Serine threonine kinase (akt) degradation / disruption compounds and methods of use

Abstract

Disclosed herein are serine threonine kinase (AKT) degradation/disruption compounds including an AKT ligand, a degradation/disruption tag, and a linker, and methods of using such compounds in the treatment of AKT-mediated diseases.

1 .- 112 . (canceled) 
     
     
         113 . A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3; 
       
         
           
           
               
               
           
         
         wherein 
         A, B and X are independently N or CR 3 , 
         Y is CH 2 , CO, SO, SO 2 , CR 4 R 5 , CONR 4 , or SO 2 NR 4 , 
         E is NH, NR 6 , O, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxyalkyl, C 1 -C 8  haloalkyl, C 1 -C 8  hydroxyalkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  heterocyclyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, OR 6 , SR 6 , NR 6 R 7 , CN, NO 2 , (CR 6 R 7 ) m NR 8 R 9 , (CR 6 R 7 ) m C(O)R 8 , (N R 6 R 7 ) m NR 8 R 9 , (NR 6 R 7 ) m C(O)R 8 , COR 6 , CO 2 R 6 , CONR 6 R 7 , NR 6 COR 7 , NR 6 SOR 7 , NR 6 SO 2 R 7 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , (CR 6 R 7 ) m -aryl, or (CR 6 R 7 ) m -heteroaryl, 
         Z 1 -Z 2  is CR 10 ═CH, N═CH, or CR 10 ═N, 
         R 1  is hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxyalkyl, aryl, C 1 -C 8  alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl, 
         R 2 , R 3 , and R 4  are independently hydrogen, halogen, amino, C 1 -C 8  alkylamino, arylamino, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, or C 1 -C 8  alkoxyalkyl, 
         R 6 , R 7 , R 8 , and R 9  are independently H, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl, 
         R 6  and R 7 , R 8  and R 9  can independently form 4-8 membered alkyl or heterocyclyl rings, 
         R 10  is hydrogen, halogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxyalkyl, 
         m=0-8 and 
         n=0-8;
 the degradation disruption tag comprises FORMULA 6; 
 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently hydrogen, C 1 -C 8  alkyl, C 1 -C 8  alkoxyalkyl, C 1 -C 8  haloalkyl, C 1 -C 8  hydroxyalkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocyclyl, C 2 -C 8  alkenyl, or C 2 -C 8  alkynyl;
 and the linker comprises FORMULA A; 
 
       
       
         
           
           
               
               
           
         
         wherein X is C═O or CH 2 , 
         Y is C═O or CH 2 , and 
         n is 0-15; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         114 . The bivalent compound of  claim 113 , wherein in Formula 3,
 A is CR 3 ;   B is N;   X is N;   Y is CO;   E is C 3 -C 8  heterocyclyl;   Z 1 -Z 2  is CR 10 ═CH;   R 1  is aryl or haloaryl;   R 2  is hydrogen;   R 3  is amino;   R 10  is hydrogen; and   n=2.   
     
     
         115 . The bivalent compound of  claim 113 , wherein in Formula 6, R 1  is C 1 -C 8  alkyl and R 2  is hydrogen. 
     
     
         116 . The bivalent compound of  claim 113 , wherein in Formula A, X is C═O and Y is C═O. 
     
     
         117 . The bivalent compound of  claim 114 , wherein in Formula 3, E is piperazinyl. 
     
     
         118 . The bivalent compound of  claim 114 , wherein in Formula 3, R 1  is 4-chlorophenyl. 
     
     
         119 . The bivalent compound of  claim 115 , wherein in Formula 6 R 1  is tert-butyl. 
     
     
         120 . The bivalent compound of  claim 116 , wherein in Formula A, n is 9 or 10. 
     
     
         121 . 4-amino-N-((S)-1-(4-chlorophenyl)-3-(4-(11-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-11-oxoundecanoyl)piperazin-1-yl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (XF050-21), and pharmaceutically acceptable salts thereof. 
     
     
         122 . 4-amino-N-((S)-1-(4-chlorophenyl)-3-(4-(12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoyl)piperazin-1-yl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (XF050-143), and pharmaceutically acceptable salts thereof. 
     
