Benzimidazole tetrahydropyran derivatives

摘要

Novel compounds described herein are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPKactivated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.;

主权项

1. A compound of structural formula I: or a pharmaceutically acceptable salt thereof, wherein: T is CR3; U is CR1; V is CR2; W is CR4; X is —O—; Y is: wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from Rb; Z is selected from:
(1) NR5,(2) —S—, and(3) —O—; each R1 is independently selected from:
(1) aryl-C2-10cycloheteroalkyl, and(2) aryl-aryl, wherein each cycloheteroalkyl and aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra; R2 is selected from halogen; R3 and R4 are each independently selected from:
(1) hydrogen,(2) halogen,(3) —C1-6alkyl,(4) —C2-6alkenyl,(5) —C2-6alkynyl,(6) —C3-10cycloalkyl,(7) —C3-10cycloalkenyl,(8) aryl,(9) heteroaryl,(10) —CN,(11) —CF3,(12) —OH,(13) —OC1-6alkyl,(14) —NH2,(15) —NHC1-6alkyl,(16) —N(C1-6alkyl)2,(17) —SC1-6alkyl,(18) —SOC1-6alkyl,(19) —SO2C1-6alkyl,(20) —NHSO2C1-6alkyl,(21) —NHC(O)C1-6alkyl,(22) —SO2NHC1-6alkyl, and(23) —C(O)NHC1-6alkyl; R5 is selected from:
(1) hydrogen,(2) —C1-6alkyl,(3) —C2-6alkenyl,(4) —(CH2)nOH,(5) —CH2CO2H, and(6) —CH2CO2C1-6alkyl; each Ra is independently selected from the group consisting of:
(1) —(CH2)m-halogen,(2) oxo,(3) —(CH2)mOH,(4) —(CH2)mN(Rj)2,(5) —(CH2)mNO2,(6) —(CH2)mCN,(7) —C1-6alkyl,(8) —(CH2)mCF3,(9) —(CH2)mOCF3,(10) —O—(CH2)m—OC1-6 alkyl,(11) —(CH2)mN(Rj)C(O)Rf,(12) —(CH2)mN(Rj)CO2Rf,(13) —(CH2)mC(═N—OH)N(Rj)2,(14) —(CH2)mOC1-6alkyl,(15) —(CH2)mO—(CH2)m—C3-7cycloalkyl,(16) —(CH2)mO—(CH2)m—C2-7cycloheteroalkyl,(17) —(CH2)mO—(CH2)m-aryl,(18) —(CH2)mO—(CH2)m-heteroaryl,(19) —(CH2)mSC1-6alkyl,(20) —(CH2)mS(O)C1-6alkyl,(21) —(CH2)mSO2C1-6alkyl,(22) —(CH2)mSO2(CH2)m—C3-7cycloalkyl,(23) —(CH2)mSO2(CH2)m—C2-7cycloheteroalkyl,(24) —(CH2)mSO2(CH2)m-aryl,(25) —(CH2)mSO2(CH2)m-heteroaryl,(26) —(CH2)mSO2NH2,(27) —(CH2)mSO2NHC1-6alkyl,(28) —(CH2)mSO2NHC3-7cycloalkyl,(29) —(CH2)mSO2NHC2-7cycloheteroalkyl,(30) —(CH2)mSO2NH-aryl,(31) —(CH2)mSO2NH-heteroaryl,(32) —(CH2)mNHSO2C1-6alkyl,(33) —(CH2)mNHSO2—C3-7cycloalkyl,(34) —(CH2)mNHSO2—C2-7cycloheteroalkyl,(35) —(CH2)mNHSO2-aryl,(36) —(CH2)mNHSO2NH-heteroaryl,(37) —(CH2)mN(Rj)—C1-6alkyl,(38) —(CH2)mN(Rj)—C3-7cycloalkyl,(39) —(CH2)mN(Rj)—C2-7cycloheteroalkyl,(40) —(CH2)mN(Rj)—C2-7cycloheteroalkenyl,(41) —(CH2)mN(Rj)-aryl,(42) —(CH2)mN(Ri)-heteroaryl,(43) —(CH2)mC(O)Rf,(44) —(CH2)mC(O)N(Rj)2,(45) —(CH2)mN(Rj)C(O)N(Rj)2,(46) —(CH2)mCO2H,(47) —(CH2)mOCOH,(48) —(CH2)mCO2Rf,(49) —(CH2)mOCORf,(50) —(CH2)mC3-7cycloalkyl,(51) —(CH2)mC3-7cycloalkenyl,(52) —(CH2)mC2-6cycloheteroalkyl,(53) —(CH2)mC2-6cycloheteroalkenyl,(54) —(CH2)maryl, and(55) —(CH2)mheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —OH, —(CH2)1-3OH, —CN, —NH2, —NH(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6 alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl, and wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH2)1-5OH, —(CH2)1-5CN, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —(CH2)1-5CF3 optionally substituted with 1, 2 or 3 —OH, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl; each Rb is independently selected from:
