Abstract:
2,4-pyrimidinedione derivatives of formula (I) having high antiviral activity against wild-type and mutant HIV-1 and low toxicity are useful for treating AIDS (I) wherein: R 1  is a C 6-10  aryl or C 3-10  heteroaryl group optionally having one or more substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  alkyl substituted with one or more halogen atoms, C 3-4  cycloalkyl, cyano, nitro, hydroxy, thiohydroxy, azido, C 1-6  alkoxy, oximino, C 1-3  alkyloximino, O—(C 1-6  alkyl)-substituted oximino, C— 1-6  alkylcarbonyl, C 3-6  cycloalkylcarbonyl, hydroxymethyl, azidomethlyl, C 1-6  alkoxymethyl, C 1-6  acyloxynethyl, carbamoyloxymethyl, anminomethyl, N—(C 1-3  alkyl)aminomethyl, N,N-di(C 1-3  alkyl)aminomethyl, carboxy, C 1-6  alkoxycarbonyl, aziridine, amino, hydroxyethylamino, cyclopropylamino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, trifluoroacetamido, C 1-6  acylamido, carbamoyl, hydroxyethylcarbamoyl, cyclopropylcarbamoyl, C 1-6  alkylcarbamoyl, di(C 1-6  alkyl)carbamoyl, aminocarbamoyl, dimethylaminocarbamoyl, hydrazino, 1,1-dimethylhydrazino, imidazolyl, triazolyl and tetrazolyl; a tetrahydropyridyl or piperidyl group optionally substituted with a C 1-6  alkyl or C 1-6  alkoxycarbonyl group; a tetrahydropyranyl group; or a tetrahydrofuryl group; R 2  is hydrogen, halogen, nitro, cyano, C 1-3  alkoxycarbonyl, C 1-3  alkylamino, di(C 1-3  alkyl)amino, C 1-3  alkylcarbamol, di(C 1-3  alkyl)carbamoyl, C 1-3  alkyl, C 3-6  cycloalkyl or benzyl; R 3  and R 4  are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino acetamido, trifluoroacetamido, azido, C 1-3  alkyl, C- 1-3  alkyl substituted with one or more halogen atoms, C 1-3  alkoxycarbonyl, carbamoyl C 1-3  alkylcarbamoyl, di(C 1-3  alkyl) carbamoyl or C- 1-3  alkoxy; A is O or S; and Z is O, S, C═O, NH or CH 2 .

Description:
This application is a national stage entry under section 371 of PCT/KR00/00166, filed on Mar. 3, 2000. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to novel pyrimidinedione derivatives, which are useful as an antiviral agent, particularly for treating acquired immunodeficiency syndrome (AIDS), a process for the preparation thereof and a pharmaceutical composition containing same as an active ingredient. 
     DESCRIPTION OF THE PRIOR ART 
     Various compounds such as AZT (3′-azido-3′-deoxythymidine), DDC (2′,3′-dideoxycytidine), DDI (2′,3′-dideoxyinosine), D4T (3′-deoxy-2′,3′-didehydrothymidine) 3TC(lamivudine), Ziagen, Nevirapine, Sustiva, Delavirdine, Indinavir, Ritonavir, Viracept, Saquinavir and Agenerase have been reported to have the ability, albeit limited, to inhibit the reproduction of AIDS virus. However, they are also known to cause undesirable side effects due to their toxicity as well as to induce the mutation of the virus, thereby increasing the resistance of the virus. 
     In order to minimize such problems, therefore, many attempts have been made. For example, there have been reported 2,4-pyrimidinedione derivatives having 1-alkoxymethyl substituents { J. Med. Chem ., 35, 4713 (1992);  J. Med. Chem ., 35, 337 (1992);  J. Med. Chem ., 34, 1508 (1991);  J. Med. Chem ., 34, 1394 (1991);  J. Med. Chem ., 34, 349 (1991);  Molecular Pharm ., 39, 805 (1991);  Tet. Lett ., 35, 4531 (1994);  J. Med. Chem ., 38, 2860 (1995);  Nucleosides and Nucleotides , 14, 575 (1995);  J. Med. Chem ., 39, 2427 (1996);  J. Med. Chem ., 42, 4500 (1999); EP 0,449,726 A1; EP 0,420,763 A2; U.S. Pat. No. 5,278,167; U.S. Pat. No. 5,318,972; U.S. Pat. No. 5,461,060; WO95/18109 A1; and U.S. Pat. No. 5,112,835}; 1-allyl or propargyl substituents (U.S. Pat. No. 5,747,500); and 1-cyclopentenylmethylene substituents (U.S. Pat. No. 5,922,727). Although these compounds exhibit improved activity against human immunodeficiency virus (HIV), there exists a need to develope non-toxic compounds having even higher potency against both wild-type and mutant HIV. 
     SUMMARY OF THE INVENTION 
     Accordingly, it is a primary object of the present invention to provide a novel compound having superior antiviral activity against both wild-type and mutant HIV-1 as well as reduced toxicity. 
     It is another object of the present invention to provide a pharmaceutical composition containing same. 
     It is a further object of the present invention to provide a process for the preparation of said novel compound. 
     In accordance with one aspect of the present invention, there is provided a novel 2,4-pyrimidinedione compound of formula(I) or a pharmaceutically acceptable salt thereof:                           
     wherein: 
     R 1  is a C 6-10  aryl or C 3-10  heteroaryl group optionally having one or more substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  alkyl substituted with one or more halogen atoms, C 3-6  cycloalkyl, cyano, nitro, hydroxy, thiohydroxy, azido, C 1-6  alkoxy, oximino, C 1-3  alkyloximino, O—(C 1-6  alkyl)-substituted oximino, C 1-6  alkylcarbonyl, C 3-6  cycloalkylcarbonyl, hydroxymethyl, azidomethyl, C 1-6  alkoxymethyl, C 1-6  acyloxymethyl, carbamoyloxymethyl, aminomethyl, N—(C 1-3  alkyl)aminomethyl, N,N-di(C 1-3  alkyl)aminomethyl, carboxy, C 1-6  alkoxycarbonyl, aziridine, amino, hydroxyethylamino, cyclopropylamino, C 1-6  alkylamino, di(C 1-6  alkyl)amino, trifluoroacetamido, C 1-6  acylamido, carbamoyl, hydroxyethylcarbamoyl, cyclopropylcarbamoyl, C 1-6  alkylcarbamoyl, di(C 1-6  alkyl)carbamoyl, aminocarbamoyl, dimethylaminocarbamoyl, hydrazino, 1,1-dimethylhydrazino, imidazolyl, triazolyl and tetrazolyl; a tetrahydropyridyl or piperidyl group optionally substituted with a c 1-6  alkyl or c 1-6  alkoxycarbonyl group; a tetrahydropyranyl group; or a tetrahydrofuryl group; 
     R 2  is hydrogen, halogen, nitro, cyano, C 1-3  alkoxycarbonyl, C 1-3  alkylamino, di(C 1-3  alkyl)amino, C 1-3  alkylcarbamoyl, di(C 1-3  alkyl)carbamoyl, C 1-6  alkyl, C 3-6  cycloalkyl or benzyl; 
     R 3  and R 4  are each independently hydrogen, halogen, hydroxy, cyano, nitro, amino, acetamido, trifluoroacetamido, azido, C 1-3  alkyl, C 1-3  alkyl substituted with one or more halogen atoms, C 1-3  alkoxycarbonyl, carbamoyl, C 1-3  alkylcarbamoyl, di(C 1-3  alkyl)carbamoyl or C 1-3  alkoxy; 
     A is O or S; and 
     Z is O, S, C═O, NH or CH 2 . 
     DETAILED DESCRIPTION OF THE INVENTION 
     Among the compounds of formula(I) of the present invention, the preferred are those wherein R 1  is a phenyl, pyridyl or N-oxopyridyl group optionally having one or more substituents as listed in formula(I). 
     The 2,4-pyrimidinedione compound of formula(I) may be prepared by coupling a compound of formula(II) with a compound of formula(III), as shown in the Reaction Scheme A:                           
     wherein: 
     R 1 , R 2 , R 3 , R 4 , A and Z have the same meanings as defined in formula(I) above; 
     Z′ is same as Z with the proviso that when A is oxygen, it can be a acetamido group; and 
     Y is a suitable leaving group, e.g., halogen, methanesulfonyl, toluenesulfonyl or trifluoromethanesulfonyl. 
     In Reaction Scheme A, the above reaction may be conducted in a solvent in the presence of a base at a temperature ranging from −10 to 100° C., wherein the molar ratio of the compound of formula(II) to the compound of formula(III) may range from 1:0.8 to 1:1.2. Representative examples of the base include lithium hydride, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate and the like. Suitable for use in this reaction is a polar solvent such as acetonitrile, hexamethylphosphoramide (HMPA), dimethylsulfoxide (DMSO) and dimethylformamide(DMF). 
     The compounds of formula(II) may in some cases be prepared in accordance with the procedure disclosed in U.S. Pat. No. 5,747,500. Alternatively, the compounds of formula(II) may be advantageously prepared in some special cases by the procedure illustrated in Reaction Scheme B:                         
                           
     In accordance with the method (i) in Reaction Scheme B, a compound of formula(IV) which may be prepared by way of a known method disclosed in, e.g.,  Ber ., 52B, 869 (1919) and  J. Med. Chem ., 7, 808 (1964), is subjected to a coupling reaction with an arylformamide derivative in a polar solvent, e.g., dimethylformamide, in the presence of a strong base, e.g., sodium hydride, under a nitrogen atmosphere to provide a compound of formula(V) (Step (a)). The compound of formula (V) is reacted with sodium methoxide in methanol to give a compound of formula(VI) (Step (b)). Then, the compound of formula(VI) is demethylated and acetylated by the action of acetylbromide to provide a compound of formula(II-a) (Step (c)). 
     In the method (ii) of Reaction Scheme B, the compound of formula (IV) is reacted with a arylacetonitrile derivative in a polar solvent, e.g., dimethylformamide, in the presence of a base, e.g., sodium hydride, to provide a compound of formula(VII) (Step (d)), which is reacted with sodium methoxide in methanol to give a compound of formula(VIII) (Step (e)). Thereafter, the compound of formula(VIII) is reacted with a base, e.g., sodium hydride, in a polar solvent, e.g., dimethylformamide, in the presence of oxygen to provide a compound of formula(IX) (Step (f)), which is hydrolyzed with an acid, e.g., hydrochloric acid, to provide a compound of formula(II-b) (Step (g)). 
     Each of the compounds of formula(II-a) and (II-b) may be converted to one of the compounds of formula(II) containing various substituents via further reactions. 
     In this regard, in accordance with another aspect of the present invention, there is provided a compound of formula(II):                           
     wherein: 
     R′ 2  is ethyl or isopropyl; 
     R′ 3  is nitro, amino, acetamido, trifluoroacetamido or C 1-3  alkoxycarbonyl; 
     R′ 4  is methyl or halogen; and 
     Z″ is C═O, NH or acetamido. 
     Exemplary compounds of formula(I) of the present invention which can be prepared in accordance with the methods described above are listed in the following Table 1: 
     
