Covalent inhibitors of cdk-7

Abstract

The disclosure includes compounds of Formula (I) wherein R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , and L are defined herein. Also disclosed is a method for treating a neoplastic disease, autoimmune disease, and inflammatory disorder with these compounds.

1 . A compound of Formula (I), or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (I) or N-oxide thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 A is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, fused hetero-bicyclic, or spiro-heterocyclic; 
 each of B, and C, independently, is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl; 
 each of Z 1 , Z 2 , Z 3 , and Z 4  independently, is a bond, (CR a R b ) p , (CR a R b ) p N(R a )(CR a R b ) q , N(R a )(CR a R b ) q N(R a ), (CR a R b ) p O(CR a R b ) q , (CR a R b ) p C≡C(CR a R b ) q , (CR a R b ) p C≡C(CR a R b ) q , C(R a )═N, O, S, C(O), N(R a ), S(O 2 ), OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(R a ), N(R a )C(O), S(O 2 )N(R a ), N(R a )S(O 2 ), OC(O)O, OC(O)S, OC(O)N(R a ), OC(O)N(R a )(CR a R b ) p+1 N(R a )(CR a R b ) q , N(R a )C(O)O, N(R a )C(O)S, N(R a )C(O)N(R b ), (CR a R b ) p N(R a )C(O)(CR a R b ) q , or (CR a R b ) p C(O)N(R a )(CR a R b ) q ; 
 each of m, n, p, and q independently, is 0, 1, 2, 3, or 4; 
 Warhead is 
 
       
         
           
           
               
               
           
         
         L 1  is N(R 7 ) if the atom which L 1  connects to ring A is a carbon atom; or L 1  is a direct bond if ring A is a heterocycloalkyl, heterocycloalkenyl, or heteroaryl and the atom which L 1  connects to ring A is a nitrogen atom; 
         L 2  is (CR a R b ) s C═C(CR a R b ) r  in which each of r, and s independently, is 1, 2, 3, or 4; 
         each of W 1 , and W 2  independently, is C(R 4 ) or N; 
         each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, —OR a , —SR a , —NR b R c , —C(O)R a , —S(O)R a , —SO 2 R a , —P(O)R b R c , —C(O)N(R b )R c , —N(R b )C(O)R c , —C(O)OR a , —OC(O)R a , —SO 2 N(R b )R c , —N(R b )SO 2 R c , -alkyl-R a , -alkyl-C(O)R a , -alkyl-NR b R c , -alkyl-C(O)N(R b )R c , -alkyl-N(R b )R c C(O), or -alkyl-N(R b )SO 2 R c ; and 
         each of R a , R b , R a , R b , and R c , independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, cyano, amine, nitro, hydroxy, —C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, dialkylamino, or alkylamino. 
       
     
     
         2 . The compound according to  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (II) 
       
         
           
           
               
               
           
         
       
       in which each of Z 1 , Z 2 , Z 3 , and Z 4  independently, is a bond, (CH 2 ) p , (CH 2 ) p NR a (CH 2 ) q , NR a (CH 2 ) q NR a , (CH 2 ) p O(CH 2 ) q , CH═N, O, S, C(O), NH, S(O 2 ), OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)NH, NHC(O), S(O 2 )NH, NHS(O 2 ), OC(O)O, OC(O)S, OC(O)NH, OC(O)NH(CH 2 ) p+1  NH(CH 2 ) q , NHC(O)O, NHC(O)S, NHC(O)NH, (CH 2 ) p NHC(O)(CH 2 ) q , or (CH 2 ) p C(O)NH(CH 2 ) q ; R 1  is H, alkyl, or alkyl-NR b R c ; and each of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, nitro, oxo, cyano, —OR a , —SR a , —NR b R c , —C(O)R a , —SO 2 R a , —C(O)NHR c , —NHC(O)R c , —SO 2 NHR c , —NHSO 2 R c , -alkyl-R a , -alkyl-C(O)R a , -alkyl-NHR c , -alkyl-C(O)NHR c , -alkyl-NHC(O), or -alkyl-NHSO 2 R c . 
     
     
         3 . The compound according to  claim 2  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (III) 
       
         
           
           
               
               
           
         
       
       in which t, is 0, 1, 2, 3 or 4; R 1  is H, low alkyl, or low alkyl-NR b R c ; each of R 3 , R 4 , and R 5 , independently, is H, alkyl, alkenyl, alkynyl, halo, or haloalkyl; and M is (CH 2 ) p , O, or N(R a ). 
     
     
         4 . The compound according to  claim 3  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is represented by Formula (IV) 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 4  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein R 1  is H, —CH 3 , or CH 2 —N(CH 3 )CH 3 ; R 4  is H, CH 3 , CF 3 , CN, or halo. 
     
     
         6 . A The compound according to  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         7 . A The compound according to  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A The compound according to  claim 1  or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof, wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition comprising a compound of Formula (I) or an N-oxide thereof as defined in  claim 1 , or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (I) or an N-oxide thereof, and a pharmaceutically acceptable diluent or carrier. 
     
     
         10 . A method of treating a neoplastic disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or an N-oxide thereof as defined in  claim 1 , or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (I) or an N-oxide thereof.