Benzimidazole hexahydrofuro[3,2-b]furan derivatives

Patent metadata

Field	Value
Publication number	US-9556193-B2
Application number	US-201314420011-A
Country	US
Kind code	B2
Filing date	Aug 16, 2013
Priority date	Aug 22, 2012
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The novel benzimidazole hexahydrofuro[3,2-B]furan derivatives of the present invention 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

What is 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 selected from:

wherein Y is unsubstituted or substituted with 1, 2, 3 or 4 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,
(2) aryl-aryl, and
(3) aryl-heteroaryl,

wherein each cycloheteroalkyl, aryl and heteroaryl 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 ) u 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, —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, —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 )qC(O)N(R e ) 2 ,
(28) —(CH 2 )qCO 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 cycloalk

Assignees

• Merck Sharp & Dohme
• Merck Shapr & Dohme Corp

Inventors

• Apgar James M
• Arasappan Ashok
• Biftu Tesfaye
• Chen Ping
• Feng Danqing
• Guidry Erin
• Hicks Jacqueline
• 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

• C07D493/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/366

  having six-membered rings, e.g. delta-lactones · CPC title

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title