Benzimidazole tetrahydropyran derivatives
View Patent ↗Novel compounds described herein are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPKactivated 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) aryl-C 2-10 cycloheteroalkyl, and
(2) aryl-aryl,
wherein each cycloheteroalkyl and aryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ;
R 2 is 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 ) n 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 i )-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) 2 , oxo, —C 1-6 alkyl, —C 1-6 alkyl substituted with 1-5 OH, —OC 1-6 alkyl, halogen, —CH 2 F, —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 , or
wherein two R b substituents and the carbon to which they are attached may form a 3 to 6 membered cycloalkyl ring, a 3-6 membered cycloalkenyl ring, a 3-6 membered cycloheteroalkyl ring or a 3-6 membered cycloheteroalkenyl ring, wherein the ring 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;
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:
(1) phenyl-pyrrolidine, and
(2) biphenyl,
wherein each pyrrolidine and 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.
9. 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 halogen;
or a pharmaceutically acceptable salt thereof.
10. 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.
11. 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.
12. 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:
(1) aryl-C 2-10 cycloheteroalkyl, and
(2) aryl-aryl,
wherein each cycloheteroalkyl and 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.
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 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.
14. The compound according to claim 1 , selected from:
or a pharmaceutically acceptable salt thereof.
15. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. 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.
17. 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.