       
         
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Comp. 
                 A 
                 Z 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
               
               
                   
               
             
             
               
                  1 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                  2 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                  3 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                  4 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                  5 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                  6 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                  7 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
               
               
                   
               
               
                  8 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
               
               
                   
               
               
                  9 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
               
               
                   
               
               
                 10 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
               
               
                   
               
               
                 11 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
               
               
                   
               
               
                 12 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
               
               
                   
               
               
                 13 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
               
               
                   
               
               
                 14 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
               
               
                   
               
               
                 15 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
               
               
                   
               
               
                 16 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
               
               
                   
               
               
                 17 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
               
               
                   
               
               
                 18 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
               
               
                   
               
               
                 19 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
               
               
                   
               
               
                 20 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 Cl 
                 Cl 
               
               
                   
               
               
                 21 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
               
               
                   
               
               
                 22 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 2 F 
                 CH 3   
               
               
                   
               
               
                 23 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 2 F 
                 CH 3   
               
               
                   
               
               
                 24 
                 O 
                 O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 25 
                 O 
                 O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 26 
                 O 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
               
               
                   
               
               
                 27 
                 O 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 28 
                 O 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 29 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CF 3   
                 CF 3   
               
               
                   
               
               
                 30 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CF 3   
                 CF 3   
               
               
                   
               
               
                 31 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CF 3   
                 CF 3   
               
               
                   
               
               
                 32 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 H 
               
               
                   
               
               
                 33 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 H 
               
               
                   
               
               
                 34 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 H 
                 H 
               
               
                   
               
               
                 35 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 H 
                 H 
               
               
                   
               
               
                 36 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 37 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 38 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 39 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 40 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 41 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 42 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 43 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 44 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 45 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 46 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
               
               
                   
               
               
                 47 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
               
               
                   
               
               
                 48 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
               
               
                   
               
               
                 49 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 2 F 
                 CH 3   
               
               
                   
               
               
                 50 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 H 
               
               
                   
               
               
                 51 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 52 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 53 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
               
               
                   
               
               
                 54 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 55 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 56 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
               
               
                   
               
               
                 57 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
               
               
                   
               
               
                 58 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 2 F 
                 CH 3   
               
               
                   
               
               
                 59 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 CH 3   
               
               
                   
               
               
                 60 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 61 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
               
               
                   
               
               
                 62 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 63 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
               
               
                   
               
               
                 64 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 NO 2   
               
               
                   
               
               
                 65 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 NO 2   
               
               
                   
               
               
                 66 
                 O 
                 NH 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 67 
                 O 
                 NH 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 68 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 69 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 70 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 71 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
               
               
                   
               
               
                 72 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 73 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 74 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
               
               
                   
               
               
                 75 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 76 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 77 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
               
               
                   
               
               
                 78 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 79 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
               
                 80 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
               
               
                   
               
               
                 81 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
               
               
                   
               
             
          
         
       
     
     Furthermore, the present invention encompasses, within its scope, pharmaceutically acceptable salts of the 2,4-pyrimidinedione compounds of formula(I). Suitable pharmaceutically acceptable salts of the compounds of formula(I) possessing strong antiviral activity against wild-type and mutant HIV-1 may include alkali or alkaline earth metal salts, e.g., sodium, potassium, magnesium and calcium salts thereof. 
     The present invention also includes within its scope pharmaceutical compositions comprising one or more of the compounds of formula(I) or their above-mentioned salts as the active ingredient, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary. 
     The pharmaceutical compositions of the invention may be formulated for administration orally or by injection. The composition for oral administration may take various forms such as tablets and gelatin capsules, which may contain conventional additives such as a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), a lubricant (e.g., silica, talc, stearic acid or its magnesium and calcium salts and polyethylene glycol). In the case of the tablet form, the composition may further comprise a binder (e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and polyvinyl pyrrolidone) and optionally a disintegrant (e.g., starch, agar and alginic acid or its sodium salt), absorbent, colorant, flavor, sweetener and the like. The composition for injection may be an isotonic solution or a suspension. 
     The composition may be sterilized and/or contain an adjuvant such as a preservative, stabilizer, wetting agent, emulsifier, a salt for controlling an osmotic pressure and/or a buffer solution, and other pharmaceutically effective materials. 
     The pharmaceutical compositions can be prepared by a conventional mixing, granulating or coating method and may contain preferably about 0.1 to 75%, more preferably about 1 to 50% of the active ingredient of this invention. The unit dosage of the composition suitable for administering a person weighing about 50 to 70 kg may contain about to 200 mg of the active ingredient. 
     The following Preparations and Examples are given for the purpose of illustration only and are not intended to limit the scope of the invention. 
     In the Preparations and Examples, unless otherwise specified, the evaporation was conducted under reduced pressure, preferably under a pressure ranging from about to 100 mmHg. 
     Preparations 
     The compounds of formula(II) having the structures (A) to (U), (II-a-1), (II-a-2) and (II-b-1) shown in Table 2 together with their melting points and NMR data were used in preparing respective compounds of formula (I) of the present invention. 
     Preparations 1 to 21 
     Each of the compounds having the specified structures (A) to (U) was prepared in accordance with the procedure described in U.S. Pat. No. 5,747,500. 
     Preparation 22: Synthesis of 5-Isopropyl-6-(3′,5′-dimethylphenylacetamido)-2,4-pyrimidinedione (Compound (II-a-1)) 
     Step 1) Synthesis of 2,4-Dichloro-5-isopropyl-6-(3′,5′-dimethylphenylformylamido)pyrimidine 
     To a magnetically stirred DMF solution (80 ml) of 3,5-dimethylformaniline (8.94 g, 60 mmol) cooled in an ice bath, 60% sodium hydride dispersion (2.88 g, 72 mmol) was added portionwise under a nitrogen atmosphere. After 10 min, 5-isopropyl-2,4,6-trichloropyrimidine (16.2 g, 72 mmol) was added thereto and the reaction mixture was allowed to warm to room temperature, followed by stirring for 24 hr. Ether was then added to the reaction mixture, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ether:hexane=1:15) to afford 3.3 g (yield 17%) of the title compound as a white solid. 
     M.p.: 151 to 153° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.12-1.24 (6H, m), 2.30 (6H, s), 3.22 (1H, m), 6.72 (2H, s), 6.96 (1H, s), 8.70 (1H, s); m/z (EI) 338 (M + ). 
     Step 2) Synthesis of 2,4-Dimethoxy-5-isopropyl-6-(3′, 5′-dimethylphenylamino)pyrimidine 
     Sodium (1.02 g, 44 mmol) was added portionwise to a stirred anhydrous methanol (40 ml) at room temperature under a nitrogen atmosphere to prepare sodium methoxide solution. The compound obtained in Step 1) (3 g, 8.88 mmol) was added to the solution and the mixture was refluxed for 4 hr. The reaction mixture was allowed to cool to room temperature and neutralized with excess ammonium chloride. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ethyl acetate:hexane=1:15) to afford 2.69 g (yield 97%) of the title compound as a white solid. 
     M.p.: 126 to 127° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.31 (6H, d, J=7.1 Hz), 2.31 (6H, s), 3.12 (1H, m), 3.92 (3H, s), 3.93 (3H, s), 6.44 (1H, s), 6.70 (1H, s), 7.21 (2H, s); m/z (EI) 301 (M + ). 
     Step 3) Synthesis of 5-Isopropyl-6-(3′,5′-dimethylphenylacetamido)-2,4-pyrimidinedione 
     The compound obtained in Step 2) (2.6 g, 8.6 mmol) was refluxed with acetyl bromide (30 ml) for 19 hr. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromat ography (eluent-ethyl acetate:hexane=2:1) to afford 2.6 g (yield 96%) of the title compound as a white solid. 
     Preparation 23: Synthesis of 5-Ethyl-6-(3′,5′-dimethylphenylacetamido)-2,4-pyrimidinedione (Compound (II-a-2)) 
     The procedure of Preparation 22 was repeated using 5-ethyl-2,4,6-trichloropyrimidine in place of 5-isopropyl-2,4,6-trichloropyrimidine to prepare the title compound. 
     Preparation 24: Synthesis of 5-Isopropyl-6-(3′-nitro-5′-methylbenzoyl)-2,4-pyrimidinedione (Compound (II-b-1)) 
     Step 1) Synthesis of 2,4-Dichloro-5-isopropyl-6-(α-cyano-3′-nitro-5′-methylbenzyl)pyrimidine 
     To a magnetically stirred DMF solution (30 ml) of 3-nitro-5-methylphenylacetonitrile (2.64 g, 15 mmol) and 5-isopropyl-2,4,6-trichloropyrimidine (4.05 g, 18 mmol) cooled in an ice bath, 60% sodium hydride dispersion (1.15 g, 30 mmol) was added portionwise under a nitrogen atmosphere. After stirring for 2 hr, the reaction mixture was allowed to warm to room temperature and stirred for 16 hr. The reaction mixture was then neutralized with aqueous ammonium chloride and ethyl ether was added thereto. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ethyl acetate:hexane=1:4) to afford 3.99 g (yield 73%) of the title compound as a white solid. 
     M.p.: 124 to 125° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.23 (3H, d, J=7.2 Hz), 1.38 (3H, d, J=7.2 Hz), 2.51 (3H, s), 3.34 (1H, m), 5.60 (1H, s), 7.57 (1H, s), 7.99 (1H, s), 8.07 (1H, s); m/z (EI) 365 (M + ). 
     Step 2) Synthesis of 2,4-Dimethoxy-5-isopropyl-6-(α-cyano-3′-nitro-5′-methylbenzyl)pyrimidine 
     To a stirred anhydrous methanol solution (60 ml) of the compound obtained in Step 1) (3.65 g, 10 mmol), sodium methoxide (3.24 g, 60 mmol) was added at room temperature under a nitrogen atmosphere and refluxed for 24 hr. The reaction mixture was then allowed to cool to room temperature and neutralized with excess ammonium chloride. After removing the solvent, the resulting residue was purified by flash chromatography (eluent-ether:hexane=1:3) to afford 1.8 g (yield 50%) of the title compound as a light yellow solid. 
     M.p.: 134 to 135° C.  1 H-NMR (200 MHz, CDCl 3 ) δ 1.15 (3H, d, J=6.7 Hz), 1.20 (3H, d, J=6.7 Hz), 2.49 (3H, s), 3.05 (1H, m), 4.00 (3H, s), 4.01 (3H, s), 5.48 (1H, s), 7.62 (1H, s), 8.00 (2H, s); m/z (EI) 356 (M + ). 
     Step 3) Synthesis of 2,4-Dimethoxy-5-isopropyl-6-(3′-nitro-5′-methylbenzoyl)pyrimidine 
     To a stirred DMF solution (20 ml) of the compound obtained in Step 2) (1.7 g, 4.7 mmol), 60% sodium hydride dispersion (283 mg, 7.1 mmol) was added at room temperature under a nitrogen atmosphere. The mixture was then stirred in the presence of oxygen. After 5 hr, the reaction mixture was neutralized with ammonium chloride and ethyl ether was added thereto. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-dichloromethane:hexane=97:3) to afford 1.039 (yield 62%) of the title compound as a white solid. 
     M.p.: 111 to 112° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.21 (6H, d, J=6.9 Hz), 2.54 (3H, s), 2.88 (1H, m), 3.93 (3H, s), 4.09 (3H, s), 8.05 (1H, s), 8.27 (1H, s), 8.44 (1H, s); m/z (EI) 345 (M + ). 
     Step 4) Synthesis of 5-isopropyl-6-(3′-nitro-5′-methylbenzoyl)-2,4-pyrimidinedione 
     The compound obtained in Step 3) (630 mg, 1.8 mmol) was refluxed with conc. hydrochloric acid (6 ml) for 4 hr and the reaction mixture was allowed to cool to room temperature. The precipitate was then collected, washed with distilled water and hexane, and dried to give 560 mg (yield 98%) of the title compound as a white solid. 
     
