Antidiabetic tricyclic compounds

Patent metadata

Field	Value
Publication number	US-10519115-B2
Application number	US-201415032191-A
Country	US
Kind code	B2
Filing date	Nov 10, 2014
Priority date	Nov 15, 2013
Publication date	Dec 31, 2019
Grant date	Dec 31, 2019

Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

First claim

What is claimed is:

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein
A is:

B is selected from the group consisting of:
(1) phenyl, and
(2) pyridyl;

R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —C 1-6 alkyl,
(4) —(CH 2 ) r —OC 1-6 alkyl,
(5) —(CH 2 ) r —C 3-6 cycloalkyl, and
(6) —(CH 2 ) r —O—(CH 2 ) r —C 3-6 cycloalkyl,

wherein each CH 2 , —C 1-6 alkyl, —OC 1-6 alkyl and —C 3-6 cycloalkyl is unsubstituted or substituted with one to four substituents selected from halogen, —C 1-6 alkyl and —(CH 2 ) v —C 3-6 cycloalkyl;
R 2 is halogen;
each R 3 when present is independently selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —C 1-6 alkyl, and
(4) —(CH 2 ) u —C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
R 4 is selected from the group consisting of:
(1) —O—CH 2 -cyclobutyl,
(2) —O-cyclohexyl,
(3) 2,6-diazospiro[3,3]heptan-2yl,
(4) piperidinyl, and
(5) phenyl,

wherein R 4 is unsubstituted or substituted with one, two, three, four or five substituents selected from R 5 ;
R 5 is selected from the group consisting of:
(1) —(CH 2 ) s halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s OH,
(4) —(CH 2 ) s CN,
(5) —(CH 2 ) s SO 2 C 1-6 alkyl, and
(6) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen, C 1-6 alkyl, and —(CH 2 ) w OH;
m is 0, 1, 2 or 3;
n is 1 or 2;
r is 0, 1,2 or 3;
s is 0, 1, 2 or 3;
t is 0, 1,2 or 3;
u is 0, 1, 2 or 3;
v is 0, 1, 2 or 3; and
w is 0, 1, 2 or 3.

2. The compound according to claim 1 wherein A is

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein B is phenyl, wherein phenyl is unsubstituted or substituted with one, two or three substituents selected from R 3 ;
or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein B is pyridyl, wherein pyridyl is unsubstituted or substituted with one, two or three substituents selected from R 3 ; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —C 1-6 alkyl, and
(4) —(CH 2 ) r —OC 1-6 alkyl,

wherein each CH 2 , —C 1-6 alkyl and —OC 1-6 alkyl is unsubstituted or substituted with one to four substituents selected from halogen, and —C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN, and
(3) —C 1-6 alkyl,

wherein each —C 1-6 alkyl is unsubstituted or substituted with one to four substituents selected from halogen, and —C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein R 1 is selected from the group consisting of:
(1) —CN,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) r —C 3-6 cycloalkyl,

wherein each CH 2 , —C 1-6 alkyl and —C 3-6 cycloalkyl is unsubstituted or substituted with one to four substituents selected from halogen, and —C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 1 is halogen, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein R 2 is F; or
a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein each R 3 when present is independently selected from the group consisting of:
(1) halogen, and
(2) —C 1-6 alkyl,

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen; or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 wherein R 5 is selected from the group consisting of:
(1) —(CH 2 ) s halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s OH,
(4) —(CH 2 ) s SO 2 C 1-6 alkyl, and
(5) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen, C 1-6 alkyl, and —(CH 2 ) w OH; or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 wherein R 5 is selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OH,
(4) —SO 2 C 1-6 alkyl, and
(5) —SO 2 —C 3-6 cycloalkyl,

wherein each —C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen, C 1-6 alkyl, and —(CH 2 ) w OH; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 wherein the absolute stereochemistry at the stereogenic carbon centers is indicated below:

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 wherein:
A is:

B is phenyl;
R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —C 1-6 alkyl, and
(4) —(CH 2 ) r —OC 1-6 alkyl,

wherein each CH 2 , —C 1-6 alkyl and —OC 1-6 alkyl is unsubstituted or substituted with one to four substituents selected from halogen, and —C 1-6 alkyl;
R 2 is halogen;
each R 3 when present is independently selected from the group consisting of:
(1) halogen, and
(2) —C 1-6 alkyl,

wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from halogen;
R 4 is selected from the group consisting of:
(1) —O—CH 2 -cyclobutyl,
(2) —O-cyclohexyl,
(3) 2,6-diazospiro[3,3]heptan-2yl,
(4) piperidinyl, and
(5) phenyl,

wherein R 4 is unsubstituted or substituted with one, two, three, four or five substituents selected from R 5 ;
R 5 is selected from the group consisting of:
(1) —(CH 2 ) s halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s OH,
(4) —(CH 2 ) s CN,
(5) —(CH 2 ) s SO 2 C 1-6 alkyl, and
(6) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen, C 1-6 alkyl, and —(CH 2 ) w OH;
m is 1; and
n is 1;
or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 wherein:
A is:

B is phenyl;
R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN, and
(3) —C 1-6 alkyl,

wherein each —C 1-6 alkyl is unsubstituted or substituted with one to four substituents selected from halogen, and —C 1-6 alkyl;
R 2 is halogen;
each R 3

Assignees

• Merck Sharp & Dohme

Inventors

• Biftu Tesfaye
• Biju Purakkattle
• Colletti Steven L
• Dang Qun
• Dhondi Pawan
• Gude Candido
• Josien Hubert
• Kar Nam Fung
• Nair Anilkumar G
• Nargund Ravi P
• Yang De-Yi
• Zhu Cheng

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K9/20

  Pills, tablets, {discs, rods (A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095)} · CPC title

• C07D221/16 Primary

  containing carbocyclic rings other than six-membered · CPC title