Cyclin-dependent kinase inhibitors and methods of use

Abstract

Compounds of Formula (I) or pharmaceutically acceptable salts thereof are provided and methods involving compounds of Formula (I) as effective inhibitors of CDK8 and/or CDK19 are also provided.

1 . A compound represented by Formula (I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
 X is —OR, ═O, or —NR 1 R 2 ; 
 R is H or C 1 -C 6  alkyl; 
 R 1  and R 2  are each independently H, C 1 -C 6  alkyl, —C(O)—C 1 -C 6  alkyl, or R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic or a 5-, 8-, or 9-membered heteroaryl ring optionally comprising one or more additional heteroatoms selected from nitrogen, sulfur, and oxygen; 
 u, v, and w together form (i), (ii), or (iii): 
 
       
         
           
           
               
               
           
         
         y and z together form (iv) or (v): 
       
       
         
           
           
               
               
           
         
       
       and
 Het is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from nitrogen, sulfur, and oxygen, and optionally substituted with NH 2 , 
 
       wherein the compound is not a compound of Formula (A): 
       
         
           
           
               
               
           
         
       
       wherein Het is selected from 7-isoquinolinyl, 6-isoquinolinyl, 5-isoquinolinyl, 6-quinolinyl, and 3-pyridyl. 
     
     
         2 .- 6 . (canceled) 
     
     
         7 . The compound of  claim 1 , wherein X is —OR and R is H or C 1 -C 6  straight-chain or C 3 -C 6  branched alkyl optionally substituted with OH, O—(C 1 -C 6  alkyl), NH 2 , NH(C 1 -C 6  alkyl), or N(C 1 -C 6  alkyl) 2 . 
     
     
         8 .- 9 . (canceled) 
     
     
         10 . The compound of  claim 1 , wherein X is —NR 1 R 2  or (R)—NR 1 R 2 . 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 10 , wherein R 1  and R 2  are each C 1 -C 6  straight-chain or C 3 -C 6  branched alkyl. 
     
     
         13 . The compound of  claim 10 , wherein R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic or a 5-, 8-, or 9-membered heteroaryl ring optionally comprising one or more additional heteroatoms selected from nitrogen, sulfur, and oxygen. 
     
     
         14 . The compound of  claim 10 , wherein R 1  and R 2 , together with the nitrogen atom to which they are attached, form triazole, morpholine, or pyrrolidine. 
     
     
         15 .- 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein X is ═O. 
     
     
         18 . The compound of  claim 1 , wherein Het is selected from isoquinolinyl, quinolinyl, indazolyl, cinnolinyl, phthalazinyl, pyridinyl, pyridazinyl, indolyl, acridinyl, pyrazinyl, benzoquinolinyl, pyrazolyl, pyrrolyl, pyrimidinyl, purinyl, pyrrolopyrimidinyl, quinoxalinyl, and quinazolinyl. 
     
     
         19 . The compound of  claim 18 , wherein Het is 6-isoquinolinyl, 7-isoquinolinyl, 6-quinazolinyl, 6-phthalazinyl, 6-indazolyl, 6-indazolyl-3-amine, or 5-indazolyl. 
     
     
         20 . The compound of  claim 19 , wherein Het is 7-isoquinolinyl. 
     
     
         21 . The compound of  claim 1 , of Formula (iv(a)′), (v(a)′), (iv(a)″), (v(a)″), (iv(b)′), (v(b)′), (iv(b)″), (v(b)″), (iv(c)″), or (v(c)″): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 X is —OR or —NR 1 R 2 ; 
 R is H or C 1 -C 6  alkyl; and 
 R 1  and R 2  are each independently H, C 1 -C 6  alkyl, or —C(O)—C 1 -C 6  alkyl, or R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic or a 5-, 8-, or 9-membered heteroaryl ring optionally comprising one or more additional heteroatoms selected from nitrogen, sulfur, and oxygen. 
 
       
     
     
         22 . The compound of  claim 1 , of Formula (iv(c)′) or (v(c)′): 
       
         
           
           
               
               
           
         
         wherein:
 X is —OR or —NR 1 R 2 ; 
 R is H or C 1 -C 6  alkyl; and 
 R 1  and R 2  are each independently H, C 1 -C 6  alkyl, or —C(O)—C 1 -C 6  alkyl, or R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic or a 5-, 8-, or 9-membered heteroaryl ring optionally comprising one or more additional heteroatoms selected from nitrogen, sulfur, and oxygen, provided that R 1  and R 2  are not both methyl. 
 
       
     
     
         23 . The compound of  claim 1 , of one of the following formulae: 
       
         
           
           
               
               
           
         
         wherein:
 X is —OH or —NR 1 R 2 ; 
 R 1  and R 2  are each independently H, C 1 -C 6  alkyl, or —C(O)—C 1 -C 6  alkyl, or R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic or a 5-, 8-, or 9-membered heteroaryl ring optionally comprising one or more additional heteroatoms selected from nitrogen, sulfur, and oxygen; 
 a, b, c, and d are each independently CR 3  or N; and 
 each R 3  is independently H or NH 2 . 
 
       
     
     
         24 . The compound of  claim 1 , of one of the following formulae: 
       
         
           
           
               
               
           
         
         wherein:
 X is —OH or —NR 1 R 2 ; and 
 R 1  and R 2  are each independently H, C 1 -C 6  alkyl, or —C(O)—C 1 -C 6  alkyl, or R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic or a 5-, 8-, or 9-membered heteroaryl ring optionally comprising one or more additional heteroatoms selected from nitrogen, sulfur, and oxygen. 
 
       
     
     
         25 . The compound of  claim 1 , of one of the following formulae: 
       
         
           
           
               
               
           
         
         wherein:
 X is —OH or —NR 1 R 2 ; 
 R 1  and R 2  are each independently H, C 1 -C 6  alkyl, —C(O)—C 1 -C 6  alkyl, or R 1  and R 2 , together with the nitrogen atom to which they are attached, form a 3- to 7-membered heterocyclic or a 5-, 8-, or 9-membered heteroaryl ring optionally comprising one or more additional heteroatoms selected from nitrogen, sulfur, and oxygen; 
 R 4  is H or C 1 -C 6  alkyl; 
 e and f are each independently CR 5  or N; and 
 each R 5  is independently be H or NH 2 . 
 
       
     
     
         26 . The compound of  claim 1 , which is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         27 . A pharmaceutical composition comprising a therapeutically effective amount of the compound of  claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         28 . (canceled) 
     
     
         29 . A method of treating a disease modulated by CDK8 and/or CDK19, comprising administering to a subject in need thereof an effective amount of the compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         30 . A method of treating cancer in a subject, wherein a cell of the cancer comprises an activated CDK8 and/or activated CDK19 or wherein the subject is identified as being in need of inhibition of CDK8 and/or CDK19 for the treatment of cancer, comprising administering to the subject an effective amount of the compound of  claim 1  or a stereoisomer or pharmaceutically acceptable salt thereof. 
     
     
         31 .- 35 . (canceled) 
     
     
         36 . The compound of  claim 1 , wherein Formula (I) is of Formula (i′), (ii′), (iii′), (iv(a)), (iv(b)), (iv(c)), (v(a)), (v(b)), or (v(c)): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomer or pharmaceutically acceptable salt thereof.