2,6-Disubstituted piperiddines as modulators

A compound of Formula I:

• wherein:
• X is C, N, O, S or SO2;
• Y is N or C;
• R1 is selected from:
• hydrogen, —SO2R14, —C0-3alkyl-S(O)R14, —SO2NR12R12, —C1-6alkyl, —C0-6alkyl-O—C1-6alkyl, —C0-6alkyl-S—C1-6alkyl, —(C0-6alkyl)-(C3-7cycloalkyl)-(C0-6alkyl), hydroxy, heterocycle, —CN, —NR12R12, —NR12COR13, —NR12SO2R14, —COR11, —CONR12R12, and phenyl,
• where said alkyl and said cycloalkyl are unsubstituted or substituted with 1-7 substituents independently selected from:
• halo, hydroxy, —O—C1-3alkyl, trifluoromethyl, C1-3alkyl, —O—C1-3alkyl, —COR11, —SO2R14, —NHCOCH3, —NHSO2CH3, -heterocycle, ═O, and —CN,
• where said phenyl and said heterocycle are unsubstituted or substituted with 1-3 substituents independently selected from:
• halo, hydroxy, C1-3alkyl, C1-3alkoxy and trifluoromethyl;
• R2 is selected from:
• hydrogen, C1-3alkyl unsubstituted or substituted with 1-3 fluoro, —O—C1-3alkyl unsubstituted or substituted with 1-3 fluoro, hydroxy, chloro, fluoro, bromo, phenyl and heterocycle;
• R3 is selected from:
• hydrogen, hydroxy, halo, C1-3alkyl unsubstituted or substituted with 1-6 substituents independently selected from fluoro, hydroxy, and —COR11, —NR12R12, —COR11, —CONR12R12, —NR12COR13, —OCONR12R12, —NR12CONR12R12, -heterocycle, —CN, —NR12—SO2—NR12R12, —NR12—SO2—R14, —SO2—NR12R12 and nitro, when Y is C;
• or
• R3 is oxygen or is absent, when Y is N;
• R4 is selected from:
• hydrogen, C1-6alkyl, trifluoromethyl, trifluoromethoxy, chloro, fluoro, bromo, and phenyl;
• R5 is selected from:
• C1-6alkyl unsubstituted or substituted with one or more substituents selected from 1-6 fluoro and hydroxyl, —O—C1-6alkyl unsubstituted or substituted with 1-6 fluoro, —CO—C1-6alkyl unsubstituted or substituted with 1-6 fluoro, —S—C1-6alkyl unsubstituted or substituted with 1-6 fluoro, -pyridyl unsubstituted or substituted with one or more substituents selected from halo, trifluoromethyl, C1-4alkyl and COR11, fluoro, chloro, bromo, —C4-6cycloalkyl, —O—C4-6cycloalkyl, phenyl unsubstituted or substituted with one or more substituents selected from halo, trifluoromethyl, C1-4alkyl and COR11, —O-phenyl unsubstituted or substituted with one or more substituents selected from halo, trifluoromethyl, C1-4alkyl and COR11, —C3-6cycloalkyl unsubstituted or substituted with 1-6 fluoro, —O—C3-6cycloalkyl unsubstituted or substituted with 1-6 fluoro, -heterocycle, —CN and —COR11;
• R6 is selected from:
• hydrogen, C1-6alkyl, trifluoromethyl, fluoro, chloro and bromo;
• R7 is nothing when X is —O—, —S—, or —SO2—;
• R7 is selected from:
• hydrogen, (C0-6alkyl)-phenyl, (C0-6alkyl)-heterocycle, (C0-6alkyl)-C3-7cycloalkyl, (C0-6alkyl)-COR11, (C0-6alkyl)-(alkene)-COR11, (C0-6alkyl)-SO3H, (C0-6alkyl)-W-C0-4alkyl, (C0-6alkyl)-CONR12-phenyl and (C0-6alkyl)-CONR15-V-COR11, when X is C or N,
• where V is selected from C1-6alkyl and phenyl,
• where W is selected from:
• a single bond, —O—, —S—, —SO—, —SO2—, —CO—, —CO2—, —CONR12— and —NR12—,
• where said C0-6alkyl is unsubstituted or substituted with 1-5 substituents independently selected from:
• halo, hydroxy, —C0-6alkyl, —O—C1-3alkyl, trifluoromethyl and —C0-2alkyl-phenyl,
• where said alkene is unsubstituted or substituted with 1-3 substituents independently selected from:
• halo, trifluoromethyl, C1-3alkyl, phenyl and heterocycle;
• where said phenyl, heterocycle, cycloalkyl and C0-4alkyl are independently unsubstituted or substituted with 1-5 substituents independently selected from:
• halo, trifluoromethyl, hydroxy, C1-6alkyl, —O—C1-3alkyl, —C0-3—COR11, —CN, —NR12R12, —CONR12R12 and —C0-3-heterocycle,
• or where said phenyl and heterocycle are fused to another heterocycle, which itself may be unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, —COR11, and —C1-4alkyl;
• R8 is selected from:
• hydrogen, hydroxy, C1-6alkyl, C1-6alkyl-hydroxy, —O—C1-3alkyl, —COR11, —CONR12R12 and —CN, when X is C, or;
• R8 is nothing when X is O, S, SO2 or N, or when a double bond joins the carbons to which R7 and R10 are attached;
• or R7 and R8 are joined together to form a ring which is selected from:
