Azabenzimidazole hexahydrofuro[3,2-b]furan derivatives

Patent metadata

Field	Value
Publication number	US-9290517-B2
Application number	US-201314419774-A
Country	US
Kind code	B2
Filing date	Aug 19, 2013
Priority date	Aug 22, 2012
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

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 selected from the group consisting of: CR 3 , N and N-oxide;
U is selected from the group consisting of: CR 1 , N and N-oxide;
V is selected from the group consisting of: CR 2 , N and N-oxide;
W is selected from the group consisting of: CR 4 , N and N-oxide,
provided that at least one of T, U, V and W is N or N-oxide;
X is selected from:
(1) —CH 2 —,
(2) —CHF—,
(3) —CF 2 —,
(4) —S—,
(5) —O—,
(6) —O—CH 2 —,
(7) —O—CH 2 CH 2 —,
(8) —NH—,
(9) —C(O)—,
(10) —NHC(O)—,
(11) —C(O)NH—,
(12) —NHSO 2 —,
(13) —SO 2 NH—, and
(14) —CO 2 —,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, NH 2 , C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and —CH 2 phenyl, and wherein each NH is unsubstituted or substituted with 1 substituent selected from: C 1-6 alkyl, CO 2 H, CO 2 C 1-6 alkyl, COC 1-6 alkyl, phenyl and —CH 2 phenyl;
Y is selected from:

wherein A is selected from: CH 2 , NH, NC 1-6 alkyl, O and S, and 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 and R 2 is independently selected from:
(1) hydrogen,
(2) halogen,
(3) CN,
(4) CF 3 ,
(5) —C 1-6 alkyl,
(6) —C 2-6 alkenyl,
(7) —C 2-6 alkynyl,
(8) —(CH 2 ) p C 3-10 cycloalkyl,
(9) —(CH 2 ) p C 3-7 cycloalkyl-aryl,
(10) —(CH 2 ) p C 3-7 cycloalkyl-heteroaryl,
(11) —(CH 2 ) p C 4-10 cycloalkenyl,
(12) —(CH 2 ) p C 4-7 cycloalkenyl-aryl,
(13) —(CH 2 ) p C 4-7 cycloalkenyl-heteroaryl,
(14) —(CH 2 ) p C 2-10 cycloheteroalkyl,
(15) —(CH 2 ) p C 2-10 cycloheteroalkenyl,
(16) —(CH 2 ) p aryl,
(17) —(CH 2 ) p aryl-C 1-8 alkyl,
(18) —(CH 2 ) p aryl-C 2-8 alkenyl,
(19) —(CH 2 ) p aryl-C 2-8 alkynyl-C 1-8 alkyl,
(20) —(CH 2 ) p aryl-C 2-8 alkynyl-C 3-7 cycloalkyl,
(21) —(CH 2 ) p aryl-C 2-8 alkynyl-C 3-7 cycloalkenyl,
(22) —(CH 2 ) p aryl-C 2-8 alkynyl-C 2-10 cycloheteroalkyl,
(23) —(CH 2 ) p aryl-C 2-8 alkynyl-C 2-10 cycloheteroalkenyl,
(24) —(CH 2 ) p aryl-C 2-8 alkynyl-aryl,
(25) —(CH 2 ) p aryl-C 2-8 alkynyl-heteroaryl,
(26) —(CH 2 ) p aryl-C 3-7 cycloalkyl,
(27) —(CH 2 ) p aryl-C 3-7 cycloalkenyl,
(28) —(CH 2 ) p aryl-C 2-10 cycloheteroalkyl,
(29) —(CH 2 ) p aryl-C 2-10 cycloheteroalkenyl,
(30) —(CH 2 ) p aryl-aryl,
(31) —(CH 2 ) p aryl-heteroaryl,
(32) —(CH 2 ) p heteroaryl,
(33) —(CH 2 ) p heteroaryl-C 3-7 cycloalkyl,
(34) —(CH 2 ) p heteroaryl-C 2-10 cycloheteroalkyl,
(35) —(CH 2 ) p heteroaryl-C 2-10 cycloheteroalkenyl,
(36) —(CH 2 ) p heteroaryl-aryl,
(37) —(CH 2 ) p heteroaryl-heteroaryl,
(38) —C 2-6 alkenyl-alkyl,
(39) —C 2-6 alkenyl-aryl,
(40) —C 2-6 alkenyl-heteroaryl,
(41) —C 2-6 alkenyl-C 3-7 cycloalkyl,
(42) —C 2-6 alkenyl-C 3-7 cycloalkenyl,
(43) —C 2-6 alkenyl-C 2-7 cycloheteroalkyl,
(44) —C 2-6 alkenyl-C 2-7 cycloheteroalkenyl,
(45) —C 2 -6 alkynyl-(CH 2 ) 1-3 —O-aryl,
(46) —C 2-6 alkynyl-alkyl,
(47) —C 2-6 alkynyl-aryl,
(48) —C 2-6 alkynyl-heteroaryl,
(49) —C 2-6 alkynyl-C 3-7 cycloalkyl,
(50) —C 2-6 alkynyl-C 3-7 cycloalkenyl,
(51) —C 2-6 alkynyl-C 2-7 cycloheteroalkyl,
(52) —C 2-6 alkynyl-C 2-7 cycloheteroalkenyl, and
(53) —C(O)NH—(CH 2 ) 0-3 phenyl,

