Plk1 selective degradation inducing compound

Abstract

The present invention provides novel compounds that induce selective polo-like kinase 1 (PLK1) degradation. Specifically, the present invention provides a bifunctional compound in which a PLK1 binding moiety and an E3 ubiquitin ligase-binding moiety are linked by a chemical linker. The present invention provides the compound, a method for preparing the same, and the use thereof. The compounds may be effectively utilized for preventing or treating PLK1 related diseases.

We claim: 
     
         1 . A compound represented by Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
   ULM-Linker-PTM  [Formula I]
   in the Formula I above,   ULM is CRBN or a VHL E3 ubiquitin ligase binding moiety;   PTM is a PLK1 binding moiety represented by Formula II:   
       
         
           
           
               
               
           
         
         {in the Formula II above, 
         R 1  is hydrogen, C 1-5  alkyl, or C 3-6  cycloalkyl; 
         R 1A  is hydrogen or C 1-3  alkyl; 
         R 2  is hydrogen, halogen, C 1-6  alkyl or —OR 2A ; 
         R 2A  is C 1-4  alkyl or C 3-6  cycloalkyl, optionally substituted by one or more halogen or hydroxy; 
         R 3  is hydrogen, halogen, —NO 2 , —CN, —OH, C 1-4  alkyl or —O(C 1-4  alkyl); 
         R 4  is selected from a single bond, 
       
       
         
           
           
               
               
           
         
         R 5  is hydrogen or C 1-4  alkyl; and 
            indicates a covalent bond that links PTM into the Linker}; and 
         the Linker is a chemical group that links ULM and PTM. 
       
     
     
         2 . The compound of  claim 1 , wherein ULM is CRBN E3 ubiquitin ligase binding moiety represented by Formula A-1: 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
          is a ring selected from 
       
       
         
           
           
               
               
           
         
         X 1  is a single bond, —CH 2 —, —NH—, —O—, —CH 2 CH 2 —, 
       
       
         
           
           
               
               
           
         
          —CO—, —COO—, —NHCO— or —CONH—; 
         X 2  is —CH 2 —, —CH(C 1-4  alkyl)-, —NH—, —N(C 1-4  alkyl)-, —O—, —CO—, —CH 2 —CH 2 —, —NH—CH 2 —, —NH—CH(C 1-4  alkyl)-, —N═CH—, —N═C(C 1-4  alkyl)- or —N═N—; 
         X 3  is hydrogen or C 1-4 alkyl; 
         X 4  is hydrogen, halogen, C 1-6  alkyl, CN, NH 2 , NO 2 , OH, COH, COOH or CF 3 ; and 
            indicates a covalent bond that links ULM into the Linker. 
       
     
     
         3 . The compound of  claim 2 , wherein ULM is a CRBN E3 ubiquitin ligase binding moiety represented by Formula A-2: 
       
         
           
           
               
               
           
         
         wherein: 
         X 2  is —CH 2 —, —CH(C 1-4  alkyl)-, —CO— or —N═N—; 
         X 3  is hydrogen or C 1-3  alkyl; and 
            indicates a covalent bond that links ULM into the Linker. 
       
     
     
         4 . The compound of  claim 1 , wherein ULM is VHL E3 ubiquitin ligase binding moiety represented by Formula B-1: 
       
         
           
           
               
               
           
         
         wherein: 
         n is an integer from 1 to 3; 
       
       
         
           
           
               
               
           
         
          is 5- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the heterocycloalkyl or the heteroaryl contains one to three heteroatoms, each heteroatom independently selected from N, O, or S; 
         Y 1  is hydrogen or C 1-4  alkyl; 
         Y 2  is C 1-4 alkyl, hydroxy(C 1-4 alkyl), —(C 0-2 alkyl)-COH, C 3-8 cycloalkyl, or phenyl; 
         Y 3  is hydrogen,   or 
       
       
         
           
           
               
               
           
         
         Y 4  is hydrogen, halogen, C 1-4 alkyl, —O(C 1-4 alkyl), C 3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, optionally substituted by halogen, —OH, —CN, —NHCOH, —NHCOCH 3 , —COH or —COCH 3 ; 
         Y 5  is hydrogen or C 1-4  alkyl; and 
            indicates a covalent bond that links ULM into the Linker. 
       
