Benzimidazole tetrahydrofuran derivatives
View Patent ↗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.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein:
T is CR 3 ;
U is CR 1 ;
V is CR 2 ;
W is CR 4 ;
X is —O—;
Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R b ;
Z is selected from:
(1) NR 5 ,
(2) —S—, and
(3) —O—;
each R 1 is independently selected from:
(1) —(CH 2 ) p aryl-aryl and
(2) —(CH 2 ) p aryl-C 2-10 cycloheteroalkyl,
wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 , and wherein each aryl and cycloheteroalkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ;
each R 2 is independently selected from: halogen;
R 3 and R 4 are each independently selected from:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —C 2-6 alkenyl,
(5) —C 2-6 alkynyl,
(6) —C 3-10 cycloalkyl,
(7) —C 3-10 cycloalkenyl,
(8) aryl,
(9) heteroaryl,
(10) —CN,
(11) —CF 3 ,
(12) —OH,
(13) —OC 1-6 alkyl,
(14) —NH 2 ,
(15) —NHC 1-6 alkyl,
(16) —N(C 1-6 alkyl) 2 ,
(17) —SC 1-6 alkyl,
(18) —SOC 1-6 alkyl,
(19) —SO 2 C 1-6 alkyl,
(20) —NHSO 2 C 1-6 alkyl,
(21) —NHC(O)C 1-6 alkyl,
(22) —SO 2 NHC 1-6 alkyl, and
(23) —C(O)NHC 1-6 alkyl;
R 5 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 2-6 alkenyl,
(4) —(CH 2 )—OH,
(5) —CH 2 CO 2 H, and
(6) —CH 2 CO 2 C 1-6 alkyl;
each R a is independently selected from the group consisting of:
(1) —(CH 2 ) m -halogen,
(2) oxo,
(3) —(CH 2 ) m OH,
(4) —(CH 2 ) m N(R j ) 2 ,
(5) —(CH 2 ) m NO 2 ,
(6) —(CH 2 ) m CN,
(7) —C 1-6 alkyl,
(8) —(CH 2 ) m CF 3 ,
(9) —(CH 2 ) m OCF 3 ,
(10) —O—(CH 2 ) m —OC 1-6 alkyl,
(11) —(CH 2 ) m N(R j )C(O)R f ,
(12) —(CH 2 ) m N(R j )CO 2 R f ,
(13) —(CH 2 ) m C(═N—OH)N(R j ) 2 ,
(14) —(CH 2 ) m OC 1-6 alkyl,
(15) —(CH 2 ) m O—(CH 2 ) m —C 3-7 cycloalkyl,
(16) —(CH 2 ) m O—(CH 2 ) m —C 2-7 cycloheteroalkyl,
(17) —(CH 2 ) m O—(CH 2 ) m -aryl,
(18) —(CH 2 ) m O—(CH 2 ) m -heteroaryl,
(19) —(CH 2 ) m SC 1-6 alkyl,
(20) —(CH 2 ) m S(O)C 1-6 alkyl,
(21) —(CH 2 ) m SO 2 C 1-6 alkyl,
(22) —(CH 2 ) m SO 2 (CH 2 ) m —C 3-7 cycloalkyl,
(23) —(CH 2 ) m SO 2 (CH 2 ) m —C 2-7 cycloheteroalkyl,
(24) —(CH 2 ) m SO 2 (CH 2 ) m -aryl,
(25) —(CH 2 ) m SO 2 (CH 2 ) m -heteroaryl,
(26) —(CH 2 ) m SO 2 NH 2 ,
(27) —(CH 2 ) m SO 2 NHC 1-6 alkyl,
(28) —(CH 2 ) m SO 2 NHC 3-7 cycloalkyl,
(29) —(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl,
(30) —(CH 2 ) m SO 2 NH-aryl,
(31) —(CH 2 ) m SO 2 NH-heteroaryl,
(32) —(CH 2 ) m NHSO 2 —C 1-6 alkyl,
(33) —(CH 2 ) m NHSO 2 —C 3-7 cycloalkyl,
(34) —(CH 2 ) m NHSO 2 —C 2-7 cycloheteroalkyl,
(35) —(CH 2 ) m NHSO 2 -aryl,
(36) —(CH 2 ) m NHSO 2 NH-heteroaryl,
(37) —(CH 2 ) m N(R j )—C 1-6 alkyl,
(38) —(CH 2 ) m N(R j )—C 3-7 cycloalkyl,
(39) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkyl,
(40) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkenyl,
(41) —(CH 2 ) m N(R j )-aryl,
(42) —(CH 2 ) m N(R j )-heteroaryl,
(43) —(CH 2 ) m C(O)R f ,
(44) —(CH 2 ) m C(O)N(R j ) 2 ,
(45) —(CH 2 ) m N(R j )C(O)N(R j ) 2 ,
(46) —(CH 2 ) m CO 2 H,
(47) —(CH 2 ) m OCOH,
(48) —(CH 2 ) m CO 2 R f ,
(49) —(CH 2 ) m OCOR f ,
(50) —(CH 2 ) m C 3-7 cycloalkyl,
(51) —(CH 2 ) m C 3-7 cycloalkenyl,
(52) —(CH 2 ) m C 2-6 cycloheteroalkyl,
