Substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero- heteraphanes and metallocenes useful for treating HCV infections
The present disclosure provides substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes, of Formula I D-M-D (Formula I) useful as antiviral agents. In certain embodiments disclosed herein M is a group —P-A-P— where A is Certain substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. Pharmaceutical compositions/and combinations containing one or more substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes and a pharmaceutically acceptable carrier are also provided by this disclosure. Methods for treating viral infections, including Hepatitis C viral infections are provided by the disclosure.
1. A process for preparing a compound of formula (I):
or HCl salt thereof;
comprising steps:
(a) converting compound (i) to compound (ii):
(b) reacting 4-bromo-1,2-diaminobenzene with compound (ii) to form compound (iii):
(c) converting compound (iii) to compound (iv) in the presence of acetic acid:
(d) converting compound (iv) to compound (v):
(e) reacting compound (v) with compound (vi) to form compound (vii):
(f) converting compound vii to compound (viii) or HCl salt of compound (viii):
and
(g) coupling compound (viii) or the HCl salt of compound (viii) with (S)-2-(methoxycarbonyl)amino)-3-methylbutanoic acid to form the compound of formula (I):
2. The process of claim 1 , wherein compound (vi) is formed by reacting [2.2]paracyclophane with Br 2 and iron powder:
3. The process of claim 1 , wherein step (b) occurs in the presence of 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDCI) to form the compound of formula (iii).
4. The process of claim 1 , wherein step (d) is conducted by stirring a mixture of compound (iv) with bis(pinacolato)diborane, potassium acetate, and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl 2 ) in anhydrous 1,4-dioxane.
5. The process of claim 1 , wherein step (e) is conducted by stirring a mixture of compound (v), compound (vi), Cs 2 CO 3 , tetrakis(triphenylphosphine)palladium (0) (Pd(PPh 3 ) 4 ), and dimethylformamide (DMF) in water.
6. The process of claim 1 , wherein step (f) is conducted by cooling a solution of compound (vii) in dichloromethane/methanol (DCM/MeOH) and adding HCl/dioxane solution.
7. The process of claim 1 , wherein compound (vii) is converted to the HCl salt of compound (viii).
8. The process of claim 1 , wherein step (g) is conducted with EDCI and hydroxybenzotriazole (HOBt) monohydrate in acetonitrile.
9. A process for preparing a compound of formula (I):
or HCl salt thereof;
comprising steps:
(a) reacting compound (v) with compound (vi) to form compound (vii):
(b) converting compound (vii) to c pound (viii) or HCl salt of compound (viii):
and
(c) coupling compound (viii) or the HCl salt of compound (viii) with (S)-2-(methoxycarbonyl)amino)-3-methylbutanoic acid to form the compound of formula (I):
10. The process of claim 9 , wherein compound (vi) is formed by reacting [2.2]paracyclophane with Br 2 and iron powder:
11. The process of claim 9 , wherein step (a) is conducted by stirring a mixture of compound (v), compound (vi), Cs 2 CO 3 , Pd(PPh 3 ) 4 , and DMF in water.
12. The process of claim 9 , wherein step (b) is conducted by cooling a solution of compound (vii) in DCM/MeOH and adding HCl/dioxane solution.
13. The process of claim 9 , wherein compound (vii) is converted to the HCl salt of compound (viii).
14. The process of claim 9 , wherein step (c) is conducted with EDCI and HOBt monohydrate in acetonitrile.