N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2

Abstract

The present invention relates to compounds of formula I:in which p, q, Y1, Y2, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R7 and R8 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: 
         p is selected from 0 and 1: 
         q is selected from 0 and 1: 
         Y 1  is selected from CH and N; 
         Y 2  is selected from CR 6  and N; 
         R 1  is —XR 1a ; wherein R 1a  is selected from C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl and a 5-9 member heteroaryl group containing from 1 to 4 heteroatoms or groups independently selected from N, C(O), 0 and S; wherein said aryl or heteroaryl of R 1a  is substituted with 1 to 5 R 9  groups independently selected from halo, amino, hydroxy, N 3 , C 1-4 alkyl, dimethyl-amino, hydroxy-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkyl, amino-substituted-C 1-4 alkyl, —C(O)OR 10  and —NHC(O)R 10 ; and X is selected from a bond, S(O) m , O, C(O), COR 11 , CR 10a R 10b , NR 11 ; wherein m is selected from 0, 1 and 2; each R 10a  and R 10b  is independently selected from halo and C 1-4 alkyl; and R 11  is selected from hydrogen and C 1-4 alkyl; 
         R 2a  and R 2b  are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino; 
         R 3a  and R 3b  are independently selected from halo, carbonyl, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino; 
         R 4a  and R 4b  are independently selected from hydrogen, halo, carbonyl, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 Cycloalkyl and C 1-4 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 , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b  and R 7  can form a 5 to 6 member unsaturated or partially saturated ring; 
         R 6  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 1-4 alkyl, amino-substituted C 1-4 alkyl, —S(O) 1-2 R 6a , —C(S)R 6a , —C(O)NR 6a R 6b , —C(NH)NR 6a R 6b  and —NR 6a C(O)R 6b ; wherein R 6a  and R 6b  are independently selected from hydrogen and C 1-4 alkyl; 
         R 7  and R 8  together with the carbon atom to which they are both attached form a 3 to 7 member saturated or partially unsaturated ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from N, C(O)O and S(O)m; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  can be unsubstituted or substituted with 1 to 3 groups independently selected from amino, hydroxy, methoxy, halo, methyl, methyl-amino and isobutyryloxy; or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1  of Formula Ia: 
       
         
           
           
               
               
           
         
         in which: 
         n is selected from 1, 2, 3 and 4; 
         p is selected from 0 and 1; 
         q is selected from 0 and 1; 
         Y 1  is selected from CH and N; 
         Y 2  is selected from CR and N; each 
         Y 4  is independently selected from N, C(O) and CR 9 ; wherein only one Y 4  is C(O); 
         R 6  is selected from hydrogen, halo, methyl and amino-carbonyl; 
         R 7  and R 8  together with the carbon atom to which they are both attached form a 3 to 7 member saturated or partially unsaturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  can be unsubstituted or substituted with 1 to 3 groups independently selected from amino, halo, hydroxy, amino-methyl and methyl-amino; 
         R 9  is selected from halo, amino, hydroxy, N 3 , dimethyl-amino, C 1-4 alkyl, halo-substituted-C 1-4 alkyl, C 1-4 alkoxy, —C(O)OR 10  and —NHC(O)R 10 ; 
         R 10  is selected from hydrogen, phenyl and naphthyl; wherein said phenyl of R 10  is unsubstituted or substituted with methoxy; or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 2  in which R 7  and R 8  together with the carbon atom to which they are both attached form a 5 member saturated or partially unsaturated ring that can optionally contain 1 to 2 heteroatoms or groups independently selected from N, O, C(O) and S(O)m; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  is substituted with 1 to 3 groups independently selected from amino, hydroxy, methoxy, halo, methyl, methyl-amino and isobutyryloxy; or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 3 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 2  in which R 7  and R 8  together with the carbon atom to which they are both attached form a 6 member saturated or partially unsaturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein n is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  is substituted with amino; or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound of  claim 5 , or the pharmaceutically acceptable salt thereof selected from: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 2  in which R 7  and R 8  together with the carbon atom to which they are both attached form a 4 member saturated or partially unsaturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  is substituted with a group selected from amino, amino-methyl and methyl-amino; or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound of  claim 7 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2  in which p and q are both 0; or the pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of  claim 9 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1  of formula II: 
       
         
           
           
               
               
           
         
         in which: 
         p is selected from 0 and 1; 
         q is selected from 0 and 1; 
         Y 1  is selected from CH and N; 
         Y 2  is selected from CR 6  and N; 
         R 1  is selected from C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl and a 5-9 member heteroaryl group containing from 1 to 4 heteroatoms selected from N, O and S; wherein said aryl or heteroaryl of R 1a  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 10  and —NHC(O)R 10 ; wherein m is selected from 0, 1 and 2; 
         each R 10a  and R 10b  is independently selected from halo and C 1-4 alkyl; and R 11  is selected from hydrogen and C 1-4 alkyl; 
         R 2a  and R 2b  are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino; 
         R 3a  and R 3b  are independently selected from halo, carbonyl, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 alkyl-amino; 
         R 4a  and R 4b  are independently selected from hydrogen, halo, carbonyl, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl and C 1-4 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 , R 3a , R 4 , R 5 , R 6a  and R 7a  can form a 5 to 6 member unsaturated or partially unsaturated ring; 
         R 6  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 1-4 alkyl and amino-substituted C 1-4 alkyl; 
         R 7  and R 8  together with the carbon atom to which they are both attached form a 3 to 7 member saturated or partially unsaturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  can be unsubstituted or substituted with 1 to 3 groups independently selected from amino, halo, hydroxy, amino-methyl and methyl-amino; or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound of  claim 11  of Formula IIa: 
       
         
           
           
               
               
           
         
         in which 
         n is selected from 1, 2, 3 and 4; 
         p is selected from 0 and 1; 
         q is selected from 0 and 1; 
         Y 1  is selected from CH and N; 
         Y 2  is selected from CR 6  and N; 
         Y 4  is selected from N and CR 9 ; 
         R 6  is selected from hydrogen, halo, methyl and amino-carbonyl; 
         R 7  and R 8  together with the carbon atom to which they are both attached form a 3 to 7 member saturated or partially unsaturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein m is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  can be unsubstituted or substituted with a group selected from amino, amino-methyl and methyl-amino; 
         R 9  is selected from halo, amino, hydroxy, N 3 , C 1-4 alkyl, halo-substituted-C 1-4 alkyl, C 1-4 alkoxy, —C(O)OR 10  and —NHC(O)R 10 ; 
         R 10  is selected from hydrogen, phenyl and naphthyl; wherein said phenyl of R 10  is unsubstituted or substituted with methoxy; or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The compound of  claim 12  in which R 7  and R 8  together with the carbon atom to which they are both attached form a 5 member saturated or partially unsaturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein in is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  is substituted with amino; or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 13 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of  claim 12  in which R 7  and R 8  together with the carbon atom to which they are both attached form a 6 member saturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein in is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  is substituted with amino; or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound of  claim 15 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 2  in which R 7  and R 8  together with the carbon atom to which they are both attached form a 4 member saturated ring that can optionally contain a heteroatom selected from N, O and S(O)m; wherein in is selected from 0, 1 and 2; wherein said saturated ring formed by R 7  and R 8  is substituted with amino; or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 17 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 12  in which p and q are both 0; or the pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 19 , or the pharmaceutically acceptable salt thereof, selected from: 
       
         
           
           
               
               
           
         
       
     
     
         21 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         22 . 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. 
     
     
         23 . The method of  claim 22 , 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.