Antiproliferative pyrimidine-based compounds

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.

We claim: 
     
         1 . A method for the treatment of abnormal cellular proliferation comprising administering an effective amount to a host in need thereof of a compound, optionally in a pharmaceutically acceptable carrier, wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein:
 X 1 , X 2 , X 3 , and X 4  are independently CH, CR 6 , or N; wherein at most 3 of X 1 , X 2 , X 3 , and X 4  are N; 
 w is 0 or 1; 
 y is 0, 1, 2, 3, or 4; 
    is either a single or double bond; 
 R is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl, —(C 0 -C 2 alkyl)(C 3 -C 8 carbocyclyl), —(C 0 -C 2 alkyl)(C 3 -C 8 heterocyclyl), —(C 0 -C 2 alkyl)(aryl), —(C 0 -C 2 alkyl)(heteroaryl), —COOalkyl, —COOarylalkyl, or —COOH; 
 each R 1  is independently selected from the group consisting of alkyl, aryl, cycloalkyl and 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 saturated 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 the group consisting of hydrogen, 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; 
 R 5  is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; 
 R x  at each occurrence is independently selected from the group consisting of 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) n —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 , and -(alkylene) m -N(R 3 )—SO 2 —R 5 ; 
 R 6  is selected independently at each instance from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl; 
 R 7  is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
           Y is NH, O, S, or NR 9 ; 
           X 5 , X 6 , X 7  are independently N or CR 8 , wherein at least one of X 5 , X 6 , and X 7  is CR 8 ; 
           R 8  is selected independently at each instance from the group consisting of R 6  and R 2 , wherein one R 8  is R 2 ; and 
           R 9  is selected from the group consisting of —C(O)H, —C(O)alkyl, —C(S)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl. 
         
       
     
     
         2 . The method of  claim 1 , wherein the host is a human. 
     
     
         3 . The method of  claim 2 , wherein the abnormal cellular proliferation is a cancer. 
     
     
         4 . The method of  claim 3 , wherein the cancer is a solid tumor. 
     
     
         5 . The method of  claim 3 , wherein the cancer is non-Hodgkin's lymphoma. 
     
     
         6 . The method of  claim 3 , wherein the cancer is cholangiocarcinoma. 
     
     
         7 . The method of  claim 3 , wherein the cancer is renal cell carcinoma. 
     
     
         8 . The method of  claim 3 , wherein the cancer is breast cancer. 
     
     
         9 . The method of  claim 8 , wherein the breast cancer is HER2-negative. 
     
     
         10 . The method of  claim 3 , wherein the cancer is lung cancer. 
     
     
         11 . The method of  claim 10 , wherein the lung cancer is small cell lung cancer. 
     
     
         12 . The method of  claim 2 , comprising administering an additional therapeutic agent. 
     
     
         13 . The method of  claim 2 , wherein y is 2. 
     
     
         14 . The method of  claim 13 , wherein two R 1  groups 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. 
     
     
         15 . The method of  claim 14 , wherein the 3-8-membered cycle is a 6-membered cycle. 
     
     
         16 . The method of  claim 15 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 2 , wherein R 2  is heterocyclo optionally independently substituted with one or more R x  groups as allowed by valance. 
     
     
         18 . The method of  claim 2 , wherein R x  at each occurrence is independently selected from the group consisting of halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl. 
     
     
         19 . The method of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . The method of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         21 . A pharmaceutical composition, comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein y is 2. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein two R 1  groups 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. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the 3-8-membered cycle is a 6-membered cycle. 
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The pharmaceutical composition of  claim 21 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         27 . The pharmaceutical composition of  claim 21 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The pharmaceutical composition of  claim 21 , wherein the compound is in the form of a pharmaceutically acceptable salt and the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulfate, bisulfate, nitrate, acetate, phosphate, and citrate. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the pharmaceutically acceptable salt is hydrochloride.