Bicyclic heterocycle compounds methods of use thereof for the treatment of herpes viruses
The present invention relates to novel Bicyclic Heterocycle Compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, X, Y, Z, R1 R5, R6, and R7 are as defined herein. The present invention also relates to compositions comprising at least one Bicyclic Heterocycle Compound, and methods of using the Bicyclic Heterocycle Compounds for treating or preventing a herpesvirus infection in a patient.
1 . A compound of structural formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
A is a bond or —O—;
X is —N— or —C(R 2 )—;
Y is —N— or —C(R 3 )—, such that only one of X and Y can be —N—;
Z is —N— or —C(R 4 )—;
R 1 is 5 to 7-membered monocyclic heterocycloalkyl or 9 or 10-membered bicyclic heterocycloalkyl, wherein said 5 to 7-membered monocyclic heterocycloalkyl group, and said 9 or 10-membered bicyclic heterocycloalkyl group can be optionally substituted with up to three R A groups, which can be the same or different, and wherein said 5 to 7-membered monocyclic heterocycloalkyl group, and said 9 or 10-membered bicyclic heterocycloalkyl group can optionally have a ring carbon atom functionalized as a carbonyl group;
R 2 is selected from H, C 1 -C 6 alkyl, —O—(C 1 -C 6 alkyl), C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, —CN, —NH 2 , —C(O)O—(C 1 -C 6 alkyl), C 3 -C 7 cycloalkyl, C 4 -C 7 heterocycloalkyl, C 6 -C 10 aryl, 5 to 7-membered monocyclic heteroaryl, and 9 or 10-membered bicyclic heteroaryl, wherein said C 3 -C 7 cycloalkyl group, said C 6 -C 10 aryl group, said 5 to 7-membered monocyclic heteroaryl group, and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with up to three RB groups, which can be the same or different, or where R 2 and R 3 , together with atoms to which they are attached, are joined to form a 5-membered heteroaryl group;
R 3 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, 5 to 7-membered monocyclic heteroaryl, —O—(5 to 7-membered monocyclic heteroaryl), C 3 -C 7 cycloalkyl, wherein said C 3 -C 7 cycloalkyl group, and any of said 5 to 7-membered monocyclic heteroaryl groups, can be optionally substituted with up to three RC groups, which can be the same or different;
R 4 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, and C 3 -C 7 cycloalkyl;
R 5 is selected from H, C 1 -C 6 alkyl, —OR 7 , —CN, —NH 2 , C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, —O—(C 1 -C 6 hydroxyalkyl), —(C 1 -C 6 alkylene)—NH—(C 1 -C 6 haloalkyl), —O—(C 1 -C 6 alkylene) m -(C 3 -C 7 cycloalkyl), —O—(C 1 -C 6 alkylene) m -(5 to 7-membered monocyclic heterocycloalkyl), and —(C 1 -C 6 alkylene) m -(5 to 7-membered monocyclic heterocycloalkyl), wherein said C 1 -C 6 alkyl group, said C 3 -C 7 cycloalkyl group, and said 5 to 7-membered monocyclic heterocycloalkyl group can each be optionally substituted with one or more substituents, each independently selected from —OH, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl, and wherein said C 1 -C 6 haloalkyl can be optionally substituted with one —NH 2 group;
R 6 represents up to 3 phenyl ring substituents, which can be the same or different, and are each independently selected from C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —CN, —NO 2 , —OR 7 , and halo;
each occurrence of R 7 is independently selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl;
each occurrence of R A is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, 5 to 7-membered monocyclic heterocycloalkyl, —C(O)—(C 1 -C 6 alkyl), and halo, wherein said 5 to 7-membered monocyclic heterocycloalkyl group can be optionally substituted with up to 3 substituents, which can be the same or different, and are each independently selected from C 1 -C 6 alkyl, 5 to 7-membered monocyclic heterocycloalkyl, and halo;
each occurrence of R B is independently selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, —O—(C 3 -C 7 cycloalkyl), —OR 7 , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, —O—(C 1 -C 6 alkylene) m -(5 to 7-membered monocyclic heterocycloalkyl), and —(C 1 -C 6 alkylene) m -(5 to 7-membered monocyclic heterocycloalkyl), and —NH 2 ;
each occurrence of R C is independently selected from C 1 -C 6 alkyl, —OR 7 , C 1 -C 6 haloalkyl, and 5 to 7-membered monocyclic heterocycloalkyl; and
each occurrence of m is independently 0 or 1.
2 . The compound of claim 1 , wherein —A—R 1 is:
3 . The compound of claim 1 , wherein X is N.
4 . The compound of claim 1 , wherein Y is N.
5 . The compound of claim 1 , wherein Z is N.
6 . The compound of claim 1 , wherein none of X, Y and Z is N.
7 . The compound of claim 1 , wherein R 2 is selected from H, —CN, cyclobutyl, pyrazolyl, pyridyl, trizolyl, oxazolyl, —CH 2 C(CH 3 ) 2 NH 2 , —CH 2 C(CH 3 ) 2 OH, —CH 2 CH(CH 3 ) OH,
wherein said pyrazolyl group, said triazolyl group, said pyridyl group, and said cyclobutyl group can be optionally substituted with up to 2 groups, which are independently selected from —CHF 2 , —CF 3 , piperdinyl, —OCH 3 , —OH, and methyl.
8 . The compound of claim 1 , wherein Y is —C(R 3 )— and R 3 is selected from H, —O-pyrazolyl, oxazolyl, —CH 2 OH, —CH 2 C(CH 3 ) 2 OH, and —CH 2 CH(CH 3 )OH.
9 . The compound of claim 1 , wherein Z is —C(R 4 )— and R 4 is selected from H, —CH 2 OH, and cyclopropyl.
10 . The compound of claim 1 , wherein R 5 is selected from H, —OH, —OCH 3 , methyl, ethyl, and cyclopropyl.
11 . The compound of claim 1 , wherein X and Y are each —CH—.
12 . The compound of claim 1 , wherein R 6 is 4-Cl or 4-CN.
13 . The compound of claim 1 , wherein R 7 is H or methyl.
14 . A compound of the structure:
or a pharmaceutically acceptable salt thereof.
15 . A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16 . The pharmaceutical composition according to claim 15 , further comprising one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents, and immunomodulators.
17 . A method of treating a patient infected with a herpesvirus, comprising the step of administering an amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, effective to treat infection by said herpesvirus in said patient.
18 . The method according to claim 17 , further comprising administering one or more additional therapeutic agents, wherein said additional therapeutic agents are selected from anti-herpes agents, and immunomodulators.