Alkyne substituted quinazoline compound and methods of use

Abstract

The invention provides alkyne substituted quinazoline compounds, such as compounds of the formula (I), which are irreversible ErbB kinase inhibitors. The compounds are useful in the treatment of diseases and disorders where ErbB kinase activity is implicated such as a hyperproliferative disorder (e.g., cancer).

1 . A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, or physiologically functional derivative thereof, wherein:
 W is N or C—CN; 
 R A  is a substituted aryl or substituted heteroaryl; 
 each R B  and R C  is independently H, C 1 -C 3  alkyl or C 3 -C 6  cycloalkyl, where each of the C 1 -C 3  alkyl and C 3 -C 6  cycloalkyl of R B  and R C  is optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo, halogen and —OR 1 ; or R B  and R C  are taken together with the nitrogen atom to which they are attached to form a 4 to 7-membered heterocyclyl, which is optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, oxo, —OR 1 , —NR 2 R 3 , C 1 -C 3  alkyl and C 3 -C 6  cycloalkyl; 
 R D  is a heterocyclyl containing 1 to 3 hetero ring atoms independently selected from oxygen, nitrogen and sulfur, where the heterocyclyl of R D  is optionally substituted with 1 to 3 groups independently selected from halogen, oxo, —OCF 3 , —OR 1 , —CF 3 , —NR 2 R 3 , C 1 -C 3  alkyl and C 3 -C 6  cycloalkyl; and 
 each R 1 , R 2  and R 3  is independently selected from H and C 1 -C 3  alkyl. 
 
     
     
         2 . The compound of  claim 1 , wherein W is N. 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein R A  is a substituted phenyl. 
     
     
         5 - 8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein each R B  and R C  is independently H, C 1 -C 3  alkyl or C 3 -C 6  cycloalkyl. 
     
     
         10 - 13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein R D  is a 4 to 10-membered heterocyclyl containing 1 to 3 hetero ring atoms independently selected from oxygen, nitrogen and sulfur, where the heterocyclyl of R D  is optionally substituted with 1 to 3 groups independently selected from halogen, oxo, —OCF 3 , —OR 1 , —CF 3 , —NR 2 R 3 , C 1 -C 3  alkyl and C 3 -C 6  cycloalkyl. 
     
     
         15 - 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , or salt, solvate, or physiologically functional derivative thereof, wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         21 . A pharmaceutical composition comprising a compound of  claim 1 , or a salt, solvate, or physiologically functional derivative thereof; and a pharmaceutically acceptable carrier. 
     
     
         22 . A method for treating a hyperproliferative disorder in an individual in need thereof comprising administering to the individual an effective amount of a compound of  claim 1 , or a salt, solvate, or physiologically functional derivative thereof. 
     
     
         23 . The method of  claim 22 , wherein the hyperproliferative disorder is a head and neck cancer, lung cancer, breast cancer, colon cancer, ovarian cancer, bladder cancer, gastric cancer, kidney cancer, skin cancer, pancreatic cancer, leukemias, lymphomas, esophageal cancer, uterine cancer or prostate cancer. 
     
     
         24 . The method of  claim 23 , wherein the hyperproliferative disorder is a breast cancer or gastric cancer. 
     
     
         25 - 26 . (canceled) 
     
     
         27 . A method of treating a brain tumor in an individual in need thereof comprising administering to the individual an effective amount of a compound of  claim 1 , or a salt, solvate, or physiologically functional derivative thereof. 
     
     
         28 . The method of  claim 27 , wherein the brain tumor is a primary brain tumor. 
     
     
         29 . The method of  claim 28 , wherein the brain tumor is a glioma. 
     
     
         30 . The method of  claim 28 , wherein the brain tumor is glioblastoma multiforme. 
     
     
         31 . The method of  claim 27 , wherein the brain tumor is a metastatic brain tumor. 
     
     
         32 . A method of preventing or delaying the development of brain metastasis of a cancer in an individual in need thereof comprising administering to the individual an effective amount of a compound of  claim 1 , or a salt, solvate, or physiologically functional derivative thereof. 
     
     
         33 - 36 . (canceled) 
     
     
         37 . A method for treating a hyperproliferative disorder in an individual in need thereof comprising administering to the individual an effective amount of the compound of  claim 20 , or a salt, solvate, or physiologically functional derivative thereof. 
     
     
         38 . A method of treating a brain tumor in an individual in need thereof comprising administering to the individual an effective amount of the compound of  claim 20 , or a salt, solvate, or physiologically functional derivative thereof. 
     
     
         39 . A method of preventing or delaying the development of brain metastasis of a cancer in an individual in need thereof comprising administering to the individual an effective amount of the compound of  claim 20 , or a salt, solvate, or physiologically functional derivative thereof.