), hydrochloric acid (HCl), hydrobromic acid (HBr), and hydroiodic acid (HI).

15. The method of claim 1 , wherein the acid is sulfuric acid (H 2 SO 4 ), phosphoric acid (H 3 PO 4 ), or hydrochloric acid (HCl).

16. The method of claim 1 , wherein the acid is chosen from formic acid, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, chloroacetic acid, and chloroacetic anhydride.

17. The method of claim 1 , wherein the acid comprises an acid chosen from sulfuric acid (H 2 SO 4 ), acetic acid, and acetic anhydride.

18. The method of claim 1 , comprising reacting a solution of the compound having formula (i) with the acid.

19. The method of claim 18 , wherein the solution comprises a solvent chosen from isopropyl acetate, dimethylformamide (DMF), N-methylpyrrolidone (NMP), and dimethylimidazolidinone (DMI).

20. The method of claim 8 , comprising reacting the compound having formula (ii) in the presence of a base chosen from NaHCO 3 , KHCO 3 , Na 3 PO 4 , Na 2 HPO 4 , K 3 PO 4 , K 2 HPO 4 , LiOCH 2 CH 3 , NaOCH 2 CH 3 , KOCH 2 CH 3 , LiOC(CH 3 ) 3 , NaOC(CH 3 ) 3 , KOC(CH 3 ) 3 , triethylamine (TEA), diisopropylethylamine (DIPEA), and triethanolamine.

21. The method of claim 13 , comprising reacting the 2-hydroxynaphthalene-1,4-dione having formula (iv) with a compound of formula (v):

wherein R 4 is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, substituted aryl groups, C(═O)R g , S(═O) 2 R e , P(═O) 2 R e , C(═O)OR e , C(═O)NR b R c , S(═O) 2 NR b R c , and P(═O) 2 NR b R c ;

wherein R b and R c each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups,

or R b and R c together with the N to which they are bonded form a heterocycle group or a substituted heterocycle group;

R e is chosen from alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups; and

R f and R g each independently is chosen from hydrogen, alkyl groups, substituted alkyl groups, alkenyl groups, substituted alkenyl groups, alkynyl groups, substituted alkynyl groups, cycloalkyl groups, substituted cycloalkyl groups, heterocycle groups, substituted heterocycle groups, aryl groups, and substituted aryl groups.

22. The method of claim 21 , wherein R f is chosen from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.