Aryl piperidine derivatives as inducers of ldl-receptor expression for the treatment of hypercholesterolemia

A compound of formula (I), and physiologically acceptable prodrugs, salts or solvates thereof;

• wherein
• Ar1 is:
• (i) phenyl, naphthyl or phenyl fused by a C3-8cycloalkyl;
• or
• (ii) heterocyclyl selected from the group consisting of:
• monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein indiyldual rings of said radicals may be independently saturated, partially unsaturated or aromatic, provided that at least one ring is aromatic;
• where Ar1 is optionally substituted by 1-4 R1 groups which may be the same or different;
• Ar2 is a phenyl group, a 5-6 membered heteroaromatic group or a bicyclic heteroaromatic group, each of which is optionally substituted by 1-4 groups independently selected from the group consisting of:
• C1-4alkyl, halogen, hydroxy, C1-4alkoxy, C1-6acyl, C1-6acyloxy, amino, C1-4alkylamino, di-C1-4alkylamino, —(CH2)nOH, —(CH2)nNRxRy, —O(CH2)nO(CH2)mORa, —O(CH2)nC(O)NRxRy, —O(CH2)nCN, C2-5alkenyl, —O(CH2)nCO2Ra, —OSO2(CH2)pCH3, —OSO2NRxRy and —CO2(CH2)pCH3;
• Ar3 is:
• (i) phenyl, naphthyl or phenyl fused by a C3-8cycloalkyl;
• or
• (ii) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5-14 ring atoms, wherein said radicals contain a total of from 1-4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, providing that at least one ring is aromatic,
• wherein Ar3 is optionally substituted by 1-4 groups independently selected from the group consisting of:
• hydroxy, C1-4alkyl, C1-4alkoxy, C2-4alkenyl, C2-4alkenyloxy, C1-4perfluoroalkoxy, C1-4alkylsulfonylamino (such as —NHSO2CH3, —NHSO2CH(CH3)2), fluoroC1-4alkylsulfonylamino (such as —NHSO2CH2CF3), C1-4alkylcarbonylamino, fluoroC1-4alkylcarbonylamino, halogen (such as chlorine), nitrile, nitro, C1-4perfluoroalkyl, C1-4alkylcarbonyl, fluoroC1-4alkylcarbonyl, C1-4alkoxycarbonyl, aminocarbonyl, C1-4alkylaminocarbonyl, di-C1-4alkylaminocarbonyl, C1-4alkylsulfonyl, C1-4alkylaminosulfonyl, di-C1-4alkylaminosulfonyl, C1-4alkylsulfonyl and C1-4alkylsulfoxy;
• E is —C1-6alkylene-;
• X is —CONRa — or —NRaCO— (where the left hand side of the linkage is attached to E);
• wherein
• R1 is halogen, C1-4alkoxy or C1-4alkyl;
• Ra is C1-4alkyl or hydrogen;
• Rx and Ry are independently hydrogen, C1-4alkyl, hydroxy or C1-4alkoxy, where Rx and Ry are not both hydroxy or both C1-4alkoxy;
• or Rx and Ry together with the nitrogen to which they are attached form a 5-membered ring which ring is optionally substituted by —O(CH2)nC(O)NRxRy, —O(CH2)nCN, —O(CH2)nO(CH2)mORa, —O(CH2)nCO2Ra, —OSO2NRxRy, —OSO2(CH2)pCH3, —(CH2)nC(O)NRxRy, —(CH2)nCN, —(CH2)nO(CH2)mORa, —(CH2)nCO2Ra, —(CH2)nC(O)Ra, —SO2NRxRy, —SO2(CH2)pCH3, —CH═CHC(O)NRxRy, —CH═CHCN, —CH═CHCO2Ra, —CO2Ra, —C(O)Ra, —C(O)NRxRy and C2-5alkenyl;
• n and m are independently 1-4;
• and
• p is 0-4.