     
         123 . A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3; 
       
         
           
           
               
               
           
         
         wherein 
         A, B and X are independently N or CR 3 , 
         Y is CH 2 , CO, SO, SO 2 , CR 4 R 5 , CONR 4 , or SO 2 NR4, 
         E is NH, NR 6 , O, C 1 -C 8  alkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxyalkyl, C 1 -C 8  haloalkyl, C 1 -C 8  hydroxyalkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  heterocyclyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, OR 6 , SR 6 , NR 6 R 7 , CN, NO 2 , (CR 6 R 7 ) m NR 8 R 9 , (CR 6 R 7 ) m C(O)R 8 , (N R 6 R 7 ) m NR 8 R 9 , (NR 6 R 7 ) m C(O)R 8 , COR 6 , CO 2 R 6 , CONR 6 R 7 , NR 6 COR 7 , NR 6 SOR 7 , NR 6 SO 2 R 7 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , (CR 6 R 7 ) m -aryl, or (CR 6 R 7 ) m -heteroaryl, 
         Z 1 -Z 2  is CR 10 ═CH, N+CH, or CR 10 ═N, 
         R 1  is hydrogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxyalkyl, aryl, C 1 -C 8  alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl, 
         R 2 , R 3 , and R 4  are independently hydrogen, halogen, amino, C 1 -C 8  alkylamino, arylamino, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, or C 1 -C 8  alkoxyalkyl, 
         R 6 , R 7 , R 8 , and R 9  are independently H, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl, 
         R 6  and R 7 , R 8  and R 9  can independently form 4-8 membered alkyl or heterocyclyl rings, 
         R 10 is hydrogen, halogen, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  alkoxy, C 1 -C 8  alkoxyalkyl, 
         m=0-8; and 
         n=0-8; 
         the degradation disruption tag comprises FORMULA 5A; 
       
       
         
           
           
               
               
           
         
         wherein 
         V, W and X are independently selected from CR 2  and N; 
         Y is selected from CO, CH 2 , and N═N; 
         Z is selected from CH 2 , NH and O; and 
         R 1  and R 2  are independently selected from hydrogen, halogen, cyano, nitro, and C 1 -C 5  alkyl;
 and the linker comprises FORMULA B; 
 
       
       
         
           
           
               
               
           
         
         wherein X is C═O or CH 2 , 
         Y is C═O or CH 2 , 
         m is 0-15, 
         n is 0-6, and 
         o is 0-15, 
       
       and pharmaceutically acceptable salts thereof. 
     
     
         124 . The bivalent compound of  claim 123 , wherein in Formula 3,
 A is CR 3 ;   B is N;   X is N;   Y is CO;   E is C 3 -C 8  heterocyclyl;   Z 1 -Z 2  is CR 10 ═CH;   R 1  is aryl or haloaryl;   R 2  is hydrogen;   R 3  is amino;   R 10  is hydrogen; and   n=2.   
     
     
         125 . The bivalent compound of  claim 123 , wherein in Formula 5A, R 1  and R 2  are each hydrogen; Y is CO; X, V and W are each CR 2 ; and Z is NH. 
     
     
         126 . The bivalent compound of  claim 123 , wherein in Formula B, X is C═O, m is 1, n is 4, o is 0 and Y is CH 2 . 
     
     
         127 . The bivalent compound of  claim 124  wherein in Formula 3, E is piperazinyl. 
     
     
         128 . The bivalent compound of  claim 124  wherein in Formula 3, R 1  is 4-chlorophenyl. 
     
     
         129 . 4-amino-N-((1S)-1-(4-chlorophenyl)-3-(4-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaoxaoctadecan-18-oyl)piperazin-1-yl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (XF050-33) and pharmaceutically acceptable salts thereof. 
     
     
         130 . A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3C; 
       
         
           
           
               
               
           
         
         the degradation disruption tag comprises FORMULA 6; 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently hydrogen, C 1 -C 8  alkyl, C 1 -C 8  alkoxyalkyl, C 1 -C 8  haloalkyl, C 1 -C 8  hydroxyalkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocyclyl, C 2 -C 8  alkenyl, or C 2 -C 8  alkynyl;
 and the linker comprises FORMULA C; 
 
       
       
         
           
           
               
               
           
         
         wherein 
         X is C═O or CH 2 , 
         Y is C═O or CH 2 , 
         R is —CH 2 —, —CF 2 —, —CH(C 1-3  alkyl)-, —C(C 1-3  alkyl)(C 1-3  alkyl)-, —CH═CH—, —C(C 1-3  alkyl)=C(C 1-3  alkyl)- , —C═C—, —O—, —NH—, —N(C 1-3  alkyl)-, —C(O)NH—, —C(O)N(C 1-3  alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring, 
         m is 0-15, and 
         n is 0-15, 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         131 . The bivalent compound of  claim 130 , wherein in Formula 6, R 1  and R 2  are each C 1 -C 8  alkyl. 
     
