Biaryltetrahydroisoquinoline piperidines as selective MCH receptor antagonists for the treatment of obesity and related disorders

A compound represented by the structural formula:

• 80
• or a pharmaceutically acceptable salt or solvate of said compound, isomer or racemic mixture wherein
• X is —CH2—, —S(O2)—, carbonyl, —CHCH3 or —C(CH3)2—;
• Y is —(CR2R3)P—, —(CR2R3)PC(O)NH—, —(CR2R3)PNH—, —C(O)NH—, —C(O)(CR2R3)PNH—, —C(O)C(O)NH— or —C(O)(CR2R3)P—;
• Z is aryl, heteroaryl, R6-substituted aryl or R6-substituted heteroaryl;
• n is 0, 2 or 3, and when n is 0, no connecting bond exists between the two carbons adjacent to the nitrogen;
• p is 1, 2 or 3;
• q is 1, 2, 3, 4, 5 or 6;
• r is 0 or 1 and when r is 0, X is directly linked to the aromatic ring;
• R1 is hydrogen, -acyl, -alkyl, -cycloalkyl, -alkyl substituted with cycloalkyl, aralkyl, heteroaralkyl, —C(O)R5, —C(O)OR5, —C(O)OR8, —C(O)NR8R9, —S(O2)R5, —S(O2) NR8R9, cycloalkylalkyl, cycloalkylalkyl substituted with R10 on the -cycloalkyl ring, heterocyclyl, aryl, heteroaryl or —CF3;
• R2 and R3 can be the same or different, each being independently hydrogen, alkoxy or alkyl;
• or R2 and R3 can be joined together and with the carbon to which they are attached to form a 3 to 7 membered ring;
• R4 is aryl, heteroaryl, R7-substituted aryl or R7 substituted heteroaryl or Y—R4 taken together is
• 81
• R5 is alkyl, aryl, aralkyl, heteroaryl, cycloalkyl or heteroaralkyl;
• R6 is 1 to 5 substituents, each R6 can be the same or different and each is independently selected from —OH, -alkoxy, —OCF3, —CN, -alkyl, halogen, —NR8R9, —CONR8R9, —NR8S(O2)R6, —S(O2)NR8R9, —S(O2)R5, —COR5, —C(O)OR8, —CF3, —CHO, —C═NOR8,
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• —(CR8R8)qNC(O)R11, —(CR8R8)qNS(O2)R12 and —(CR8R8)qNR8R9 wherein the R8 groups are independently selected;
• R7 is 1 to 5 substituents, each R7 can be the same or different and each is independently selected from hydrogen, —OH, -alkoxy, —OCF3, —CN, -alkyl, halogen, —NR8R9, —CONR8R9, —NR8S(O2)R6, —S(O2)NR8R9, —S(O2)R5, —COR5, —C(O)OR8, —CF3, -alkyleneNR8R9, —CHO, —C═NOR8 and —NR8C(O)R5, or two adjacent R7 groups can be joined together with two O atoms to form a methylene dioxy or ethylene dioxy group, —(CR8R8)qNR8R9, —(CR8R8)qNC(O)R11 and —(CR8R8)qNS(O2)R12, wherein the R8 groups are independently selected;
• R8 is hydrogen or -alkyl;
• R9 is hydrogen, -alkyl, -aryl or -heteroaryl;
• R10 is —OH, -alkoxy, —C(O)NR8R9, —NR8R9, —NR8S(O2)R5, —NR8C(O)NR8R9, —NR8C(O)R5, —NR8C(O)OR5, —C(O)OH or —C(O)OR5;
• R11 is alkyl, aryl, alkoxy or —NR8R9;
• and
• R12 is alkyl, aryl or —NR8R9.