NOVEL INDOLE DERIVATIVES USEFUL AS ANTI-DIABETIC AGENTS

摘要

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated 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 selected from the group consisting of: CR3, N and N-oxide; U is selected from the group consisting of: CR1, N and N-oxide; V is selected from the group consisting of: CR2, N and N-oxide; W is selected from the group consisting of: CR4, N and N-oxide; X is absent or selected from:
(1) —CH2—,(2) —CHF—,(3) —CF2—,(4) —S—,(5) —S(O)—,(6) —S(O)2—,(7) —O—,(8) —O—CH2—,(9) —CH2—O—,(10) —CH2—S—,(11) —NH—,(12) —C(O)—,(13) —NHC(O)—,(14) —C(O)NH—,(15) —NHSO2—,(16) —SO2NH—, and(17) —CO2—, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, NH2, C1-6alkyl, CO2H, CO2C1-6alkyl, COC1-6alkyl, phenyl and —CH2phenyl, and wherein each NH is unsubstituted or substituted with 1 substituent selected from: C1-6alkyl, CO2H, CO2C1-6alkyl, COC1-6alkyl, phenyl and —CH2phenyl; Y is selected from:
(1) —C1-6alkyl,(2) —C2-6alkynyl,(3) —CHF—,(4) —CF2—,(5) C3-10cycloalkyl,(6) C3-10cycloalkenyl,(7) C2-10cycloheteroalkyl,(8) C2-10cycloheteroalkenyl,(9) aryl,(10) heteroaryl, and wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb; Z is selected from:
(1) hydrogen,(2) oxo,(3) —CN,(4) —CF3,(5) —C1-6alkyl,(6) —(CH2)t-halogen,(7) —(CH2)nCOC1-6alkyl,(8) —(CH2)nCO2H,(9) —(CH2)nOCOH,(10) —(CH2)nCO2Ri,(11) —(CH2)nOCORi,(12) —(CH2)nOH,(13) —(CH2)nC(O)N(Rg)2,(14) —(CH2)nC(O)(CH2)nN(Rg)2,(15) —(CH2)nOC(O)(CH2)nN(Rg)2,(16) —(CH2)n—NHC(O)C1-6alkyl,(17) —(CH2)nNHSO2Ri,(18) —(CH2)nSO2C1-6alkyl,(19) —(CH2)nSO2NHRg,(20) —(CH2)nSO2NHC(O)Ri,(21) —(CH2)nSO2NHCO2Ri,(22) —(CH2)nSO2NHCON(Rg)2,(23) —(CH2)nC(O)NHSO2Ri,(24) —(CH2)nNHC(O)N(Rg)2,(25) —(CH2)nC3-10cycloalkyl-CO2Re,(26) heteroaryl,(27) —C2-10cycloheteroalkenyl,(28) —C2-10cycloheteroalkyl, and(29) —(CH2)nP(O)(ORj)2, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from C1-6alkyl, —OH and —NH2, wherein each NH is unsubstituted or substituted with 1 substituent selected from Rc, and wherein each alkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, aryl 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) hydrogen,(2) halogen,(3) CN,(4) CF3,(5) —C1-6alkyl,(6) —C2-6alkenyl,(7) —C2-6alkynyl,(8) —(CH2)pC3-10cycloalkyl,(9) —(CH2)pC3-7cycloalkyl-aryl,(10) —(CH2)pC3-7cycloalkyl-heteroaryl,(11) —(CH2)pC4-10cycloalkenyl,(12) —(CH2)pC4-7cycloalkenyl-aryl,(13) —(CH2)pC4-7cycloalkenyl-heteroaryl,(14) —(CH2)pC2-10cycloheteroalkyl,(15) —(CH2)pC2-10cycloheteroalkenyl,(16) —(CH2)paryl,(17) —(CH2)paryl-C1-8alkyl,(18) —(CH2)paryl-C2-8alkenyl,(19) —(CH2)paryl-C2-8alkynyl-C1-8alkyl,(20) —(CH2)paryl-C2-8alkynyl-C3-7cycloalkyl,(21) —(CH2)paryl-C2-8alkynyl-C3-