       
         
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Prep. No. 
                 Comp. 
                 Structure 
                 M.p. (° C.) 
                   1 H-NMR 
               
               
                   
               
             
             
               
                  1 
                 (A) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 238-239 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.16(6H, d, J=6.9Hz), 2.35-2.49(7H, m), 7.35(2H, s), 7.53(2H, s). 
               
               
                   
               
               
                  2 
                 (B) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 249-250 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 0.97(3H, t, J=7.4Hz), 2.17(2H, q, J=7.4Hz), 2.39(6H, s), 7.32(1H, s), 7.50(2H, s). 
               
               
                   
               
               
                  3 
                 (C) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 251-252 
                 (200 MHz, CD 3 OD/DMSO-d 6 ) δ: 1.36(6H, d, J=6.9Hz), 2.38(1H, m), 2.46(3H, s), 7.26(1H, d, J=9.0Hz), 7.43(1H, d, J=8.4Hz), 7.52(1H, s). 
               
               
                   
               
               
                  4 
                 (D) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 235-236 
                 (200 MHz, CD 3 OD/DMSO-d 6 ) δ: 0.99(3H, t, J=7.4Hz), 2.17(2H, q, J=7.4Hz), 2.50(3H, s), 7.44(1H, d, J=9.4Hz), 7.59(1H, d, J=8.8Hz), 7.70(1H, m). 
               
               
                   
               
               
                  5 
                 (E) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 233-234 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.06(6H, d, J=7.0Hz), 2.32(1H, m), 7.07(1H, m), 7.25-7.38(2H, m). 
               
               
                   
               
               
                  6 
                 (F) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 211-212 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 0.88(3H, t, J=7.3Hz), 2.06(2H, q, J=7.3Hz), 7.06(1H, m), 7.32-7.37(2H, m) 
               
               
                   
               
               
                  7 
                 (G) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 220-221 
                 (200 MHz, CD 3 OD) δ: 1.16(6H, d, J=7.0Hz), 2.45(1H, m), 7.61-8.02(5H, m) 
               
               
                   
               
               
                  8 
                 (H) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 218-219 
                 (200 MHz, CD 3 OD) δ: 0.98(3H, t, J=7.5Hz), 2.17(2H, q, J=7.5Hz), 7.58-8.03(5H, m) 
               
               
                   
               
               
                  9 
                 (I) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 220-221 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.17(6H, d, J=6.8Hz), 2.39(1H, m), 8.21(1H, s), 8.37(2H, s). 
               
               
                   
               
               
                 10 
                 (J) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 227-228 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.13(6H, d, J=7.0Hz), 2.35-2.50(4H, m), 7.42-7.72(4H, m), 9.82(1H, s). 
               
               
                   
               
               
                 11 
                 (K) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 236-237 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 0.97(3H, t, J=7.5Hz), 2.18(2H, q, J=7.5Hz), 2.44(3H, s), 7.28-7.71(4H, m), 9.70(1H, s). 
               
               
                   
               
               
                 12 
                 (L) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 252-253 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.11(6H, d, J=6.9Hz), 2.33(1H, m), 7.61-7.73(3H, m). 
               
               
                   
               
               
                 13 
                 (M) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 242-243 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 0.90(3H, t, J=7.5Hz), 2.07(2H, q, J=7.5Hz), 7.59(1H, t, J=1.8Hz), 7.67(2H, d, J=1.8Hz). 
               
               
                   
               
               
                 14 
                 (N) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 254-255 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.17(6H, d, J=6.9Hz), 2.25-2.45(4H, m), 7.50-7.71(3H, m). 
               
               
                   
               
               
                 15 
                 (O) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 218-219 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.10(6H, d, J=6.9Hz), 2.32-2.52(4H, m), 5.41(2H, d, J=47.0Hz), 7.51-7.70(3H, m), 9.15(1H, s), 9.66(1H, s). 
               
               
                   
               
               
                 16 
                 (P) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 224-225 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 0.98(3H, t, J=7.4Hz), 2.16(2H, q, J=7.4Hz), 2.47(3H, s), 5.43(2H, d, J=47.2Hz), 7.54-7.71(3H, m). 
               
               
                   
               
               
                 17 
                 (Q) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 229-230 
                 (200 MHz, CD 3 OD) δ: 1.20(6H, d, J=7.1Hz), 2.33(6H, s), 3.35(1H, m), 6.64(2H, s), 6.83(1H, s). 
               
               
                   
               
               
                 18 
                 (R) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 221-222 
                 (200 MHz, CD 3 OD) δ: 0.90(3H, t, J=7.4Hz), 2.17-2.25(8H, m), 6.62(2H, s), 6.78(1H, s). 
               
               
                   
               
               
                 19 
                 (S) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 225-226 
                 (200 MHz, CDCl 3 ) δ: 1.34(6H, d, J=7.0Hz), 2.35(6H, s), 3.11(1H, m), 7.14(1H, s), 7.16(2H, s), 9.30(1H, s). 
               
               
                   
               
               
                 20 
                 (T) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 224-225 
                 (200 MHz, DMSO-d 6 ) δ: 1.17(6H, d, J=6.8Hz), 3.22(1H, m), 7.42(2H, s), 7.56(1H, s), 10.96(1H, s), 11.18(1H, s). 
               
               
                   
               
               
                 21 
                 (U) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 224-225 
                 (200 MHz, CDCl 3 ) δ: 1.14(3H, t, J=7.5Hz), 2.36(6H, s), 2.55(2H, q, J=7.5Hz), 7.06(1H, s), 7.16-7.26(3H, m), 9.04(1H, s) 
               
               
                   
               
               
                 22 
                 (II-a-1) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 224-226 
                 (200 MHz, CDCl 3 ) δ: 1.12-1.33(6H, m), 2.02-2.15(3H, m), 2.31(6H, s), 2.90(1H, m), 6.99(3H, s) 
               
               
                   
               
               
                 23 
                 (II-a-2) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 238-239 
                 (200 MHz, CDCl 3 ) δ: 0.93(3H, t, J=7.5Hz), 2.05-2.15(3H, m), 2.24-2.40(8H, m), 6.94-6.99(3H, m) 
               
               
                   
               
               
                 24 
                 (II-b-1) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 254-256 
                 (200 MHz, CDCl 3 /CD 3 OD) δ: 1.12(6H, d, J=7.0Hz), 2.40(1H, m), 2.54(3H, s), 8.11(1H, s), 8.37(1H, s), 8.49(1H, s) 
               
               
                   
               
             
          
         
       
     
    
    
     EXAMPLE 1 
     Synthesis of 1-(4′-Picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 1) 
     To a magnetically stirred DMF solution (5 ml) of compound (A) obtained in Preparation 1 (286 mg, 1 mmol) maintained at room temperature, were added anhydrous potassium carbonate (276 mg, 2 mmol), lithium iodide (134 mg, 1 mmol), and 4-picolyl chloride hydrochloride (164 mg, 1 mmol), in this order. After stirring for 16 hr, the solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ethyl acetate:hexane=3:1) to afford 120 mg (yield 32%) of the title compound as a white solid. 
     M.p.: 264 to 265° C.;  1 H-NMR (200 MHz; CDCl 3 ) δ 1.12 (3H, d, J=6.7 Hz), 1.23 (3H, d, J=6.7 Hz), 2.30-2.40 (7H, m), 4.66 (1H, d, J=16.3 Hz), 4.88 (1H, d, J=16.3 Hz), 6.98-7.36 (5H, m), 8.41-8.44 (2H, m), 9.91 (1H, s); m/z (EI) 377 (M + ). 
     EXAMPLE 2 
     Synthesis of 1-(3′-Picolyl)-5-isopropyl-6-(3′, 5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 2) 
     The procedure of Example 1 was repeated using 3-picolyl chloride hydrochloride in place of 4-picolyl chloride hydrochloride to prepare the title compound. 
     M.p.: 179 to 180° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J=6.9 Hz), 1.22 (3H, d, J=6.9 Hz), 2.20-2.38 (7H, m), 4.71 (1H, d, J=16.0 Hz), 4.93 (1H, d, J=16.0 Hz), 7.09-7.56 (5H, m), 8.29-8.43 (2H, m), 10.18 (1H, s); m/z (EI) 377 (M + ). 
     EXAMPLE 3 
     Synthesis of 1-(2′-Picolyl)-5-isopropyl-6-(3′, 5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 3) 
     The procedure of Example 1 was repeated using 2-picolyl chloride hydrochloride in place of 4-picolyl chloride hydrochloride to prepare the title compound. 
     M.p.: 214 to 215° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J=6.9 Hz), 1.23 (3H, d, J=6.9 Hz), 2.20-2.40 (7H, m), 4.77 (1H, d, J=16.8 Hz), 5.16 (1H, d, J=16.8 Hz), 7.01-7.48 (6H, m), 8.36 (2H, m), 9.90 (1H, s); m/z (EI) 377 (M + ). 
     EXAMPLES 4 to 65 
     The procedure of Example 1 was repeated to obtain the 2,4-pyrimidinedione derivatives of Examples 4-65 shown in Table 3. 
     
