Inhibitors of influenza viruses replication

• US 9,394,302 B2
• Filed: 03/24/2015
• Issued: 07/19/2016
• Est. Priority Date: 08/01/2011
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charifson, Paul S., Clark, Michael P., Bandarage, Upul K., Bethiel, Randy S., Boyd, Michael J., Davies, Ioana, Deng, Hongbo, Duffy, John P., Farmer, Luc J., Gao, Huai, Gu, Wenxin, Kennedy, Joseph M., Ledford, Brian, Ledeboer, Mark W., Maltais, Francois, Perola, Emanuele, Wang, Tiansheng
• Primary Examiner(s): Otton, Alicia L
• Assistant Examiner(s): CALVILLO, Y JEANMARIE Z
• Application Number:
  US14/666,567
• Publication Number:
  US 20150191468A1
• Time in Patent Office: 483 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

This invention provides methods of preparing 3-(pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridines and 3-(pyrimidin-2-yl)-1H-pyrazolo[3,4-b]pyridines, or pharmaceutically acceptable salts thereof that are useful for inhibiting the replication of influenza viruses in a biological sample or patient, reducing the amount of influenza viruses in a biological sample or patient, and treating influenza in a patient.

Claims

1. A method preparing a compound 2:

2. The method of claim 1, wherein the demethylation of step iii) further comprises reacting compound 9a with LiOH to form Compound 2.

3. The method of claim 1, wherein the reaction of compound 6a with compound 7a to form compound 8a occurs in the presence of a palladium catalyst, wherein the palladium catalyst is formed by mixing Pd₂(dba)₃ and XPhos.

4. The method of claim 1, wherein the reaction of compound 6a with compound 7a to form compound 8a occurs in the presence of 2-methyl tetrahydrofuran and water.

5. The method of claim 1, wherein the deprotection of compound 8a occurs in the presence of hydrochloric acid.

6. The method of claim 2, wherein the demethylation of step iii) occurs in the presence of tetrahydrofuran and water.