Amine-linked c3-glutarimide degronimers for target protein degradation

Abstract

This invention provides amine-linked C 3 -glutarimide Degronimers and Degrons for therapeutic applications as described further herein, and methods of use and compositions thereof as well as methods for their preparation.

We claim: 
     
         1 . A Degronimer consisting of a Degron covalently linked to a Targeting Ligand, wherein the Degronimer is of Formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or N-oxide thereof; 
         wherein:
 W 1  is CR 6 R 7 , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, or P(O)NH 2 ; 
 W 2  is CR 8 R 9 , C═O, C═S, C═CH 2 , SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, or P(O)NH 2 ; 
 X is NH, NR 3 , CH 2 , CHR 3 , C(R 3 ) 2 , O, or S; 
 n is 0, 1, or 2; 
    is a single or double bond; 
 R 1  is selected from: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           R 2  is alkyl or hydrogen; 
           or R 1  and R 2  are combined to form a 4, 5, 6, 7, 8, 9, or 10 membered heterocyclo or heteroaryl species, wherein the heterocyclo or heteroaryl species is substituted with R 12  at any desired position, and wherein the heterocyclo or heteroaryl species is optionally further substituted with one or more substituents selected from R 5 ; 
           R 3  is selected at each instance from: alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkene, and alkyne; 
           R 4  is selected at each instance from: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl; 
           or two R 4  substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring; 
           R 5  and R 14  are independently selected at each instance from: hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl; 
           R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 , are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, —NHalkyl, and —Nalkyl 2 ; 
           or R 6  and R 7  together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O; 
           or R 8  and R 9  together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O; 
           or R 10  and R 11  together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O; 
           or R 6  and R 8  form a 1 or 2 carbon bridged ring; 
           or R 6  and R 10  form a 1 or 2 carbon bridged ring; 
           or R 8  and R 10  form a 1 or 2 carbon bridged ring; 
           or R 14  and R 6  form a 3, 4, 5, or 6 carbon fused ring; 
           or R 14  and R 10  form a 3, 4, 5, or 6 carbon fused ring; 
           or R 14  and R 8  form a 1 or 2 carbon bridged ring; 
           or R 14  and R 4  form a 3, 4, 5, or 6 carbon fused ring wherein R 5  is on the carbon alpha to R 13  or a 1, 2, 3, or 4 carbon bridged ring wherein R 5  is not on the carbon alpha to R 13 ; 
           R 12  is Linker-Targeting Ligand; 
           Linker is a chemical group that covalently attaches the Degron to a Targeting Ligand; 
           and Targeting Ligand is a small molecule that binds to a Targeted Protein, wherein the Targeted Protein is a mediator of abnormal cellular proliferation in a host in need of such therapy. 
         
       
     
     
         2 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A method for treating a patient with abnormal cellular proliferation comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. 
     
     
         5 . The method of  claim 4 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 5 , wherein the abnormal cellular proliferation is a cancer. 
     
     
         7 . The method of  claim 6 , wherein the cancer is a solid tumor. 
     
     
         8 . The method of  claim 6 , wherein the cancer is a hematological cancer. 
     
     
         9 . The method of  claim 5 , wherein the Targeted Protein is the androgen receptor. 
     
     
         10 . The method of  claim 5 , wherein the Targeted Protein is the estrogen receptor. 
     
     
         11 . The method of  claim 5 , wherein the Targeted Protein is the epidermal growth factor receptor. 
     
     
         12 . The compound of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 12 , wherein Linker is selected from: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1  and X 2  are independently selected from bond, NH, NR 25 , CH 2 , CHR 25 , C(R 25 ) 2 , O, and S; 
         R 20 , R 21 , R 22 , R 23 , and R 24  are independently selected from bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —C(—O—R 26 )H—, —C(—NHR 25 )H—, —C(—NH 2 )H—, —C(—NR 25   2 )H—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25   2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —CR 27 R 28 —, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, and alkyne; 
         R 25  is selected at each instance from: alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl; 
         R 26  is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne; and 
         R 27  and R 28  are independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6  spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O. 
       
     
     
         14 . The compound of  claim 13 , wherein the Targeted Protein is the androgen receptor. 
     
     
         15 . The compound of  claim 13 , wherein the Targeted Protein is the estrogen receptor. 
     
     
         16 . The compound of  claim 13 , wherein the Targeted Protein is the epidermal growth factor receptor. 
     
     
         17 . The compound of  claim 13 , wherein R 27  and R 28  are hydrogen. 
     
     
         18 . The compound of  claim 13 , wherein the Linker is: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 13 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 13 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 13 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 13 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 13 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 13 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 13 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A Degronimer consisting of a Degron covalently linked to a Targeting Ligand, wherein the Degronimer is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or N-oxide thereof; 
         wherein R 12  is Linker-Targeting Ligand; 
         Linker is a chemical group that covalently attaches the Degron to a Targeting Ligand; 
         and Targeting Ligand is a small molecule that binds to a Targeted Protein, wherein the Targeted Protein is a mediator of abnormal cellular proliferation in a host in need of such therapy. 
       
     
     
         27 . The compound of  claim 26 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1  and X 2  are independently selected from bond, NH, NR 25 , CH 2 , CHR 25 , C(R 25 ) 2 , O, and S; 
         R 20 , R 21 , R 22 , R 23 , and R 24  are independently selected from bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —C(—O—R 26 )H—, —C(—NHR 25 )H—, —C(—NH 2 )H—, —C(—NR 25   2 )H—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25   2 )alkyl-, -alkyl(R 27 )-alkyl(R 28 )—, —CR 27 R 28 —, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, polyethylene glycol, poly(lactic-co-glycolic acid), alkene, haloalkyl, alkoxy, and alkyne; 
         R 25  is selected at each instance from: alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl; 
         R 26  is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne; and 
         R 27  and R 28  are independently selected from hydrogen, alkyl, amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6  spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O. 
       
     
     
         28 . The compound of  claim 27 , wherein the Targeted Protein is the androgen receptor. 
     
     
         29 . The compound of  claim 27 , wherein the Targeted Protein is the estrogen receptor. 
     
     
         30 . The compound of  claim 27 , wherein the Targeted Protein is the epidermal growth factor receptor. 
     
     
         31 . The compound of  claim 27 , wherein the Linker is: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 27 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 27 , wherein the Linker is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 27 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 27 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 27 , wherein the compound is selected from