Degradation of protein kinases by conjugation of protein kinase inhibitors with e3 ligase ligand and methods of use

Abstract

The present application provides bifunctional compounds of Formula (X): or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases. The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.

1 . A compound of Formula X: 
       
         
           
           
               
               
           
         
         wherein:
 the Targeting Ligand (TL) is of Formula TL-II, TL-III, TL-IV, or TL-V: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 A is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R 9 ; 
 X 2  is O, S, or NR 10 , 
 X 3  is N or CR 11 ; 
 each R 6  is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, NH 2 , (C 1 -C 4 ) alkylamino, (C 1 -C 4 ) dialkylamino, NHS(O) 2 (C 1 -C 4 ) alkyl, or N((C 1 -C 4 ) alkyl)S(O) 2 (C 1 -C 4 ) alkyl; 
 R 7  is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl; 
 each R 8  and each R 9  are independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; 
 R 10  is H or (C 1 -C 4 ) alkyl; 
 R 11  is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; 
 q1 is 0, 1, 2, 3, or 4; and 
 q2 is 0, 1, or 2; or 
 
       
       
         
           
           
               
               
           
         
         wherein:
 B 1  is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R 15 , 
 B 2  is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R 16 , 
 R 12  is H or (C 1 -C 4 ) alkyl; 
 each R 13  is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; 
 R 14  is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl; 
 
         each R 15  and each R 16  are independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; and
 r1 is 0, 1, 2, 3 or 4; or 
 
       
       
         
           
           
               
               
           
         
         wherein:
 B 3  is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R 19 , 
 B 4  is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R 20 ; 
 R 17  is H or (C 1 -C 4 ) alkyl; 
 R 18  is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; and 
 each R 19  and each R 20  are independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; or 
 
       
       
         
           
           
               
               
           
         
         wherein:
 B 5  is (C 6 -C 10 ) aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, S, and O, wherein the aryl or heteroaryl are optionally substituted with one to three R 26 , 
 Y 1  is C(O)NR 25  or NR 25 C(O); 
 R 21  is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl; 
 R 22  and R 23  are each independently H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; 
 each R 24  is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, or C(O)(C 1 -C 4 ) alkyl; 
 R 25  is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl; 
 each R 26  is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; and 
 s2 is 0, 1, 2, or 3; 
 
         wherein the Targeting Ligand is bonded to the Linker via the 
       
       
         
           
           
               
               
           
         
          in TL-II, 
       
       
         
           
           
               
               
           
         
          in TL-III, 
       
       
         
           
           
               
               
           
         
          in TL-IV, and 
       
       
         
           
           
               
               
           
         
          in TL-V;
 the Linker is a bond, a carbon chain, carbocyclic ring, or heterocyclic ring that serves to link the Targeting Ligand with the Degron, 
 
         wherein
 the carbon chain optionally comprises one, two, three, or more heteroatoms selected from N, O, and S, 
 
         and wherein 
         the carbon chain optionally comprises two or more unsaturated chain carbon atoms, 
         and wherein, 
         one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substituents selected from oxo, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 3  alkoxy, OH, halogen, NH 2 , NH(C 1 -C 3  alkyl), N(C 1 -C 3  alkyl) 2 , CN, C 3 -C 8  cycloalkyl, heterocyclyl, phenyl, and heteroaryl; and
 the Degron is of Formula D1: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 Y is a bond, (CH 2 ) 1-6 , (CH) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 35 , (CH 2 ) 0-6 —NR 35 C(O), (CH 2 ) 0-6 —NH, or (CH 2 ) 0-6 —NR 36 , and wherein the Degron is bonded to the Linker via the Y; 
 Z 3  is C(O) or C(R 37 ) 2 ; 
 R 35  is H or C 1 -C 6  alkyl; 
 R 36  is C 1 -C 6  alkyl or C(O)—C 1 -C 6  alkyl; 
 each R 37  is independently H or C 1 -C 3  alkyl; 
 each R 38  is independently C 1 -C 3  alkyl; 
 R 39  is H, deuterium, C 1 -C 3  alkyl, F, or C 1 ; 
 each R 40  is independently halogen, OH, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy; 
 q is 0, 1, or 2; and 
 v is 0, 1, 2, or 3, 
 
         or a stereoisomer or pharmaceutically acceptable salt thereof. 
       
     
     
         2 .- 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein the Targeting Ligand is of Formula TL-II. 
     
     
         13 .- 19 . (canceled) 
     
     
         20 . The compound of  claim 1 , wherein the Targeting Ligand is of Formula TL-III. 
     
     
         21 .- 28 . (canceled) 
     
     
         29 . The compound of  claim 1 , wherein the Targeting Ligand is of Formula TL-IV. 
     
     
         30 .- 34 . (canceled) 
     
     
         35 . The compound of  claim 1 , wherein the Targeting Ligand is of Formula TL-V. 
     
     
         36 .- 49 . (canceled) 
     
     
         50 . The compound of  claim 1 , wherein the Targeting Ligand is of Formula TL-IIa, TL-IIIa, TL-IVa, or TL-Va: 
       
         
           
           
               
               
           
         
       
     
     
         51 . The compound of  claim 1 , wherein the Linker is of Formula L1: 
       
         
           
           
               
               
           
         
         or stereoisomer thereof, wherein
 p1 is an integer selected from 0 to 12; 
 p2 is an integer selected from 0 to 12; 
 p3 is an integer selected from 1 to 6; 
 each W is independently absent, CH 2 , O, S, or NR 34 ; 
 Z 1  is absent, C(O), CH 2 , O, (CH 2 ) j NR 34 , O(CH 2 ) j C(O)NR 34 , C(O)NR 34 , (CH 2 ) j C(O)NR 34 , NR 34 C(O), (CH 2 ) j NR 34 C(O), C(O)NR 34 (CH 2 ) j C(O)NR 34 , C(O)(CH 2 ) j C(O)NR 34 , (CH 2 ) k NR 34 (CH 2 ) j C(O)NR 34 , or NR 34 (CH 2 ) j C(O)NR 34 ; 
 each R 34  is independently H or C 1 -C 3  alkyl; 
 j is 1, 2, or 3; 
 k is 1, 2, or 3; and 
 Q 1  is absent, C(O), NHC(O)(CH 2 ) 0-1 , OCH 2 C(O), O(CH 2 ) 1-2 , or 
 
       
       
         
           
           
               
               
           
         
         wherein the Linker is covalently bonded to the Degron via the   next to Q 1 , and covalently bonded to the Targeting Ligand (TL) via the   next to Z 1 . 
       
     
     
         52 . The compound of  claim 51 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         53 .- 55 . (canceled) 
     
     
         56 . The compound of  claim 1 , wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         57 .- 59 . (canceled) 
     
     
         60 . A pharmaceutical composition comprising a therapeutically effective amount of the compound  claim 1 , or stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         61 .- 62 . (canceled) 
     
     
         63 . A method of treating a hematologic cancer, comprising administering to a subject in need thereof an effective amount of the compound of  claim 1 . 
     
     
         64 .- 75 . (canceled) 
     
     
         76 . The compound of  claim 1 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a stereoisomer or pharmaceutically acceptable salt thereof. 
       
     
     
         77 . The method of  claim 63 , wherein the hematologic cancer is leukemia. 
     
     
         78 . The method of  claim 63 , wherein the hematologic cancer is lymphoma.