Azabenzimidazole tetrahydrofuran derivatives

Patent metadata

Field	Value
Publication number	US-9868733-B2
Application number	US-201314419825-A
Country	US
Kind code	B2
Filing date	Aug 19, 2013
Priority date	Aug 22, 2012
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

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

What is claimed is:

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein:
T is N;
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, 4 or 5 substituents selected from R b ;
Z is NR 5 ;
each R1 is independently selected from:
(1) —(CH 2 ) p aryl-aryl, and
(2) —(CH 2 ) p aryl-heteroaryl,

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 heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , provided that when Y is:

and R 1 is biphenyl, then R 1 is substituted with 1, 2, 3 or 4 substituents independently selected from R a ;
R 2 is selected from halogen;
R 4 is selected from hydrogen, halogen, and —C 1-6 alkyl;
R 5 is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 1-6 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) halogen,
(2) —(CH 2 ) m OH,
(3) —C(O)R f ,
(4) —C 2-6 cycloheteroalkyl,
(5) —SO 2 —C 3-7 cycloalkyl, and
(6) -heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —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, and —CO 2 C 1-6 alkyl, and wherein cycloheteroalkyl 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 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, and —SO 2 C 1-6 alkyl;
each R b is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 1-6 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 1-6 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 , —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 Rj 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 Y is selected from:

wherein Y is substituted with 1, 2, 3, 4 or 5 substituents selected from R b ; or
a pharmaceutically acceptable salt thereof.

3. 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.

4. The compound according to claim 1 , wherein
each R 1 is independently selected from:
(1) biphenyl,
(2) phenyl-naphthalene,
(3) phenyl-pyridine, and
(4) phenyl-dihydropyrrolopyrazole,

wherein each phenyl, naphthalene, pyridine a

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
• Arasappan Ashok

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/397

  having four-membered rings, e.g. azetidine · CPC title

• A61K31/366

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

• A61K31/19

  Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60) · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title