US 8,895,596 B2Granted

Cyclic benzimidazole derivatives useful as anti-diabetic agents

AssigneeMerck Sharp & Dohme Corp.

InventorsJinlong Jiang, Andrew J. Kassick, Ahmet Kekec, Iyassu K. Sebhat

Life of this patent

Estimating the term…

Abstract

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Claims23

Dependent claims

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from:
(1) —O—,
(2) —O—CH2—,
(3) —S—,
(4) —S—CH2—,
(5) —NRd—,
(6) —NRd—CH2—,
(7) —CH2—, and
(8) —CH2—CH2—,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
hydroxy, halogen, —C1-6alkyl, —CO2C1-6alkyl, and —COC1-6alkyl;
Y is selected from:
(1) —C3-7cycloalkyl, and
(2) —C3-6cycloheteroalkyl,
wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb;
Z is selected from:
(1) —(CH2)nCO2H,
(2) —(CH2)nCO2Ri,
(3) —(CH2)nNHCORi
(4) —(CH2)nSO2NHC(O)Ri,
(5) —(CF12)nNHSO2Ri,
(6) —(CH2)nC(O)NHSO2Ri,
(7) heteroaryl, and
(8) —C2-10cycloheteroalkyl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from C1-6alkyl, and —OH, and wherein each cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rc;
each R1 and R2 is independently selected from:
(1) halogen,
(2) —(CH2)paryl,
(3) biphenyl, and
(4) —(CH2)pheteroaryl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each biphenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that one and only one of R1 and R2 is halogen;
R3 and R4 are each independently selected from:
(1) hydrogen,
(2) halogen,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —CN,
(7) —CF3,
(8) —OC1-6alkyl,
(9) —SO2C1-6alkyl,
(10) —SO2NHC1-6alkyl, and
(11) —C(O)NHC1-6alkyl,
wherein each alkyl is unsubstituted or substituted with 1, 2 or 3 halogens;
R5 is selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) —CH2CO2H, and
(4) —CH2CO2C1-6alkyl;
each Ra is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH2)mOH,
(4) —(CH2)mN(Rj)2,
(5) —(CH2)mCN,
(6) —C1-6alkyl,
(7) —(CH2)mCF3,
(8) —(CH2)mOCF3,
(9) —(CF12)mSC1-6alkyl,
(10) —(CH2)mS(O)2C1-6alkyl,
(11) —(CH2)mS(O)2N(C1-6alkyl)2,
(12) —(CH2)mC(O)N(Rj)2,
(13) —(CH2)mN(Rj)C(O)Rf,
(14) —(CH2)mC(O)Rf,
(15) —(CH2)mCO2Rf,
(16) —(CH2)mOC(O)Rf,
(17) —(CH2)mC3-7cycloalkyl,
(18) —(CH2)mC3-7cycloalkenyl,
(19) —(CH2)mC2-6cycloheteroalkyl,
(20) —(CH2)mC2-6cycloheteroalkenyl,
(21) —(CH2)maryl, and
(22) —(CH2)mheteroaryl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
oxo, —(CH2)0-3OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, and —CO2C1-6alkyl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —(CH2)0-3OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, and —CO2C1-6alkyl;
each Rb is independently selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) aryl,
(4) heteroaryl,
(5) —C3-6cycloalkyl,
(6) —C3-6cycloalkenyl,
(7) —C3-6cycloheteroalkyl,
(8) halogen,
(9) —OH,
(10) —OC1-6alkyl,
(11) —CF3,
(12) —CN, and
(13) —SO2C1-6alkyl,
wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with 1, 2 or 3 halogens;
each Rc is independently selected from:
(1) hydrogen,
(2) halogen,
(3) oxo,
(4) —(CH2)rOH,
(5) —(CH2)rN(Re)2,
(6) —(CH2)rCN,
(7) —C1-6alkyl,
(8) —CF3,
(9) —(CH2)rC3-7cycloalkyl, and
(10) —(CH2)rC2-6cycloheteroalkyl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
oxo, —OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, and —CF3, and wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, and —CF3;
each Rd is independently selected from:
(1) hydrogen, and
(2) C1-6alkyl;
each Re is independently selected from:
(1) hydrogen, and
(2) C1-6alkyl,
wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
—OH, oxo, halogen, C1-6alkyl, and —OC1-6alkyl;
each Rf is independently selected from:
(1) C1-6alkyl,
(2) C4-7cycloalkyl,
(3) C4-7cycloalkenyl,
(4) C3-7cycloheteroalkyl,
(5) C3-7cycloheteroalkenyl,
(6) aryl, and
(7) heteroaryl,
wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, and —CF3;
each Ri is independently selected from:
(1) hydrogen,
(2) C1-6alkyl,
(3) C4-7cycloalkyl,
(4) C4-7cycloalkenyl,
(5) C3-7cycloheteroalkyl,
(6) C3-7cycloheteroalkenyl,
(7) aryl, and
(8) heteroaryl,
wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —OH, —CN, —NH2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —OCOC1-6alkyl, and —OCO2C1-6alkyl;
each Rj is independently selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) —C3-6cycloalkyl, and
(4) —C3-6cycloheteroalkyl,
wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
—OH, oxo, halogen, C1-6alkyl, —OC1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2;
n is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2, or 3;
and
r is 0, 1 or 2.

