# US 8,785,634 B2 · Spiropiperidine prolylcarboxypeptidase inhibitors

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- Number: US 8,785,634 B2
- Document ID: US8785634B2
- Status: Granted
- Kind: B2
- Application number: 13/638,976
- Filed: 2011-04-21
- Published: 2013-01-24
- Granted: 2014-07-22
- Earliest claimed: 2010-04-26
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Fa-Xiang Ding; JinLong Jiang; Dong-Ming Shen; Hong Shen; Zhi-Cai Shi
- Inventors: Fa-Xiang Ding; JinLong Jiang; Dong-Ming Shen; Hong Shen; Zhi-Cai Shi
- Web page: https://patentgrep.com/patent/US8785634B2

## CPC

- C07D 491/20: Spiro-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07D 491/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1 wherein each R3 is independently selected from the group consisting of:
(1) -aryl, and
(2) -heteroaryl,
wherein each aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rc; or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2 wherein each R3 is independently selected from the group consisting of:
(1) -phenyl, and
(2) -pyridine,
wherein each phenyl and pyridine is unsubstituted or substituted with one to three groups independently selected from Rc; or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1 wherein each X is independently selected from the group consisting of:
(1) —CH2—,
(2) —CH2CH2—, and
(3) —SO2—,
wherein each CH2 is unsubstituted or substituted with one or two substituents selected from Ra; or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The compound of claim 4 wherein each X is independently selected from the group consisting of:
(1) —CH2—, and
(2) —SO2—,
wherein CH2 is unsubstituted or substituted with one or two substituents selected from Ra; or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1 wherein each R4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) —C1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: —OH, halogen, —C1-6alkyl, —CN, —OC1-6 alkyl, —CO2H, and —CO2C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The compound of claim 6 wherein R4 is hydrogen; or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1 wherein each R2 is independently selected from the group consisting of:
(1) hydrogen,
(2) —1-6 alkyl,
(3) oxo, and
(4) —OH;
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The compound of claim 8 wherein R2 is hydrogen; or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1
R1 is pyridine, wherein pyridine is unsubstituted or substituted with one to three groups independently selected from Rb;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1 wherein
each X is independently selected from the group consisting of:
(1) —CH2—,
(2) —CH2CH2—, and
(3) —SO2—,
wherein each CH2 is unsubstituted or substituted with one or two substituents selected from Ra;
each R2 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl,
(3) oxo, and
(4) —OH;
each R3 is independently selected from the group consisting of:
(1) -aryl, and
(2) -heteroaryl,
wherein each aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rc;
each R4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) —C1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to three substituents selected from the group consisting of: —OH, halogen, —C1-6alkyl, —CN, —OC1-6 alkyl, —CO2H, and —CO2C1-6 alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1 wherein:
each X is independently selected from the group consisting of:
(1) —CH2—, and
(2) —SO2—,
wherein CH2 is unsubstituted or substituted with one or two substituents selected from Ra;
R1 is pyridine, wherein pyridine is unsubstituted or substituted with one to three groups independently selected from Rb;
R2 is hydrogen;
each R3 is independently selected from the group consisting of:
(1) -phenyl, and
(2) -pyridine,
wherein each phenyl and pyridine is unsubstituted or substituted with one to three groups independently selected from Rc;
R4 is hydrogen;
or a pharmaceutically acceptable salt thereof.

### Claim 13

A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

### Claim 15 (depends on 1)

A composition comprising a compound according to claim 1 and a compound selected from simvastatin, ezetimibe, taranabant and sitagliptin; and a pharmaceutically acceptable carrier.