5-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-(1h-pyrazol-1-yl)pyrazolo [1,5-a]pyrimidine derivatives and related compounds as trk kinase inhibitors for treating cancer

Abstract

The application relates to inhibitors of Trk kinases useful in the treatment of Trk kinase associated diseases and disorders, having the Formula:wherein A, L, X, X1, and Y are described herein.

1 - 39 . (canceled) 
     
     
         40 . A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein m is 0, 1, 2, 3, 4, or 5; 
         wherein Q is N or CR 9 ; 
         wherein R 9 , when present, is H, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, 3- to 8-membered heterocycloalkyl, (C 6 -C 10 ) aryl, or 5- to 10-membered heteroaryl; and 
         wherein each occurrence of R 7 , when present, is independently (C 1 - .C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         41 . The compound of  claim 40 , wherein m is 1, 2, or 3. 
     
     
         42 . The compound of  claim 41 , wherein each occurrence of R 7  is halogen. 
     
     
         43 . The compound of  claim 41 , wherein each occurrence of R 7  is fluoro. 
     
     
         44 . The compound of  claim 40 , wherein Q is CR 9 . 
     
     
         45 . The compound of  claim 44 , wherein R 9  is (C 1 -C 6 ) haloalkyl. 
     
     
         46 . The compound of  claim 40 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         47 . A pharmaceutical composition comprising:
 (i) a therapeutically effective amount of the compound of  claim 40  or a pharmaceutically acceptable salt thereof; and   (ii) a pharmaceutically acceptable carrier.   
     
     
         48 . A method for treating cancer characterized by a Trk kinase or a Trk kinase fusion in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of  claim 40  or a pharmaceutically acceptable salt thereof. 
     
     
         49 . The method of  claim 48 , wherein the cancer is pediatric glioma or congenital mesoblastic nephroma. 
     
     
         50 . The method of  claim 48 , wherein the cancer is salivary gland cancer, bone cancer, a soft tissue sarcoma, a glioma, thyroid cancer, ovarian cancer, pancreatic cancer, non-small cell lung cancer, breast cancer, or colorectal cancer. 
     
     
         51 . The method of  claim 48 , wherein the cancer is a soft tissue sarcoma, a glioma, thyroid cancer, salivary gland cancer, breast cancer, non-small cell lung cancer, colorectal cancer, or ovarian cancer. 
     
     
         52 . The method of  claim 48 , wherein the cancer is lung cancer, breast cancer, colorectal cancer, thyroid cancer, a glioma, or a salivary gland cancer. 
     
     
         53 . A method of treating a cancer characterized by a Trk kinase or a Trk kinase fusion in a subject in need thereof comprising administering to the subject an effective amount of a compound having a structure: 
       
         
           
           
               
               
           
         
         wherein Q is N or CR 9 ; and 
         wherein R 9 , when present, is H, halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, 3- to 8-membered heterocycloalkyl, (C 6 -C 10 ) aryl, or 5- to 10-membered heteroaryl, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         54 . The method of  claim 53 , wherein the cancer is pediatric glioma or congenital mesoblastic nephroma. 
     
     
         55 . The method of  claim 53 , wherein the cancer is salivary gland cancer, bone cancer, a soft tissue sarcoma, a glioma, thyroid cancer, ovarian cancer, pancreatic cancer, non-small cell lung cancer, breast cancer, or colorectal cancer. 
     
     
         56 . The method of  claim 53 , wherein the cancer is a soft tissue sarcoma, a glioma, thyroid cancer, salivary gland cancer, breast cancer, non-small cell lung cancer, colorectal cancer, or ovarian cancer. 
     
     
         57 . The method of  claim 53 , wherein the cancer is lung cancer, breast cancer, colorectal cancer, thyroid cancer, a glioma, or a salivary gland cancer.