144 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/578,302Filed 21 Feb 2011 · us provisional application
Priority: 25 Feb 2010
Published: US 2012/0309736 A16 Dec 2012
Granted: 25 Nov 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/366
Lactones: having six-membered rings, e.g. delta-lactones
A61K 31/397
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having four-membered rings, e.g. azetidine
A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles

Family

Application61/307,909Us provisional application · filed 25 Feb 2010
US 2012/0309736 A1Pre-grant publication · published 6 Dec 2012
US 8,895,596 B2This patent

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

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Abstract

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from:
(1) —O—,
(2) —O—CH2—,
(3) —S—,
(4) —S—CH2—,
(5) —NRd—,
(6) —NRd—CH2—,
(7) —CH2—, and
(8) —CH2—CH2—,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
hydroxy, halogen, —C1-6alkyl, —CO2C1-6alkyl, and —COC1-6alkyl;
Y is selected from:
(1) —C3-7cycloalkyl, and
(2) —C3-6cycloheteroalkyl,
wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb;
Z is selected from:
(1) —(CH2)nCO2H,
(2) —(CH2)nCO2Ri,
(3) —(CH2)nNHCORi
(4) —(CH2)nSO2NHC(O)Ri,
(5) —(CF12)nNHSO2Ri,
(6) —(CH2)nC(O)NHSO2Ri,
(7) heteroaryl, and
(8) —C2-10cycloheteroalkyl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from C1-6alkyl, and —OH, and wherein each cycloheteroalkyl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rc;
each R1 and R2 is independently selected from:
(1) halogen,
(2) —(CH2)paryl,
(3) biphenyl, and
(4) —(CH2)pheteroaryl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each biphenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that one and only one of R1 and R2 is halogen;
R3 and R4 are each independently selected from:
(1) hydrogen,
(2) halogen,
(3) —C1-6alkyl,
(4) —C2-6alkenyl,
(5) —C2-6alkynyl,
(6) —CN,
(7) —CF3,
(8) —OC1-6alkyl,
(9) —SO2C1-6alkyl,
(10) —SO2NHC1-6alkyl, and
(11) —C(O)NHC1-6alkyl,
wherein each alkyl is unsubstituted or substituted with 1, 2 or 3 halogens;
R5 is selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) —CH2CO2H, and
(4) —CH2CO2C1-6alkyl;
each Ra is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH2)mOH,
(4) —(CH2)mN(Rj)2,
(5) —(CH2)mCN,
(6) —C1-6alkyl,
(7) —(CH2)mCF3,
(8) —(CH2)mOCF3,
(9) —(CF12)mSC1-6alkyl,
(10) —(CH2)mS(O)2C1-6alkyl,
(11) —(CH2)mS(O)2N(C1-6alkyl)2,
(12) —(CH2)mC(O)N(Rj)2,
(13) —(CH2)mN(Rj)C(O)Rf,
(14) —(CH2)mC(O)Rf,
(15) —(CH2)mCO2Rf,
(16) —(CH2)mOC(O)Rf,
(17) —(CH2)mC3-7cycloalkyl,
(18) —(CH2)mC3-7cycloalkenyl,
(19) —(CH2)mC2-6cycloheteroalkyl,
(20) —(CH2)mC2-6cycloheteroalkenyl,
(21) —(CH2)maryl, and
(22) —(CH2)mheteroaryl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
