US 8,410,284 B2 · Cyclic benzimidazole derivatives useful as anti-diabetic agents

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.

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X is selected from:
(1) —CH2—,
(2) —CHF—,
(3) —CF2—,
(4) —S—,
(5) —O—,
(6) —O—CH2—,
(7) —NH—,
(8) —C(O)—,
(9) —NHC(O)—,
(10) —C(O)NH—,
(11) —NHSO2—,
(12) —SO2NH—, and
(13) —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) C3-10cycloalkyl,
(2) C3-10cycloalkenyl,
(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) —(CH2)mP(O)(OH)2,
(2) —(CH2)mP(O)H(OH),
(3) —(CH2)mP(O)(C1-6alkyl)2,
(4) —(CH2)mP(O)(OC1-6alkyl)2,
(5) —(CH2)mP(O)(OH)(C1-6alkyl),
(6) —(CH2)mP(O)(OH)(OC1-6alkyl),
(7) —(CH2)mP(O)(C1-6alkyl)(OC1-6alkyl),
(8) —(CH2)mP(O)(OH)(O—(CH2)0-4-aryl),
(9) —(CH2)mP(O)(NRgC(Rh)2CO2H)2,
(10) —(CH2)mP(O)(NRgC(Rh)2CO2C1-6alkyl)2,
(11) —(CH2)mP(O)(OH)(NRgC(Rh)2CO2H)2,
(12) —(CH2)mP(O)(OH)(NRgC(Rh)2CO2C1-6alkyl),
(13) —(CH2)mP(O)(NRgC(Rh)2CO2C1-6alkyl)(O—Ri),
(14) —(CH2)mP(O)(OC(Rh)2OC(O)C1-6alkyl)2,
(15) —(CH2)mP(O)(OH)(OC(Rh)2OC(O)C1-6alkyl),
(16) —(CH2)mP(O)(OH)(—O—(CH2)1-4—S(O)C1-6alkyl),
(17) —(CH2)mP(O)(—O—(CH2)1-4—S(O)C1-6alkyl)2,
(18) —(CH2)mP(O)(OH)(—O—(CH2)1-4—SC(O)C1-6alkyl),
(19) —(CH2)mP(O)(—O—(CH2)1-4—SC(O)C1-6alkyl)2,
(20) —(CH2)mP(O)(—O—(CH2)1-4—O),
(21) —(CH2)w—P(O)(Rv—Rn)Ro,
(22) —(CH2)w—P(O)(Rk—Rn)Rm—Rn, and
(23)
provided that when Rv is —O— or when Rk and Rm are both —O—, then Rn attached to —O— is independently selected from —H, —C1-6alkyl, —C(Rq)2—OC(O)Rs, and —C(Rq)2—O—C(O)ORs, provided that when Rv is —NH— or when Rk and Rm are both —NH—, then Rn attached to —NH— is independently selected from —H and —C(Ru)2C(O)ORs, provided that when Rk is —O— and Rm is —NH—, then Rn attached to —O— is independently selected from —H, —C1-6alkyl, aryl unsubstituted or substituted with 1, 2 or 3 substituents selected from Rw, and heteroaryl unsubstituted or substituted with 1, 2 or 3 substituents selected from Rw, and Rn attached to —NH— is independently selected from —H and —C(Ru)2COORs, 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, 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) biphenyl,
(18) —(CH2)pheteroaryl,
(19) —C2-6alkenyl-alkyl,
(20) —C2-6alkenyl-aryl,
(21) —C2-6alkenyl-heteroaryl,
(22) —C2-6alkenyl-C3-7cycloalkyl,
(23) —C2-6alkenyl-C3-7cycloalkenyl,
(24) —C2-6alkenyl-C2-7cycloheteroalkyl,
(25) —C2-6alkenyl-C2-7cycloheteroalkenyl,
(26) —C2-6alkynyl-(CH2)1-3—O-aryl,
(27) —C2-6alkynyl-alkyl,
(28) —C2-6alkynyl-aryl,
(29) —C2-6alkynyl-heteroaryl,
(30) —C2-6alkynyl-C3-7cycloalkyl,
(31) —C2-6alkynyl-C3-7cycloalkenyl,
(32) —C2-6alkynyl-C2-7cycloheteroalkyl,
(33) —C2-6alkynyl-C2-7cycloheteroalkenyl, and
(34) —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 and alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from:
halogen, CF3, —OH, —NH2, —C1-6alkyl, —OC1-6alkyl, —NHC1-6alkyl, and —N(C1-6alkyl)2, and wherein each cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents 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, and provided that if R1 or R2 is hydrogen, then at least one of R3 and R4 is not hydrogen;
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) —CH2CO2H, and
(4) —CH2CO2C1-6alkyl;
each Ra is independently selected from the group consisting of:
(1) halogen,
(2) oxo,
(3) —(CH2)rOH,
(4) —(CH2)rN(Rj)2,
(5) —(CH2)mNO2,
(6) —(CH2)rCN,
(7) —C1-6alkyl,
(8) —(CH2)rCF3,
(9) —(CH2)rOCF3,
(10) —OCH2OC1-6alkyl,
(11) —OCH2-aryl,
