MACROCYCLIC INHIBITORS OF FLAVIVIRIDAE VIRUSES

• US 20130344029A1
• Filed: 06/07/2013
• Published: 12/26/2013
• Est. Priority Date: 06/08/2012
• Status: Active Grant

• Current Assignee: Cypralis Limited (Eurofins Scientific SE), Gilead Sciences Inc.
• Original Assignee: Selcia Ltd. (Eurofins Scientific SE), Gilead Sciences Inc.
• Inventors: Aciro, Caroline, Steadman, Victoria Alexandra, Lazarides, Linos, Dean, David Kenneth, Keats, Andrew John, Siegel, Dustin Scott, Schrier, Adam James, Jansa, Petr, Mackman, Richard, Pettit, Simon Neil, Poullennac, Karine G., Dunbar, Neil Andrew, Highton, Adrian John, Karki, Kapil Kumar
• Granted Patent: US 9,090,653 B2
• Time in Patent Office: Days
• US Class Current: 424/85.4
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/504 forming part of bridged ring systems
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/15 Depsipeptides; Derivatives thereof
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: A61K 39/29 Hepatitis virus
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/18 : Bridged systems
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 498/08 : Bridged systems
• CPC Class Codes: C07D 498/18 : Bridged systems
• CPC Class Codes: C07D 498/22 : in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07K 19/00 : Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 5/02 : containing at least one abnormal peptide link
• CPC Class Codes: C07K 5/06034 : the side chain containing 2 to 4 carbon atoms
• CPC Class Codes: C07K 5/06052 : Val-amino acid
• CPC Class Codes: C07K 5/0606 : the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• CPC Class Codes: C07K 5/06078 : and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06086 : with the first amino acid being basic
• CPC Class Codes: C07K 5/06139 : with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06191 : containing heteroatoms different from O, S, or N
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided are compounds of Formula I:

• • and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein A¹ is ethenylene, propenylene, butenylene, ethylene, propylene, butylene, oxypropylene, oxypropenylene, pyrazolylene, phenylene or pyrimidinylene.

3. The compound of claim 1, wherein A² is isoquinolinylene, phenylene or halophenylene.

4. The compound of claim 1, wherein X¹ is —

O—

or —

NH—

;

one of R^1a and R^1b is H and the other is methyl;

R² is iso-propyl;

R⁵ is methyl and R⁶ is H or methyl.

5. The compound of claim 1, wherein R^3a is H or methyl;

R^3b is H;

R^4a is H, —

OH, methoxy, or trifluoroethoxy; and

R^4b is H.

6. The compound of claim 1, which is a compound of Formula II:

7. The compound of claim 1, wherein A² is heteroarylene;

A¹ is (C₂-C₅)alkylene, (C₂-C₅)alkenylene, or (C₂-C₅)alkynylene, wherein A¹ is optionally substituted with one or more (C₁-C₄)alkyl;

R^3a is H or (C₁-C₈)alkyl; and

R^4a is H, —

OH or (C₁-C₄)alkoxy.

8. The compound of claim 1, which is

9. The compound of claim 1, wherein A² is arylene;

and A¹ is (C₂-C₅)alkylene, (C₂-C₅)alkenylene, (C₂-C₅)alkynylene, —

O—

(C₂-C₅)alkylene, or —

O—

(C₂-C₄)alkenylene, wherein A¹ is optionally substituted with one or more (C₁-C₄)alkyl;

R^3a is H or (C₁-C₄)alkyl; and

R^4a is H, —

OH, (C₁-C₄)alkoxy or halo(C₁-C₄)alkoxy.

10. The compound of claim 1, which is

11. The compound of claim 1, wherein A² is arylene;

and A¹ is pyrazolylene, phenylene or pyrimidinylene.

12. The compound of claim 1, which is

13. The compound of claim 1, wherein A² is haloarylene;

and A¹ is —

O—

(C₂-C₅)alkylene or —

O—

(C₂-C₄)alkenylene.

14. The compound of claim 1, which is

15. The compound of claim 1, wherein A¹ is (C₂-C₅)alkylene or (C₂-C₅)alkenylene;

R⁵ is methyl, or R⁵ forms

16. The compound of claim 1, which is

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof and a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17, further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin, HCV NS3 protease inhibitors, HCV NS5a inhibitors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, and TLR-7 agonists;

or a mixture thereof.

19. The pharmaceutical composition of claim 18, wherein the at least one addition therapeutic agent is ribavirin, telaprevir, boceprevir or sofosbuvir.

20. A method for treating a Flaviviridae viral infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.

21. The method of claim 20, wherein the viral infection is caused by a Hepatitis B virus or a Hepatitis C virus.

22. The method of claim 21, wherein the viral infection causes a disease selected from the group consisting of dengue fever, yellow fever, hepatitis C, Japanese encephalitis, Kyasanur forest disease, Murray valley encephalitis, St. Louis encephalitis, tick-borne encephalitis or West Nile encephalitis.

23. A method for treating a Coronaviridae viral infection in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.

24. The method of claim 23, wherein the viral infection is caused by a SARS coronarirus.

25. The method of claim 24, wherein the viral infection causes a disease selected from the group consisting of severe acute respiratory syndrome (SARS), cancer, inflammation, obesity, acquired immune deficiency syndrome (AIDS), or cirrhosis.

26. A method for providing immunomodulation to a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, isotope, stereoisomer, mixture of stereoisomers, tautomer, ester or prodrug thereof.