Quinazoline analogs as receptor tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9676791-B2
Application number	US-201213607016-A
Country	US
Kind code	B2
Filing date	Sep 7, 2012
Priority date	Aug 14, 2003
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

This invention provides quinazoline analogs of Formula I:

where A is bonded to at least one of the carbons at the 5, 6, 7 or 8 position of the bicyclic ring, and the ring is substituted by up to two independent R 3 groups. The invention also includes methods of using compounds of Formula I as type I receptor tyrosine kinase inhibitors and for the treatment of hyperproliferative diseases such as cancer.

First claim

What is claimed is:

1. A process for preparing compounds including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound comprising Formula 12:

R 1 is a substituted or unsubstituted, monocyclic or bicyclic, aryl or heteroaryl moiety;
R 2 is H or a substituted or unsubstituted C 1-8 alkyl, allyl, and substituted benzyl;
R 6 is hydrogen;
R 8 and R 9 are independently selected from the group consisting of hydrogen, trifluoromethyl, C 1 -C 10 alkyl, (CH 2 ) 0-4 C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, wherein said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, partially unsaturated heterocyclyl, and heterocyclylalkyl is optionally substituted with one to five groups independently selected from the group consisting of oxo, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, cyano, nitro, OR 6 , NR 6 R 8 , SR 6 , trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl;
or R 8 and R 9 together with the atoms to which they are attached may be independently joined to complete a 3 to 10 membered cycloalkyl ring or heterocycloalkyl ring optionally containing one or more additional heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 , wherein each ring carbon may be optionally substituted with one to three groups independently selected from the group consisting of halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, OR 8 , NR 6 R 8 , SR 6 , heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, provided said ring does not contain two adjacent O or two adjacent S atoms
comprising:
(a) condensing a quinazoline of Formula 9:

wherein R 1 , R 2 , R 3 and R 6 are as defined above, with thioCDI in a suitable organic solvent, which is treated in situ with an amino alcohol of Formula 10:

wherein X is R 8 or R 9 , to provide a thiourea of Formula 11:

(b) reacting the thiourea of Formula 11 to provide an oxazoline of Formula 12.

2. The process of claim 1 , wherein the reaction of the thiourea in step (b) is performed by treating the thiourea with tosyl chloride and NaOH in a mixture of THF and water at room temperature.

3. The process of claim 1 , wherein the reaction of the thiourea in step (b) is performed by treating the thiourea with a carbodiimidate in a suitable organic solvent.

4. The process of claim 3 , wherein the carbodiimidate is selected front the group consisting of EDCI, DCC and DCI.

5. The process of claim 3 , wherein the suitable organic solvent is selected from the group consisting of THF, DMF, DCM and DCE.

6. The process of claim 3 , wherein the reaction in step (b) is performed at room temperature or between 45° C. and 90° C.

7. The process of claim 1 , wherein the suitable organic solvent of step (a) is a mixture of THF and DCE.

8. The process of claim 1 , wherein the compound of Formula 12 is selected from the structures:

9. The process of claim 1 , wherein the compound of Formula 12 has the structure:

and pharmaceutically acceptable salts thereof.

Assignees

• Wallace Eli
• Topalov George
• Lyssikatos Joseph
• Buckmelter Alexandre
• Zhao Qian
• Array Biopharma Inc

Inventors

• Wallace Eli
• Topalov George
• Lyssikatos Joseph
• Buckmelter Alexandre
• Zhao Qian

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D498/10 Primary

  Spiro-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title