       
         
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Ex. No. 
                 A 
                 Z 
                 R 1   
                 R 2   
                 R 3   
                 R 4   
                   1 H-NMR (200 MHz, CDCl 3 ) δ 
                 M.p. (° C.) 
               
               
                   
               
             
             
               
                  4 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.97(3H, t, J=7.3Hz), 2.05(1H, m), 2.20- 2.35(7H, m), 4.70(1H, d, J=16.4Hz), 4.90(1H, d, J=16.4Hz), 6.98-7.01(2H, m), 7.27(1H, s), 7.34(2H, s), 8.41-8.44 (2H, m), 9.25(1H, s). 
                 267-268 
               
               
                   
               
               
                  5 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.95(3H, t, J=7.3Hz), 2.02(1H, s), 2.20-2.40(7H, m), 4.72(1H, d, J=16.4Hz), 4.90(1H, d, J=16.4Hz), 7.14(1H, s), 7.34(2H, s), 7.52(1H, m), 8.29-8.43(2H, m), 9.25(1H, s). 
                 197-198 
               
               
                   
               
               
                  6 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.95(3H, t, J=7.1Hz), 2.05(1H, m), 2.20-2.40(7H, m), 4.81(1H, d, J=16.4Hz), 5.14(1H, d, J=16.4Hz), 7.01-7.52(6H, m), 8.40(1H, m), 9.11(1H, s). 
                 235-236 
               
               
                   
               
               
                  7 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
                 1.14(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.22-2.38(4H, m), 4.63(1H, d, J=16.3Hz), 4.94(1H, d, J=16.3Hz), 7.00-7.36(5H, m), 8.41-8.45(2H, m), 9.56(1H, s). 
                 207-209 
               
               
                   
               
               
                  8 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
                 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.27(1H, m), 2.34(3H, s), 4.64(1H, d, J=15.6Hz), 5.00(1H, d, J=16.4Hz), 7.10-7.53(5H, m), 8.27-8.42(2H, m), 9.41(1H, s). 
                 211-212 
               
               
                   
               
               
                  9 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
                 1.13(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz), 2.20-2.35(4H, m), 4.69(1H, d, J=16.4Hz), 5.29(1H, d, J=16.4Hz), 7.00-7.52(6H, m), 8.37(1H, m), 9.15(1H, s). 
                 187-189 
               
               
                   
               
               
                 10 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
                 0.98(3H, t, J=7.3Hz), 2.05(1H, m), 2.20- 2.37(7H, m), 4.70(1H, d, J=16.4Hz), 4.92(1H, d, J=16.4Hz), 7.00-7.37(5H, m), 8.44-8.46(2H, m), 10.39(1H, s). 
                 233-234 
               
               
                   
               
               
                 11 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
                 0.95(3H, t, J=7.3Hz), 2.02(1H, m), 2.05(1H, m), 2.33(3H, s), 4.72(1H, d, J=16.4Hz), 5.02(1H, d, J=16.4Hz), 7.11-7.56(5H, m), 8.30-8.44(2H, m). 
                 189-190 
               
               
                   
               
               
                 12 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
                 0.96(3H, t, J=7.3Hz), 2.03(1H, m), 2.22(1H, m), 2.33(3H, s), 4.74(1H, d, J=16.4Hz), 5.23(1H, d, J=16.4Hz), 7.02-7.53(6H, m), 8.39(1H, m), 9.17(1H, s). 
                 158-159 
               
               
                   
               
               
                 13 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
                 1.15(3H, d, J=7.0Hz), 1.23(3H, d, J=7.0Hz), 2.26(1H, m), 4.63(1H, d, J=16.2Hz), 4.94(1H, d, J=16.2Hz), 6.97-7.26(5H, m), 8.43-8.46(2H, m), 8.90(1H, s). 
                 189-190 
               
               
                   
               
               
                 14 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
                 1.12(3H, d, J=6.7Hz), 1.21(3H, d, J=6.7Hz), 2.23(1H, m), 4.63(1H, d, J=15.8Hz), 5.06(1H, d, J=15.8Hz), 7.01-7.54(5H, m), 8.26(1H, m), 8.42(1H, m), 9.49(1H, s). 
                 227-230 
               
               
                   
               
               
                 15 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
                 1.15(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz), 2.23(1H, m), 4.62(1H, d, J=16.6Hz), 5.31(1H, d, J=16.6Hz), 6.95-7.54(6H, m), 8.37(1H, m), 9.10(1H, s). 
                 214-215 
               
               
                   
               
               
                 16 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
                 0.97(3H, t, J=7.4Hz), 2.02(1H, m), 2.25(1H, m), 4.65-4.92(2H, m), 6.99-7.40(5H, m), 8.43-8.46(2H, m), 9.73(1H, s). 
                 223-224 
               
               
                   
               
               
                 17 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
                 0.96(3H, t, J=7.3Hz), 2.00(1H, m), 2.22(1H, m), 4.68(1H, m), 5.04(1H, m), 7.03-7.27(4H, m), 7.54(1H, m), 8.28-8.44(2H, m), 9.89(1H, s). 
                 217-218 
               
               
                   
               
               
                 18 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
                 0.97(3H, t, J=7.5Hz), 2.01(1H, m), 2.22(1H, m), 4.76(1H, m), 5.31(1H, m), 6.95-7.55(6H, m), 8.37(1H, m), 9.03(1H, s). 
                 206-207 
               
               
                   
               
               
                 19 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
                 1.12(3H, d, J=6.9Hz), 1.25(3H, d, J=6.9Hz), 2.21(1H, m), 4.59(1H, d, J=16.6Hz), 4.99(1H, d, J=16.6Hz), 6.98(2H, d, J=5.9Hz), 7.55(3H, s), 8.44(2H, d, J=5.9Hz). 
                 232-233 
               
               
                   
               
               
                 20 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 Cl 
                 Cl 
                 0.98(3H, t, J=7.5Hz), 2.05(1H, m), 2.28(1H, m), 4.68(1H, d, J=16.5Hz), 5.02(1H, d, J=16.5Hz), 6.98(2H, d, J=5.9Hz), 7.54-7.74(3H, m), 8.45(2H, d, J=5.9Hz), 9.36(1H, s). 
                 243-245 
               
               
                   
               
               
                 21 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
                 1.14(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.20-2.38(4H, m), 4.61(1H, d, J=16.3Hz), 4.95(1H, d, J=16.3Hz), 6.97-8.44(7H, m), 9.35(1H, s). 
                 248-249 
               
               
                   
               
               
                 22 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 2 F 
                 CH 3   
                 1.07(3H, d, J=6.7Hz), 1.18(3H, d, J=6.7Hz), 2.25(1H, m), 2.32(3H, s), 4.61(1H, d, J=16.4Hz), 4.84(1H, d, J=16.4Hz), 5.29(2H, d, J=47.2Hz), 6.97(2H, d, J=5.9Hz), 7.39-7.53(3H, m), 8.32(2H, d, J=5.9Hz). 
                 190 (dec.) 
               
               
                   
               
               
                 23 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 2 F 
                 CH 3   
                 0.97(3H, t, J=7.5Hz), 2.04(1H, m), 2.25(1H, m), 2.36(3H, s), 4.68(1H, d, J=15.0Hz), 4.94(1H, d, J=15.0Hz), 5.33(2H, d, J=47.2Hz), 6.98-7.01(2H, m), 7.42-7.54(3H, m), 8.39-8.42(2H, m), 9.48(1H, s). 
                 227-228 
               
               
                   
               
               
                 24 
                 O 
                 O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.14(6H, d, J=7.1Hz), 2.27(6H, s), 2.84(1H, m), 4.88(2H, s), 6.44(2H, s), 6.75(1H, s), 7.11(2H, dd, J=4.5Hz, J=1.6Hz), 8.54(2H, dd, J=4.5Hz, J=1.6Hz), 9.79(1H, s). 
                 213-215 
               
               
                   
               
               
                 25 
                 O 
                 O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.94(3H, t, J=7.5Hz), 2.21(2H, q, J=7.5Hz), 2.27(6H, s), 4.92(2H, s), 6.45(2H, s), 6.76(1H, s), 7.13(2H, d, J=6.1Hz), 8.54(2H, d, J=6.1Hz), 8.95(1H, s). 
                 229-230 
               
               
                   
               
               
                 26 
                 O 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
                 1.21(6H, d, J=6.9Hz), 3.33(1H, m), 5.20(2H, s), 6.81-7.11(5H, m), 8.43-8.46(2H, m), 9.70(1H, s). 
                 198-199 
               
               
                   
               
               
                 27 
                 O 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.26(6H, d, J=6.9Hz), 2.21(6H, s), 3.52(1H, m), 5.25(2H, s), 6.65(2H, s), 6.80(1H, s, 7.01(2H, d, J=5.7Hz), 8.50(2H, d, J=5.7Hz), 10.82(1H, s). 
                 186-187 
               
               
                   
               
               
                 28 
                 O 
                 S 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 1.07(3H, t, J=7.5Hz), 2.23(6H, s), 2.73(2H, q, J=7.5Hz), 5.21(2H, s), 6.68(2H, s), 6.82(1H, s), 6.98(2H, d, J=6.3Hz), 8.48(2H, d, J=6.3Hz), 8.97(1H, s). 
                 191-192 
               