(53) —(CH 2 ) m C 2-6 cycloheteroalkenyl,
(54) —(CH 2 ) m aryl, and
(55) —(CH 2 ) m heteroaryl,
wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: —OH, —(CH 2 ) 1-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , oxo, —C 1-6 alkyl, —C 1-6 alkyl substituted with 1-5 OH, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, 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, —(CH 2 ) 1-5 OH, —(CH 2 ) 1-5 CN, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —C 1-6 alkyl substituted with 1-5 OH, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —(CH 2 ) 1-5 CF 3 optionally substituted with 1, 2 or 3 —OH, —CO 2 H, —CO 2 C 1-6 alkyl, —SO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl;
each R b is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 2-6 alkenyl,
(4) —(CH 2 ) n —C 3-10 cycloalkyl,
(5) —(CH 2 ) n —C 3-10 cycloalkenyl,
(6) —(CH 2 ) n —C 2-10 cycloheteroalkyl,
(7) —(CH 2 ) n —C 2-10 cycloheteroalkenyl,
(8) —(CH 2 ) n -aryl,
(9) —(CH 2 ) n -heteroaryl,
(10) oxo,
(11) —(CH 2 ) n —CF 3 ,
(12) —(CH 2 ) n —CN,
(13) —(CH 2 ) t -halogen,
(14) —(CH 2 ) s —OH,
(15) —(CH 2 ) n —NO 2 ,
(16) —(CH 2 ) n —NH 2 ,
(17) —(CH 2 ) n —NH(C 1-6 alkyl),
(18) —(CH 2 ) n —N(C 1-6 alkyl) 2 ,
(19) —(CH 2 ) n —NHCO 2 H,
(20) —(CH 2 ) n —OC 1-6 alkyl,
(21) —(CH 2 ) n —OC 2-6 alkenyl,
(22) —(CH 2 ) n —COC 1-6 alkyl,
(23) —(CH 2 ) n —CO 2 H,
(24) —(CH 2 ) n —OCOH,
(25) —(CH 2 ) n —CO 2 R i ,
(26) —(CH 2 ) n —OC(O)R i ,
(27) —(CH 2 ) q —C(O)N(R e ) 2 ,
(28) —(CH 2 ) q —CO 2 N(R e ) 2 ,
(29) —(CH 2 ) n —C(O)(CH 2 ) n N(R g ) 2 ,
(30) —(CH 2 ) n —OC(O)(CH 2 ) n N(R g ) 2 ,
(31) —(CH 2 ) n —N(R e )C(O)C 1-6 alkyl,
(32) —(CH 2 ) n —N(R e )SO 2 R i ,
(33) —(CH 2 ) n —SO 2 C 1-6 alkyl,
(34) —(CH 2 ) n —SO 2 N(R e )R g ,
(35) —(CH 2 ) n —SO 2 N(R e )C(O)R i ,
(36) —(CH 2 ) n —SO 2 N(R e )CO 2 R i ,
(37) —(CH 2 ) n —SO 2 N(R e )CON(R g ) 2 ,
(38) —(CH 2 ) n —C(O)N(R e )SO 2 R i ,
(39) —(CH 2 ) n —N(R e )C(O)N(R g ) 2 ,
(40) ═N(OH), and
(41) ═N(OC 1-6 alkyl),
wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: —C 1-6 alkyl, —OH, halogen and —NH 2 wherein each NH is unsubstituted or substituted with 1 substituent selected from R c , and wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R c ;
each R c is independently selected from:
(1) halogen,
(2) oxo,
(3) —(CH 2 ) r OH,
(4) —(CH 2 ) r N(R e ) 2 ,
(5) —(CH 2 ) r CN,
(6) —C 1-6 alkyl,
(7) —CF 3 ,
(8) —C 1-6 alkyl-OH,
(9) —OCH 2 OC 1-6 alkyl,
(10) —(CH 2 ) r OC 1-6 alkyl,
(11) —OCH 2 aryl,
(12) —(CH 2 ) r SC 1-6 alkyl,
(13) —(CH 2 ) r C(O)R f ,
(14) —(CH 2 ) r C(O)N(R e ) 2 ,
(15) —(CH 2 ) r CO 2 H,
(16) —(CH 2 ) r CO 2 R f ,
(17) —(CH 2 ) r C 3-7 cycloalkyl,
(18) —(CH 2 ) r C 2-6 cycloheteroalkyl,
(19) —(CH 2 ) r aryl, and
(20) —(CH 2 ) r heteroaryl,
wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R h ) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl 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(R h ) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl and heteroaryl;
each R e , R g and R h is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —O—C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;
