# US 8,569,299 B2 · Prolylcarboxypeptidase inhibitors

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- Number: US 8,569,299 B2
- Document ID: US8569299B2
- Status: Granted
- Kind: B2
- Application number: 13/702,622
- Filed: 2011-06-03
- Published: 2013-06-06
- Granted: 2013-10-29
- Earliest claimed: 2010-06-08
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Thomas H. Graham; Wensheng Liu; Iyassu K. Sebhat; Dong-Ming Shen; Zhi-Cai Shi
- Inventors: Thomas H. Graham; Wensheng Liu; Iyassu K. Sebhat; Dong-Ming Shen; Zhi-Cai Shi
- Web page: https://patentgrep.com/patent/US8569299B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds of structural formulas I-1 and I-2 are inhibitors of prolylcarboxypeptidase (PrCP). The compounds of the present invention are useful for the prevention and treatment of conditions related to the 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-1 and I-b:
or a pharmaceutically acceptable salt thereof; wherein
X is independently selected from the group consisting of: N and CR8;
Y is independently selected from the group consisting of: NR5 or CR6R7;
Z is independently selected from the group consisting of: N and CR4;
each R1 is independently selected from the group consisting of:
(1) —(CH2)n C3-7cycloalkyl,
(2) —(CH2)n C2-6cycloheteroalkyl,
(3) —(CH2)n aryl, and
(4) —(CH2)n heteroaryl,
wherein each CH2, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Ra;
each R2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl;
each R3 is independently selected from the group consisting of:
(1) —C1-6 alkyl,
(2) —(CH2)m C3-7cycloalkyl,
(3) —(CH2)m C2-6cycloheteroalkyl,
(4) —(CH2)m aryl,
(5) —(CH2)m biphenyl, and
(6) —(CH2)m heteroaryl,
wherein each CH2, alkyl, cycloalkyl, cycloheteroalkyl, aryl, biphenyl and heteroaryl is unsubstituted or substituted with one to four groups independently selected from Rb;
each R4 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —(CH2)pCO2H,
(4) —(CH2)pCO2C1-6 alkyl,
(5) —(CH2)pCOC1-6 alkyl,
(6) —(CH2)p—NRh—C1-6 alkyl,
(7) —(CH2)p—O—C1-6 alkyl,
(8) —(CH2)p—S—C1-6 alkyl,
(9) —(CH2)p C3-7cycloalkyl,
(10) —(CH2)p C2-6cycloheteroalkyl,
(11) —(CH2)p aryl, and
(12) —(CH2)p heteroaryl,
wherein each CH2, alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rc;
each R5 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —(CH2)qCO2H,
(4) —(CH2)qCO2C1-6 alkyl,
(5) —(CH2)qCO—C1-6 alkyl,
(6) —(CH2)qCO—C3-6 cycloalkyl,
(7) —(CH2)qCO—C2-6 cycloheteroalkyl,
(8) —(CH2)qCO-aryl,
(9) —(CH2)qCO-heteroaryl,
(10) —(CH2)u—NRh—C1-6 alkyl,
(11) —(CH2)u—O—C1-6 alkyl,
(12) —(CH2)u—S—C1-6 alkyl,
(13) —(CH2)qC3-7cycloalkyl,
(14) —(CH2)qC2-6cycloheteroalkyl,
(15) —(CH2)qaryl, and
(16) —(CH2)qheteroaryl,
wherein each CH2, alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rd;
each R6 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl,
(3) —(CH2)vCF3,
(4) —(CH2)vOCF3,
(5) —(CH2)vN(Rh)2,
(6) —(CH2)vCONH(C1-4 alkyl),
(7) —(CH2)vCON(C1-4 alkyl)2,
(8) —(CH2)v—NRh—CO—C1-4 alkyl,
(9) —(CH2)v—NRh—CO2—C1-4 alkyl,
(10) —(CH2)v—NRh—(CH2)0-2—C3-6cycloalkyl,
(11) —(CH2)v—NRh—(CH2)0-2—C2-6cycloheteroalkyl,
(12) —(CH2)v—NRh—(CH2)0-2-aryl,
