Imidazole Amines As Inhibitors Of Beta-secretase

A method for the treatment, prevention or amelioration of a disease or disorder characterized by elevated [3-amyloid deposits or [3-amyloid levels in a patient which comprises providing said patient with a therapeutically effective amount of a compound of formula I

• wherein
• Q is O, S or CH2;
• W is O, S or CH2;
• X is N, NO, SOm, O or CH;
• Y is N, NO, SOm, O or CR10;
• Z is N, NO, SOm, O or CR11 with the proviso that when X is CH, Y is CR10 and Z is CR11 then one of Q or W must be O or S;
• m is 0, 1 or 2;
• n is 0 or 1;
• R1 and R2 are each independently H or an optionally substituted C1-C4alkyl group;
• R3 and R4 are each independently H, or an optionally substituted C1-C4 alkyl group or R3 and R4 may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R5 and R6 are each independently H, halogen, NO2, CN, OR12, CO2R13, COR14, NR17R18, SOpNR19R20 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C8cycloalkyl group each optionally substituted;
• R7 and R8 are each independently H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R7 and R8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R9 is H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R10 and R11 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
• R12, R13, R14 and R15 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R17, R18, R19 and R20 are each independently H, C1-C4alkyl, C3-C8cycloalkyl or R17 and R18 or R19 and R20 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
• and
• p is 0, 1 or 2;
• or
• a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I

• wherein
• Q is O, S or CH2;
• W is O, S or CH2;
• X is N, NO, SOm, O or CH;
• Y is N, NO, SOm, O or CR10;
• Z is N, NO, SOm, O or CR11 with the proviso that when X is CH, Y is CR10 and Z is CR11 then one of Q or W must be O or S;
• m is 0, 1 or 2;
• n is 0 or 1;
• R1 and R2 are each independently H or an optionally substituted C1-C4alkyl group;
• R3 and R4 are each independently H, or an optionally substituted C1-C4 alkyl group or R3 and R4 may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R5 and R6 are each independently H, halogen, NO2, CN, OR12, CO2R13, COR14, NR17R18, SOpNR19R20 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C8cycloalkyl group each optionally substituted;
• R7 and R8 are each independently H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R7 and R8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R9 is H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R10 and R11 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
• R12, R13, R14 and R15 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R17, R18, R19 and R20 are each independently H, C1-C4alkyl, C3-C8cycloalkyl or R17 and R18 or R19 and R20 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
• and
• p is 0, 1 or 2;
• or
• a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

A process for the preparation of a compound of formula Ia

• wherein
• Q is O, S or CH2;
• W is O, S or CH2;
• X is N, NO, SOm, O or CH;
• Y is N, NO, SOm, O or CR10;
• Z is N, NO, SOm, O or CR11 with the proviso that when X is CH, Y is CR10 and Z is CR11 then one of Q or W must be O or S;
• m is 0, 1 or 2;
• n is 0 or 1;
• R1 and R2 are each independently H or an optionally substituted C1-C4alkyl group;
• R3 and R4 are each independently H, or an optionally substituted C1-C4 alkyl group or R3 and R4 may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R5 and R6 are each independently H, halogen, NO2, CN, OR12, CO2R13, COR14, NR17R18, SOpNR19R20 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl or C3-C8cycloalkyl group each optionally substituted;
• R7 and R8 are each independently H, halogen, NO2, CN, OR15, NR17R18 or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, 02-06alkynyl, C3-C8cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R7 and R8 may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S;
• R9 is an optionally substituted aryl or heteroaryl group;
• R10 and R11 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted;
• R12, R13, R14 and R15 are each independently H or a C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R17, R18, R19 and R20 are each independently H, C1-C4alkyl, C3-C8cycloalkyl or R17 and R18 or R19 and R20 may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
• and
• p is 0, 1 or 2
• which process comprises reacting a compound of formula II
• wherein Hal is Cl or Br and R1, R2, R3, R4, R5, R6, R7, R8, n, O, W, X, Y and Z are as described for formula la hereinabove with an optionally substituted aryl or heteroaryl group having a leaving group selected from B(OH)2, Sn(nBu)3 or Sn(CH3)3 in the presence of a palladium catalyst optionally in the presence of a solvent.