each R j is independently selected from:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) C 3-6 cycloalkyl,
(4) —C(O)R i ,
(5) —CO 2 R i , and
(6) —SO 2 R i ,
wherein alkyl and cycloalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ;
each R f and R i is independently selected from:
(1) C 1-6 alkyl,
(2) —(CH 2 ) r C 4-7 cycloalkyl,
(3) —(CH 2 ) r C 4-7 cycloalkenyl,
(4) —(CH 2 ) r C 3-7 cycloheteroalkyl,
(5) —(CH 2 ) r C 3-7 cycloheteroalkenyl,
(6) —(CH 2 ) r aryl, and
(7) —(CH 2 ) r 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, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, 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.
2. The compound according to claim 1 wherein T is CR 3 ; U is CR 1 ; V is CR 2 ; and W is CR 4 , wherein R 3 is hydrogen or halogen; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 wherein T is CR 3 ; U is CR 1 ; V is CR 2 ; and W is CR 4 , wherein R 3 is hydrogen or halogen; and R 2 is halogen; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 , wherein T is CR 3 ; U is CR 1 ; V is CR 2 ; and W is CR 4 , wherein R 3 is hydrogen or halogen; R 2 is halogen; and R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , wherein Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 , wherein Y is:
wherein Y is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 , wherein Z is NR 5 ; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 , wherein each R 1 is independently selected from: aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ; and
R 2 is selected from halogen;
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 , wherein each R 1 is independently selected from: biphenyl, wherein each phenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , and
R 2 is selected from halogen;
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 , wherein each R 1 is independently selected from: biphenyl, wherein each phenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ; and
R 2 is F or Cl;
or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 , wherein R 3 is hydrogen or halogen; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 , wherein R 3 is hydrogen or F; R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 wherein:
T is CR 3 ;
U is CR 1 ;
V is CR 2 ;
W is CR 4 ;
X is —O—;
Y is:
wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R b ;
Z is NR 5 ;
each R 1 is independently selected from: aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ;
R 2 is halogen;
R 3 is hydrogen or halogen;
R 4 is hydrogen; and
R 5 is hydrogen;
or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 wherein:
T is CR 3 ;
U is CR 1 ;
V is CR 2 ; and
W is CR 4 ;
X is —O—;
Y is:
wherein Y is unsubstituted or substituted with 1, 2 or 3 substituents selected from R b ;
Z is NR 5 ;
each R 1 is independently selected from: aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ;
R 2 is halogen;
R 3 is hydrogen or halogen;
R 4 is hydrogen; and
R 5 is hydrogen;
or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
16. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a compound selected from simvastatin, ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.
18. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.