Therapeutic compounds
Inventors
McCauley, John A. • Liverton, Nigel J. • Harper, Steven • McIntyre, Charles J. • Rudd, Michael T.
Assignees
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Publication Number
US-8591878-B2
Publication Date
2013-11-26
Expiration Date
Abstract
A class of macrocyclic compounds of formula (I), wherein R1, R3, R4, Ra, Rb, A, B, Z, M, W and n are defined herein, that are useful as inhibitors of viral proteases, particularly the hepatitis C virus (HCV) NS3 protease, are provided. Also provided are processes for the synthesis and use of such macrocyclic compounds for treating or preventing HCV infection.
Core Innovation
The patent describes compounds of formula (I) and pharmaceutically acceptable salts thereof, with variable parameters including n, R1, R2, R3, R4, R6, R7, R8, R9, R10, Q, Z, W, M, ring A and ring B, each defined by specified selection lists and substitution or heteroatom count limits. The disclosure includes multiple specific embodiments of the compounds within the broad formula (I), illustrated by structural variants and specific example compounds and intermediate structures.
Ring A is selected from 8- to 14-membered fused carbobi- and carbotricyclic ring systems containing 0 to 4 heteroatoms selected from N, O and S. Ring B is selected from N-linked 4- to 9-membered heterocycles containing one N atom, with 0 or 1 additional heteroatom selected from N, O and S, and substituted by 0 to 2 R10; optional formation of additional rings by taking adjacent substituents together is also disclosed.
The disclosure positions the compounds as inhibitors directed to hepatitis C virus NS3 protease activity and as compounds for treating or preventing hepatitis C infection. It also discloses pharmaceutical compositions comprising compounds of formula (I), optionally with a second therapeutic agent including HCV protease inhibitors, NS5B polymerase inhibitors, and immunomodulators including α/β/γ-interferon.
Claims Coverage
The provided claim material centers on one broad independent claim defining formula (I) compounds and therapeutic use language for hepatitis C infection. Across the provided items, the claims cover a broad macrocyclic chemical scaffold with extensive substituent and ring constraints, plus inhibition of hepatitis C virus protease and treatment or prevention of hepatitis C infection.
Compound of formula (I) with defined substituent and ring parameters
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is defined by n, R1, R2, R3, Het, R4, R6, Q, R7, R8, R9, R10, Z, ring B, W, M and ring A selections, with specified group membership lists, substitution limits, and heteroatom count limits.
Optional ring formation via adjacent substituents
Adjacent substituents of R4, R8 or R9 can optionally be taken together to form a cyclic ring, including a 3- to 6-membered cyclic ring or, for R8 and R9, a 4- to 8-membered monocyclic ring with additional heteroatoms.
Inhibiting hepatitis C virus protease and treating hepatitis C infection
A method that administers to a human or animal with hepatitis C infection a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to inhibit hepatitis C virus protease and/or treat or prevent hepatitis C virus infection.
The claim coverage centers on the structurally defined compound of formula (I) and pharmaceutically acceptable salts thereof, with extensive constraints on multiple substituent variables and ring systems. It also includes therapeutic use language directed to hepatitis C virus protease inhibition and hepatitis C infection.
Stated Advantages
Inhibits hepatitis C virus protease.
Treats hepatitis C virus infection.
Prevents hepatitis C infection.
Documented Applications
Use of the compounds for treating or preventing hepatitis C infection in humans or animals.
Administration to a human or animal with hepatitis C infection using a therapeutically effective amount to inhibit hepatitis C virus protease and/or treat or prevent hepatitis C virus infection.
Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with pharmaceutically acceptable carrier, optionally with second therapeutic agents including HCV protease inhibitors and/or NS5B polymerase inhibitors and immunomodulators including α/β/γ-interferon.
A cell based HCV replication assay with LRMS/IC50 values for numbered examples.
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