Pyrimidine-based antiproliferative agents

Abstract

This invention is in the area of pyrimidine-based compounds for the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.

What is claimed is: 
     
         1 . A compound of Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 y is 0, 1, 2, 3 or 4; 
 R is hydrogen or C 1 -C 6 alkyl; 
 each R 1  is independently alkyl, aryl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes heteroatoms O, N, or S in place of a carbon in the chain and two R 1 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle; 
 R 2  is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4  any of which may be optionally independently substituted with one or more R x  groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; 
 m is 0, 1, or 2; 
 n is 0, 1, or 2; 
 R 3  and R 4  at each occurrence are independently selected from: 
 (i) hydrogen or 
 (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; or R 3  and R 4  together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring; 
 R 5  is selected from: 
 (i) hydrogen or 
 (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; 
 R x  at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O)—R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 , -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; 
 R 6  is selected independently at each instance from: hydrogen, halogen, alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl; 
 R 7  is selected from: 
 
       
         
           
           
               
               
           
         
         or R 7  is selected from cycloalkyl, heterocycle, and alkyl, each of which cycloalkyl, heterocycle, and alkyl groups is optionally substituted with one or more substituents selected from amino, —NHR 14 , —NR 14 R 15 , hydroxyl, OR 14 , R 6 , and R 2 ; 
         R 14  and R 15  are independently selected from: hydrogen, alkyl, alkenyl, alkynyl, —C(O)H, —C(O)alkyl, —C(S)alkyl, aryl, —SO 2 alkyl, heteroaryl, arylalkyl, and heteroarylalkyl. 
         Y is NH, O, S, or NR 9 ; 
         X 1 , X 2 , X 3  and X 4  are independently N or CR, wherein at least one of X 1 , X 2 , X 3 , X 4 , and X 5  are CR; 
         R 8  is selected independently at each instance from: R 6  and R 2 , wherein one R 8  is R 2 ; and 
         R 9  is selected from: —C(O)H, —C(O)alkyl, —C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. 
       
     
     
         2 . The compound of  claim 1  of Formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1 , wherein X 1  and X 2  are CH. 
     
     
         4 . The compound of  claim 1  of Formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound of  claim 1 , wherein at least one R 1  is alkyl. 
     
     
         6 . The compound of  claim 1 , wherein two R 1 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached form a 3-8-membered cycle. 
     
     
         7 . The compound of  claim 1 , wherein two R 1 s on the same ring atom together with the ring atom to which they are attached form cyclohexyl. 
     
     
         8 . The compound of  claim 1 , wherein y is 2. 
     
     
         9 . The compound of  claim 1 , wherein y is 3. 
     
     
         10 . The compound of  claim 1  of Formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of  claim 1 , wherein R is H. 
     
     
         12 . The compound of  claim 1 , wherein R is methyl or ethyl. 
     
     
         13 . The compound of  claim 1  of Formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 1 , wherein, R 2  is -(alkylene) m -S(O)—NR 3 R 4 . 
     
     
         15 . The compound of  claim 14 , wherein n is 2. 
     
     
         16 . The compound of  claim 1 , wherein, R 2  is -(alkylene) m -S(O)—NR 3 R 4 . 
     
     
         17 . The compound of  claim 1 , wherein R 2  is -(alkylene) m -heterocyclo optionally independently substituted with one or more R x  groups as allowed by valance. 
     
     
         18 . The compound of  claim 1 , wherein R 2  is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1 , wherein R 2  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 1 , wherein the compound is selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         22 . A method for the treatment of a disorder associated with abnormal cellular proliferation comprising administering an effective amount to a host in need thereof of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof optionally in a pharmaceutically acceptable carrier. 
     
     
         23 . The method of  claim 22 , wherein the host is a human.