(1) hydrogen,(2) —C1-6alkyl,(3) —C2-6alkenyl,(4) —(CH2)n—C3-10cycloalkyl,(5) —(CH2)n—C3-10cycloalkenyl,(6) —(CH2)n—C2-10cycloheteroalkyl,(7) —(CH2)n—C2-10cycloheteroalkenyl,(8) —(CH2)n-aryl,(9) —(CH2)n-heteroaryl,(10) oxo,(11) —(CH2)n—CF3,(12) —(CH2)n—CN,(13) —(CH2)t-halogen,(14) —(CH2)s—OH,(15) —(CH2)n—NO2,(16) —(CH2)n—NH2,(17) —(CH2)n—NH(C1-6alkyl),(18) —(CH2)n—N(C1-6alkyl)2,(19) —(CH2)n—NHCO2H,(20) —(CH2)n—OC1-6 alkyl,(21) —(CH2)n—OC2-6alkenyl,(22) —(CH2)n—COC1-6alkyl,(23) —(CH2)n—CO2H,(24) —(CH2)n—OCOH,(25) —(CH2)n—CO2Ri,(26) —(CH2)n—OC(O)Ri,(27) —(CH2)q—C(O)N(Re)2,(28) —(CH2)q—CO2N(Re)2,(29) —(CH2)n—C(O)(CH2)nN(Rg)2,(30) —(CH2)n—OC(O)(CH2)nN(Rg)2,(31) —(CH2)n—N(Re)C(O)C1-6alkyl,(32) —(CH2)n—N(Re)SO2Ri,(33) —(CH2)n—SO2C1-6alkyl,(34) —(CH2)n—SO2N(Re)Rg,(35) —(CH2)n—SO2N(Re)C(O)Ri,(36) —(CH2)n—SO2N(Re)CO2Ri,(37) —(CH2)n—SO2N(Re)CON(Rg)2,(38) —(CH2)n—C(O)N(Re)SO2Ri,(39) —(CH2)n—N(Re)C(O)N(Rg)2,(40) ═N(OH), and(41) ═N(OC1-6alkyl), wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C1-6alkyl, —OH, halogen and —NH2 wherein each NH is unsubstituted or substituted with 1 substituent selected from Rc, and wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rc, or wherein two Rb substituents and the carbon to which they are attached may form a 3 to 6 membered cycloalkyl ring, a 3-6 membered cycloalkenyl ring, a 3-6 membered cycloheteroalkyl ring or a 3-6 membered cycloheteroalkenyl ring, wherein the ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rc; each Rc is independently selected from:
(1) halogen,(2) oxo,(3) —(CH2)rOH,(4) —(CH2)rN(Re)2,(5) —(CH2)rCN,(6) —C1-6alkyl,(7) —CF3,(8) —C1-6alkyl-OH,(9) —OCH2OC1-6alkyl,(10) —(CH2)rOC1-6alkyl,(11) —OCH2aryl,(12) —(CH2)rSC1-6alkyl,(13) —(CH2)rC(O)Rf,(14) —(CH2)rC(O)N(Re)2,(15) —(CH2)rCO2H,(16) —(CH2)rCO2Rf,(17) —(CH2)rC3-7cycloalkyl,(18) —(CH2)rC2-6cycloheteroalkyl,(19) —(CH2)raryl, and(20) —(CH2)rheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(Rh)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6 alkyl, —C3-7cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —N(Rh)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6 alkyl, —C3-7cycloalkyl and heteroaryl; each Re, Rg and Rh is independently selected from:
(1) hydrogen,(2) —C1-6alkyl, and(3) —O—C1-6alkyl, wherein alkyl is 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; each Rj is independently selected from:
(1) hydrogen,(2) C1-6alkyl,(3) C3-6cycloalkyl,(4) —C(O)Ri,(5) —CO2Ri, and(6) —SO2Ri, wherein alkyl and cycloalkyl 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(C1-6 alkyl)2; each Rf and Ri is independently selected from:
(1) C1-6alkyl,(2) —(CH2)rC4-7cycloalkyl,(3) —(CH2)rC4-7cycloalkenyl,(4) —(CH2)rC3-7cycloheteroalkyl,(5) —(CH2)rC3-7cycloheteroalkenyl,(6) —(CH2)raryl, and(7) —(CH2)rheteroaryl, 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, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6 alkyl, —C3-7cycloalkyl, and heteroaryl; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2; s is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4, and u is 0, 1, 2, 3 or 4.