US 9,540,364 B2 · Benzimidazole tetrahydrofuran derivatives

Abstract

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.

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) —(CH2)paryl-aryl and
(2) —(CH2)paryl-C2-10 cycloheteroalkyl,
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 aryl and cycloheteroalkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from Ra;
each R2 is independently 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) —SOC1-6 alkyl,
(19) —SO2C1-6alkyl,
(20) —NHSO2C1-6 alkyl,
(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)—OH,
(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)mNHSO2—C1-6alkyl,
(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(Rj)-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), —N(C1-6alkyl)2, oxo, —C1-6alkyl, —C1-6alkyl substituted with 1-5 OH, —OC1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C1-6alkyl, —C3-7 cycloalkyl, 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, —C1-6 alkyl 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, —SO2C1-6 alkyl, —C3-7 cycloalkyl, 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;
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, —CO2C1-6 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)rC4-7 cycloalkyl,
(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, —CO2C1-6alkyl, —C3-7cycloalkyl, and heteroaryl;
n is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
p is 0, 1, 2, or 3;
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.

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Benzimidazole tetrahydrofuran derivatives

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Benzimidazole tetrahydrofuran derivatives

Life of this patent

Abstract

Claims18