• 1H-indene, 2,3-dihydro-1H-indene, 2,3-dihydro-benzofuran, 1,3-dihydro-isobenzofuran, 2,3-dihydro-benzothiofuran, 1,3-dihydro-isobenzothiofuran, 6H-cyclopenta[d]isoxazol-3-ol, cyclopentane and cyclohexane,
• where said ring is unsubstituted or substituted with 1-5 substituents independently selected from:
• halo, trifluoromethyl, hydroxy, C1-3alkyl, —O—C1-3alkyl, —C0-3—COR11, —CN, —NR12R12, —CONR12R12 and —C0-3-heterocycle;
• R9 and R10 are independently selected from:
• hydrogen, hydroxy, C1-6alkyl, C1-6alkyl-COR11, C1-6alkyl-hydroxy, —O—C1-3alkyl, ═O when R9 or R10 is connected to the ring via a double bond and halo;
• or R7 and R9, or R8 and R10, are joined together to form a ring which is phenyl or heterocycle,
• where said ring is unsubstituted or substituted with 1-7 substituents independently selected from:
• halo, trifluoromethyl, hydroxy, C1-3alkyl, —O—C1-3alkyl, —COR11, —CN, —NR12R12 and —CONR12R12;
• R11 is independently selected from:
• hydroxy, hydrogen, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl, C3-6 cycloalkyl,
• where said alkyl, phenyl, benzyl or cycloalkyl group is unsubstituted or substituted with 1-3 substituents independently selected from:
• halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl;
• R12 is selected from:
• hydrogen, C1-6 alkyl, benzyl, phenyl and C3-6 cycloalkyl,
• where said alkyl, phenyl, benzyl or cycloalkyl group is unsubstituted or substituted with 1-3 substituents independently selected from:
• halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl and trifluoromethyl;
• R13 is selected from:
• hydrogen, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl and C3-6 cycloalkyl,
• where said alkyl, phenyl, benzyl or cycloalkyl group is unsubstituted or substituted with 1-3 substituents independently selected from:
• halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl, and trifluoromethyl;
• R14 is selected from:
• hydroxy, C1-6 alkyl, —O—C1-6alkyl, benzyl, phenyl and C3-6 cycloalkyl,
• where said alkyl, phenyl, benzyl or cycloalkyl group is unsubstituted or substituted with 1-3 substituents independently selected from:
• halo, hydroxy, C1-3alkyl, C1-3alkoxy, —CO2H, —CO2—C1-6 alkyl and trifluoromethyl;
• R15 is hydrogen or C1-4alkyl, or R15 is joined via a 1-5 carbon tether to one of the carbons of V to form a ring;
• R17, R19, R20 and R21 are independently selected from:
• hydrogen, hydroxy, C1-6alkyl, C1-6alkyl-COR11, C1-6alkyl-hydroxy, —O—C1-3alkyl, trifluoromethyl and halo;
• R16 and R18 are independently selected from:
• hydroxy, C1-6alkyl, C1-6alkyl-COR11, C1-6alkyl-hydroxy, —O—C1-3alkyl and halo,
• where said alkyl is unsubstituted or substituted with 1-6 substituents independently selected from fluoro and hydroxyl;
• or R16 and R18 together form a bridge consisting of —C1-4alkyl-, —C0-2alkyl-O—C1-3alkyl- or —C1-3alkyl-O—C0-2alkyl-, where said alkyl is unsubstituted or substituted with 1-2 substituents independently selected from:
• oxy where the oxygen is joined to said bridge via a double bond, fluoro, hydroxy, methoxy, methyl and trifluoromethyl;
• R22 selected from:
• hydrogen, phenyl, C1-6alkyl which is substituted or unsubstituted with 1-6 substituents selected from:
• —COR11, hydroxy, fluoro, chloro and —O—C1-3alkyl;
• or R2 and R22 together are a linker, forming a heterocycle ring, said linker selected from (with the left side of the linker being bonded to the amide nitrogen at R22):
• —CH2(CR23R23)1-3—, —CH2—NR24—, —NR12—CR23R23—, —CH2O—, —CH2SO2—, —CH2SO—, —CH2S—, —CR23R23—;
• R23 is independently selected from:
• hydrogen, C1-3alkyl unsubstituted or substituted with 1-6 substituents independently selected from fluoro and hydroxy, COR13, SO2R14, SO2NR12R12, hydroxy, halo, —NR12R12, —COR11, —CONR12R12, —NR12COR13, —OCONR12R12, —NR12CONR12R12, heterocycle, —CN, —NR12—SO2—NR12R12, —NR12—SO2—R14, and —SO2—NR12R12;
• or one R23 is ═O and the other R23 is absent;
• where R24 is selected from:
• hydrogen, C1-3alkyl where said alkyl is unsubstituted or substituted with 1-6 substituents independently selected from fluoro and hydroxy, COR13, SO2R14 and SO2NR12R12;
• n is selected from 0, 1 and 2;
• the dashed line represents an optional bond;
• and pharmaceutically acceptable salts thereof and individual diastereomers thereof.