Hpk1 inhibitors and methods of using same

Abstract

Thienopyridinone compounds of Formula (I) and pharmaceutically acceptable salts thereof are described. In these compounds, one of X1; X2, and X3 is S and the other two are each independently CR, wherein R and all other variables are as defined herein. The compounds are shown to inhibit HPK1 kinase activity and to have in vivo antitumor activity. The compounds can be effectively combined with pharmaceutically acceptable carriers and also with other immunomodulatory approaches, such as a checkpoint inhibition or inhibitors of tryptophan oxidation. Formula (I).

1 . A compound represented by Formula (I-C): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R is H, —F, —Cl, —Br, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )alkylene-OH or 4-7 membered monocyclic heterocyclyl optionally substituted with 1-3 groups selected from —F, —Cl, —Br, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkoxy, or —CO 2 —(C 1 -C 4 )alkyl; 
         R 1  is —NR a R b  or —OR a1 ; 
         R a  for each occurrence is independently —H, —(C 1 -C 6 )alkyl, —(CH 2 ) n —(C 3 -C 7 )cycloalkyl, —(CH 2 ) n -3-7 membered monocyclic heterocyclyl, —(CH 2 ) n -bridged (C 6 -C 12 )cycloalkyl, optionally substituted —(CH 2 ) n -5-10 membered heteroaryl; or —(CH 2 ) n -6-12 membered bridged heterocyclyl, wherein —(C 1 -C 6 )alkyl, —(CH 2 ) n —(C 3 -C 7 )cycloalkyl, —(CH 2 ) n -3-7 membered monocyclic heterocyclyl, —(CH 2 ) n -bridged (C 6 -C 12 )cycloalkyl, —(CH 2 ) n -5-10 membered heteroaryl, or —(CH 2 ) n -6-12 membered bridged heterocyclyl, is optionally substituted with 1-3 groups selected from —F, —Cl, —Br, —CN, —NH 2 , —OH, oxo, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkoxy, —(C 1 -C 4 )alkylene-OH, or —(C 1 -C 4 )alkylene-NH 2 ; 
         R b  for each occurrence is independently —H or —(C 1 -C 6 )alkyl; or, 
         R a  and R b , together with the nitrogen to which they are attached, form —(C 3 -C 10 )heterocyclyl; 
         R a1  for each occurrence is independently —H, (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, 3-10 membered heterocyclyl, (C 6 -C 10 )aryl, or 3-10 membered heteroaryl; 
         R 4  and R 5 , together with the nitrogen to which they are attached, form 4-7 membered monocyclic heterocyclyl or 6-12 membered bridged heterocyclyl, wherein the 4-7 membered monocyclic heterocyclyl or 6-12 membered bridged heterocyclyl is optionally substituted with 1-3 groups selected from —F, —Cl, —Br, —CN, —NH 2 , —OH, oxo, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, —(C 1 -C 4 )alkoxy, —(C 1 -C 4 )haloalkoxy, —(C 1 -C 4 )alkylene-OH, or —(C 1 -C 4 )alkylene-NH 2 ; 
         R 6  for each occurrence is independently —F, —Cl, —Br, —CN, —NH 2 , —OH, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 6 )alkoxy, —(C 1 -C 6 )haloalkoxy, —(C 1 -C 6 )alkylene-OH, or —(C 1 -C 6 )alkylene-NH 2 ; 
         m is 0, 1, 2, or 3; and 
         n is 0, 1, or 2. 
       
     
     
         2 - 6 . (canceled) 
     
     
         7 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II-C): 
       
         
           
           
               
               
           
         
       
     
     
         8 - 9 . (canceled) 
     
     
         10 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (III-C): 
       
         
           
           
               
               
           
         
       
     
     
         11 - 13 . (canceled) 
     
     
         14 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4  and R 5 , together with the nitrogen to which they are attached, form —N-alkyl-piperazinyl or morpholinyl, wherein the piperazinyl or morpholinyl is optionally substituted with 1-2 groups selected from —F, —Cl, —Br, —OH, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )haloalkyl, or —(C 1 -C 4 )alkoxy. 
     
     
         15 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R a  for each occurrence is independently —H, —(CH 2 ) n —(C 3 -C 6 )cycloalkyl, —(CH 2 ) n -3-6 membered monocyclic heterocyclyl, wherein the —(CH 2 ) n —(C 3 -C 6 )cycloalkyl or —(CH 2 ) n -3-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups selected from —F, —Cl, —Br, —CN, —NH 2 , —OH, —(C 1 -C 4 )alkyl, or —(C 1 -C 4 )alkoxy; and n is 0 or 1. 
     
     
         16 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R is H, —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkoxy, N-piperazinyl optionally substituted with —CO 2 —(C 1 -C 4 )alkyl. 
     
     
         17 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R is H. 
     
     
         18 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4  and R 5 , together with the nitrogen to which they are attached, form —N-methyl-piperazinyl or morpholinyl, both of which are optionally substituted with one or two methyl. 
     
     
         19 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R a  for each occurrence is independently —H; —(C 3 -C 6 )cycloalkyl optionally substituted with —OH; —(CH 2 ) n -tetrahydro-2H-pyran; morpholinyl; piperidinyl optionally substituted with —F, —OH or methyl; or tetrahydrofuran; and n is 0 or 1. 
     
     
         20 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . A method for treating a subject with cancer, comprising: administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and an effective second anti-cancer treatment. 
     
     
         23 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and an effective amount of an immunomodulatory agent such as a checkpoint inhibitor or an inhibitor of tryptophan oxidation.