               
                   
               
               
                 29 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CF 3   
                 CF 3   
                 1.14(3H, d, J=6.9Hz), 1.24(3H, d, J=6.9Hz), 2.18(1H, m), 4.51(1H, d, J=16.3Hz), 5.28(1H, d, J=16.3Hz), 6.95(2H, d, J=6.1Hz), 8.07(1H, s), 8.11(2H, s), 8.37(2H, d, J=6.1Hz). 
                 236-237 
               
               
                   
               
               
                 30 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CF 3   
                 CF 3   
                 0.97(3H, t, J=7.3Hz), 2.00-2.35(2H, m), 4.60(1H, m), 5.22(1H, m), 6.94-6.98(2H, m), 8.07(3H, s), 8.35-8.38(2H, m), 9.73(1H, s). 
                 208-209 
               
               
                   
               
               
                 31 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CF 3   
                 CF 3   
                 1.14(3H, t, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.16(1H, m), 4.51(1H, d, J=16.4Hz), 5.51(1H, d, J=16.4Hz), 6.94-7.49(3H, m), 8.03-8.32(4H, m), 9.61(1H, s). 
                 185-186 
               
               
                   
               
               
                 32 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 H 
                 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.26-2.36(4H, m), 4.65(1H, d, J=16.0Hz), 4.86(1H, d, J=16.0Hz), 6.97(2H, d, J=5.9Hz), 7.25-7.60(4H, m), 8.38(2H, d, J=5.9Hz). 
                 226-227 
               
               
                   
               
               
                 33 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 H 
                 0.97(3H, t, J=7.4Hz), 2.06(1H, m), 2.26(1H, m), 2.34(3H, s), 4.72(1H, d, J=16.0Hz), 4.84(1H, d, J=16.0Hz), 6.99-7.02(2H, m), 7.29-7.62(4H, m), 8.41-8.44(2H, m), 9.93(1H, s). 
                 218-219 
               
               
                   
               
               
                 34 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 H 
                 H 
                 1.15(3H, d, J=6.9Hz), 1.25(3H, d, J=6.9Hz), 2.34(1H, m), 4.70(1H, d, J=16.4Hz), 4.87(1H, d, J=16.4Hz), 6.99-7.82(7H, m), 8.40-8.44(2H, m), 10.16(1H, s). 
                 238-239 
               
               
                   
               
               
                 35 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 H 
                 H 
                 0.97(3H, t, J=7.4Hz), 2.05(1H, m), 2.24(1H, m), 4.65-4.94(2H, m), 6.99-7.80(7H, m), 8.40-8.44(2H, m), 9.68(1H, s). 
                 219-220 
               
               
                   
               
               
                 36 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.08(3H, d, J=6.9Hz), 1.21(3H, d, J=6.9Hz), 2.20-2.40(7H, m), 4.59(1H, d, J=15.6Hz), 5.07(1H, d, J=15.6Hz), 7.02-7.12(5H, m), 7.18(1H, s), 7.26(2H, s), 8.85(1H, s). 
                 199-200 
               
               
                   
               
               
                 37 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.93(3H, t, J=7.3Hz), 2.02(1H, m), 2.12-2.28(7H, m), 4.64(1H, d, J=15.6Hz), 5.07(1H, d, J=15.6Hz), 7.02-7.26(8H, m), 8.97(1H, s). 
                 221-222 
               
               
                   
               
               
                 38 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.12(3H, d, J=6.9Ha), 1.22(3H, d, J=6.9Hz), 2.20-2.40(7H, m), 4.77(1H, d, J=16.0Hz), 4.98(1H, d, J=16.0Hz), 7.23-7.32(5H, m), 8.00(2H, d, J=8.5Hz), 8.97(1H, s). 
                 203-204 
               
               
                   
               
               
                 39 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.07(3H, d, J=6.9Hz), 1.20(3H, d, J=6.9Hz), 2.20-2.40(7H, m), 3.69(3H, s), 4.50(1H, d, J=15.2Hz), 5.07(1H, d, J=15.2Hz), 6.57-7.31(7H, m), 8.74(1H, s). 
                 156-157 
               
               
                   
               
               
                 40 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.10(3H, d, J=6.7Hz), 1.21(3H, d, J=6.7Hz), 2.11(3H, s), 2.25-2.38(7H, m), 4.34(1H, d, J=15.8Hz), 5.23(1H, d, J=15.8Hz), 6.66(1H, s), 6.77(1H, s), 6.83(1H, s), 7.19(1H, s), 7.27(2H, s), 8.72(1H, s). 
                 226-227 
               
               
                   
               
               
                 41 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.96(3H, t, J=7.5Hz), 2.08(1H, m), 2.20-2.40(7H, m), 4.84(1H, d, J=16.6Hz), 5.00(1H, d, J=16.6Hz), 7.25-7.32(5H, m), 7.98-8.05(2H, m), 9.43(1H, s). 
                 230-231 
               
               
                   
               
               
                 42 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.92(3H, t, J=7.3Hz), 2.05(1H, m), 2.10-2.40(7H, m), 3.69(3H, s), 4.56(1H, d, J=15.4Hz), 5.07(1H, d, J=15.4Hz), 6.59-7.26(7H, m), 9.25(1H, s). 
                 157-158 
               
               
                   
               
               
                 43 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.12(3H, d, J=6.9Hz), 1.22(3H, d, J=6.9Hz), 2.22-2.40(7H, m), 4.54(1H, d, J=16.3Hz), 4.99(1H, d, J=16.3Hz), 6.50-6.60(3H, m), 7.24(1H, s), 7.35(2H, s), 9.25(1H, s). 
                 208-209 
               
               
                   
               
               
                 44 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.12(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.25(6H, s), 2.30(1H, m), 4.62(1H, d, J=15.9Hz), 5.33(1H, d, J=15.9Hz), 7.19-7.30(3H, m), 7.51(2H, s), 7.58(1H, s), 9.92(1H, s). 
                 184-185 
               
               
                   
               
               
                 45 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.05(3H, d, J=6.7Hz), 1.15(3H, d, J=6.7Hz), 2.22-2.32(10H, m), 4.44(1H, d, J=16.0Hz), 4.90(1H, d, J=16.0Hz), 6.69-6.72(2H, m), 7.16(1H, s), 7.19(2H, s), 8.20(1H, d, J=5.5Hz), 8.82(1H, s). 
                 269-270 
               
               
                   
               
               
                 46 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 F 
                 1.15(3H, d, J=7.0Hz), 1.20(3H, d, J=7.0Hz), 2.21(1H, m), 2.24(3H, s), 2.34(3H, s), 4.42(1H, d, J=16.2Hz), 4.96(1H, d, J=16.2Hz), 6.70-7.26(5H, m), 8.21(1H, d, J=5.9Hz), 9.25(1H, s). 
                 217-218 
               
               
                   
               
               
                 47 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
                 1.14(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.22-2.38(4H, m), 2.41(3H, s), 4.46(1H, d, J=16.2Hz), 5.07(1H, d, J=16.2Hz), 6.77-8.30(6H, m), 9.50(1H, s). 
                 253-254 
               
               
                   
               
               
                 48 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
                 1.15(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.23(1H, m), 2.44(3H, s), 4.41(1H, d, J=16.2Hz), 5.18(1H, d, J=16.2Hz), 6.75-8.30(6H, m), 9.42(1H, s). 
                 234-236 
               
               
                   
               
               
                 49 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 2 F 
                 CH 3   
                 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.26-2.37(7H, m), 4.48(1H, d, J=16.5Hz), 5.04(1H, d, J=16.5Hz), 5.31(2H, d, J=47.2Hz), 6.75-6.78(2H, m), 7.39-7.52(3H, m), 8.24(1H, m), 8.85(1H, s). 
                 253-255 
               
               
                   
               
               
                 50 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 H 
                 1.13(3H, d, J=7.0Hz), 1.23(3H, d, J=7.0Hz), 2.24-2.39(7H, m), 4.54(1H, d, J=16.1Hz), 4.95(1H, d, J=16.1Hz), 6.77-8.28(7H, m), 8.96(1H, s). 
                 219-220 
               
               
                   
               
               
                 51 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.15(3H, d, J=6.7Hz), 1.24(3H, d, J=6.7Hz), 2.28-2.42(7H, m), 4.55(1H, d, J=16.4Hz), 4.97(1H, d, J=16.4Hz), 6.94-6.96(2H, m), 7.26(1H, s), 7.35(2H, s), 8.18(1H, m), 9.29(1H, s). 
                 253-254 
               
               
                   
               
               
                 52 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.96(3H, t, J=7.5Hz), 2.05(1H, m), 2.20-2.30(7H, m), 2.40(3H, s), 4.57(1H, d, J=16.3Hz), 4.96(1H, d, J=16.3Hz), 6.79-6.82(2H, m), 7.24(1H, s), 7.31(2H, s), 8.29(1H, d, J=4.6Hz), 9.55(1H, s). 
                 211-212 
               
               
                   
               
               
                 53 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 F 
                 0.97(3H, t, J=7.4Hz), 2.02(1H, m), 2.22-2.31(4H, m), 2.42(3H, s), 4.56(1H, d, J=16.8Hz), 5.02(1H, d, J=16.8Hz), 6.79-7.33(5H, m), 8.30(1H, m), 9.64(1H, s). 
                 183-184 
               
               
                   
               
               
                 54 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.98(3H, t, J=7.5Hz), 2.10(1H, m), 2.25-2.32(7H, m), 4.59(1H, d, J=15.6Hz), 4.96(1H, d, J=15.6Hz), 6.94-6.97(2H, m), 7.27(1H, s), 7.33(2H, s), 8.19(1H, m), 9.34(1H, s). 
                 217-218 
               
               
                   
               
               
                 55 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.11(3H, d, J=6.7Hz), 1.21(3H, d, J=6.7Hz), 2.22-2.38(13H, m), 4.37(1H, d, J=16.0Hz), 5.05(1H, d, J=16.0Hz), 6.56(2H, s), 7.19(1H, s), 7.27(2H, s), 9.70(1H, s). 
                 232-233 
               
               
                   
               
               
