US 8,569,299 B2Granted

Prolylcarboxypeptidase inhibitors

AssigneeMerck Sharp & Dohme Corp.

InventorsThomas H. Graham, Wensheng Liu, Iyassu K. Sebhat, Dong-Ming Shen, Zhi-Cai Shi

Life of this patent

Estimating the term…

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.

Claims22

Dependent claims

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.

150 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/702,622Filed 3 Jun 2011 · us provisional application
Priority: 8 Jun 2010
Published: US 2013/0143859 A16 Jun 2013
Granted: 29 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…

Family

Application61/352,593Us provisional application · filed 8 Jun 2010
US 2013/0143859 A1Pre-grant publication · published 6 Jun 2013
US 8,569,299 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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.

150 more elements

Facts

Application

13/702,622Filed 3 Jun 2011 · us provisional application

Priority

8 Jun 2010

Published

US 2013/0143859 A16 Jun 2013

Granted

29 Oct 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/454
Containing further heterocyclic ring systems: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…