     
         132 . The bivalent compound of  claim 130 , wherein in Formula C,
 X is CH 2 ,   Y is C═O,   R is —C(O)NH—,   m is 1, and   n is 10.   
     
     
         133 . The bivalent compound of  claim 131 , wherein in Formula 6, R 1  is tert-butyl and R 2  is methyl. 
     
     
         134 . N 1 -(2-(((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)ethyl)-N 12 -((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)dodecanediamide (XF050-98), and pharmaceutically acceptable salts thereof. 
     
     
         135 . A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3C; 
       
         
           
           
               
               
           
         
         the degradation disruption tag comprises FORMULA 5A; 
       
       
         
           
           
               
               
           
         
         wherein 
         V, W, and X are independently selected from CR 2  and N; 
         Y is selected from CO, CH 2 , and N═N; 
         Z is selected from CH 2 , NH and O; and 
         R 1  and R 2  are independently selected from hydrogen, halogen, cyano, nitro, and C 1 -C 5  alkyl;
 and the linker comprises FORMULA C; 
 
       
       
         
           
           
               
               
           
         
         wherein 
         X is C═O or CH 2 , 
         Y is C═O or CH 2 , 
         R is —CH 2 —, —CF 2 —, —CH(C 1-3  alkyl)-, —C(C 1-3  alkyl)(C 1-3  alkyl)-, —CH═CH—, —C(C 1-3  alkyl)=C(C 1-3  alkyl)-, —C═C—, —O—, —NH—, —N(C 1-3  alkyl)-, —C(O)NH—, —C(O)N(C 1-3  alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring, 
         m is 0-15, and 
         n is 0-15, and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         136 . The bivalent compound of  claim 135 , wherein in Formula 5A, R 1  and R 2  are each hydrogen, Y is CO, X, V and W are each CR 2 , and Z is NH. 
     
     
         137 . The bivalent compounds of  claim 135 , wherein in Formula C,
 X is CH 2 , Y is CH 2 , R is —C(O)NH—, m is 1 and n is 7.   
     
     
         138 . 3-(((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)amino)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)propanamide (XF042-170), and pharmaceutically acceptable salts thereof. 
     
     
         139 . A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, wherein the AKT ligand comprises FORMULA 3J; 
       
         
           
           
               
               
           
         
         the degradation disruption tag comprises FORMULA 6; 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently hydrogen, C 1 -C 8  alkyl, C 1 -C 8  alkoxyalkyl, C 1 -C 8  haloalkyl, C 1 -C 8  hydroxyalkyl, C 3 -C 7  cycloalkyl, C 3 -C 7  heterocyclyl, C 2 -C 8  alkenyl, or C 2 -C 8  alkynyl;
 and the linker comprises FORMULA C; 
 
       
       
         
           
           
               
               
           
         
         wherein 
         X is C═O or CH 2 , 
         Y is C═O or CH 2 , 
         R is —CH 2 —, —CF 2 —, —CH(C 1-3  alkyl)-, —C(C 1-3  alkyl)(C 1-3  alkyl)-, —CH═CH—, —C(C 1-3  alkyl)=C(C 1-3  alkyl)-, —C═C—, —O—, —NH—, —N(C 1-3  alkyl)-, —C(O)NH—, —C(O)N(C 1-3  alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring, 
         m is 0-15, and 
         n is 0-15, and 
         pharmaceutically acceptable salts thereof. 
       
     
     
         140 . The bivalent compound of  claim 139 , wherein in Formula 6, R 1  is C 1 -C 8  alkyl and R 2  is hydrogen or C 1 -C 8  alkyl. 
     
     
         141 . The bivalent compounds of  claim 139 , wherein in Formula C,
 X is CH 2 , Y is C═O, R is —C(O)NH—, m is 1 and n is 10.   
     
     
         142 . (2S,4R)-1-((S)-2-(11-(3-(3-(3-(4-(1-aminocyclobutyl)phenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)propanamido)undecanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (XF067-18) and pharmaceutically acceptable salts thereof.