Azabenzimidazole tetrahydropyran derivatives

Patent metadata

Field	Value
Publication number	US-9382243-B2
Application number	US-201314419842-A
Country	US
Kind code	B2
Filing date	Aug 16, 2013
Priority date	Aug 22, 2012
Publication date	Jul 5, 2016
Grant date	Jul 5, 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 N;
U is —CR 1 —;
V is —CR 2 —;
W is —CR 4 —;
X is selected from:
(1) —S—,
(2) —O—, and
(3) —NH—;

Y is selected from:

wherein Y is 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) phenyl,
(2) phenyl-pyrrolidine,
(3) biphenyl, and
(4) phenyl-pyridine,

wherein each cycloheteroalkyl, phenyl, 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 4 is selected from
(1) hydrogen,
(2) halogen, and
(3) —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) F,
(2) oxo,
(3) —OH,
(4) —CH 2 OH,
(5) —C(CH 3 ) 2 CH 2 OH,
(6) —C(CH 3 ) 2 OH,
(7) —CF 2 C(CH 3 ) 2 OH,
(8) —CH 2 C(CH 3 ) 2 OH,
(9) —CH(CF 3 )NH-cyclopropyl,
(10) —NHCO 2 CH 3 ,
(11) —CN,
(12) —CH 2 F,
(13) —CH 2 CF 3 ,
(14) —CH(NH 2 )CF 3 ,
(15) —NHCO 2 CH 2 CH(OH)CH 2 OH,
(16) —NHCO 2 (CH 2 ) 2 -imidazole,
(17) —NHCO 2 (CH 2 ) 2 -morpholine,
(18) —NHCO 2 (CH 2 ) 2 N(CH 3 ) 2 ,
(20) —OCH(CH 3 )CH 2 OH,
(21) —O-cyclobutyl,
(22) —O-oxetane,
(23) —O-tetrahydrothiopyran,
(24) —SO 2 CH 3 ,
(25) —CH 2 SO 2 CH 3 ,
(26) —(CH 2 ) 2 SO 2 CH 3 ,
(27) —SO 2 (CH 2 ) 2 CH 3 ,
(28) —SO 2 CH(CH 3 ) 2 ,
(29) —SO 2 CH 2 CH(CH 3 ) 2 ,
(30) —SO 2 CH 2 C(CH 3 ) 2 OH,
(31) —SO 2 -cyclopropyl,
(32) —SO 2 -cyclopentyl,
(33) —SO 2 -oxetane,
(34) —SO 2 CH 2 -oxetane,
(35) —SO 2 -azetidine,
(36) —SO 2 -piperidine,
(37) —SO 2 NH 2 ,
(38) —SO 2 NH(CH 2 ) 2 OH,
(39) —SO 2 NH(CH 2 ) 2 N(CH 3 ) 2 ,
(40) —SO 2 NH-cyclopropyl,
(41) —NHCH(CH 3 )(CH 2 ) 2 SO 2 CH 3 ,
(42) —C(O)pyrrolidine,
(43) —C(O)piperidine,
(44) —C(O)NHCH 3 ,
(45) —CH 2 CH(NH 2 )CO 2 H,
(46) —(CH 2 ) 3 CO 2 H,
(47) —CO 2 CH 3 ,
(48) —CO 2 CH(CH 3 ) 2 ,
(49) —CH(CF 3 )morpholine,
(50) pyrrolidine,
(51) pyrazole,
(52) triazole,
(53) pyrimidine,
(54) imidazole,
(55) oxadiazole, and
(56) oxazole;

each R b is independently selected from:
(1) —C 1-6 alkyl, and
(2) —(CH 2 )s-OH,

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 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 , and
(8) —C 1-6 alkyl-OH;

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 is independently selected from:
(1) pyrrolidine,
(2) piperidine,
(3) —(CH 2 ) 2 -imidazole, and
(4) —(CH 2 ) 2 -morpholine,

wherein each cycloheteroalkyl 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, and —CO 2 C 1-6 alkyl;
each R i is independently selected from C 1-6 alkyl;
r is 0, 1 or 2;
s is 0, 1, 2, 3 or 4; and
u is 0, 1, 2, 3 or 4.

2. The compound according to claim 1 , wherein X is —O—; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein Y is:

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

4. 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.

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

wherein each pyrrolidine, phenyl, and pyridine 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.

6. The compound according to claim 1 , wherein R 4 is hydrogen; and R 5 is hydrogen; or a pharmaceutically acceptable salt thereof.

7. A compound selected from:

or a pharmaceutically acceptable salt thereof.

8. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. 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.

10. A compound selected from:

or a pharmaceutically acceptable salt thereof.

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

• A61K31/366

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

• A61K31/4985

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

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/397

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

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title