(12) —(CH2)rC(═N—OH)N(Rj)2,
(13) —(CH2)rOC1-6alkyl,
(14) —(CH2)rO-aryl,
(15) —OCH2phenyl,
(16) —(CH2)rSC1-6alkyl,
(17) —(CH2)rS(O)C1-6alkyl,
(18) —(CH2)rS(O)2C1-6alkyl,
(19) —(CH2)mNHS(O)2C1-6alkyl,
(20) —(CH2)mS(O)2N(C1-6alkyl)2,
(21) —(CH2)rC(O)Rf,
(22) —(CH2)rC(O)N(Rj)2,
(23) —(CH2)rN(Rj)C(O)Rf,
(24) —(CH2)mN(Rj)C(O)N(Rj)2,
(25) —(CH2)rCO2H,
(26) —(CH2)rOC(O)H,
(27) —(CH2)rCO2Rf,
(28) —(CH2)rOC(O)Rf,
(29) —(CH2)rC3-7cycloalkyl,
(30) —(CH2)rC3-7cycloalkenyl,
(31) —(CH2)rC2-6cycloheteroalkyl,
(32) —(CH2)rC2-6cycloheteroalkenyl,
(33) —(CH2)raryl, and
(34) —(CH2)rheteroaryl,
wherein each CH2 is unsubstituted or substituted with 1 or 2 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, phenyl, CH2phenyl, heteroaryl and CH2heteroaryl, and wherein alkyl, cycloalkyl, cycloheteroalkyl, phenyl, 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, 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) aryl,
(7) heteroaryl,
(8) halogen,
(9) —OH,
(10) —NO2,
(11) —NH2,
(12) —NH(C1-6alkyl),
(13) —N(C1-6alkyl)2,
(14) —OC1-6alkyl,
(15) —(CH2)qCO2H,
(16) —(CH2)qCO2C1-6alkyl,
(17) —CF3,
(18) —CN,
(19) —SO2C1-6alkyl, and
(20) —(CH2)qCON(Re)2,
wherein each CH2 is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, 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, —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, and
(2) 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(C1-6alkyl)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 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;
Rk, Rm and Rv are each independently selected from
(1) —O—, and
(2) —NH—;
each Rn is independently selected from:
(1) hydrogen,
(2) —C1-6alkyl,
(3) aryl,
(4) —C(Rq)2—OC(O)Rs,
(5) —C(Rq)2—O—C(O)ORs, and
(6) —C(Ru)2C(O)ORs,
wherein alkyl and aryl are unsubstituted or substituted with 1 or 2 substituents selected from Rw;
each Ro is independently selected from:
the group consisting of
(1) hydrogen,
(2) —C1-6alkyl,
(3) —CF3,
(4) —CHF2,
(5) —CH2F, and
(6) —CH2OH,
wherein alkyl is unsubstituted or substituted with 1 or 2 substituents selected from Rw;
each Rp is independently selected from:
(1) aryl, and
(2) heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substituents selected from Rw;
each Rq is independently selected from:
(1) hydrogen, and
(2) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with 1 or 2 substituents selected from Rw;
each Rs is independently selected from:
—C1-6alkyl, wherein alkyl is unsubstituted or substituted with 1 or 2 substituents selected from Rw;
each Ru is independently selected from:
(1) hydrogen, and
(2) —C1-6alkyl, or Ru and Ru together with the carbon they are attached form a C3-7cycloalkyl ring
wherein alkyl is unsubstituted or substituted with 1 or 2 substituents selected from Rw;
each Rw is independently selected from:
(1) halogen,
(2) CN,
(3) —C1-6alkyl,
(4) —O—C1-6alkyl,
(5) —O—CF3,
(6) —NH(C1-6alkyl),
(7) —N(C1-6alkyl)2,
(8) —S—C1-6alkyl,
(9) —CO2C1-6alkyl,
(10) —CONH(C1-6alkyl),
(11) —CON(C1-6alkyl)2, and
(12) phenyl,
wherein alkyl and phenyl are unsubstituted or substituted with 1 or 2 substituents selected from halogen and —C1-6alkyl;
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;
and
w is 0, 1, 2, 3 or 4.

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Cyclic benzimidazole derivatives useful as anti-diabetic agents

Life of this patent

Cyclic benzimidazole derivatives useful as anti-diabetic agents

Life of this patent

Abstract

Claims17