Prolylcarboxypeptidase inhibitors

Patent metadata

Field	Value
Publication number	US-9365539-B2
Application number	US-201113642646-A
Country	US
Kind code	B2
Filing date	May 6, 2011
Priority date	May 11, 2010
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

Compounds of structural formula I are inhibitors of prolylcarboxypeptidase (PrCP). The compounds of the present invention are useful for the prevention and treatment of conditions related to the enzymatic activity of PrCP such as abnormal metabolism, including obesity; diabetes; metabolic syndrome; obesity related disorders; and diabetes related disorders.

First claim

What is claimed is:

1. A compound of structural formula I-1 or I-2:

or a pharmaceutically acceptable salt thereof; wherein
“a” is absent;
X is independently selected from N and CR 5 ;
each R 1 is independently selected from the group consisting of: —C 2-6 cycloheteroalkyl, and —(CH 2 ) 2 phenyl, wherein each CH 2 , cycloheteroalkyl and phenyl is unsubstituted or substituted with one to three groups independently selected from R a ;
each R 2 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R b ;
each R 3 is independently selected from the group consisting of:
(1) —(CH 2 ) n aryl, and
(2) —(CH 2 ) n heteroaryl,

wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R c ;
each R 4 is independently selected from the group consisting of: —(CH 2 ) s aryl, wherein each CH 2 and aryl is unsubstituted or substituted with one to three substituents selected from R d ;
each R 5 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R e ;
each R a is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) oxo,
(4) —C 1-6 alkyl,
(5) —OC 1-6 alkyl,
(6) halogen,
(7) —CF 3 ,
(8) —OCF 3 ,
(9) —CN,
(10) —C(O)C 1-6 alkyl,
(11) —CO 2 H,
(12) —CO 2 C 1-6 alkyl,
(13) —(CH 2 ) t C 3-7 cycloalkyl,
(14) —(CH 2 ) t C 2-6 cycloheteroalkyl,
(15) —(CH 2 ) 0-1 aryl,
(16) —CH(phenyl) 2 ,
(17) —(CH 2 ) t heteroaryl,
(18) —SO 2 C 1-6 alkyl,
(19) —SO 2 N(R f ) 2 ;
(20) —SO 2 —C 3-7 cycloalkyl,
(21) —SO 2 —C 2-6 cycloheteroalkyl,
(22) —SO 2 -aryl-, and
(23) —SO 2 -heteroaryl;

each R b is independently selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OC 1-6 alkyl,
(4) —CO 2 H, and
(5) —CO 2 C 1-6 alkyl,

wherein alkyl can be substituted with one to three fluorines;
each R c is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) oxo,
(4) —C 1-6 alkyl,
(5) —OC 1-6 alkyl,
(6) halogen,
(7) —CF 3 ,
(8) —OCF 3 ,
(9) —CN,
(10) —CO 2 H, and
(11) —CO 2 C 1-6 alkyl;

each R d is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) oxo,
(4) —C 1-6 alkyl,
(5) —OC 1-6 alkyl,
(6) halogen,
(7) —CF 3 ,
(8) —OCF 3 ,
(9) —CN,
(10) —CO 2 H, and
(11) —CO 2 C 1-6 alkyl;

each R e is independently selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OC 1-6 alkyl,
(4) —CO 2 H, and
(5) —CO 2 C 1-6 alkyl,

wherein alkyl can be substituted with one to three fluorines;
each R f is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl;

n is selected from 0, 1, 2, and 3;
r is selected from 0, 1, 2, 3 and 4;
s is selected from 0, 1, 2 and 3; and
t is selected from 0, 1, 2 and 3.

2. The compound of claim 1 wherein R 2 is hydrogen; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein X is independently selected from N and CH; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein R 4 is -phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents selected from R d ; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein
X is independently selected from N and CH;
each R 1 is independently selected from the group consisting of: —C 2-6 cycloheteroalkyl, and —(CH 2 ) 2 phenyl, wherein each CH 2 , cycloheteroalkyl and phenyl is unsubstituted or substituted with one to three groups independently selected from R a ;
R 2 is hydrogen;
each R 3 is independently selected from the group consisting of:
(1) —(CH 2 ) n aryl, and
(2) —(CH 2 ) n heteroaryl,

wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R c ;
each R 4 is independently selected from the group consisting of: —(CH 2 ) s aryl, wherein each CH 2 , and aryl is unsubstituted or substituted with one to three substituents selected from R d ;
or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein:
“a” is absent;
X is independently selected from N and CH;
each R 1 is independently selected from the group consisting of: —C 2-6 cycloheteroalkyl, and —(CH 2 ) 2 phenyl, wherein each CH 2 , cycloheteroalkyl and phenyl is unsubstituted or substituted with one to three groups independently selected from R a ;
R 2 is hydrogen;
each R 3 is independently selected from the group consisting of:
(1) —(CH 2 ) n aryl, and
(2) —(CH 2 ) n heteroaryl,

wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R c ; and
R 4 is -phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents selected from R d ;
or a pharmaceutically acceptable salt thereof.

7. A compound of structural formula I-1 or I-2:

or a pharmaceutically acceptable salt thereof; wherein:
“a” is absent;
X is independently selected from N and CH;
each R 1 is independently selected from the group consisting of:
(1) pyrrolidine, and
(2) —(CH 2 ) 2 -phenyl,

wherein each CH 2 , pyrrolidine and phenyl is unsubstituted or substituted with one to three groups independently selected from R a ;
R 2 is hydrogen;
each R 3 is independently selected from the group consisting of:
(1) —(CH 2 ) 0-2 phenyl,
(2) —(CH 2 ) 0-2 pyridine,
(3) —(CH 2 ) 0-2 pyrimidine,
(4) —(CH 2 ) 0-2 pyrazine, and
(5) —(CH 2 ) 0-2 imidazole,

wherein each CH 2 , phenyl, pyridine, pyrimidine, pyrazine and imidazole is unsubstituted or substituted with one to three substituents selected from R c ; and
R 4 is -phenyl, wherein phenyl is unsubstituted or substituted with one to three substituents selected from R d ;
or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable carrier.

Assignees

• Hale Jeffrey J
• Jiang Jinlong
• Shen Dong-Ming
• Shi Zhi-Cai
• Shu Min
• Wu Zhicai
• Yang Cangming
• Merck Sharp & Dohme

Inventors

• Hale Jeffrey J
• Jiang Jinlong
• Shen Dong-Ming
• Shi Zhi-Cai
• Shu Min
• Wu Zhicai
• Yang Cangming

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title