1-pyridazin-/triazin-3-yl-piper(-azine)/idine/pyrolidine derivatives and compositions thereof for inhibiting the activity of shp2

Abstract

The present invention relates to compounds of formula I:in which m, Y1, Y2, Y3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a and R5b 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 of formula I: 
       
         
           
           
               
               
           
         
         in which: 
         m is selected from 0, 1 and 2; 
         p is selected from 0 and 1; 
         Yi is selected from CH and N; 
         Y 2  is selected from CR 5  and N; 
         Y 3  is selected from NH and CR 7 R 8 ; 
         Ri is selected from C6-ioaryl, C 3- 8Cycloalkyl, C3-8Cycloalkenyl and a 5-9 member heteroaryl group containing from 1 to 4 heteroatoms selected from N, 0 and S: wherein said aryl or heteroaryl of Ri is substituted with 1 to 5 R 9  groups independently selected from halo, amino, hydroxy, N 3 , C 1-4 alkyl, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkyl, amino-substituted-C 1-4 alkyl, —C(O)OR H > and —NHC(O)Ri 0 ; 
         Ri O  is selected from hydrogen, phenyl and naphthyl; wherein said phenyl of Rio is unsubstituted or substituted with methoxy; 
         R 2a  and R 2b  are independently selected from hydrogen, C 1 -alkyl, C 1 -alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1 -alkyl-amino; 
         R 3a  and R 3b  are independently selected from hydrogen, halo, carbonyl, C 1 -alkyl, C 1 -alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1 -alkyl-amino; 
         R 4a  and R{circumflex over ( )} are independently selected from hydrogen, halo, carbonyl, C 1 -alkyl, C 1 -alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1 -alkyl-amino; 
         R 5a  and R 5b  are independently selected from hydrogen, carbonyl, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino; 
         wherein any two groups selected from R 2a , R3a, R ta  and R 7  can form a 5 to 6 member unsaturated, partially unsaturated ring or saturated ring optionally containing a ring nitrogen: 
       
       Re is selected from hydrogen, halo, cyano, C 1-4 alkyl, C 1 -alkoxy, amino-carbonyl, halo-substituted C 1 -alkyl, halo-substituted C 1 -alkoxy, hydroxy-substituted C 1 -alkyl, amino-substituted C 1-4 alkyl, —S(O) 1-2 R 6a , —C(S)R 6a , —C(O)NR 6a R 6b , —CCN{circumflex over ( )}NR 6 {circumflex over ( )} and —NR 6a C(O)R 6b ; wherein R 6a  and R 3/4  are independently selected from hydrogen and C 1 -alkyl;
 R7 is selected from hydrogen, C 1 -alkyl, C 3-6 cycloalkyl, C 6 -ioaryl and a 5-9 member heteroaryl group containing from 1 to 4 heteroatoms selected from N, 0 and S; R 7  and R{circumflex over ( )} together with the carbon atoms to which they are both attached can form a pyrrolidinyl or cyclopropyl group optionally substituted with amino; 
 R 8  is selected from amino, amino-methyl and methyl-amino; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1  of Formula 1a: 
       
         
           
           
               
               
           
         
         in which: 
         m is selected from 0 and 1; 
         n is selected from 1, 2, 3, 4 and 5; 
         Yi is selected from CH and N; 
         Y 2  is selected from CR 5  and N; 
         R4a is selected from hydrogen, methyl and hydroxy; 
         Re is selected from hydrogen, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino-carbonyl, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkoxy, hydroxy-substituted C 1 -alkyl, amino-substituted C 1-4 alkyl, —S(O) 1-2 R 6a , —C(S)P V,a , —C(O)NR 6a R 6b , —CCNlTjNR{circumflex over ( )}Pv* and —NR 6a C(O)R 6b ; wherein R 6a  and R 3/4  are independently selected from hydrogen and C 1 -alkyl; 
         R7 is selected from hydrogen, methyl, phenyl, pyrazinyl and pyridinyl; R7 and R{circumflex over ( )} together with the carbon atoms to which they are both attached can form a cyclopropyl group substituted with amino; 
         R 8  is selected from amino and methyl-amino; 
         R 9  is selected from halo, amino, hydroxy, N 3 , C 1 -alkyl, halo-substituted-C 1 -alkyl, C 1 -alkoxy, —C(O)ORio and —NHC(O)Ri 0 ; 
         Rio is selected from hydrogen, phenyl and naphthyl; wherein said phenyl of Rio is unsubstituted or substituted with methoxy; or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 2 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1  of formula 1b: 
       
         
           
           
               
               
           
         
         in which; 
         Y 1  is selected from CH and N; 
         Y 2  is selected from CR<5 and N; 
         Ri is selected from thiophen-2-yl and 1H-indol-7-yl; wherein said thiophen-2-yl can be substituted with a group selected from methyl and chloro; 
         R<5 is selected from hydrogen, halo and methyl; 
         R 8  is selected from amino and methyl-amino; or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 4 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1  of formula Ic: 
       
         
           
           
               
               
           
         
         in which: 
         n is selected from 1, 2, 3, 4 and 5; 
         Yi is selected from CH and N; 
         Y 2  is selected from CR<5 and N; 
         R 3a  is selected from C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino; R4a is selected from hydrogen, C 1-4 alkyl, C 1 -alkoxy, amino, hydroxy, C 3-8 cycloalkyl and Ci. 4 alkyl-amino; 
         R<5 is selected from hydrogen, halo and methyl; 
         R 9  is selected from halo, amino, hydroxy, N 3 , C 1 -alkyl, halo-substituted-C 1 -alkyl, C 1 -alkoxy, —C(O)ORio and —NHC(O)Ri 0 ; 
         Rio is selected from hydrogen, phenyl and naphthyl; wherein said phenyl of Ri 3  is unsubstituted or substituted with methoxy; or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound of  claim 6 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound of  claim 1 , or the pharmaceutically acceptable salt thereof selected from: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound of  claim 1 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . A pharmaceutical composition comprising a compound of  claim 1  or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         11 . 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. 
     
     
         12 . The method of  claim 11 , 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.