Benzodiazepine derivatives as RSV inhibitors
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Respiratory Syncytial Virus (RSV). The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV infection. The invention also relates to methods of treating an RSV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
1. A compound represented by Formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or methyl;
R 2 and R 5 are each independently hydrogen or methyl;
A is selected from the groups below:
R 3 is phenyl optionally substituted with one to three substituents selected from the group consisting of hydrogen, halo, —CF 3 , —OCF 3 , —CH 3 , —SO 2 Me, and cyano;
R 4 is selected from aryl and heteroaryl; wherein R 4 is optionally substituted with 1 to 3 substituents independently selected from halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , —NH—(C 1 -C 6 )alkyl, —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 —NH—(C 1 -C 6 )alkyl, —NH—SO 2 —(C 1 -C 6 )alkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, C 1 -C 8 -alkoxy, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—,
each R 6 is independently selected from halogen, methyl, CF 3 and cyano;
and n is 0 to 2.
2. The compound of claim 1 , wherein R 4 is selected from the following by removal of one hydrogen atom:
wherein each of the above shown is optionally substituted.
3. The compound of claim 1 , wherein R 4 is optionally substituted by one, two or three substituents independently selected from the group consisting of: halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , optionally substituted —NH—(C 1 -C 6 )alkyl, optionally substituted —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, optionally substituted —SO 2 —(C 1 -C 6 )alkyl, optionally substituted —SO 2 —NH—(C 1 -C 6 )alkyl, optionally substituted —NH—SO 2 —(C 1 -C 6 )alkyl, optionally substituted 3- to 12-membered heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 1 -C 8 -alkenyl, optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted —C 3 -C 8 -cycloalkenyl, and optionally substituted —C 1 -C 8 -alkoxy.
4. The compound of claim 1 , wherein R 4 is optionally substituted by one, two or three of the following substituents:
CH 3 , CN, fluoro, chloro, CH 3 O—, CH 3 C(O)—, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—, —CF 3 , CF 3 O—,
5. The compound of claim 1 , represented by Formula (IVb-1), (IVb-2), (IVb-3), or (IVb-4), or a pharmaceutically acceptable salt thereof,
wherein R 1 , R 2 , and R 5 are hydrogen, R 3 is phenyl, R 6 is fluorine or chlorine, and n is 0 or 1.
6. A pharmaceutical composition, comprising the compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
7. A method of treating an RSV infection in an subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound claim 1 .
8. The compound of claim 1 , wherein A is
9. The compound of claim 1 , wherein n is 0.
10. The compound of claim 1 , wherein R 1 , R 2 and R 5 are hydrogen.
11. The compound of claim 1 , wherein R 3 is unsubstituted phenyl.
12. The compound of claim 1 , wherein R 4 is selected from the groups below
each of which is optionally substituted.
13. The compound of claim 5 , wherein R 4 is selected from the groups below