Pharmacokinetically improved compounds

A compound of the formula A:

• or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
• R1 is lower alkyl;
• R2 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
• R3 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
• A is N or C—H;
• B is N, C—H, C—(SO2—R4), or C—CO—R4;
• D is N, C—H, C—(SO2—R4) or C—CO—R4;
• E is N or C—H;
• wherein only one of A, B or E may be N, and one of B or D is C—(SO2—R4) or C—CO—R4;
• R4 is a group having the formula:
• —NH—R41,
• —N(R42)(R43),
• and
• —N(R46)2;
• R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, —(CH2)a—N(H)(R51) and —(CH2)a—N(R52)(R53);
• R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
• R52 and R53 are taken together with the nitrogen to which they are attached to faun a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
• a is 1 to 6;
• R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
• R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, —(CH2)a—N(H)(R51) and —(CH2)a—N(R52)(R53);
• R44 is selected from is selected from the group consisting of —(CH2)q—N(R12)(R13), —(CH2)r—N(R11)—(CH2)sC(O)R14, —(CH2)q—C(O)R14, —(CH2)rC(O)—(CH2)sOR11, —(CH2)rC(O)—(CH2)sN(R12)(R13), and —(CH2)rO—(CH2)s—C(O)R14,
• each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
• each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
• or R12 and R13 may be taken together with the nitrogen to which they are attached foam a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
• each R14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
• q is 1 to 6:
• r is 0 to 6;
• s is 0 to 6;
• R45 is selected from is selected from the group consisting of —(CH2)v—N(R25)(R2), —(CH2)v—N(R21)—(CH2)w—C(O)R24, —(CH2)v—C(O)R24, —(CH2)t—C(O)—(CH2)wOR21, —(CH2)t—C(O)(CH2)w—N(R22)(R23), —(CH2)v—O—(CH2)w—C(O)R24;
• each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
• each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
• or R22 and R23 may be taken together with the nitrogen to which they are attached faun a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,
• each R24 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
• R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;
• t is 0 to 6;
• v is 1 to 6;
• w is 0 to 6;
• x is 1 or 2;
• y is 1 or 2;
• and
• R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O—C2-C6alkyl.