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 ,
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a ,
provided that at least one of and only one of R 1 and R 2 is selected from the group consisting of: hydrogen, halogen, —CN, —CF 3 , —C 1-6 alkyl, —C 2-6 alkenyl and —C 2-6 alkynyl;
R 3 and R 4 are each independently absent or 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 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) —(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 O—SO 2 C 1-6 alkyl,
(23) —(CH 2 ) m SO 2 (CH 2 ) m —C 3-7 cycloalkyl,
(24) —(CH 2 ) m SO 2 (CH 2 ) m —C 2-7 cycloheteroalkyl,
(25) —(CH 2 ) m SO 2 (CH 2 ) m -aryl,
(26) —(CH 2 ) m SO 2 (CH 2 ) m -heteroaryl,
(27) —(CH 2 ) m SO 2 NH 2 ,
(28) —(CH 2 ) m SO 2 NHC 1-6 alkyl,
(29) —(CH 2 ) m SO 2 NHC 3-7 cycloalkyl,
(30) —(CH 2 ) m SO 2 NHC 2-7 cycloheteroalkyl,
(31) —(CH 2 ) m SO 2 NH-aryl,
(32) —(CH 2 ) m SO 2 NH-heteroaryl,
(33) —(CH 2 ) m NHSO 2 —C 1-6 alkyl,
(34) —(CH 2 ) m NHSO 2 —C 3-7 cycloalkyl,
(35) —(CH 2 ) m NHSO 2 —C 2-7 cycloheteroalkyl,
(36) —(CH 2 ) m NHSO 2 -aryl,
(37) —(CH 2 ) m NHSO 2 NH-heteroaryl,
(38) —(CH 2 ) m N(R j )—C 1-6 alkyl,
(39) —(CH 2 ) m N(R j )—C 3-7 cycloalkyl,
(40) —(CH 2 ) m N(R j )—(CH 2 ) m —C 3-7 cycloalkyl,
(41) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkyl,
(42) —(CH 2 ) m N(R j )—(CH 2 ) m —C 2-7 cycloheteroalkyl,
(43) —(CH 2 ) m N(R j )—C 2-7 cycloheteroalkenyl,
(44) —(CH 2 ) m N(R j )—(CH 2 ) m —C 2-7 cycloheteroalkenyl,
(45) —(CH 2 ) m N(R j )-aryl,
(46) —(CH 2 ) m N(R j )—(CH 2 ) m -aryl,
(47) —(CH 2 ) m N(R j )-heteroaryl,
(48) —(CH 2 ) m N(R j )—(CH 2 ) m -heteroaryl,
(49) —(CH 2 ) m C(O)R f ,
(50) —(CH 2 ) m C(O)N(R j ) 2 ,
(51) —(CH 2 ) m N(R j )C(O)N(R j ) 2 ,
(52) —(CH 2 ) m CO 2 H,
(53) —(CH 2 ) m OCOH,
(54) —(CH 2 ) m CO 2 R f ,
(55) —(CH 2 ) m OCOR f ,
(56) —(CH 2 ) m C 3-7 cycloalkyl,
(57) —(CH 2 ) m C 3-7 cycloalkenyl,
(58) —(CH 2 ) m C 2-6 cycloheteroalkyl,
(59) —(CH 2 ) m C 2-6 cycloheteroalkenyl,
(60) —(CH 2 ) m aryl, and
(61) —(CH 2 ) m heteroaryl,

wherein each CH 2 is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —(CH 2 ) 1 -30H, —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 , —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 substituent

Assignees

• Merck Sharp & Dohme

Inventors

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

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4985

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title