Substituted piperidines and methods of use

A compound of Formula I

• 72
• wherein Y is —NH—, —CH2—, or —O—;
• wherein R is selected from
• a) alkyl,
• b) —(CH2)n-cycloalkyl,
• c) —(CH2)n-aryl, and
• d) —(CH2)n-heterocyclyl;
• wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 groups selected from R4;
• the heterocyclyl group is optionally substituted with 1 to 3 groups selected from R4 and oxo;
• and the alkyl group is optionally substituted with 1 to 3 groups selected from R5;
• wherein R1a, R1b, R1c, R1d, R1e, and R1f are independently selected from R4;
• or wherein R1a and R1b or R1d and R1c form oxo;
• or wherein R1e and R1c form an alkylenyl or alkenylenyl bridge;
• or wherein R1a, R1b, R1c, and R1d together with the piperazine ring forms an optionally substituted 1,2,3,4-tetrahydro-quinoxalinyl ring;
• wherein R2 is selected from
• a) alkyl,
• b) —(CH2)-cycloalkyl,
• c) —(CH2)n-aryl,
• d) —(CH2)n-heterocyclyl,
• 73
• wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 groups selected from R4;
• the heterocyclyl group is optionally substituted with 1 to 3 groups selected from R4 and oxo;
• and the alkyl group is optionally substituted with 1 to 3 groups selected from R5;
• wherein R3 is independently selected from H, halo, amino, haloalkyl, alkyl, phenyl, haloalkoxy, and alkoxy;
• or wherein R3 is an alkenylene bridge;
• wherein R4 is selected from H, alkyl, —(CH2)n-cycloalkyl, —(CH2)n-aryl, —(CH2)n-heterocyclyl, halo, —(CH2)n—OR9, —NR9SO2R7, —[C(R7)2]pNR9SO2R7, —[C(R7)2]pNR9C(O)R7, —N(R9)2, —C(O)NR9R9, —NR9C(O)R7, —NR9CO2R7, cyano, —COOR9, —(CH2)n—C═OR7, —(CH2)n—C═SR7, —(CH2)n—C═(NR9)R7, —NR9C═(NR7)N(R9)2, —[C(R7)2]pN(R9)2, nitro, —SO2N(R9)2, —S(O)mR7, —C(R7)2SO2CF3, hydroxyalkyl, haloalkyl and haloalkoxy;
• wherein R5 is selected from halo, —OR9, NHSO2R7, —N(R9)2, cyano, —COR7, —[C(R7)2]nN(R9)2, nitro, —SO2N(R9)2, —S(O)mR7, haloalkyl, and haloalkoxy;
• wherein R6 is selected from aryl and heteroaryl, wherein R6 is optionally substituted with one or more R3;
• wherein R7 is selected from H, alkyl, —(CH2)n-cycloalkyl, —(CH2)n-heterocyclyl, —(CH2)n-aryl, aminoalkyl, alkylamino, alkenyl, alkylcarbonylaminoalkyl, alkylthioalkyl, alkylaminoalkyl, alkoxyalkyl and alkoxy;
• wherein R8 is selected from
• a) heterocyclyl,
• b) aminoalkyl,
• c) aminoalkylamino,
• d) alkylaminoalkylamino,
• e) alkylaminoalkyl,
• f) arylaminoalkyl,
• g) arylalkylaminoalkyl,
• h) heterocyclylalkylaminoalkyl,
• i) aryl,
• j) alkyl,
• k) aralkyl,
• l) heterocyclylalkyl,
• m) cycloalkylalkyl,
• n) —OR9
• o) aminoalkoxy,
• p) N-(heterocyclylalkyl)amino,
• q) aralkyl where the alkyl portion is substituted with amino, hydroxy or alkylamino, and
• r) heterocyclylalkylenyl where the alkylenyl portion is substituted with amino, hydroxy or alkylamino;
• wherein the cycloalkyl and aryl groups are optionally substituted with 1 to 3 groups selected from R4;
• the heterocyclyl groups are optionally substituted with 1 to 3 groups selected from R4 and oxo;
• and the alkyl groups are optionally substituted with 1 to 3 groups selected from R5;
• wherein R9 is selected from H, alkyl, alkenyl, cycloalkyl-(CH2)n—, heterocyclyl-(CH2)n—, aryl-(CH2)n—, aminoalkyl, alkylcarbonylaminoalkyl, cycloalkylaminoalkyl, cycloalkylalkylaminoalkyl, heteroarylaminoalkyl, heteroarylalkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, heteroaryloxyalkyl, heteroarylalkyloxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylaminoalkyl, hydroxyalkyl and alkoxyalkyl;
• wherein Ra are independently selected from H, and alkyl or the two Ra's together form cycloalkyl;
• wherein k is 0 or 1;
• wherein m is 0, 1 or 2;
• wherein n is 0, 1, 2, 3 or 4;
• wherein p is 1 or 2;
• and
• wherein q is 1 or 2;
• provided R6 is not ortho-substituted;
• further provided R6 is not thienyl or 3-indolyl;
• further provided R2 is not unsubstituted 5-membered saturated or partially unsaturated heterocyclyl;
• further provided R is ortho substituted with R4 when n is 0 and when R is —(CH2)n—aryl;
• further provided R is not unsubstituted 2-pyrimidinyl, or benzodioxolylmethyl;
• and further provided R2 is not —(C═O)oxiranyl;
• and a pharmaceutically-acceptable salt thereof.