Indolylalkylpyridin-2-amines for the inhibition of beta-secretase

A method for the treatment of a disease or disorder associated with excessive BACE activity in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I

• wherein
• R1 and R2 are each independently H, halogen, CN, OR6, CO2R7, COR8, NR11R12 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R3 is H, halogen or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R4 is H, halogen, NR13R14, OR15 or a C1-C6alkyl or aryl group each group optionally substituted;
• R5 is H or an optionally substituted C1-C6alkyl group;
• R6 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R7, R8 and R15 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• and
• R11, R12, R13 and R14 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted or R11R12 or R13R14 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
• or
• 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
• R1 and R2 are each independently H, halogen, CN, OR6, CO2R7, COR8, NR11R12 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R3 is H, halogen or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R4 is H, halogen, NR13R14, OR15 or a C1-C6alkyl or aryl group each group optionally substituted;
• R5 is H or an optionally substituted C1-C6alkyl group;
• R6 is a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R7, R8 and R15 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• and
• R11, R12, R13 and R14 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted or R11R12 or R13R14 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
• or
• a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

A method for the preparation of a compound of formula Ia

• wherein
• R1 and R2 are each independently H, halogen, CN, OR6, CO2R7, COR8, NR11R12 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R3 is H, halogen or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R4 is H, halogen, NR13R14, OR15 or a C1-C6alkyl or aryl group each group optionally substituted;
• R5 is H or an optionally substituted C1-C6alkyl group;
• R6 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• R7, R8 and R15 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted;
• and
• R11, R12, R13 and R14 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloheteroalkyl, aryl or heteroaryl group each group optionally substituted or R11R12 or R13R14 may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S
• which process comprises:
• reacting a compound of formula II
• wherein R1, R2 and R3 are as described hereinabove with a compound of formula III
• wherein R4 is as described hereinabove;
• Hal is Cl, Br or I;
• and P is a protecting group in the presence of a base optionally in the presence of a solvent to give the protected indolylalkylpyridin-2-amine intermediate;
• and reacting said intermediate with an acid to give the desired compound of formula Ia.