(13) —(CH2)v—NRh—(CH2)0-2-heteroaryl,
(14) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OH,
(15) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OC1-6 alkyl,
(16) —(CH2)v—S—C1-4 alkyl,
(17) —(CH2)v—SO2C1-4 alkyl,
(18) —(CH2)v—SO2-phenyl,
(19) —(CH2)v—NRh—SO2C1-4 alkyl,
(20) —(CH2)v—NRh—SO2phenyl,
(21) —(CH2)vC3-7cycloalkyl,
(22) —(CH2)vC2-6cycloheteroalkyl,
(23) —(CH2)varyl, and
(24) —(CH2)vheteroaryl,
wherein each CH2, alkyl, cycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from Re;
each R7 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rf;
each R8 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl;
each R9 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl;
wherein alkyl is unsubstituted or substituted with one to three substituents selected from Rg;
each Ra is independently selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —OH,
(4) —C1-6alkyl,
(5) —OC1-6alkyl,
(6) —CF3, and
(7) —OCF3;
each Rb is independently selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —OH,
(4) —C1-6alkyl,
(5) —OC1-6alkyl,
(6) —CF3, and
(7) —OCF3;
each Rc is independently selected from the group consisting of:
(1) halogen, and
(2) —C1-6 alkyl;
each Rd is independently selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —OH,
(4) —C1-6alkyl,
(5) —OC1-6alkyl,
(6) —CF3,
(7) —OCF3, and
(8) —C(O)C1-6alkyl;
each Re is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —CN,
(4) —OH,
(5) —C1-6alkyl,
(6) —OC1-6alkyl,
(7) —CF3,
(8) —OCF3, and
(9) —C3-6 cycloalkyl;
each Rf is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) C1-6 alkyl;
each Rg is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) C1-6 alkyl;
each Rh is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-6 alkyl;
m is selected from 0, 1, 2, and 3;
n is selected from 0, 1, 2, and 3;
p is selected from 0, 1, 2, and 3;
q is selected from 0, 1, 2, and 3;
r is selected from 0, 1 and 2;
s is selected from 1 and 2;
t is selected from 0, 1, 2, and 3;
u is 1, 2, or 3; and
v is selected from 0, 1, 2, and 3.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R2 is hydrogen; or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1 wherein each R3 is —(CH2)m aryl, wherein each CH2 and aryl is unsubstituted or substituted with one to three groups independently selected from Rb;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compound of claim 3 wherein each R3 is phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from Rb;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1 wherein each R1 is independently selected from the group consisting of:
(1) —(CH2)n aryl, and
(2) —(CH2)n heteroaryl,
wherein each CH2, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Ra;
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The compound of claim 5 wherein each R1 is phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from Ra; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1 wherein each R4 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —(CH2)p heteroaryl,
wherein each CH2, alkyl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rc;
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 7)