                 56 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 F 
                 F 
                 1.15(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.23(1H, m), 2.36(6H, s), 4.34(1H, d, J=16.2Hz), 5.18(1H, d, J=16.2Hz), 6.58(2H, s), 7.01-7.20(3H, m), 9.25(1H, s). 
                 176-178 
               
               
                   
               
               
                 57 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 Cl 
                 1.13(3H, d, J=6.9Hz), 1.23(3H, d, J=6.9Hz), 2.20(1H, m), 2.35(6H, s), 4.22(1H, d, J=16.3Hz), 5.30(1H, d, J=16.3Hz), 6.54(2H, s), 7.46(2H, s), 7.50(1H, s), 9.35(1H, s). 
                 172-173 (foam) 
               
               
                   
               
               
                 58 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 2 F 
                 CH 3   
                 1.12(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.22-2.35(10H, m), 4.35(1H, d, J=16.0Hz), 5.13(1H, d, J=16.0Hz), 5.31(2H, d, J=47.2Hz), 6.56(2H, s), 7.37-7.50(3H, m), 9.06(1H, s). 
                 197-198 (foam) 
               
               
                   
               
               
                 59 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 Cl 
                 CH 3   
                 1.13(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.20-2.35(10H, m), 4.32(1H, d, J=16.0Hz), 5.19(1H, d, J=16.0Hz), 6.56(2H, s), 7.27-7.50(3H, m), 9.34(1H, s). 
                 222-223 
               
               
                   
               
               
                 60 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 CH 3   
                 CH 3   
                 0.95(3H, t, J=7.5Hz), 2.02(1H, m), 2.20-2.33(13H, m), 4.45(1H, d, J=16.0Hz), 5.05(1H, d, J=16.0Hz), 6.59(2H, s), 7.22(1H, s), 7.29(2H, s), 9.45(1H, s). 
                 211-212 
               
               
                   
               
               
                 61 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Ethyl 
                 F 
                 F 
                 1.15(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.23(1H, m), 2.36(6H, s), 4.34(1H, d, J=16.2Hz), 5.18(1H, d, J=16.2Hz), 6.58(2H, s), 7.01-7.20(3H, m), 9.25(1H, s). 
                 176-178 
               
               
                   
               
               
                 62 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 CH 3   
                 1.14(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.30-2.40(7H, m), 4.69(1H, d, J=16.4Hz), 4.86(1H, d, J=16.4Hz), 7.27-7.37(5H, m), 8.52(1H, m), 9.50(1H, s). 
                 236-238 
               
               
                   
               
               
                 63 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 Cl 
                 1.16(3H, d, J=6.7Hz), 1.22(3H, d, J=6.7Hz), 2.30(1H, m), 2.40(3H, s), 4.77(2H, s), 7.27-7.56(5H, m), 8.56(1H, d, J=5.1Hz), 9.27(1H, s). 
                 220-221 
               
               
                   
               
               
                 64 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 NO 2   
                 (CDCl 3 /CD 3 OD) δ 1.11(3H, d, J=7.1Hz), 1.23(3H, d, J=7.1Hz), 2.23(1H, m), 2.49(3H, s), 4.63(1H, d, J=16.2Hz), 4.98(1H, d, J=16.2Hz), 7.02(2H, d, J=5.7Hz), 7.84(1H, s), 8.27-8.35(4H, m). 
                 256-257 
               
               
                   
               
               
