Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds

A method for preventing the onset of Alzheimer's disease in a human patient at risk for developing Alzheimer's disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:

• 56
• wherein:
• W is a cyclic group selected from the group consisting of:
• 57 58
• wherein
• ring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring C, together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring;
• Y is represented by the formula:
• 59
• R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
• R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy;
• Q is oxygen, sulfur, —S(O)—, —S(O)2—, —C(O)— or —C(S)—;
• Z is represented by the formula -T-CX′X″V—, wherein T is selected from the group consisting of a bond covalently linking R1 to —CX′X″—, oxygen, sulfur and —NR6, wherein R6 is hydrogen, acyl, alkyl, aryl or heteroaryl,
• X′ is hydrogen, hydroxy or fluoro,
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• V is selected from the group consisting of alkylene or substituted alkylene,
• or R1 and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic;
• X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkenyl, heteroaryl and heterocyclic;
• or X and one of R4 and the atoms to which they are attached form a double bond;
• t is an integer from 0 to 2;
• f is an integer from 0 to 2;
• n is an integer equal to 1 or 2;
• and pharmaceutically acceptable salts thereof provided that neither of X′ and X″ can be hydroxy or fluoro when T is other than a covalent bond linking R1 to —CX′X″—.

A method for treating a human patient with Alzheimer's disease in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I:

• 60
• wherein:
• W is a cyclic group selected from the group consisting of:
• 61 62
• wherein
• ring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring C, together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring;
• Y is represented by the formula:
• 63
• R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
• R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy;
• Q is oxygen, sulfur, —S(O)—, —S(O)2—, —C(O)— or —C(S)—;
• Z is represented by the formula -T-CX′X″V—, wherein T is selected from the group consisting of a bond covalently linking R1 to —CX′X″—, oxygen, sulfur and —NR6—, wherein R6 is hydrogen, acyl, alkyl, aryl or heteroaryl,
• X′ is hydrogen, hydroxy or fluoro,
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• V is selected from the group consisting of alkylene or substituted alkylene,
• or R1 and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic;
• X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkenyl, heteroaryl and heterocyclic;
• or X and one of R4 and the atoms to which they are attached form a double bond;
• t is an integer from 0 to 2;
• f is an integer from 0 to 2;
• n is an integer equal to 1 or 2;
• and pharmaceutically acceptable salts thereof provided that neither of X′ and X″ can be hydroxy or fluoro when T is other than a covalent bond linking R1 to —CX′X″—.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I:

• 64
• wherein:
• W is a cyclic group selected from the group consisting of:
• 65 66
• wherein
• ring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring C, together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring;
• Y is represented by the formula:
• 67
• R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
• R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy;
• Q is oxygen, sulfur, —S(O)—, —S(O)2—, —C(O)— or —C(S)—;
• Z is represented by the formula -T-CX′X″V—, wherein T is selected from the group consisting of a bond covalently linking R1 to —CX′X″—, oxygen, sulfur and —NR6—, wherein R6 is hydrogen, acyl, alkyl, aryl or heteroaryl,
• X′ is hydrogen, hydroxy or fluoro,
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• V is selected from the group consisting of alkylene or substituted alkylene,
• or R1 and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic;
• X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkenyl, heteroaryl and heterocyclic;
• or X and one of R4 and the atoms to which they are attached form a double bond;
• t is an integer from 0 to 2;
• f is an integer from 0 to 2;
• n is an integer equal to 1 or 2;
• and pharmaceutically acceptable salts thereof provided that neither of X′ and X″ can be hydroxy or fluoro when T is other than a covalent bond linking R1 to —CX′X″—.

A compound of formula I:

• 68
• wherein:
• W is a cyclic group selected from the group consisting of:
• 69 70
• wherein
• ring A, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring B, together with the atoms to which it is attached, forms a carbocyclic or heterocyclic ring selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• ring C, together with the atoms to which it is attached, forms a heteroaryl or heterocyclic ring;
• Y is represented by the formula:
• 71
• R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
• R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• each R4 is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl and heterocyclic;
• R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, aryl, aryloxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted amino, heteroaryl, heterocyclic, thioalkoxy and substituted thioalkoxy;
• Q is oxygen, sulfur, —S(O)—, —S(O)2—, —C(O)— or —C(S)—;
• Z is represented by the formula -T-CX′X″V—, wherein T is selected from the group consisting of a bond covalently linking R1 to —CX′X″—, oxygen, sulfur and —NR6—, wherein R6 is hydrogen, acyl, alkyl, aryl or heteroaryl,
• X′ is hydrogen, hydroxy or fluoro,
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• V is selected from the group consisting of alkylene or substituted alkylene,
• or R1 and Z together form an aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic;
• X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkenyl, heteroaryl and heterocyclic;
• or X and one of R4 and the atoms to which they are attached form a double bond;
• t is an integer from 0 to 2;
• f is an integer from 0 to 2;
• n is an integer equal to 1 or 2;
• and pharmaceutically acceptable salts thereof provided that neither of X′ and X″ can be hydroxy or fluoro when T is other than a covalent bond linking R1 to —CX′X″—.