3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

A compound of structural formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein
• each n is independently 0, 1, or 2;
• X, Y and Z are independently selected from the group consisting of:
• (1) CR1,
• (2) NR2,
• (3) N,
• (4) O, and
• (5) S;
• with the provisos that at least one of X, Y and Z is not CR1 and two of X, Y, and Z cannot be O and/or S;
• Ar is phenyl substituted with one to five R3 substituents;
• each R1 is independently selected from the group consisting of
• hydrogen,
• halogen,
• hydroxy,
• cyano,
• C1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
• C1-10 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
• C1-10 alkylthio, wherein alkylthio is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
• C2-10 alkenyl, wherein alkenyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, COOH, and COOC1-6 alkyl,
• (CH2)nCOOH,
• (CH2)nCOOC1-6 alkyl,
• (CH2)nCONR4R5, wherein R4 and R5 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CH2)n-phenyl, (CH2)n—C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
• or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
• (CH2)n—NR4R5,
• (CH2)n—OCONR4R5,
• (CH2)n—SO2NR4R5,
• (CH2)n—SO2R6,
• (CH2)n—NR7SO2R6,
• (CH2)n—NR7CONR4R5,
• (CH2)n—NR7COR7,
• (CH2)n—NR7CO2R6,
• (CH2)n—COR7,
• (CH2)n—C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• (CH2)n-aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano, hydroxy, NR7SO2R6, SO2R6, CO2H, COOC1-6 alkyl, C1-6 alkyl, and
• C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• (CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and
• (CH2)n-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• wherein any methylene (CH2) carbon atom in R1 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl unsubstituted or substituted with one to five halogens;
• each R2 is independently selected from the group consisting of
• hydrogen,
• C1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
• C2-10 alkenyl, wherein alkenyl is unsubstituted or substituted with one to five substituents independently selected from halogen or hydroxy,
• (CH2)nCOOH,
• (CH2)nCOOC1-6 alkyl,
• (CH2)nCONR4R5, wherein R4 and R5 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CH2)n-phenyl, (CH2)n—C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
• or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, (CH2)nCOOC1-6 alkyl, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens or one phenyl;
• (CH2)n—COR7,
• (CH2)n—SO2NR4R5,
• (CH2)n—SO2R6,
• (CH2)n—C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• (CH2)n-aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, cyano, hydroxy, NR7SO2R6, SO2R6, CO2H, C1-6 alkyloxycarbonyl, C1-6 alkyl, and
• C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• (CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and
• (CH2)n-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• wherein any methylene (CH2) carbon atom in R2 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl unsubstituted or substituted with one to five halogens;
• each R3 is independently selected from the group consisting of
• hydrogen,
• halogen,
• cyano,
• hydroxy,
• C1-6 alkyl, unsubstituted or substituted with one to five halogens, and
• C1-6 alkoxy, unsubstituted or substituted with one to five halogens;
• R6 is independently selected from the group consisting of tetrazolyl, thiazolyl, (CH2)n-phenyl, (CH2)n-C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and wherein any methylene (CH2) carbon atom in R6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, C1-4 alkyl, and C1-4 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
• each R7 is hydrogen or R6;
• R8, R9 and R10 are each independently selected from the group consisting of
• hydrogen,
• cyano,
• (CH2)nCOOH,
• (CH2)nCOOC1-6 alkyl,
• C1-6 alkyloxycarbonyl,
• C1-10 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkoxy, and phenyl-C1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens,
• (CH2)n-aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• (CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• (CH2)n-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens,
• (CH2)n—C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and
• (CH2)nCONR4R5, wherein R4 and R5 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CH2)n-phenyl, (CH2)n—C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens;
• or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, (CH2)nCOOC1-6 alkyl, C1-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens or one phenyl;
• and
• wherein any methylene (CH2) carbon atom in R8, R9 or R10 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl unsubstituted or substituted with one to five halogens.