                 65 
                 O 
                 C═O 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Isopropyl 
                 CH 3   
                 NO 2   
                 1.13(3H, d, J=6.7Hz), 1.23(3H, d, J=6.7Hz), 2.22(1H, m), 2.37(3H, s), 2.46(3H, s), 4.41(1H, d, J=16.2Hz), 5.25(1H, d, J=16.2Hz), 6.75-6.79(2H, m), 7.76(1H, s), 8.21-8.28(3H, m), 9.76(1H, s). 
                 237-238 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 66 
     Synthesis of 1-(4′-Picolyl)-5-isopropyl-6-(3′, 5′-dimethylphenylamino)-2,4-pyrimidinedione (Compound 66) 
     To a magnetically stirred DMF solution (10 ml) of compound (II-a-1) obtained in Preparation 22 (630 mg, 2 mmol) at room temperature, were added anhydrous potassium carbonate (552 mg, 4 mmol), lithium iodide (268 mg, 2 mmol), and 4-picolyl chloride hydrochloride (328 mg, 2 mmol). After stirring for 24 hr, the solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-ethyl acetate) to give 276 mg (yield 34%) of 1-(4′-picolyl)-5-isopropyl-6-(3′, 5′-dimethylphenylacetamido)-2,4-pyrimidinedione. The compound thus obtained was then refluxed in methanol (10 ml) with sodium methoxide (110 mg, 2 mmol) for 6 hr. The reaction mixture was allowed to cool to room temperature and neutralized with excess ammonium chloride. The solvent was removed under reduced pressure and the resulting residue was purified by flash chromatography (eluent-methanol:ether=8:92) to afford 280 mg (yield 88%) of the title compound as a white solid. 
     M.p.: 272 to 273° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.20 (6H, d, J=6.9 Hz), 2.24 (6H, s), 2.90 (1H, m), 4.90 (2H, s), 6.27 (2H, s), 6.61 (1H, s), 7.04-7.06 (2H, m), 8.42-8.45 (2H, m); m/z (EI) 364 (M + ). 
     EXAMPLE 67 
     Synthesis of 1-(4′-Picolyl)-5-ethyl-6-(3′, 5′-dimethylphenylamino)-2,4-pyrimidinedione (Compound 67) 
     The procedure of Example 66 was repeated using compound (II-a-2) obtained in Preparation 23 in place of compound (II-a-1) to prepare the title compound. 
     M.p.: 250 to 251° C.;  1 H-NMR (200 MHz, CDCl 3 /CD 3 OD) δ 0.99 (3H, t, J=7.5 Hz), 2.24 (6H, s), 2.37 (2H, q, J=7.5 Hz), 4.91 (2H, s), 6.31 (2H, s), 6.62 (1H, s), 7.04-7.07 (2H, m), 8.40-8.43 (2H, m); m/z (EI) 350 (M + ). 
     EXAMPLE 68 
     Synthesis of 1-(N-oxo-4′-Picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 68) 
     Compound 1 obtained in Example 1 (2.26 g, 6 mmol) was stirred with m-chloroperbenzoic acid (2.72 g, 9 mmol) in dichloromethane (120 ml) at room temperature. After 6 hr, the solvent was removed and the residue was purified by flash chromatography (eluent-chloroform:methanol=93:7) to afford 2 g (yield 84%) of the title compound as a white solid. 
     M.p.: 254 to 255° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J=6.7 Hz), 1.22 (3H, d, J=6.7 Hz), 2.25-2.36 (7H, m), 4.69 (2H, s), 7.05-7.41 (5H, m), 8.05-8.09 (2H, m), 9.52 (1H, s); m/z (EI) 393 (M + ). 
     EXAMPLE 69 
     Synthesis of 1-(N-oxo-3′-Methyl-4′-picolyl)-5-isopropyl-6-(3′, 5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 69) 
     Compound 45 obtained in Example 45 (834 mg, 2.13 mmol) was stirred with m-chloroperbenzoic acid (969 mg, 3.2 mmol) in dichloromethane (40 ml) at room temperature. After 5 hr, the solvent was removed and the residue was purified by flash chromatography (eluent-ethyl acetate:methanol=7:1) to afford 860 mg (yield 99%) of the title compound as a white solid. 
     M.p.: 223 to 224° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.13 (3H, d, J=6.7 Hz), 1.23 (3H, d, J=6.7 Hz), 2.25-2.40 (10H, m), 4.56 (1H, d, J=16.0 Hz), 4.85 (1H, d, J=16.0 Hz), 6.93 (1H, m), 7.31 (1H, s), 7.37 (2H, s), 8.10 (1H, m), 10.08 (1H, s); m/z (EI) 407 (M + ). 
     EXAMPLE 70 
     Synthesis of 1-(N-oxo-3′, 5-Dimethyl-4′-picolyl)-5-Isopropyl-6-(3′, 5′-dimethylbenzoyl)-2,4-Pyrimidinedione (Compound 70) 
     Compound 55 obtained in Example 55 (840 mg, 2 mmol) was stirred with m-chloroperbenzoic acid (942 mg, 3 mmol) in dichloromethane (40 ml) at room temperature. After 20 hr, the solvent was removed and the residue was purified by flash chromatography (eluent-dichloromethane:methanol=15:1) to afford 800 mg (yield 95%) of the title compound as a white solid. 
     M.p.: 241 to 242° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.12 (3H, d, J=6.7 Hz), 1.22 (3H, d, J=6.7 Hz), 2.30-2.34 (13H, m), 4.41 (1H, d, J=16.0 Hz), 54.98 (1H, d, J=16.0 Hz), 6.80 (2H, s), 7.27 (1H, m), 7.34 (2H, s), 9.21 (1H, s); m/z (EI) 421 (M + ). 
     EXAMPLE 71 
     Synthesis of 1-(N-oxo-3′,5′-Dimethyl-4′-picolyl)-5-isopropyl-6-(3′,-chloro-5-methylbenzoyl)-2,4-pyrimidinedione (Compound 71) 
     Compound 59 obtained in Example 59 (860 mg, 2 mmol) was stirred with m-chloroperbenzoic acid (942 mg, 3 mmol) in dichloromethane (40 ml) at room temperature. After 21 hr, the solvent was removed and the residue was purified by flash chromatography (eluent-ethyl acetate:hexane=10:1) to afford 870 mg (yield 98%) of the title compound as a white solid. 
     M.p.: 2 to 226° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.13 (3H, d, J=6.9 Hz), 1.22 (3H, d, J=6.9 Hz), 2.22-2.36 (13H, m), 4.39 (1H, d, J=16.0 Hz), 5.04 (1H, d, J=16.0 Hz), 6.80 (2H, s), 7.33-7.54 (3H, m), 9.14 (1H, s); m/z (EI) 441 (M + ). 
     EXAMPLE 72 
     Synthesis of 1-(3′-Acetoxymethyl-4′-picolyl)-5-Isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 72) 
     Compound 69 obtained in Example 69 (800 mg, 1.96 mmol) was dissolved in acetic anhydride (10 ml) and the solution was heated in an oil bath (120-140° C.) with stirring for 4 hr. The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (eluent-ethyl acetate:hexane=2:1) to afford 150 mg (yield 17%) of the title compound as a syrup. 
       1 H-NMR (200 MHz, CDCl 3 ) δ 1.14 (3H, d, J=6.7 Hz), 1.28 (3H, d, J=6.7 Hz), 2.16 (3H, s), 2.22-2.40 (7H, m), 4.68 (1H, d, J=16.2 Hz), 4.88 (1H, d, J=16.2 Hz), 5.08 (2H, s), 7.00-7.02 (2H, m), 7.26 (1H, s), 7.36 (2H, s), 8.44 (1H, m); m/z (EI) 449 (M + ). 
     EXAMPLE 73 
     Synthesis of 1-(3′-Acetoxymethyl-5′-methyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 73) 
     Compound 70 obtained in Example 70 (300 mg, 0.71 mmol) was dissolved in acetic anhydride (3 ml) and the solution was heated in an oil bath (120-130° C.) with stirring for 2 hr. The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (eluent-ethyl acetate:hexane=1:1) to afford 110 mg (yield 33%) of the title compound as a foam. 
       1 H-NMR (200 MHz, CDCl 3 ) δ 1.13 (3H, d, J=6.9 Hz), 1.23 (3H, d, J=6.9 Hz), 2.10-2.41 (10H, m), 4.53 (1H, d, J=16.0 Hz), 4.96 (1H, d, J=16.0 Hz), 5.00 (2H, s), 6.78-6.81 (2H, m), 7.24 (1H, s), 7.34 (2H, s); m/z (EI) 463 (M + ). 
     EXAMPLE 74 
     Synthesis of 1-(3′-Acetoxymethyl -5′-methyl-4-picolyl)-5-isopropyl-6-(3′-chloro-5′-methylbenzoyl)-2,4-pyrimidinedione (Compound 74) 
     Compound 71 obtained in Example 71 (700 mg, 1.58 mmol) was dissolved in acetic anhydride (10 ml) and the solution was heated in an oil bath (120-130° C.) with stirring for 5 hr. The solvent was then removed under reduced pressure and the residue was purified by flash chromatography (eluent-ethyl acetate:hexane=2:1) to afford 115 mg (yield 15%) of the title compound as a foam. 
       1 H-NMR (200 MHz, CDCl 3 ) δ 1.14 (3H, d, J=6.9 Hz), 1.24 (3H, d, J=6.9 Hz), 2.16 (3H, s), 2.20-2.32 (4H, m), 2.42 (3H, s), 4.48 (1H, d, J=16.3 Hz), 5.00 (2H, s), 5.06 (1H, d, J=16.3 Hz), 6.76 (2H, d, J=5.9 Hz), 7.32 (1H, s), 7.39 (1H, s), 7.52 (1H, s), 9.46 (1H, s); m/z (EI) 483 (M + ). 
     EXAMPLE 75 
     Synthesis of 1-(3′-Hydroxymethyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 75) 
     Compound 72 obtained in Example 72 (100 mg, 0.22 mmol) was stirred with ammonium hydroxide (0.5 ml) in methanol (5 ml) at room temperature. After 6 hr, the solvent was evaporated in vacuo and the resulting residue was recrystallized from methanol-chloroform to give 70 mg (yield 77%) of the title compound as a white solid. 
     M.p.: 256 to 257° C.;  1 H-NMR (200 MHZ, DMSO-d 6 ) δ 1.05 (3H, d, J=6.8 Hz), 1.11 (3H, d, J=6.8 Hz), 2.15 (1H, m), 2.28 (6H, s), 4.44 (2H, d, J=5.5 Hz), 4.59 (1H, d, J=16.7 Hz), 4.70 (1H, d, J=16.7 Hz), 5.35 (1H, t, J=5.5 Hz), 6.90 (1H, m), 7.15 (1H, s), 7.32 (1H, s), 7.55 (2H, s), 8.25 (1H, m), 11.66 (1H, s); m/z (EI) 407 (M + ). 
     EXAMPLE 76 
     Synthesis of 1-(3′-Hydroxymethyl-5′-methyl-4′-picolyl)-5-isopropyl-6-(3′, 5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 76) 
     Compound 73 obtained in Example 73 (150 mg, 0.32 mmol) was stirred with ammonium hydroxide (0.5 ml) in methanol (5 ml) at room temperature. After 5 hr, the solvent was evaporated in vacuo and the resulting residue was recrystalized from methanol-chloroform to give 100 mg (yield 74%) of the title compound as a white solid. 
     M.p.: 234 to 236° C.;  1 H-NMR (200 MHZ, DMSO-d 6 ) δ 1.05 (3H, d, J=6.7 Hz), 1.11 (3H, d, J=6.7 Hz), 2.15 (1H, m), 2.26 (9H, s), 4.37 (2H, d, J=5.3 Hz), 4.51 (1H, d, J=17.1 Hz), 4.72 (1H, d, J=17.1 Hz), 5.29 (1H, t, J=5.3 Hz), 6.72 (1H, s), 6.93 (1H, s), 7.30 (1H, s), 7.51 (2H, s), 11.64 (1H, s); m/z (EI) 421 (M + ). 
     EXAMPLE 77 
     Synthesis of 1-(3′-Hydroxymethyl-5′-methyl-4′-picolyl)-5-isopropyl-6-(3′-chloro-5′-methylbenzoyl)-2,4-pyrimidinedione (Compound 77) 
     Compound 74 obtained in Example 74 (100 mg, 0.21 mmol) was stirred with ammonium hydroxide (0.5 ml) in methanol (5 ml) at room temperature. After 6 hr, the solvent was evaporated in vacuo and the resulting residue was recrystallized from methanol-chloroform to afford 78 mg (yield 85%) of the title compound as a white solid. 
     M.p.: 238 to 240° C.;  1 H-NMR (200 MHz, DMSO-d 6 ) δ 1.05 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=6.8 Hz), 2.11 (1H, m), 2.27 (3H, s), 2.49 (3H, s), 4.37 (2H, d, J=5.7 Hz), 4.47 (1H, d, J=17.1 Hz), 4.82 (1H, d, J=17.1 Hz), 5.27 (1H, t, J=5.7 Hz), 6.75 (1H, s), 6.93 (1H, s), 7.56 (1H, s), 7.66 (1H, s), 7.74 (1H, s), 11.63 (1H, s); m/z (EI) 441 (M + ). 
     EXAMPLE 78 
     Synthesis of 1-(3′-Methoxycarbonyl-4′-picolyl)-5-isopropyl-6-(31,51-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 78) 
     Compound 62 obtained in Example 62 (100 mg, 0.25 mmol) was stirred with potassium carbonate (138 mg, 1 mmol) and distilled water (0.5 ml) in methanol (5 ml) at room temperature. After 18 hr, the reaction mixture was acidified with glacial acetic acid and the solvent was evaporated in vacuo. The resulting residue was purified by flash chromatography (eluent-ethyl acetate:hexane=4:1) to afford 74 mg (yield 68%) of the title compound as a white solid. 
     M.p.: 138 to 140° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.14 (3H, d, J=6.9 Hz), 1.23 (3H, d, J=6.9 Hz), 2.28-2.38 (7H, m), 3.98 (3H, s), 4.68 (1H, d, J=16.0 Hz), 5.00 (1H, d, J=16.0 Hz), 7.21-7.33 (4H, m), 7.73 (1H, s), 8.54 (1H, m), 9.45 (1H, s); m/z (EI) 435 (M + ). 
     EXAMPLE 79 
     Synthesis of 1-(3′-Carbamoyl-4′-picolyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 79) 
     Compound 62 obtained in Example 62 (60 mg, 0.15 mmol)was stirred with conc. sulfuric acid (1 ml) in an oil bath (80° C.). After 10 min, the reaction mixture was allowed to cool to room temperature and poured into distilled water (10 ml). The resulting precipitate was collected by filtration, washed with distilled water and hexane, and dried in vacuo to afford 38 mg (yield 61%) of the title compound as a white solid. 
     M.p.: 295 to 296° C.;  1 H-NMR (500 MHZ, DMSO-d 6 ) δ 1.03 (3H, d, J=6.9 Hz), 1.10 (3H, d, J=6.9 Hz), 2.14 (1H, m), 2.25 (6H, s), 4.67 (1H, d, J=17.6 Hz), 4.75 (1H, d, J=17.6 Hz), 7.26 (1H, dd, J=5.0 Hz, J=1.7 Hz), 7.29 (1H, s), 7.53 (2H, s), 7.63 (1H, d, J=2.5 Hz), 7.69 (1H, s), 8.04 (1H, d, J=2.1 Hz), 8.40 (1H, d, J=5.0 Hz), 11.71 (1H, s); m/z (EI) 420 (M + ). 
     EXAMPLE 80 
     Synthesis of 1-(3′-Carbamoyl-4′-picolyl)-5-isopropyl-6-(3′-chloro-5′-methylbenzoyl)-2,4-pyrimidinedione (Compound 80) 
     Compound 63 obtained in Example 63 (90 mg, 0.21 mmol) was stirred with conc. sulfuric acid (1 ml) in an oil bath (80° C.). After 10 min, the reaction mixture was allowed to cool to room temperature and poured into distilled water (10 ml). The resulting precipitate was collected by filtration, washed with distilled water and hexane, and dried in vacuo to afford 87 mg (yield 92%) of the title compound as a white solid. 
     M.p.: 284 to 285° C.;  1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.03 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=6.8 Hz), 2.12 (1H, m), 2.29 (3H, s), 4.68 (1H, d, J=17.3 Hz), 4.76 (1H, d, J=17.3 Hz), 7.29 (1H, dd, J=5.0 Hz, J=1.7 Hz), 7.58 (1H, s), 7.63 (1H, d, J=2.5 Hz), 7.71 (1H, s), 7.74 (1H, s), 7.80 (1H, s), 8.04 (1H, d, J=2.5 Hz), 8.41 (1H, d, J=5.0 Hz), 11.72 (1H, s); m/z (EI) 440 (M + ). 
     EXAMPLE 81 
     Synthesis of 1-(4′-Aminobenzyl)-5-isopropyl-6-(3′,5′-dimethylbenzoyl)-2,4-pyrimidinedione (Compound 81) 
     Compound 38 obtained in Example 38 (50 mg, 0.12 mmol) in methanol (5 ml) was stirred under an atmosphere of hydrogen in the presence of platinium oxide catalyst (10 mg) at room temperature for 4 hr. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography (eluent-ethyl acetate:hexane=1:1) to afford 32 mg (yield 70%) of the title compound as a yellow solid. 
     M.p.: 173 to 175° C.;  1 H-NMR (200 MHz, CDCl 3 ) δ 1.07 (3H, d, J=6.9 Hz), 1.20 (3H, d, J=6.9 Hz), 2.20-2.40 (7H, m), 3.57 (2H, s), 4.46 (1H, d, J=15.2 Hz), 5.00 (1H, d, J=15.2 Hz), 6.35 (2H, d, J=8.3 Hz), 6.81 (2H, d, J=8.3 Hz), 7.21 (1H, s), 7.26 (2H, s), 8.86 (1H, s); m/z (EI) 391 (M + ). 
     Antiviral Activity and Cytotoxicity Test 
     The in vitro anti-HIV-1 assays were based on the inhibition of the virus-induced cytopathic effect in MT-4 cells, as described in  J. Med. Chem , 34, 349 (1991). 
     First, MT-4 cells were suspended in a culture medium at a concentration of 1×10 4  cells/ml and infected with 500 TCID 50  (50% cell culture infective dose)/well of HIV-1. Immediately after the virus infection, 100 μl of the cell suspension was added to each of the wells of a flat-bottomed microtiter tray containing various concentrations of the test compounds (1) to (81). After incubating for 4 or days at 37° C., the number of viable cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, as disclosed in  J. Virol. Methods , 20, 309 (1988). 
     The cytotoxicity of the compounds of the present invention was assessed in parallel with their antiviral activity. It was based on the viability of mock-infected host cells as determined by the MTT method (see J. Virol. Methods, 20, 309 (1988)). MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil) was employed as a comparative compound. 
     The results of the tests are shown in Table 4. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Ex. No. 
                   
