alpha- and beta-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors

Compound represented by the formula:

• 186
• wherein:
• R represents hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, alkoxycarbonyl, alkoxyalkyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;
• R′ represents hydrogen and radicals as defined for R3 or R and R′ together with the nitrogen to which they are attached represent heterocycloalkyl and heteroaryl radical;
• R1 represents hydrogen, —CH2SO2NH2, —CH2CO2CH3, —CO2CH3, —CONH2, —CH2C(O)NHCH3, —C(CH3)2(SH), —C(CH3)2(SCH3), —C(CH3)2(S[O]CH3), —C(CH3)2(S[O]2CH3), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl radicals, and amino acid side chains selected from asparagine, S-methyl cysteine and methionine and the sulfoxide (SO) and sulfone (SO2) derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, β-methyl serine, aspartic acid, beta-cyanoalanine and valine side chains;
• R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radials, —NO2, —C=N, CF3, —OR9, —SR9, wherein R9 represents hydrogen and alkyl radicals;
• R3 represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkyl and the sulfone and sulfoxide derivatives thereof;
• R4 represents hydrogen and radicals as defined by R3;
• R7 and R7′independently represent radicals as defined for R3 and amino acid side chains selected from the group consisting of valine, isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, and t-butylglycine or R7 and R7′ together with the carbon atom to which they are attached form a cycloalkyl radical;
• R8 represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals and radicals represented by the formulas C(O)R16, CO2R16, SO2R16, SR16, CONR16R17, CF3 and NR16R17;
• wherein R16 and R17 independently represent hydrogen and radicals as defined for R3, or R16 and R17 together with a nitrogen to which they are attached in the formula NR16R17 represent heterocycloalkyl and heteroaryl radicals;
• n represents an integer of from 0 to 6.

Compound represented by the formula:

• 187
• wherein:
• R represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, arylpxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, alkoxyalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;
• R′ represents hydrogen and radicals as defined for R3 or R and R′ together with the nitrogen to which they are attached represent heterocycloalkyl and heteroaryl radical;
• R1 represents hydrogen, —CH2SO2NH2, —CH2CO2CH3, -CO2CH3, —CONH2, —CH2C(O)NHCH3, —C(CH3)2(SH), —C(CH3)2(SCH3), —C(CH3)2(S[O]CH3), —C(CH3)2(S[O]2CH3), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl radicals, and amino acid side chains selected from asparagine, S-methyl cysteine and methionine and the sulfoxide (SO) and sulfone (SO2) derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, aspartic acid, beta-cyano alanine and valine side chains;
• R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, —N02, —C=N, CF3, —OR9, —SR9, wherein R9 represents hydrogen and alkyl radicals;
• R3 represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkyl radicals and the sulfone and sulfoxide derivatives thereof;
• R4 represents hydrogen and radicals as defined for R3;
• R7 and R7′ independently represent radicals as defined for R3 and amino acid side chains selected from the group consisting of valine, isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, and t-butylglycine or R7 and R7′ together with the carbon atom to which they are attached form a cycloalkyl radical;
• R8 represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl and heterbaryl radicals and radicals represented by the formulas C(O)R16, CO2R16, SO2R16, SR16, CONR16R17, CF3 and NR16R17;
• wherein R16 and R17 independently represent hydrogen and radicals as defined for R3, or R16 and R17 together with a nitrogen to which they are attached in the formula NR16R17 represent heterocycloalkyl and heteroaryl radicals;
• n represents an integer of from 0 to 6.

Compound represented by the formula:

• 188
• wherein:
• R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, alkoxyalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;
• R′ represents hydrogen and radicals as defined for R3 or R and R′ together with the nitrogen to which they are attached represent heterocycloalkyl and heteroaryl radical;
• R1 represents hydrogen, —CH2SO2NH2, —CH2CO2CH3, —CO2CH3, —CONH2, —CH2C(O)NHCH3, —C(CH3)2(SH), —C(CH3)2(SCH3), —C(CH3)2(S[O]CH3), —C(CH3)2(S[O]2CH3), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl radicals, and amino acid side chains selected from asparagine, S-methyl cysteine and methionine and the sulfoxide (SO) and sulfone (SO2) derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, aspartic acid, beta-cyano alanine and valine side chains;
• R1′ and R1Δ independently represent hydrogen and radicals as defined for R1, or one of R1′ and R1, together with R1 and the carbon atoms to which R1, R1′ and R1Δ are attached, represent a cycloalkyl radical;
• R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radials;
• —NO2, —C=N, CF3, —OR9 and —SR9, wherein R9 represents hydrogen and alkyl radicals;
• R3 represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstitute( aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkyl radicals and the sulfone and sulfoxide derivatives thereof;
• R4 represents hydrogen and radicals as defined by R3;
• R7 and R7′ independently represent radicals as defined for R3 and amino acid side chains selected from the group consisting of valine, isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, and t-butylglycine or R7 and R7 together with the carbon atom to which they are attached form a cycloalkyl radical;
• R8 represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals and radicals represented by the formulas C(O)R16, CO2R16, SO2R16, SR16, CONR16R17, CF3 and NR16R17;
• wherein R16 and R17 independently represent hydrogen and radicals as defined for R3, or R16 and R17 together with a nitrogen to which they are attached in the formula NR16R17 represent heterocycloalkyl and heteroaryl radicals;
• n represents an integer of from 0 to 6.

A compound represented by the formula:

• 189
• wherein:
• P1 and p2 independently represent hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical;
• R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, —NO2, —CrN, CF3, —OR9, —SR9, wherein R9 represents hydrogen and alkyl radicals;
• R3 represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical, and thioalkyl, alkylthioalkyl and arylthioalkyl and the sulfone and sulfoxide derivatives thereof;
• R4 represents hydrogen and radicals as defined by R3;
• R7 and R7, independently represent radicals as defined for R3;
• amino acid side chains selected from the group consisting of valine, isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, and t-butylglycine;
• radicals represented by the formulas —C(O)R16, —CO2R16, —SO2R16, —SR16, —CONR16R17, —CF3 and —NR16R17;
• or R7 and R7, together with the carbon atom to which they are attached form a cycloalkyl radical;
• R8 represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals and radicals represented by the formulas C(O)R16, CO2R16, SO2R16, SR16, CONR16R17, CF3 and NR16R17;
• wherein R16 and R17 independently represent hydrogen and radicals as defined for R3, or R16 and R17 together with a nitrogen to which they are attached in the formula NR16R17 represent heterocycloalkyl and heteroaryl radicals;
• n represents an integer of from 0 to 6.