HCV NS3 protease inhibitors
Inventors
Rudd, Michael T. • McCauley, John • Liverton, Nigel • Grisé-Bard, Christiane • Brochu, Marie-Christine • Charron, Sylvie • Aulakh, Virender • Bachand, Benoit • Beaulieu, Patrick • Zaghdane, Helmi • Han, Yongxin • Ferrara, Marco • Harper, Steven • Summa, Vincenzo • Chackalamannil, Samuel • Venkatraman, Srikanth • Shah, Unmesh • Velazquez, Francisco
Assignees
Merck Canada Inc • Istituto di Ricerche di Biologia Molecolare P Angeletti SpA • MSD Italia SRL • Merck Sharp and Dohme LLC
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Publication Number
US-9328138-B2
Publication Date
2016-05-03
Expiration Date
Abstract
The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
Core Innovation
The invention relates to compounds of formula (I), or pharmaceutically acceptable salt forms thereof, with variable substituent definitions for Y, R1-R5, Z, W, A, B, n, and X. Y is CH or N, Z is C or N, W is a bond, O or NR, A is absent, O or N, and B is (CH2)m, with n in the range of 1 to 4. The disclosure includes extensive allowable heteroaryl and heterocycle options, together with optional fluoro substitution and optionally substituted phosphate groups.
The structural variability specifically includes multiple permitted forms of R1 such as OC1-6alkyl variants, OC1-6alkyl-het1, OC1-6alkyl-OH, OC1-6alkyl-NRaRb, O-het1, OC1-6alkylCO2H, OC1-6alkylC(=O)-het1, O(CH2)1-6OC(=O)CH2NRaRb, OC1-6alkyl-C1-6alkoxy, OC1-6alkyl-C1-6alkoxy-C1-6alkoxy, OC(O)NRaRb, OC1-6alkyl-S-het1, OC1-6alkyl-phosphate, pyridinyl, and thiazolyl. Het1 is defined as naphthyl optionally substituted with OH, C1-6alkyl, or halo; a heteroaryl selected from 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms selected from N, O and S; or a heterocycle selected from 4-7 membered monocyclic or 6-10 membered polycyclic bridged, linearly fused or spirocyclic saturated or unsaturated non-aromatic rings having 1-4 heteroatoms selected from N, O and S.
The document also describes stereochemically defined steroid-like quinoline carboxamide compounds having an N-[(1-methylcyclopropyl)sulfonyl] group and a fused-ring carboxamide scaffold. The side-chain ether or propoxy substituents vary among piperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, piperazinyl, and methoxy-containing embodiments, with pharmaceutically acceptable salts included. The subject matter further identifies HCV antiviral macrocyclic compounds as HCV NS3 protease inhibitors in the provided material.
Claims Coverage
The provided content includes broad independent claim coverage for a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a separate independent selection claim covering specific stereochemically defined steroid-like quinoline carboxamides. The inventive features center on extensive variable-substituent definitions across the formula (I) framework and on enumerated N-[(1-methylcyclopropyl)sulfonyl] carboxamide structures with specific ether or propoxy side-chain substitutions.
Formula (I) compound with defined variable substituents
A compound of formula (I) or a pharmaceutically acceptable salt thereof, where Y is CH or N and the substituent pattern is defined by R1-R5, Z, W, A, B, n, and X with extensive allowable functional-group and ring options.
R1 functional groups and het1 attachment options
R1 is selected from the explicit set of OC1-6alkyl, OC1-6alkyl-het1, OC1-6alkyl-OH, OC1-6alkyl-NRaRb, O-het1, OC1-6alkylCO2H, OC1-6alkylC(=O)-het1, O(CH2)1-6OC(=O)CH2NRaRb, OC1-6alkyl-C1-6alkoxy, OC1-6alkyl-C1-6alkoxy-C1-6alkoxy, OC(O)NRaRb, OC1-6alkyl-S-het1, OC1-6alkyl-phosphate, (CH2)1-6-het1, pyridinyl, and thiazolyl, with the phosphate group optionally substituted by 1, 2 or 3 C1-6alkyl.
Het1 defined as naphthyl, heteroaryl, or heterocycle
Het1 is selected from naphthyl optionally substituted with OH, C1-6alkyl, or halo; a heteroaryl selected from 5- and 6-membered aromatic rings having 1, 2 or 3 heteroatoms selected from N, O and S; or a heterocycle selected from 4-7 membered monocyclic or 6-10 membered polycyclic bridged, fused, or spirocyclic saturated or unsaturated non-aromatic rings having 1-4 heteroatoms selected from N, O and S.
Optional fluoro and phosphate substitution rules
An alkyl is optionally substituted with 1 or 2 fluoro substituents, and the phosphate group is optionally substituted with 1, 2 or 3 C1-6alkyl substituents.
Stereochemically defined steroid-like quinoline carboxamides
A compound selected from stereochemically defined steroid-like small-molecule carboxamides having an N-[(1-methylcyclopropyl)sulfonyl] group and enumerated ether or propoxy side-chain substitutions such as 2-(piperidin-1-yl)ethoxy, 2-(morpholin-4-yl)ethoxy, 3-(morpholin-4-yl)propoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(piperidin-1-yl)propoxy, 3-(pyrrolidin-1-yl)propoxy, 3-(4-methylpiperazin-1-yl)propoxy, and a 26-methoxy variant, or pharmaceutically acceptable salts thereof.
Claim coverage is dominated by the broad formula (I) definition with extensive substituent variability across Y, R1-R5, Z, W, A, B, n, and X, including het1 selection and optional fluoro and phosphate substitution rules. The claims also include a narrower Markush selection of specific stereochemically defined steroid-like quinoline carboxamides featuring an N-[(1-methylcyclopropyl)sulfonyl] group and enumerated ether or propoxy side chains.
Stated Advantages
Treating or preventing HCV infection through HCV NS3 protease inhibition.
Documented Applications
HCV antiviral use as NS3 protease inhibitors, including treating or preventing HCV infection.
Pharmaceutical composition use with ribavirin as a second therapeutic agent.
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