The compound of claim 7 wherein each R4 is —C1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three groups independently selected from Rc;
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1 wherein each R5 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —(CH2)qheteroaryl,
wherein each CH2, alkyl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rd;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1 wherein each R5 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl,
wherein each alkyl is unsubstituted or substituted with one to three groups independently selected from Rd;
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1 wherein each R6 is independently selected from the group consisting of:
(1) —(CH2)vN(Rh)2,
(2) —(CH2)v—NRh—(CH2)0-2—C3-6cycloalkyl,
(3) —(CH2)v—NRh—(CH2)0-2-aryl,
(4) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OH,
(5) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OC1-6 alkyl, and
(6) —(CH2)vC2-6cycloheteroalkyl,
wherein each CH2, alkyl, cycloalkyl, cycloheteroalkyl and aryl is unsubstituted or substituted with one to three substituents selected from Re;
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The compound of claim 11 wherein each R6 is independently selected from the group consisting of:
(1) —(CH2)vN(Rh)2,
(2) —(CH2)v—NRh—(CH2)0-2—C3-6cycloalkyl,
(3) —(CH2)v—NRh—(CH2)0-2-aryl,
(4) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OC1-6 alkyl, and
(5) —(CH2)vC2-6cycloheteroalkyl,
wherein each CH2, alkyl, cycloalkyl, cycloheteroalkyl and aryl is unsubstituted or substituted with one to three substituents selected from Re;
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1 wherein each R6 is independently selected from the group consisting of:
(1) —(CH2)vN(Rh)2,
(2) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OH, and
(3) —(CH2)vC2-6cycloheteroalkyl,
wherein each CH2, alkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from Re;
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The compound of claim 13 wherein each R6 is independently selected from the group consisting of:
(1) —(CH2)vN(Rh)2, and
(2) —(CH2)vC2-6cycloheteroalkyl,
wherein each CH2, alkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from Re;
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The compound of claim 1 wherein Z is CR4; or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound of claim 1 wherein:
X is independently selected from the group consisting of: N and CR8;
Y is independently selected from the group consisting of: NR5 or CR6R7;
Z is independently selected from the group consisting of: N and CR4;
R1 is independently selected from the group consisting of:
(1) —(CH2)n aryl, and
(2) —(CH2)n heteroaryl,
wherein each CH2, aryl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Ra;
R2 is hydrogen;
R3 is —(CH2)m aryl, wherein each CH2 and aryl is unsubstituted or substituted with one to three groups independently selected from Rb;
R4 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —(CH2)p heteroaryl,
wherein each CH2, alkyl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rc;
R5 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6 alkyl, and
(3) —(CH2)qheteroaryl,
wherein each CH2, alkyl and heteroaryl is unsubstituted or substituted with one to three groups independently selected from Rd;
R6 is independently selected from the group consisting of:
(1) —(CH2)vN(Rh)2,
(2) —(CH2)v—NRh—(CH2)0-2—C3-6cycloalkyl,
(3) —(CH2)v—NRh—(CH2)0-2-aryl,
(4) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OH,
(5) —(CH2)v—NRh—(CH2)1-2—O—(CH2)1-2—OC1-6 alkyl, and
(6) —(CH2)vC2-6cycloheteroalkyl,
wherein each CH2, alkyl, cycloalkyl, cycloheteroalkyl and aryl is unsubstituted or substituted with one to three substituents selected from Re;
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The compound of claim 1 wherein:
X is independently selected from the group consisting of: N and CH;
Y is independently selected from the group consisting of: NR5 or CR6R7;
Z is CR4;
R1 is phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from Ra;
R2 is hydrogen;
R3 is phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from Rb;
R4 is independently selected from the group consisting of: hydrogen, and —C1-6 alkyl, wherein each alkyl is unsubstituted or substituted with one to three groups independently selected from Rc;
R5 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6 alkyl,
wherein each alkyl is unsubstituted or substituted with one to three groups independently selected from Rd;
R6 is independently selected from the group consisting of:
(1) —(CH2)vN(Rh)2, and
(2) —(CH2)vC2-6cycloheteroalkyl,
wherein each CH2, alkyl and cycloheteroalkyl is unsubstituted or substituted with one to three substituents selected from Re;
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The compound of claim 17 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

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

### Claim 20 (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.

### Claim 21 (depends on 1)

A method of treating a disorder, condition, or disease responsive to the inhibition of prolylcarboxypeptidase in a patient suffering from said disorder, condition, or disease, comprising administration of a therapeutic effective amount of a compound according to claim 1, wherein the disorder, condition, or disease responsive to the inhibition of prolylcarboxypeptidase is selected from the group consisting of hypertension, insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, kidney cancer, lower back pain, cardiac hypertrophy, left ventricular hypertrophy, gallbladder disease, gout, osteoarthritis, obstructive sleep apnea, heart arrhythmias, myocardial infarction, sexual dysfunction, infertility, hirsutism, infertility, obesity-related gastro-esophageal reflux, inflammation, Pickwickian syndrome, systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, constipation, irritable bowel syndrome, inflammatory bowel syndrome, hyperglycemia, low glucose tolerance, obesity, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, vascular restenosis, Crohn's disease, ulcerative colitis, pancreatitis, retinopathy, nephropathy, neuropathy, and ovarian hyperandrogenism.

### Claim 22 (depends on 21)

The method of claim 21 wherein the disorder, condition, or disease is obesity.