US 8,796,258 B2 · Cyclic azabenzimidazole derivatives useful as anti-diabetic agents

Abstract

Novel compounds of 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.

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
T is N;
U is CR1;
V is CR2;
W is CR4;
X is selected from:
(1) —O—, and
(2) —O—CH2—;
Y is selected from:
(1) C3-l0cycloalkyl,
(2) C3-l0cycloalkenyl,
(3) C2-10cycloheteroalkyl,
(4) C2-10cycloheteroalkenyl,
(5) aryl, and
(6) heteroaryl,
wherein cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from Rb;
Z is selected from:
(1) oxo,
(2) —CF3,
(3) —C1-6alkyl,
(4) —(CH2)t-halogen,
(5) —(CH2)nCO2H,
(6) —(CH2)nOH, and
(7) —(CH2)nSO2C1-6alkyl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from C1-6alkyl, —OH and —NH2,and wherein each alkyl 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-l0cycloalkenyl,
(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-C2-10cycloheteroalkyl,
(28) —(CH2)paryl-C2-10cycloheteroalkenyl,
(29) —(CH2)paryl-aryl,
(30) —(CH2)paryl-heteroaryl,
(31) —(CH2)pheteroaryl,
(32) —C2-6alkenyl-alkyl,
(33) —C2-6alkenyl-aryl,
(34) —C2-6alkenyl-heteroaryl,
(35) —C2-6alkenyl-C3-7cycloalkyl,
(36) —C2-6alkenyl-C3-7cycloalkenyl,
(37) —C2-6alkenyl-C2-7cycloheteroalkyl,
(38) —C2-6alkenyl-C2-7cycloheteroalkenyl,
(39) —C2-6alkynyl-(CH2)1-3—O-aryl,
(40) —C2-6alkynyl-alkyl,
(41) —C2-6alkynyl-aryl,
(42) —C2-6alkynyl-heteroaryl,
(43) —C2-6alkynyl-C3-7cycloalkyl,
(44) —C2-6alkynyl-C3-7cycloalkenyl,
(45) —C2-6alkynyl-C2-7cycloheteroalkyl,
(46) —C2-6alkynyl-C2-7cycloheteroalkenyl, and
(47) —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, 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;
each R4 is independently selected from:
(1) hydrogen,
(2) halogen,
(3) —C1-6 alkyl,
(4) —C2-6 alkenyl,
(5) —C2-6 alkynyl,
(6) —CN,
(7) —CF3,
(8) —OH,
(9) —OC1-6alkyl,
(10) —NH2,
(11) —NHC1-6alkyl,
(12) —N(C1-6alkyl)2,
(13) —SC1-6alkyl,
(14) —SOC1-6alkyl,
(15) —SO2C1-6alkyl,
(16) —NHSO2C1-6alkyl,
(17) —NHC(O)C1-6alkyl,
(18) —SO2NHC1-6alkyl, and
(19) —C(O)NHC1-6alkyl;
R5is selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) —CH2CO2H, and
(4) —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—OC1-6alkyl,
(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-heterolaryl,
(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)mSO2NHC3-7cycloalkyl,
(27) —(CH2)mSO2NHC2-7cycloheteroalkyl,
(28) —(CH2)mSO2NH-aryl,
(29) —(CH2)mSO2NH-heteroaryl,
(30) —(CH2)mNHSO2—C1-6alkyl,
(31) —(CH2)mNHSO2—C3-7cycloalkyl,
(32) —(CH2)mNHSO2—C2-7cycloheteroalkyl,
(33) —(CH2)mNHSO2-aryl,
(34) —(CH2)mNHSO2NH-heteroaryl,
(35) —(CH2)mN(Rj)—C1-6alkyl,
(36) —(CH2)mN(Rj)—C3-7cycloalkyl,
(37) —(CH2)mN(Rj)—C2-7cycloheteroalkyl,
(38) —(CH2)mN(Rj)—C2-7cycloheteroalkenyl,
(39) —(CH2)mN(Rj)-aryl,
(40) —(CH2)mN(Rj)-heteroaryl,
(41) —(CH2)mC(O)Rf,
(42) —(CH2)mC(O)N(Rj)2,
(43) —(CH2)mN(Rj)C(O)N(Rj)2,
(44) —(CH2)mCO2H,
(45) —(CH2)mOCOH,
(46) —(CH2)mCO2Rf,
(47) —(CH2)mOCORf,
(48) —(CH2)mC3-7cycloalkyl,
(49) —(CH2)mC3-7cycloalkenyl,
(50) —(CH2)mC2-6cycloheteroalkyl,
(51) —(CH2)mC2-6cycloheteroalkenyl,
(52) —(CH2)maryl, and
(53) —(CH2)mheteroaryl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 substituents selected from:
oxo, —(CH2)l-3OH, —CN, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —C1-6alkyl (CH3) , 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, -SO2C1-6 alkyl, —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) —NO2,
(12) —NH2,
(13) —NH(C1-6alkyl),
(14) —N(C1-6alkyl)2,
(15) —OC1-6alkyl,
(16) —(CH2)qCO2H,
(17) —(CH2)qCO2C1-6alkyl,
(18) —CF3,
(19) —CN,
(20) —SO2C1-6alkyl, and
(21) —(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;
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, —C 1-6alkyl, —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, —C 1-6alkyl, —OC 1-6alkyl, halogen, —CH2F, —CHF2, —CF3, —CO2H, —CO2C 1-6alkyl, —C3-7cycloalkyl and heteroaryl;
each Re, Rg and Rh is independently selected from:
(1) hydrogen,
(2) —C1-6alkyl, and
(3) —O—C1-6alkyl,
wherein 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 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) 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, —NH2, —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;
and
t is 0,1,2,3or 4.

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Cyclic azabenzimidazole derivatives useful as anti-diabetic agents

Life of this patent

Cyclic azabenzimidazole derivatives useful as anti-diabetic agents

Life of this patent

Abstract

Claims22