# US 8,785,638 B2 · Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,638 B2 - Document ID: US8785638B2 - Status: Granted - Kind: B2 - Application number: 13/320,519 - Filed: 2010-05-17 - Published: 2012-03-08 - Granted: 2014-07-22 - Earliest claimed: 2009-05-15 - Assignees: Katholieke Universiteit Leuven - Applicants: Dorothée Bardiot; Patrick Chaltin; Frauke Christ; Zeger Debyser; Marc De Maeyer; Arnaud Marchand; Damien Marchand; Arnout Voet - Inventors: Dorothée Bardiot; Patrick Chaltin; Frauke Christ; Zeger Debyser; Marc De Maeyer; Arnaud Marchand; Damien Marchand; Arnout Voet - Web page: https://patentgrep.com/patent/US8785638B2 ## CPC - C07D 495/20: Spiro-condensed systems - A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine - A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 31/12: Antivirals - A61P 31/18: for HIV - C07D 495/04: Ortho-condensed systems - C07D 495/14: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to a series of compounds having antiviral activity, more specifically HIV (Human Immunodeficiency Virus) replication inhibiting properties. The invention also relates to methods for the preparation of such compounds, as well as to novel intermediates useful in one or more steps of such syntheses. The invention also relates to pharmaceutical compositions comprising an effective amount of such compounds as active ingredients. This invention further relates to the use of such compounds as medicines or in the manufacture of a medicament useful for the treatment of animals suffering from viral infections, in particular HIV infection. This invention further relates to methods for the treatment of viral infections in animals by the administration of a therapeutic amount of such compounds, optionally combined with one or more other drugs having anti-viral activity. ## Claims ### Claim 1 A compound having the formula, or a tautomer, stereo-isomer, solvate, hydrate, or salt thereof. ### Claim 2 (depends on 1) A method for the preparation of the compounds according to claim 1 comprising the steps of: reacting a beta-ketonitrile of formula R1—C(O)CH2CN with a compound of formula R6C(O)CH2R5 in the presence of sulfur and a strong base in a polar protic solvent or in a polar aprotic solvent at a temperature between 60° C. to 100° C.; reacting the obtained 2-aminothiophene reaction product of the previous step with a compound of formula R4C(O)CH2CH2R3 in the presence of trimethyl chlorosilane in a polar aprotic solvent at a temperature between 50° C. and 200° C.; optionally, reacting the compound obtained in the previous step with a compound having a structure of the formula R2a-leaving group and/or R2b-leaving group through a nucleophilic substitution. ### Claim 3 (depends on 1) A method for the preparation of the compounds according to claim 1 comprising the steps of: reacting a cyanoacetate derivative of formula ROC(O)CH2CN with a compound of formula R6C(O)CH2R5 in the presence of sulfur and a strong base in a polar protic solvent or in a polar aprotic solvent at a temperature between 20° C. to 100° C.; reacting the previously obtained 2-amino-4,5-disubstituted-thiophene-3-carboxylate derivative with a compound of formula R4C(═CHCOOZ2)OZ2 in an apolar aprotic solvent at a temperature between 80° C. and 140° C. to obtain an enamine intermediate which undergoes an intramolecular ring cyclization in the presence of a strong base in a polar protic solvent to provide a 5,6-substituted-4-hydroxythieno[2,3-1)]pyridine-5-carboxylate derivative; the 4-hydroxyl function can then be converted to an halogen with standard procedures know to the skilled in the art; the ester function can then be reduced to a primary alcohol which is immediately oxidized into an aldehyde following standard procedures known to the skilled in the art; the 5,6-substituted-4-halogenothieno[2,3-b]pyridine-5-carbaldehyde derivative is then converted into a 2-(5,6-substituted-4-halogenothieno[2,3-b]pyridin-5-yl)-2-hydroxyacetate derivative using an addition of trimethylsilylcyanide in the presence of zinc iodide followed by hydrolysis in acidic conditions; the R2a and or R2b residues can then be introduced following procedures known to the skilled in the art; substituting the 4-halogen atom from the previously obtained compound in a specific manner (amination, alkylation, arylation) with suitable chemical reagents to obtain the desired compounds; hydrolyzing the ester compounds obtained in the previous step to obtain the desired free carboxylic acid derivatives. ### Claim 4 (depends on 1) A pharmaceutical composition comprising the compound according to claim 1 as an active ingredient in admixture with at least a pharmaceutically acceptable carrier. ### Claim 5 (depends on 4) The pharmaceutical composition according to claim 4, wherein said pharmaceutical composition has antiretroviral activity. ### Claim 6 (depends on 5) The pharmaceutical composition according to claim 5, wherein said pharmaceutical composition has anti-HIV activity. ### Claim 7 (depends on 4) The pharmaceutical composition according to claim 4, further comprising a compound with antiviral activity selected from reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors and compounds with other mechanisms of action. ### Claim 8 (depends on 1) A method of treatment of a retroviral infection in an animal or mammal, comprising administering to the animal or mammal in need of such treatment a therapeutically effective amount of a compound according to claim 1. ### Claim 9 A compound having the formula, or a pharmaceutically acceptable salt thereof.