oxo, —(CH2)0-3OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, and —CO2C1-6alkyl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —(CH2)0-3OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, and —CO2C1-6alkyl;
each Rb is independently selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) aryl,
(4) heteroaryl,
(5) —C3-6cycloalkyl,
(6) —C3-6cycloalkenyl,
(7) —C3-6cycloheteroalkyl,
(8) halogen,
(9) —OH,
(10) —OC1-6alkyl,
(11) —CF3,
(12) —CN, and
(13) —SO2C1-6alkyl,
wherein each alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with 1, 2 or 3 halogens;
each Rc is independently selected from:
(1) hydrogen,
(2) halogen,
(3) oxo,
(4) —(CH2)rOH,
(5) —(CH2)rN(Re)2,
(6) —(CH2)rCN,
(7) —C1-6alkyl,
(8) —CF3,
(9) —(CH2)rC3-7cycloalkyl, and
(10) —(CH2)rC2-6cycloheteroalkyl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
oxo, —OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, and —CF3, and wherein alkyl, cycloalkyl, and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, and —CF3;
each Rd is independently selected from:
(1) hydrogen, and
(2) C1-6alkyl;
each Re is independently selected from:
(1) hydrogen, and
(2) C1-6alkyl,
wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
—OH, oxo, halogen, C1-6alkyl, and —OC1-6alkyl;
each Rf is independently selected from:
(1) C1-6alkyl,
(2) C4-7cycloalkyl,
(3) C4-7cycloalkenyl,
(4) C3-7cycloheteroalkyl,
(5) C3-7cycloheteroalkenyl,
(6) aryl, and
(7) heteroaryl,
wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —OH, —CN, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, and —CF3;
each Ri is independently selected from:
(1) hydrogen,
(2) C1-6alkyl,
(3) C4-7cycloalkyl,
(4) C4-7cycloalkenyl,
(5) C3-7cycloheteroalkyl,
(6) C3-7cycloheteroalkenyl,
(7) aryl, and
(8) heteroaryl,
wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
oxo, —OH, —CN, —NH2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —OCOC1-6alkyl, and —OCO2C1-6alkyl;
each Rj is independently selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) —C3-6cycloalkyl, and
(4) —C3-6cycloheteroalkyl,
wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from:
—OH, oxo, halogen, C1-6alkyl, —OC1-6alkyl, —NH2, —NH(C1-6alkyl), and —N(C1-6alkyl)2;
n is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2, or 3;
and
r is 0, 1 or 2.

144 more elements

Facts

Application

13/578,302Filed 21 Feb 2011 · us provisional application

Priority

25 Feb 2010

Published

US 2012/0309736 A16 Dec 2012

Granted

25 Nov 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification19 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 31/366
Lactones: having six-membered rings, e.g. delta-lactones
A61K 31/397
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having four-membered rings, e.g. azetidine
A61K 31/4184
1,3-Diazoles: condensed with carbocyclic rings, e.g. benzimidazoles