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 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 selected from “O”, “N”, “S”, S(O)”, or “S(O) 2 ”, where the heterocyclyl 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 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein R A  is a substituted aryl. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 3 , wherein R A  is 3-chloro-4-fluorophenyl. 
     
     
         7 . The compound of  claim 1 , wherein R A  is a substituted heteroaryl. 
     
     
         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 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein each R B  and R c  is independently H or C 1 -C 3  alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo, halogen and —OR 1 . 
     
     
         13 . The compound of  claim 1 , wherein 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 up 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. 
     
     
         14 . The compound of  claim 1 , wherein R D  is a 4 to 10-membered heterocyclyl containing 1 to 3 hetero ring atoms selected from “O”, “N”, “S”, S(O)”, or “S(O) 2 ”, where the heterocyclyl is optionally substituted with 1 to 3 groups independently selected from halogen, oxo, —OCF 3 , —CF 3 , —NR 2 R 3 , C 1 -C 3  alkyl and C 3 -C 6  cycloalkyl. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 14 , wherein R D  is tetrahydrofuran-3-yl, 3-oxabicyclo[3.1.0]hexan-6-yl or 3-oxabicyclo[3.1.0]hexan-1-yl. 
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 1 , or salt, solvate, or physiologically functional derivative thereof, wherein the compound is selected from the group consisting of:
 (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-(tetrahydrofuran-3-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide,   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-((S)-tetrahydrofuran-2-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide,   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-((R)-tetrahydrofuran-2-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide,   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-((1R,5S,6s)-3-oxa-bicyclo[3.1.0]hexan-6-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide,   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-(3-oxa-bicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide,   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-((1R,5S)-3-oxa-bicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide, and   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-((1S,5R)-3-oxa-bicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide.   
     
     
         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 . (canceled) 
     
     
         25 . The method of  claim 22 , wherein the hyperproliferative disorder is an erlotinib-resistant cancer. 
     
     
         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 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         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 . (canceled) 
     
     
         34 . A kit comprising a compound of  claim 1 , or a salt, solvate, or physiologically functional derivative thereof. 
     
     
         35 . (canceled) 
     
     
         36 . (canceled)