                   
                   
               
               
                 (Compound) 
                 CD 50  (μg/ml)* 
                 ED 50  (μg/ml)** 
                 S.I. (CD 50 /ED 50 )*** 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                  1 
                 22.6 
                 0.0026 
                 8,600 
               
               
                  2 
                 27.2 
                 0.0036 
                 7,578 
               
               
                  3 
                 26.1 
                 0.0055 
                 4,788 
               
               
                  4 
                 64.0 
                 0.0027 
                 23,940 
               
               
                  5 
                 18.7 
                 0.012 
                 1,553 
               
               
                  6 
                 28.2 
                 0.0127 
                 2,215 
               
               
                  7 
                 22.7 
                 0.0034 
                 6,597 
               
               
                  8 
                 28.16 
                 0.008 
                 3,451 
               
               
                  9 
                 40.5 
                 0.0119 
                 3,401 
               
               
                 10 
                 51.7 
                 0.0101 
                 5,133 
               
               
                 11 
                 47.4 
                 0.0178 
                 2,658 
               
               
                 12 
                 38.9 
                 0.0542 
                 716 
               
               
                 13 
                 42.3 
                 0.0124 
                 3,414 
               
               
                 14 
                 29.81 
                 0.049 
                 612 
               
               
                 15 
                 49.87 
                 0.053 
                 943 
               
               
                 16 
                 50.6 
                 0.0601 
                 841 
               
               
                 17 
                 74.3 
                 0.112 
                 663 
               
               
                 18 
                 93.2 
                 0.1189 
                 784 
               
               
                 19 
                 11.28 
                 0.003 
                 3,394 
               
               
                 20 
                 32.9 
                 0.012 
                 2,758 
               
               
                 21 
                 55.07 
                 0.0023 
                 23,501 
               
               
                 22 
                 92.8 
                 0.002 
                 48,305 
               
               
                 MKC-442 
                 27.7 
                 0.005 
                 5,544 
               
               
                 23 
                 52.1 
                 0.003 
                 15,245 
               
               
                 24 
                 15.8 
                 0.010 
                 1,628 
               
               
                 25 
                 &gt;100 
                 0.018 
                 &gt;5,557 
               
               
                 26 
                 6.5 
                 0.003 
                 2,112 
               
               
                 27 
                 8.5 
                 0.002 
                 5,747 
               
               
                 28 
                 12.5 
                 0.004 
                 3,516 
               
               
                 29 
                 44.9 
                 1.867 
                 24 
               
               
                 30 
                 52.3 
                 1.935 
                 27 
               
               
                 31 
                 11.7 
                 1.8 
                 6 
               
               
                 32 
                 40.4 
                 0.003 
                 12,039 
               
               
                 33 
                 57.1 
                 0.011 
                 5,073 
               
               
                 34 
                 37.4 
                 0.014 
                 2,663 
               
               
                 35 
                 &gt;100 
                 0.0606 
                 &gt;1,650 
               
               
                 36 
                 8.01 
                 0.004 
                 2,170 
               
               
                 37 
                 5.78 
                 0.003 
                 2,066 
               
               
                 38 
                 5.65 
                 0.005 
                 1,172 
               
               
                 39 
                 7.46 
                 0.003 
                 2,654 
               
               
                 40 
                 7.97 
                 0.0348 
                 229 
               
               
                 41 
                 4.63 
                 0.009 
                 497 
               
               
                 42 
                 2.14 
                 0.002 
                 921 
               
               
                 43 
                 7.16 
                 0.0035 
                 2,057 
               
               
                 44 
                 8.17 
                 1.80 
                 5 
               
               
                 MKC-442 
                 27.7 
                 0.005 
                 5,544 
               
               
                 45 
                 &gt;100 
                 0.0098 
                 &gt;10,170 
               
               
                 46 
                 22.9 
                 0.0024 
                 9,691 
               
               
                 47 
                 93.75 
                 0.0027 
                 35,133 
               
               
                 48 
                 12.07 
                 0.0030 
                 4,021 
               
               
                 49 
                 64.39 
                 0.0076 
                 8,440 
               
               
                 50 
                 47.68 
                 0.0029 
                 16,351 
               
               
                 51 
                 17.1 
                 0.0010 
                 17,812 
               
               
                 52 
                 14.3 
                 0.0010 
                 14,684 
               
               
                 53 
                 37.8 
                 0.0031 
                 12,110 
               
               
                 54 
                 8.7 
                 0.0017 
                 4,992 
               
               
                 55 
                 9.9 
                 0.0010 
                 10,274 
               
               
                 56 
                 87.2 
                 0.0044 
                 19,648 
               
               
                 57 
                 9.46 
                 0.0028 
                 3,411 
               
               
                 58 
                 36.03 
                 0.0025 
                 14,300 
               
               
                 59 
                 8.68 
                 0.0021 
                 4,126 
               
               
                 60 
                 17.5 
                 0.0026 
                 6,739 
               
               
                 61 
                 37.5 
                 0.0151 
                 2,475 
               
               
                 62 
                 9.15 
                 0.0016 
                 5,858 
               
               
                 63 
                 8.55 
                 0.0029 
                 2,966 
               
               
                 64 
                 46 
                 0.0096 
                 4,801 
               
               
                 65 
                 44.08 
                 0.0075 
                 5,916 
               
               
                 66 
                 &gt;100 
                 0.08 
                 &gt;1,287 
               
               
                 MKC-442 
                 27.7 
                 0.005 
                 5,544 
               
               
                 67 
                 54.5 
                 0.42 
                 130 
               
               
                 68 
                 56.9 
                 0.0145 
                 3,928 
               
               
                 69 
                 48.25 
                 0.0125 
                 3,853 
               
               
                 70 
                 25.84 
                 0.0055 
                 4,712 
               
               
                 71 
                 25.44 
                 0.0082 
                 3,092 
               
               
                 72 
                 38.49 
                 0.0088 
                 4,365 
               
               
                 73 
                 39.65 
                 0.0067 
                 5,903 
               
               
                 74 
                 28.81 
                 0.0134 
                 2,152 
               
               
                 75 
                 42.06 
                 0.0031 
                 13,444 
               
               
                 76 
                 38.39 
                 0.0084 
                 4,561 
               
               
                 77 
                 23.51 
                 0.0115 
                 2,052 
               
               
                 78 
                 40.79 
                 0.0075 
                 5,414 
               
               
                 79 
                 &gt;100 
                 0.0091 
                 &gt;10,942 
               
               
                 80 
                 27.83 
                 0.0111 
                 2,507 
               
               
                 81 
                 9.63 
                 0.015 
                 648 
               
               
                 MKC-442 
                 27.7 
                 0.005 
                 5,544 
               
               
                   
               
               
                 Foot note:  
               
               
                 *CD 50 : Cytotoxic concentration that causes death of MT-4 cells by 50%  
               
               
                 **ED 50 : Effective concentration for the inhibition of the proliferation of HIV-1 by 50%  
               
               
                 ***S.I.: Selectivity index = (CD 50 /ED 50 )  
               
             
          
         
       
     
     Antiviral Activity Against Mutant HIV-1 
     Antiviral activities of the inventive compounds were determined against Y181C which is representative HIV-1 mutant having high resistance against anti-HIV-1 nonnucleosides, e.g., Nevirapine, by the MTT method. MKC-442 was employed as a comparative compound. 
     The representative results of the tests are shown in Table 5. 
     
       
         
               
               
               
             
           
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Compound 
                 EC 50  (μM)* 
               
               
                   
                   
               
             
             
               
                   
                 1 
                 0.005-0.014 
               
               
                   
                 4 
                 0.010-0.041 
               
               
                   
                 MKC-442 
                 13.4** 
               
               
                   
                   
               
               
                   
                 Foot note:  
               
               
                   
                 *EC 50 : Effective concentration for the inhibition of the proliferation of mutant HIV-1 by 50%  
               
               
                   
                 **Reference: J. Med. Chem., 42, 4500 (1999)  
               
             
          
         
       
     
     As the above results show, the novel antiviral 2,4-pyrimidinedione derivatives of the present invention possess high antiviral activity against HIV-1, both wild-type and mutant HIV-1, and at the same time show high selectivity indices, i.e., low toxicity. The inventive compounds can therefore be used as a drug for treating AIDS. 
     While the invention has been described with respect to the specific embodiments, it should be recognized that various modifications and changes may be made by those skilled in the art to the invention which also fall within the scope of the invention as defined by the appended claims.