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US 8,785,634 B2Granted
Spiropiperidine prolylcarboxypeptidase inhibitors
AssigneeMerck Sharp & Dohme Corp.
InventorsFa-Xiang Ding, JinLong Jiang, Dong-Ming Shen, Hong Shen, Zhi-Cai Shi
Life of this patent
Estimating the term…
Abstract
Compounds of structural formula (I) are inhibitors of prolylcarboxypeptidase (PrCP). The compounds of the present invention are useful for the prevention and treatment of conditions related to enzymatic activity of PrCP such as abnormal metabolism, including obesity; diabetes; metabolic syndrome; obesity related disorders; and diabetes related disorders.
Claims15
A compound of structural formula I:
- or a pharmaceutically acceptable salt thereof;
- wherein
- T, U, V and W are C or CH;
- each X is independently selected from the group consisting of:
- (1) —CH2—,
- (2) —CH2CH2—,
- (3) —SO2—,
- (4) —C(O)—, and
- (5) —C(O)CH2—,
- wherein each CH2 is unsubstituted or substituted with one or two substituents selected from Ra;
- each R1 is independently selected from the group consisting of:
- pyrrolidine, azabicyclo[2.2.1]heptane, pyridine, pyrazine, pyridazine, pyrimidine, thiophene, benzodioxole, naphthalene, benzofuran, oxazole, thiazole, triazole, benzisoxazole, and imidazopyrimidine, wherein each, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rb:
- each R2 is independently selected from the group consisting of:
- (1) hydrogen,
- (2) —C1-6 alkyl,
- (3) —C1-6 alkoxy,
- (4) halogen,
- (5) oxo, and
- (6) —OH;
- each R3 is independently selected from the group consisting of:
- (1) —(CH2)m—C3-7cycloalkyl,
- (2) —(CH2)m—C3-7cycloalkenyl,
- (3) —(CH2)m—C2-6cycloheteroalkyl,
- (4) —(CH2)m—C3-7cycloheteroalkenyl,
- (5) —(CH2)m-aryl, and
- (6) —(CH2)m-heteroaryl,
- wherein each CH2, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with one, two or three groups independently selected from Rc;
- each R4 is independently selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —CN,
- (4) —CF3,
- (5) —OCF3,
- (6) —OH,
- (7) —OC1-6 alkyl, and
- (8) —C1-6 alkyl,
- wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of:
- —OH, halogen, —C1-6 alkyl, —CN, —OC1-6 alkyl, —CO2H, and —CO2C1-6 alkyl;
- each Ra is independently selected from the group consisting of:
- (1) —C1-6 alkyl,
- (2) —(CH2)nCO2H,
- (3) —(CH2)nCO2C1-6 alkyl,
- (4) —(CH2)n—OH,
- (5) oxo,
- (6) —(CH2)n—O—C1-6 alkyl,
- (7) —(CH2)n—N(Rd)2, and
- (8) —(CH2)n—S—C1-6 alkyl,
- wherein each CH2, and alkyl is unsubstituted or substituted with one or two groups independently selected from:
- —OH, —C1-6 alkyl, halogen, —CN, —OC1-6 alkyl, —CO2H, and —CO2C1-6 alkyl;
- each Rb is independently selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —CF3,
- (4) —OCF3,
- (5) —OC1-6 alkyl, and
- (6) —C1-6 alkyl,
- wherein each alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of:
- —OH, —C1-6 alkyl, halogen, —CN, and —CO2C1-6 alkyl;
- each Rc is independently selected from the group consisting of:
- (1) hydrogen,
- (2) halogen,
- (3) —C1-6 alkyl,
- (4) —CN,
- (5) oxo,
- (6) —OH,
- (7) —OC1-6 alkyl,
- (8) —CF3, and
- (9) —OCF3,
- wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of:
- —OH, —C1-6 alkyl, halogen, —CN, —OC1-6 alkyl, —CO2H, and —CO2C1-6 alkyl;
- each Rd is independently selected from the group consisting of:
- (1) hydrogen, and
- (2) —C1-6 alkyl;
- m is selected from 0, 1, 2, 3 and 4;
- n is selected from 0, 1, 2, 3 and 4;
- q is selected from 0, 1, 2, 3 and 4;
- r is selected from 0, 1, 2, and 3;
- and
- s is selected from 0, 1, 2 and 3.
76 more elements
A compound selected from the group consisting of:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.