Inhibitors of influenza viral entry
Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for acute treatment of influenza infections to control this virus and prevent epidemic/pandemic situations from developing. Described herein are fast-acting, orally active acylated amino-substituted heterocyclyl compounds effective to control this virus. In one aspect, described herein is a method of treating an influenza infection in a subject comprising administering to the subject the compounds described herein.
1. A compound is selected from the group of compounds consisting of:
wherein
X is CH or N;
R d is one to nine substituents independently selected from alkyl, halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl;
R f is selected from H, alkyl, aryl, and arylalkyl;
R e is one to five substituents independently selected from halo, haloalkyl, aryl, arylalkyl and —NO 2 ;
R g is one to four substituents independently selected from halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl, and
R a , R b and R c are independently selected from H, alkyl and aryl, or any two of R a , R b and R c , together with the C atom to which they are attached define a cycloalkyl, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CH.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R f is H or Me.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R e is selected from —NO 2 , Cl and —CF 3 .
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R d is selected from H and halo and R g is selected from H, halo, haloalkyl and C 3 -C 5 cycloalkyl.
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein halo is F and haloalkyl is CF 3 .
7. A compound of formula II or a pharmaceutically acceptable salt thereof
wherein
R h is alkyl or cycloalkyl; and
R e is haloalkyl, X is CH, and n is 1 to 4, and R f is H or Me.
8. The compound of claim 7 , wherein R e is haloalkyl, X is R h is an alkyl group.
9. The compound of claim 7 , wherein n is 1.
10. The compound of claim 7 , wherein R e is CF 3 .
11. The compound of claim 7 , wherein R e is at the 4-position of the aryl ring, para to the carbonyl group.
12. The compound of claim 7 , wherein R h is a tert-butyl group or an isopropyl group.
13. A compound selected from the group of compounds consisting of:
or a pharmaceutically acceptable salt thereof.
14. A method of treating an influenza infection in a subject by the administration of a composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient and or a pharmaceutically acceptable salt.
15. The method of claim 14 further comprising co-administration to the subject a neuraminidase inhibitor comprising oseltamivir, zanamivir, peramivir, or any combination thereof.