Benzimidazole tetrahydrofuran derivatives

Patent metadata

Field	Value
Publication number	US-9540364-B2
Application number	US-201314420024-A
Country	US
Kind code	B2
Filing date	Aug 15, 2013
Priority date	Aug 22, 2012
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

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.

First claim

The invention claimed is:

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

Assignees

• Merck Sharp & Dohme

Inventors

• Apgar James M
• Biftu Tesfaye
• Chen Ping
• Feng Danqing
• Hicks Jacqueline D
• Kekec Ahmet
• Leavitt Kenneth J
• Li Bing
• Sebhat Iyassu
• Qian Xiaoxia
• Wei Lan
• Wilkening Robert R
• Wu Zhicai

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title