Heterocyclic sulfonamide inhibitors of beta amyloid production

A compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

• wherein:
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, and (CH2)n(1,3)dioxane, where n is 2 to 5;
• R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl(substituted)alkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH(OH)phenyl, CH(OH)substituted phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, N-substituted-piperidinyl, piperidinyl, substituted piperidinyl, tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted phenyl, alkylNHR7, and substituted alkylNHR7;
• with the proviso that R3 and R4 are not both hydrogen;
• R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkylOH, substituted alkylOH, alkylSR8, or substituted alkylSR8;
• R8 is alkyl, substituted alkyl, benzyl, or substituted benzyl;
• or R3 and R4 may be joined to form a ring;
• R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH2cycloalkyl, substituted CH2cycloalkyl, benzyl, substituted benzyl, and CH2CH2QR9;
• Q is O, NH or S;
• R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl;
• R6 is selected from the group consisting of hydrogen, halogen and CF3;
• T is
• W is C, wherein W provides the point of attachment to the SO2 group;
• X is S;
• Y and Z are independently C or CR10 ;
• R10 is selected from the group consisting of hydrogen and halogen;
• provided that when the compound contains one or more chiral centers, at least one of the chiral centers must be of S-stereochemistry.

A compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (1) has the structure:

• wherein:
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, and (CH2)n(1,3)dioxane, where n is 2 to 5;
• R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl(substituted)alkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH(OH)phenyl, CH(OH)substituted phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, N-substituted-piperidinyl, piperidinyl, substituted piperidinyl, tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted phenyl, alkylNHR7, and substituted alkylNHR7;
• with the proviso that R3 and R4 are not both hydrogen;
• R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkylOH substituted alkylOH, alkylSR8, or substituted alkylSR8;
• R8 is alkyl, substituted alkyl, benzyl, or substituted benzyl;
• or R3 and R4 may be joined to form a ring;
• R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH2cycloalkyl, substituted CH2cycloalkyl, benzyl, substituted benzyl, and CH2CH2QR9;
• Q is O, NH or S;
• R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl;
• R6 is halogen;
• T is
• W is C, wherein W provides the point of attachment to the SO2 group;
• X is S;
• Y and Z are independently C or CR10;
• R10 is selected from the group consisting of hydrogen and halogen;
• provided that when the compound contains one or more chiral centers, at least one of the chiral centers must be of S-stereochemistry.

A compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

• wherein:
• R1 and R2 are hydrogen;
• R3 is hydrogen;
• R4 is a lower alkyl of S-stereochemistry;
• R5 is hydrogen;
• R6 is halogen;
• T is
• X is S;
• W, Y and Z are C, wherein W provides the point of attachment to the SO2 group.

A compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

• wherein:
• R1 and R2 are hydrogen;
• R3 is hydrogen;
• R4 is a lower alkyl of S-stereochemistry;
• R5 is hydrogen;
• R6 is hydrogen or halogen;
• T is
• X is O;
• W, Y and Z are C, wherein W provides the point of attachment to the SO2 group.

A compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

• wherein:
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, and (CH2)n(1,3)dioxane, where n is 2 to 5;
• R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl(substituted)alkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH(OH)phenyl, CH(OH)substituted phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, N-substituted-piperidinyl, piperidinyl, substituted piperidinyl, tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted phenyl, alkylNHR7, and substituted alkylNHR7;
• with the proviso that R3 and R4 are not both hydrogen;
• R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkylOH, substituted alkylOH, alkylSR8, or substituted alkylSR8;
• R8 is alkyl, substituted alkyl, benzyl, or substituted benzyl;
• or R3 and R4 may be joined to form a ring;
• R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH2cycloalkyl, substituted CH2cycloalkyl, benzyl, substituted benzyl, and CH2CH2QR9;
• Q is O, NH or S;
• R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl;
• R6 is selected from the group consisting of hydrogen, halogen and CF3;
• T is
• W, Y and Z are independently selected from the group consisting of C, CR10 and N;
• R10 is selected from the group consisting of hydrogen and halogen, with the proviso that at least one of W, Y and Z must be C;
• X is selected from the group consisting of O, S, SO2, and NR11;
• R11 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, and substituted phenyl;
• provided that when the compound contains one or more chiral centers, at least one of the chiral centers must be of S-stereochemistry.

A compound of Formula (I), or pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

• wherein:
• R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, CF3, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, and (CH2)n(1,3)dioxane, where n is 2 to 5;
• R3 is selected from the group consisting of hydrogen, alkyl, and substituted alkyl;
• R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, substituted alkylcycloalkyl, phenyl(substituted)alkyl, alkylOH, substituted alkylOH, alkylOBn, substituted alkylOBn, alkylpyridyl, substituted alkylpyridyl, alkylfuranyl, substituted alkylfuranyl, CH(OH)phenyl, CH(OH)substituted phenyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, N-substituted-piperidinyl, piperidinyl, substituted piperidinyl, tetrahydrothiopyran, substituted tetrahydrothiopyran, 2-indane, substituted 2-indane, phenyl, substituted phenyl, alkylNHR7, and substituted alkylNHR7;
• with the proviso that R3 and R4 are not both hydrogen;
• R7 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, benzyl, substituted benzyl, alkylOH, substituted alkylOH, alkylSR8, or substituted alkylSR8;
• R8 is alkyl, substituted alkyl, benzyl, or substituted benzyl;
• or R3 and R4 may be joined to form a ring;
• R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH2cycloalkyl, benzyl, substituted benzyl, and CH2CH2QR9;
• Q is O, NH or S;
• R9 is lower alkyl, substituted lower alkyl, phenyl, or substituted phenyl;
• R6 is selected from the group consisting of hydrogen, halogen and CF3;
• T is
• W, Y and Z are independently selected from the group consisting of C, CR10 and N;
• R10 is selected from the group consisting of hydrogen and halogen, with the proviso that at least one of W, Y and Z must be C;
• X is selected from the group consisting of O, S, SO2, and NR11;
• R11 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, and substituted phenyl;
• provided that when the compound contains one or more chiral centers, at least one of the chiral centers must be of S-stereochemistry.

A process for resolving a chirally pure N-[(5-chloro-2-thienyl)sulfonyl]-3-ethylnorvaline for use in preparing a chirally pure α-amino acid, comprising the steps of:

• (a) forming a mixture of (+)-ephedrine hemihydrate and N-[(5-chloro-2-thienyl)sulfonyl]-3-ethylnorvaline in ethanol at a molar ratio of 1:1;
• (b) heating to at least 80° C. to dissolve the solids;
• (c) cooling the mixture to allow it to form a precipitate;
• (d) washing the precipitate with ethanol and ethyl acetate to give diastereomeric salt;
• (e) recrystallizing the diastereomeric salt;
• (f) extracting the recrystallized diastereomeric salt to provide an organic extract;
• (g) washing the organic extract, and
• (h) drying and optionally concentrating the organic extract to provide chirally pure N-[(5-chloro-2-thienyl)sulfonyl]-3-ethylnorvaline.

A method for producing chirally pure a-amino acids comprising the steps of:

• (a) reacting an aldehyde and potassium cyanide with an α-methylbenzylamine or hydrochloride salt thereof and filtering to provide product (a);
• (b) reacting sulfuric acid and product (a);
• (c) neutralizing the acid the reaction of (b);
• (d) extracting product (b) from the neutralized acid;
• (e) mixing product (b) in hydrochloric acid to provide a salt of chirally pure α-amino acid;
• and
• (f) neutralizing the salt of chirally pure α-amino acid to provide the chirally pure α-amino acid.