Tetrahydropyranochromene gamma secretase inhibitors

The compound of claim 105 wherein

• the compound of formula (I) is selected from the group consisting of the compounds of formulas (Iv), (Ivi), (Ivii), (I.A1f), (I.A1h), (I.A2f), (I.A2 g), and (I.A2h), and
• n is 2, and
• the L1 groups are bound to the phenyl moiety as shown in (IIA)
• and Ar is selected from the group consisting of p-Cl-phenyl-, p-CN-phenyl-, p-CF3-phenyl, p-CH3CH2SO7phenyl, p-Br-phenyl, m,p-di-F-phenyl, m,p-di-CN-phenyl, p-CH3O-phenyl, p-CF3CH2Ophenyl pyridyl, and pyridyl substituted with 1 or 2 substituents independently selected from the group consisting of:
• halogen, alkyl, —CN, —CF3, —O—(C1-C5)alkyl, —O-(halo(C1-C6)alkyl), —C(O)—O—(C1-C6)alkyl, -alkylene-OH, halo(C1-C6), hydroxyalkoxy-, and alkoxyalkoxy-, and
• said L1 groups are F

A process for preparing a compound of the formula:

• said process comprising reacting:
• (1) a mixture comprising:
• (a) a compound of the formula:
• and
• (b) a compound of the formula:
• and
• (c) a suitable organic solvent;
• with
• (2) either:
• (a) a basic amine, and a compound of the formula
• or
• (b) a basic amine, and a compound of the formula
• wherein:
• R1A and R2A are each independently selected from the group consisting of:
• H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroalkyl, substituted aryl, and substituted heteroaryl;
• wherein said substituted groups are substituted with one or more substituents each independently selected from the group consisting of:
• —NO2, —NO, —SO2R7B, —SO2-aryl, —SO2-heteroaryl, —SO2OR7B, —CN, —COOH, halo, —CF3, —Oaryl, —Oheteroaryl, —COOR7B, —CONH2, —CONHR7B, CON(R7B)2, —CHO, —OR7B, —COR7B, —SH, —SR7B, —OH, aryl, and heteroaryl;
• R3A and R4A are each independently selected from the group consisting of:
• —NO2, —NO, —SO2R7B, —SO2-aryl, —SO2-heteroaryl, —SO2OR7B, —ON, —COOH, halo, —CF3, —Oaryl, —Oheteroaryl, —COOR7B, —CONH2, —CONHR7B, CON(R7B)2, —CHO, —OR7B, —COR7B, —SH, —SR78, —OH, aryl, and heteroaryl;
• R5A is selected from the group consisting of:
• H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroalkyl, aryl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroalkyl, substituted aryl, and substituted heteroaryl;
• and wherein:
• said substituted alkyl groups are substituted with one or more substituents each independently selected from the group consisting of:
• halo, —NO2, —CN, and —OR12A;
• and
• said substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted heteroalkyl, substituted aryl, and substituted heteroaryl groups are substituted with one or more substituents each independently selected from the group consisting of:
• halo, —NO2, —CN, and —OR'2A, alkyl and halo substituted alkyl (e.g., F substituted alkyl, such as, for example, —CF3);
• R6A is selected from the group consisting of:
• halo, and —OSO2R5A;
• R7A is selected from the group consisting of:
• unsubstituted aryl, aryl substituted with at least one electron withdrawing group, heteroaryl, and heteroaryl substituted with at least one electron withdrawing group;
• Each R7B is independently selected from the group consisting of:
• alkyl, cycloalkyl and heteroalkyl;
• R8A is selected from the group consisting of:
• halo, and —OC(O)R7A;
• R12A is alkyl;
• and
• R13A is selected from the the group consisting of:
• alkyl, alkoxyalkyl, hydroxyalkyl, alkanoyl, aryl, heteroaryl, aroyl, and carbamoyl, and preferably alkyl.

A process for preparing a compound of the formula:

• said process comprising reacting:
• (1) a mixture comprising:
• (a) 2,3,5-triflorobenzaldehyde, and
• (b) CH2(C(O)OCH3)2;
• and
• (c) anhydrous dichloromethane;
• with
• (2)
• wherein:
• said process is carried out at a temperature within the range of about −40° C. to about 40° C.:
• the molar ratio of 2,3,5-triflorobenzaldehyde to CH2(C(O)OCH3)2 is about 1:0.8 to about 1:1.2, and preferably 1:1;
• the molar ratio of 2,3,5-triflorobenzaldehyde to mesyl chloride is about 1:1 to about 1:4, and preferably 1:1;
• and
• the molar ratio of mesyl chloride to TEA is about 1:2 to about 1:3, and preferably about 1:2.

A processes for preparing a compound of the formula:

• said process comprising reacting:
• (1) a mixture comprising:
• (a) 4-nitrobenzaldehyde, and
• (b) CH2(C(O)OCH3)2:
• and
• (c) anhydrous dichloromethane;
• with
• (2)
• wherein:
• said process is carried out at a temperature within the range of about −40° C. to about 40° C.;
• the molar ratio of 4-nitrobenzaldehyde to Cl-12(C(O)OCH3)2 is about 1:0.8 to about 1:1.2:
• the molar ratio of 4-nitrobenzaldehyde to mesyl chloride is about 1:1 to about 1:4;
• and
• the molar ratio of mesyl chloride to TEA is about 1:2 to about 1:3,

A process for preparing a compound of the formula:

• said process comprising reacting:
• (1) a mixture comprising:
• (a) 4-chlorobenzaldehyde, and
• (b) CH2(C(O)OCH3)2;
• and
• (c) dichloromethane (preferably anhydrous);
• with
• (2)
• wherein:
• said process is carried out at a temperature within the range of about −40° C. to about 40° C.;
• the molar ratio of 4-chlorobenzaldehyde to CH2(C(O)OCH3)2 is about 1:0.8 to about 1:1.2;
• the molar ratio of 4-chlorobenzaldehyde to mesyl chloride is about 1:1 to about 1:4;
• and
• the molar ratio of mesyl chloride to TEA is about 1:2 to about 1:3.

A process for preparing a compound of the formula:

• said process comprising reacting:
• (1) a mixture comprising:
• (a) benzaldehyde, and
• (b) CH2(C(O)OCH3)2;
• and
• (c) dichloromethane (preferably anhydrous);
• with
• (2)
• wherein:
• said process is carried out at a temperature within the range of about −40° C. to about 40° C.;
• the molar ratio of benzaldehyde to CH2(C(O)OCH3)2 is about 1:0.8 to about 1:1.2;
• the molar ratio of benzaldehyde to mesyl chloride is about 1:1 to about 1:4;
• and the molar ratio of mesyl chloride to TEA is about 1:2 to about 1:3.