7cycloalkenyl,(22) —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkyl,(23) —(CH2)paryl-C2-8alkynyl-C2-10cycloheteroalkenyl,(24) —(CH2)paryl-C2-8alkynyl-aryl,(25) —(CH2)paryl-C2-8alkynyl-heteroaryl,(26) —(CH2)paryl-C3-7cycloalkyl,(27) —(CH2)paryl-C3-7cycloalkenyl,(28) —(CH2)paryl-C2-10cycloheteroalkyl,(29) —(CH2)paryl-C2-10cycloheteroalkenyl,(30) —(CH2)paryl-aryl,(31) —(CH2)paryl-heteroaryl,(32) —(CH2)pheteroaryl,(33) —C2-6alkenyl-alkyl,(34) —C2-6alkenyl-aryl,(35) —C2-6alkenyl-heteroaryl,(36) —C2-6alkenyl-C3-7cycloalkyl,(37) —C2-6alkenyl-C3-7cycloalkenyl,(38) —C2-6alkenyl-C2-7cycloheteroalkyl,(39) —C2-6alkenyl-C2-7cycloheteroalkenyl,(40) —C2-6alkynyl-(CH2)1-3—O-aryl,(41) —C2-6alkynyl-alkyl,(42) —C2-6alkynyl-aryl,(43) —C2-6alkynyl-heteroaryl,(44) —C2-6alkynyl-C3-7cycloalkyl,(45) —C2-6alkynyl-C3-7cycloalkenyl,(46) —C2-6alkynyl-C2-7cycloheteroalkyl,(47) —C2-6alkynyl-C2-7cycloheteroalkenyl, and(48) —C(O)NH—(CH2)0-3phenyl, 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 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra, provided that at least one of and only one of R1 and R2 is selected from the group consisting of: hydrogen, halogen, —CN, —CF3, —C1-6alkyl, —C2-6alkenyl and —C2-6alkynyl; R3 and R4 are each absent or 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) —CH2CO2H, and(4) —CH2CO2C1-6alkyl; R6 is selected from:
(1) hydrogen,(2) —C1-6alkyl,(3) —(CH2)mOC1-6alkyl,(4) halogen,(5) —(CH2)mCN,(6) —(CH2)mCF3,(7) —(CH2)mOCF3,(8) —(CH2)mCHF2,(9) —(CH2)mCH2F,(10) —(CH2)mSO2C1-6alkyl,(11) —(CH2)mCO2H,(12) —(CH2)mCO2C1-6alkyl,(13) —(CH2)mC(O)H,(14) —(CH2)mC(O)NH2,(15) —(CH2)mC3-6cycloalkyl,(16) —(CH2)mC2-7cycloheteroalkyl,(17) —(CH2)maryl, and(18) —(CH2)mheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH2)0-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH2)0-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl; 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—OC1-6alkyl,(11) —(CH2)mC(O)N(Rj)2,(12) —(CH2)mC(═N—OH)N(Rj)2,(13) —(CH2)mOC1-6alkyl,(14) —(CH2)mO—(CH2)m—C3-7cycloalkyl,(15) —(CH2)mO—(CH2)m—C2-7cycloheteroalkyl,(16) —(CH2)mO—(CH2)m-aryl,(17) —(CH2)mO—(CH2)m-heteroaryl,(18) —(CH2)mSC1-6alkyl,(19) —(CH2)mS(O)C1-6alkyl,(20) —(CH2)mSO2C1-6alkyl,(21) —(CH2)mSO2C3-7cycloalkyl,(22) —(CH2)mSO2C2-7cycloheteroalkyl,(23) —(CH2)mSO2-aryl,(24) —(CH2)mSO2-heteroaryl,(25) —(CH2)mSO2NHC1-6alkyl,(26) —(CH2)mSO2N(C1-6alkyl)2,(27) —(CH2)mSO2NHC3-7cycloalkyl,(28) —(CH2)mSO2NHC2-7cycloheteroalkyl,(29) —(CH2)mSO2NH-aryl,(30) —(CH2)mSO2NH-heteroaryl,(31) —(CH2)mNHSO2—C1-6alkyl,(32) —(CH2)mNHSO2—C3-7cycloalkyl,(33) —(CH2)mNHSO2—C2-7cycloheteroalkyl,(34) —(CH2)mNHSO2-aryl,(35) —(CH2)mNHSO2NH-heteroaryl,(36) —(CH2)mN(Rj)—C1-6alkyl,(37) —(CH2)mN(Rj)—C3-7cycloalkyl,(38) —(CH2)mN(Rj)—C2-7cycloheteroalkyl,(39) —(CH2)mN(Rj)—C2-7cycloheteroalkenyl,(40) —(CH2)mN(Rj)-aryl,(41) —(CH2)mN(Rj)-heteroaryl,(42) —(CH2)mC(O)Rf,(43) —(CH2)mC(O)N(Rj)2,(44) —(CH2)mN(Rj)C(O)N(Rj)2,(45) —(CH2)mCO2H,(46) —(CH2)mOCOH,(47) —(CH2)mCO2Rf,(48) —(CH2)mOCORf,(49) —(CH2)mC3-7cycloalkyl,(50) —(CH2)mC3-7cycloalkenyl,(51) —(CH2)mC2-6cycloheteroalkyl,(52) —(CH2)mC2-6cycloheteroalkenyl,(53) —(CH2)maryl, and(54) —(CH2)mheteroaryl, wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH2)0-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —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, —(CH2)0-5OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —SO2C1-6alkyl, —C3-7cycloalkyl, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl; each Rb is independently selected from:
(1) hydrogen,(2) —C1-6alkyl,(3) —C3-6cycloalkyl,(4) —C3-6cycloalkenyl,(5) —C2-6cycloheteroalkyl,(6) —C2-6cycloheteroalkenyl,(7) aryl,(8) heteroaryl,(9) —(CH2)t-halogen,(10) —(CH2)s-OH,(11) —(CH2)sNO2,(12) —(CH2)sNH2,(13) —(CH2)sNH(C1-6alkyl),(14) —(CH2)sN(C1-6alkyl)2,(15) —(CH2)sOC1-6alkyl,(16) —(CH2)qCO2H,(17) —(CH2)qCO2C1-6alkyl,(18) —(CH2)sCF3,(19) —(CH2)sOCF3,(20) —(CH2)sCHF2,(21) —(CH2)sCH2F,(22) —(CH2)sCN,(23) —(CH2)sSO2C1-6alkyl, and(24) —(CH2)sCON(Re)2, wherein each CH2 is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 halogens, and wherein two Rb substituents together with the atom to which they are attached may form a C3-6cycloalkyl ring or a C2-6cycloheteroalkyl ring; 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, —CO2C1-6alkyl, —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, —CO2C1-6alkyl, —C3-7cycloalkyl and heteroaryl; each Re, Rg and Rh is independently selected from:
(1) hydrogen,(2) —C1-6alkyl, and(3) —O—C1-6alkyl, wherein each 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, and(5) —SO2Ri, wherein each alkyl and cycloalkyl 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 Rf and Ri 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 each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is 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, —C3-7cycloalkyl, and heteroaryl; each a independently selected from 0, 1 or 2; each b independently selected from 0, 1 or 2; each n independently selected from 0, 1, 2, 3 or 4; each m independently selected from 0, 1, 2, 3 or 4; each p independently selected from 0, 1, 2, or 3; each q independently selected from 0, 1, 2, 3 or 4; each r independently selected from 0, 1 or 2; each s independently selected from 0, 1, 2, 3 or 4; and each t independently selected from 0, 1, 2, 3 or 4.