Pyrimidines and uses thereof

Abstract

The invention relates to pyrimidines and uses thereof, including to inhibit lysophosphatidic acid acyltransferase β (LPAAT-β) activity and/or proliferation of cells such as tumor-cells.

1 . A compound or physiologically acceptable salt thereof, wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 X, Y and Z are N, CH or CR where R is alkyl, alkoxy, Cl, Br, NH 2 , NHR′ or NR′R″ where R′ and R″ independently are alkyl; 
 Q is NR, RN—(CH 2 ) n , (CH 2 ) n —NR, O, O—(CH 2 ) n , (CH 2 ) n —O, S, S—(CH 2 ) n  or (CH 2 ) n —S, where n is 1-10 and R is H or alkyl; 
 R 1  is H, OH, alkyl, alkoxy, Cl, F, Br, CR 3  where R 3  is Cl 3 , F 3  or Br 3 , NH 2 , NHR or NRR′ where R and R′ independently are alkyl; 
 R 2  and R 7  are independently H, OH, alkyl, alkoxy, Cl, F, Br, I or CR 3  where R 3  is Cl 3 , F 3  or Br 3 ; 
 R 3  is H, alkyl, alkoxy, Cl, CCl 3 , NH 2 , NHR or NRR′ where R and R′ independently are alkyl or acyl; 
 R 4 , R 5 , and R 6  are independently H, OH, alkyl, alkenyl, alkynyl, alkoxy, (CH 2 ) n —OR where R is H or alkyl and n is 1-10, Cl, F, Br, CR 3  where R 3  is Cl 3 , F 3  or Br 3 , acyl, heterocycle, N + (═O)O − , C≡N, N 3 , B(OH) 2 , SH, SR or S(═O) 2 R where R is alkyl, NH 2 , NHR or NRR′ where R and R′ independently are alkyl, or R 4  and R 5  or R 5  and R 6  are taken together with the benzene ring to form a heterocycle; 
 and with the proviso that two of X, Y and Z are N. 
 
     
     
         2 . The compound or salt thereof of  claim 1  wherein X and Y of the compound or salt thereof are N. 
     
     
         3 . The compound or salt thereof of  claim 1  wherein Q of the compound or salt thereof is NH. 
     
     
         4 . The compound or salt thereof of  claim 1  wherein R 4  or R 5  of the compound or salt thereof is acyl. 
     
     
         5 . The compound or salt thereof of  claim 1  wherein R 1  of the compound or salt thereof is alkyl, alkoxy or Cl. 
     
     
         6 . The compound or salt thereof of  claim 1  wherein R 2  of the compound or salt thereof is Cl or Br. 
     
     
         7 . The compound or salt thereof of  claim 1  wherein R 3  of the compound or salt thereof is alkyl or NH 2 . 
     
     
         8 . The compound or salt thereof of  claim 1  wherein R 4  or R 5  of the compound or salt thereof is alkyl, Cl, Br, CF 3 , CH 2 —OH, (CH 2 ) 2 —OH, N + (═O)O − , C≡N, or C(═O)R wherein R is alkyl or alkoxy, or R 4  and R 5  are taken together with the benzene ring to form indazole. 
     
     
         9 . The compound or salt thereof of  claim 1  wherein the compound is any one of compounds 1-192 of Table 1, or physiologically acceptable salts thereof. 
     
     
         10 . The compound or salt thereof of  claim 1  in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         11 . The compound or salt thereof of  claim 10  wherein X and Y of the compound or salt thereof are N. 
     
     
         12 . The compound or salt thereof of  claim 10  wherein Q of the compound or salt thereof is NH. 
     
     
         13 . The compound or salt thereof of  claim 10  wherein R 4  or R 5  of the compound or salt thereof is acyl. 
     
     
         14 . The compound or salt thereof of  claim 10  wherein R 1  of the compound or salt thereof is alkyl, alkoxy or Cl. 
     
     
         15 . The compound or salt thereof of  claim 10  wherein R 2  of the compound or salt thereof is Cl or Br. 
     
     
         16 . The compound or salt thereof of  claim 10  wherein R 3  of the compound or salt thereof is alkyl or NH 2 . 
     
     
         17 . The compound or salt thereof of  claim 10  wherein R 4  or R 5  of the compound or salt thereof is alkyl, Cl, Br, CF 3 , CH 2 —OH, (CH 2 ) 2 —OH, N + (═O)O − , C≡N, or C(═O)R wherein R is alkyl or alkoxy, or R 4  and R 5  are taken together with the benzene ring to form indazole. 
     
     
         18 . The compound or salt thereof of  claim 10  wherein the compound is any one of compounds 1-192 of Table 1, or physiologically acceptable salts thereof. 
     
     
         19 . A method for reducing the activity of lysophosphatidic acid acyltransferase β (LPAAT-β) comprising contacting LPAAT-β with a compound or salt thereof according to  claim 1  in an amount effective to reduce LPAAT-β activity. 
     
     
         20 .- 29 . (canceled) 
     
     
         30 . A method for inhibiting the proliferation of a cell in which the activity of lysophosphatidic acid acyltransferase β (LPAAT-β) is required for the proliferation of the cell comprising contacting the cell with a compound or salt thereof according to  claim 1  in an amount effective to inhibit the proliferation of the cell. 
     
     
         31 .- 40 . (canceled) 
     
     
         41 . A method for treating a cancer in which lysophosphatidic acid acyltransferase β (LPAAT-β) activity is associated comprising administering to an animal in need, a compound or salt thereof according to  claim 1  in an amount effective to treat the cancer. 
     
     
         42 .- 50 . (canceled) 
     
     
         51 . A coated medical device for inhibiting the proliferation of a cell in which the activity of lysophosphatidic acid acyltransferase β (LPAAT-β) is required for the proliferation of the cell comprising a medical device coated with a compound or salt thereof according to  claim 1 . 
     
     
         52 .- 59 . (canceled)