Compounds and compositions for inhbiting the activity of shp2

Abstract

The present invention relates to compounds of formula I:in which Y1, Y2, Y3, Y4 R1, R2, R4a, R4b, R5a, R5b, R6a and R6b are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.

We claim: 
     
         1 . A compound, or a pharmaceutically acceptable salt thereof, of formula II: 
       
         
           
           
               
               
           
         
         in which: 
         Y 5  is selected from N and CH; 
         Y 6  is selected from CH 2  and NH; 
         R 1  is selected from R 1a  and —SR 1a ; wherein R 1a  is selected from phenyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl; wherein said phenyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl is unsubstituted or substituted with 1 to 3 R 4  groups; wherein each R 4  group is independently selected from halo, amino, morpholino, pyrrolidinyl, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy and halo-substituted-C 1-3 alkyl; 
         R 4a  and R 4b  are each independently selected from hydrogen, hydroxy and fluoro; with proviso that R 4a  and R 4b  cannot both be OH; 
         R 5a  is selected from amino and amino-methyl; 
         R 5b  is selected from C 1-6 alkyl, methoxy-carbonyl, C 3-6 cycloalkyl-C 1-3 alkyl, hydroxy-substituted C 1-3 alkyl, C 1-2 alkoxy-substituted C 1-3 alkyl and a 5 to 6 member heteroaryl ring containing 1 to 4 heteroatoms selected from O, S and N; wherein said C 1-6 alkyl or C 1-2 alkoxy-substituted C 1-3 alkyl of R 5b  is unsubstituted or substituted with 1-3 fluorines; or R 5a  and R 5b , together with the carbon atom to which R 5a  and R 5b  are attached, form a group selected from: 
       
       
         
           
           
               
               
           
         
         wherein *C represents the carbon atom to which R 5a  and R 5b  are attached; R 10  is amino; R 11a  is selected from hydrogen, hydroxy, fluoro, C 1-2 alkyl and hydroxy-methyl; R 11b  is selected from fluoro, methyl and hydrogen; R 11c  is selected from hydrogen, C 1-2 alkyl and hydroxy-methyl; R 12  is selected from hydrogen, halo, hydroxy, C 1-3 alkyl, halo-substituted-C 1-3 alkyl, halo-substituted-C 1-3 alkoxy and C 1-3 alkoxy; and R 13  is selected from hydrogen, halo and C 1-2 alkyl; and 
         R 6a  and R 6b  are each independently selected from hydrogen, hydroxy and fluoro; with proviso that R 6a  and R 6b  cannot both be OH. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         4 . A method of treatment comprising administering a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to a person in need of such treatment in an effective amount for the prophylactic or therapeutic treatment of a disease or disorder which is mediated by the activity of SHP2. 
     
     
         5 . The method of  claim 4 , wherein the disease or disorder mediated by the activity of SHP2 is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous-cell carcinoma of the head and neck, gastric carcinoma, anaplastic large-cell lymphoma and glioblastoma. 
     
     
         6 . A compound, or a pharmaceutically acceptable salt thereof, which is: