Sulfonamides and derivatives thereof that modulate the activity of endothelin

A compound that has formula IV:

• 45
• or pharmaceutically acceptable derivatives thereof, wherein:
• X is S or —C(R3)═C(R4)—;
• R1 is halo or lower alkyl;
• R2 is lower alkyl;
• R3 and R4 are independently selected from among hydrogen, halo, cyano, cyanoalkyl, C(O)R41, alkyl, alkenyl, cycloalkyl and aryl, or together form alkylene or alkenylene, where R41 is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylamino or arylsulfonylarylamino;
• R5 is lower alkyl or —(CH2)xC(O)(CH2)yCH3;
• R6 is lower alkyl, —(CH2)xC(O)(CH2)yCH3, or heteroaryl;
• R7 is hydrogen, hydroxy, alkoxy, lower alkyl, S(O)2NHR50 and OS(O)2NR38R39;
• where R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl;
• x and y are each independently 0 to 14;
• R50 is hydrogen, lower alkyl, lower alkoxy or heteroaryl;
• Y and R8 are selected from (i) or (ii) as follows:
• (i) Y is O;
• and R8 is CONR38R39, CN, heteroaryl, alkylsulfonyl, (CH2)xC(O)(CH2)yCH3, alkyl, halide, pseudohalide, hydroxyalkyl, C(O)(CH2)xS(O)2(CH2)yCH3 or C(═N—OR38)(CH2)yCH3;
• or
• (ii) Y and R8 together with the atoms to which they are attached, form a 3 to 16 membered unsubstituted or substituted cyclic or heterocyclic ring;
• R9 is H;
• Y1 and Y2 are each independently carbon or nitrogen;
• a is 1 if Y2 is carbon;
• a is 0 if Y2 is nitrogen;
• b is 1 if Y1 is carbon;
• b is 0 if Y1 is nitrogen;
• and
• W is NH.