Substituted seven-membered heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment of diabetes

Patent metadata

Field	Value
Publication number	US-8980929-B2
Application number	US-201113643121-A
Country	US
Kind code	B2
Filing date	May 16, 2011
Priority date	May 21, 2010
Publication date	Mar 17, 2015
Grant date	Mar 17, 2015

Abstract

The present invention is directed to novel amino-substituted seven-membered heterocyclic compounds of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

First claim

What is claimed is:

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
X is O or S;
V is selected from the group consisting of:

Ar is phenyl optionally substituted with one to five R 1 substituents;
each R 1 is independently selected from the group consisting of
halogen,
cyano,
hydroxy,
C 1-6 alkyl, optionally substituted with one to five fluorines, and
C 1-6 alkoxy, optionally substituted with one to five fluorines;

each R 2 is independently selected from the group consisting of
hydrogen,
hydroxy,
halogen,
cyano,
heteroaryl,
C 1-10 alkoxy, wherein alkoxy is optionally substituted with one to five substituents independently selected from fluorine and hydroxy,
C 1-10 alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy,
C 2-10 alkenyl, wherein alkenyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy,
(CH 2 )-aryl, wherein aryl is optionally substituted with one to five substituents independently selected hydroxy, halogen, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,
(CH 2 )-heteroaryl, wherein heteroaryl is optionally substituted with one to three substituents independently selected from hydroxy, halogen, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,
(CH 2 )-heterocyclyl, wherein heterocyclyl is optionally substituted with one to three substituents independently selected from oxo, hydroxy, halogen, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,
(CH 2 )—C 3-6 cycloalkyl, wherein cycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, cyano, nitro, CO 2 H, C 1-6 alkyloxycarbonyl, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines,
(CH 2 )—COOH,
(CH 2 )—COOC 1-6 alkyl,
(CH 2 )—NR 4 R 5 ,
(CH 2 )—CONR 4 R 5 ,
(CH 2 )—OCONR 4 R 5 ,
(CH 2 )—SO 2 NR 4 R 5 ,
(CH 2 )—SO 2 R 6 ,
(CH 2 )—NR 7 SO 2 R 6 ,
(CH 2 )—NR 7 CONR 4 R 5 ,
(CH 2 )—NR 7 COR 7 , and
(CH 2 )—NR 7 CO 2 R 6 ;

wherein any individual methylene (CH 2 ) carbon atom is optionally substituted with one to two substituents independently selected from fluorine, hydroxy, C 1-4 alkyl, and C 1-4 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;
R 3a , R 3b and R 3c are each independently hydrogen or C 1-4 alkyl optionally substituted with one to five fluorines;
R 4 and R 5 are each independently selected from the group consisting of
hydrogen,
(CH 2 )-phenyl,
(CH 2 )—C 3-6 cycloalkyl, and
C 1-6 alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxy and wherein phenyl and cycloalkyl are optionally substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;

or R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said heterocyclic ring is optionally substituted with one to three substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines;
each R 6 is independently C 1-6 alkyl, wherein alkyl is optionally substituted with one to five substituents independently selected from fluorine and hydroxyl;
R 7 is hydrogen or R 6 ; and
R 8 is selected from the group consisting of
-hydrogen,
—(CH 2 )-phenyl,
—(CH 2 )-heteroaryl,
—(CH 2 )—C 3-6 cycloalkyl,
—SO 2 C 1-6 alkyl,
—CH 2 SO 2 C 1-6 alkyl,
—SO 2 C 3-6 cycloalkyl, and
—C 1-6 alkyl, wherein each alkyl residue is optionally substituted with one to five substituents independently selected from fluorine and hydroxy and wherein phenyl, heteroaryl, and each cycloalkyl residue are optionally substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines.

2. The compound of claim 1 wherein Ar is optionally substituted with one to three substituents independently selected from the group consisting of fluorine, chlorine, bromine, methyl, trifluoromethyl, and trifluoromethoxy.

3. The compound of claim 2 wherein Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.

4. The compound of claim 1 wherein R 3a , R 3b and R 3c are each hydrogen.

5. The compound of claim 1 of structural formula Ia having the indicated absolute stereochemical configuration at the two stereogenic carbon atoms marked with an *:

6. The compound of claim 1 of structural formulae Ic and Id having the indicated stereochemical configuration at the three stereogenic carbon atoms marked with an *:

wherein X, Ar, and V are as defined in claim 1 .

7. The compound of claim 6 of structural formula Ic having the indicated absolute stereochemical configuration at the three stereogenic carbon atoms marked with an *:

8. The compound of claim 7 wherein V is selected from the group consisting of:

9. The compound of claim 7 wherein V is selected from the group consisting of:

10. The compound of claim 4 wherein R 2 is selected from the group consisting of:
hydrogen;
cyano;
CONH 2 ;
C 1-3 alkyl, wherein alkyl is optionally substituted with one to five fluorines; and
C 3-5 cycloalkyl, wherein cycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, and C 1-4 alkyl, wherein alkyl is optionally substituted with one to five fluorines.

11. The compound of claim 4 wherein R 8 is selected from the group consisting of:
-hydrogen;
-phenyl;
-heteroaryl;
—C 3-6 cycloalkyl;
—SO 2 C 1-3 alkyl;
—CH 2 SO 2 C 1-3 alkyl;
—SO 2 C 3-6 cycloalkyl; and
—C 1-5 alkyl; wherein each alkyl residue is optionally substituted with one to five substituents independently selected from fluorine and hydroxy and wherein phenyl, heteroaryl, and each cycloalkyl residue are optionally substituted with one to five substituents independently selected from halogen, hydroxy, C 1-6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are optionally substituted with one to five fluorines.

12. The compound of claim 1 wherein

Assignees

• Hicks Jacqueline D
• Biftu Tesfaye
• Chen Ping
• Qian Xiaoxia
• Wilkening Robert R
• Merck Sharp & Dohme

Inventors

• Hicks Jacqueline D
• Biftu Tesfaye
• Chen Ping
• Qian Xiaoxia
• Wilkening Robert R

Classifications

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61K31/4162

  condensed with heterocyclic ring systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title