Fused tetracycle derivatives and methods of use thereof for the treatment of viral diseases
View Patent ↗The present invention relates to novel Fused Tetracycle Derivatives of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, A′, B, G, R 1 , U, V, W, W′, X, X′, Y and Y′ are as defined herein. The present invention also relates to compositions comprising at least one Fused Tetracycle Derivative, and methods of using the Fused Tetracycle Derivatives for treating or preventing HCV infection in a patient.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein:
A and A′ are each independently a 5-membered monocyclic heterocycloalkyl, wherein said 5-membered monocyclic heterocycloalkyl group can be optionally and independently substituted on one or more ring carbon atoms with R 13 , such that any two R 13 groups on the same ring, together with the carbon atom(s) to which they are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered heterocycloalkyl group, wherein said 5-membered monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently selected from N(R 4 ) and Si(R 16 ) 2 ;
G is selected from —C(R 3a ) 2 —C(R 3 ) 2 —O—, —C(R 3 ) 2 —C(R 3 ) 2 —C(R 3 ) 2 —O—, —C(R 3 ) 2 —C(R 3 ) 2 —N(R 5 )— and C(R 3 ) 2 —C(O)—N(R 5 )—;
R 2 is selected from H, C 1 -C 6 alkyl and halo;
each occurrence of R 3 is independently selected from H or C 1 -C 6 alkyl and wherein two R 3 groups that are attached to the same carbon atom, together with the carbon atom to which they are attached, join to form a spirocyclic 3 to 6-membered cycloalkyl group;
both R 3a groups, together with the common carbon atom to which they are each attached, join to form a spirocyclic 3-6 membered carbocyclic group or a spirocyclic 3 to 6-membered heterocycloalkyl group;
each occurrence of R 4 is independently selected from —C(O)R 11 and —C(O)—[C(R 7 ) 2 ]N(R 6 )C(O)O—R 11 ;
R 5 is selected from H, C 1 -C 6 alkyl and aryl;
each occurrence of R 6 is independently selected from H and C 1 -C 6 alkyl;
each occurrence of R 7 is independently selected from C 1 -C 6 alkyl, 3 to 6-membered cycloalkyl and aryl;
each occurrence of R 10 is independently selected from H and halo;
each occurrence of R 11 is independently C 1 -C 6 alkyl;
each occurrence of R 13 is independently selected from H, C 1 -C 6 alkyl and halo; and
each occurrence of R 16 is independently C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein the group:
has the structure:
3. The compound of claim 1 , wherein A and A′ are each:
and each occurrence of R 13 is independently H, CH 3 or F.
4. The compound of claim 1 , wherein each occurrence of R 4 is independently —C(O)CH(R 7 )NHC(O)O—R 11 .
5. The compound of claim 3 , wherein each occurrence of R 4 is:
6. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising an effective amount of the compound of claim 2 and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition according to claim 7 , further comprising a second therapeutic agent selected from the group consisting of HCV antiviral agents, immunomodulators, and anti-infective agents.
9. The pharmaceutical composition according to claim 8 , further comprising a third therapeutic agent selected from the group consisting of HCV protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.