     
     
         5 . The compound of  claim 4 , wherein ULM is a VHL E3 ubiquitin ligase binding moiety selected from Formula B-2-1 or Formula B-2-2: 
       
         
           
           
               
               
           
         
         wherein: 
       
       
         
           
           
               
               
           
         
          is a 5-membered heteroaryl ring selected from oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, oxadiazole, pyrrole, pyrrolidine, furan, dihydrofuran, or tetrahydrofuran; 
         Y 1  is hydrogen or C 1-3  alkyl; 
         Y 4  is C 1-4  alkyl or C 3-5  cycloalkyl, optionally substituted by hydrogen or halogen; and 
            indicates a covalent bond that links ULM into the Linker. 
       
     
     
         6 . The compound of  claim 1 , wherein Formula II is represented by Formula III: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C 1-5  alkyl or C 3-6  cycloalkyl; 
         R 2  is hydrogen or —OR 2A ; 
         R 2A  is C 1-4  alkyl, C 3-6  cycloalkyl, CF 3  or —(C 1-3  alkylene)-OH; 
         R 3  is hydrogen or halogen; and 
            indicates a covalent bond that links PTM into the Linker. 
       
     
     
         7 . The compound of  claim 1 , wherein the Linker is represented by Formula L: 
       
         
           
           
               
               
           
         
         wherein: 
            and   are each independently bond; 
         L ULM  is covalently bonded to ULM moiety through   that is linked thereto, 
         L PTM  is covalently bonded to PTM moiety through   that is linked thereto, 
         L ULM , L PTM  and L INT  are independently selected from null, a single bond, —CH 2 —, —NH—, —O—, —S—, —SO—, —SO 2 —, —CO—, —CH 2 CH 2 —, 
       
       
         
           
           
               
               
           
         
          —CH 2 CH 2 O—, —OCH 2 CH 2 —, —CH 2 CH 2 S—, —SCH 2 CH 2 —, —COO—, —CONH—, —NHCO—, or 
       
       
         
           
           
               
               
           
         
          optionally substituted by one or more C 1-6  alkyl, C 3-8  cycloalkyl, halogen, hydroxy, amino, nitro, cyano or haloalkyl {wherein 
       
       
         
           
           
               
               
           
         
          is cycloalkyl, heterocycloalkyl, aryl or heteroaryl}; and 
         p is an integer from 1 to 30. 
       
     
     
         8 . The compound of  claim 7 , wherein:
 L ULM  is   
       
         
           
           
               
               
           
         
         L U1  is selected from a single bond, —CH 2 —, —CH 2 CH 2 —, —CH═CH—, —C≡C—, —NH—, —NCH 3 —, —CO—, —NHCO—, or —O—; 
         L U2  is selected from a single bond, —CH 2 —, —NH—, —O—, —CO—, or —CONH—; and 
       
       
         
           
           
               
               
           
         
          is null or a ring selected from 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl. 
       
     
     
         9 . The compound of  claim 7 , wherein:
 L PTM  is   
       
         
           
           
               
               
           
         
         L P1  is selected from a single bond, —O—, —S—, —NH—, —N(C 1-4 alkyl)-, —CH 2 —, —CH(C 1-4 alkyl)-, —CH 2 NH—, or —CH 2 CH 2 —; 
         L P2  is selected from a single bond, —CO—, —COCH 2 —, —NHCO—, —NHCOCH 2 —, —HET-, or —HET-CH 2 — {wherein HET is 5- to 6-membered heterocyclyl or heteroaryl containing one or more N, S, or O atoms}; and 
       
       
         
           
           
               
               
           
         
          is null, amino substituted with C 1-8  alkyl, or a ring selected from 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl. 
       
     
     
         10 . The compound of  claim 7 , wherein: 
       
         
           
           
               
               
           
         
       
       is 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
          is null or a ring selected from 3- to 10-membered cycloalkyl, 4- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl. 
         L INT1  and L INT2  are each independently selected from —CH 2 —, —NH—, —NCH 3 —, —O—, —S—, —SO—, —SO 2 —, —CO—, —CH 2 CH 2 O—, —OCH 2 CH 2 —, —CH 2 CH 2 S—, —SCH 2 CH 2 —, —COO—, —CONH—, or —NHCO—; and 
         q and r are each independently an integer from 1 to 10. 
       
     
     
         11 . The compound of  claim 1 , wherein the compound is selected from one of Compound 1 to Compound 175. 
     
     
         12 . The compound of  claim 1 , wherein the compound is a bifunctional compound that induces PLK1 protein degradation. 
     
     
         13 . The compound of  claim 12 , wherein the compound induces selective PLK1 protein degradation. 
     
     
         14 . A method for preventing or treating a PLK1 related disease comprising administering a compound according to  claim 1 , a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. 
     
     
         15 . The method of  claim 14 , wherein the PLK1 related disease is a disease selected from a cancer, a benign tumor, or a neurological disease.