Antidiabetic substituted heteroaryl compounds

Patent metadata

Field	Value
Publication number	US-9834563-B2
Application number	US-201415039607-A
Country	US
Kind code	B2
Filing date	Dec 17, 2014
Priority date	Dec 19, 2013
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention relates to a compound represented by formula (I): and pharmaceutically acceptable salts thereof. The compounds of formula I 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
ring A is a monocyclic heteroaryl containing 1 to 2 N heteroatoms;
X is
(1) bond,
(2) —O—,
(3) NH,
(4) —(C 1-6 )alkyl-O—, wherein the alkyl or oxygen attaches to ring A,
(5) —O—(C 1-6 )alkyl-O—, or
(6) —(C 1-6 )alkyl-N(H)—, wherein the alkyl or nitrogen attaches to ring A;

R 1 is
(1) (C 3-7 )cycloalkyl,
(2) heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting N, S, and O,
(3) heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S,
(4) —S(O) 2 (C 1-3 )alkyl, or
(6) —(CH 2 ) q -aryl,

wherein each heterocycloalkyl, heteroaryl, aryl, or cycloalkyl groups are unsubstituted or substituted with 1 to 2 substitutents each independently R 5 ;
R 2 is
(1) (C 1-6 )alkyl,
(2) halo(C 1-6 )alkyl,
(3) hydroxy(C 1-6 )alkyl, or
(4) halo;

R 3 is
(1) (C 1-6 )alkyl, or
(2) halo;

R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;

R 5 is
(1) oxo,
(2) hydroxy,
(3) (C 1-6 )alkyl,
(4) halo(C 1-6 )alkyl,
(5) hydroxy(C 1-6 )alkyl,
(6) cyano,
(7) phenyl,
(8) —S(O) 2 (C 1-3 )alkyl,
(9) —(C 1-3 )alkyl-S(O) 2 (C 1-3 )alkyl, or
(10) —(C 1-3 )alkyl-N(H)—S(O) 2 (C 1-3 )alkyl;

R 6 is
(1) hydrogen,
(2) (C 1-6 )alkyl, or
(3) (C 3-7 )cycloalkyl;

n is 0, 1, 2, or 3;
m is 0 or 1;
k is 0, 1, 2 or 3; and
q is 0,1,2, or 3.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a bond, —O—, —N(H)—, —(CH 2 ) 3 —NH—, —(CH 2 ) 2 —NH—, —CH 2 —N(H)—, —(CH 2 ) 4 —O—, —(CH 2 ) 3 —O—, —(CH 2 ) 2 —O—, —CH 2 —O— or —O—(CH 2 ) 3 —O—.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein ring A is pyridinyl or pyrimidinyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

5. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein
ring A is a bicyclic heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S;
X is
(1) bond,
(2) —O—,
(3) NH,
(4) —(C 1-6 )alkyl-O—, wherein the alkyl or oxygen attaches to ring A,
(5) —O—(C 1-6 )alkyl-O—, or
(6) —(C 1-6 )alkyl-N(H)—, wherein the alkyl or nitrogen attaches to ring A;

R 1 is
(1) (C 3-7 )cycloalkyl,
(2) heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting N, S, and O,
(3) heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S,
(4) —S(O) 2 (C 1-3 )alkyl, or
(6) —(CH 2 ) q -aryl,

wherein each heterocycloalkyl, heteroaryl, aryl, or cycloalkyl groups are unsubstituted or substituted with 1 to 2 substitutents each independently R 5 ;
R 2 is
(1) (C 1-6 )alkyl,
(2) hydroxy(C 1-6 )alkyl, or
(3) halo;

R 3 is
(1) (C 1-6 )alkyl, or
(2) halo;

R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;

R 5 is
(7) oxo,
(8) hydroxy,
(9) (C 1-6 )alkyl,
(10) halo(C 1-6 )alkyl,
(11) hydroxy(C 1-6 )alkyl,
(12) cyano,
(7) phenyl,
(8) —S(O) 2 (C 1-3 )alkyl,
(9) —(C 1-3 )alkyl-S(O) 2 (C 1-3 )alkyl, or
(10) —(C 1-3 )alkyl-N(H)—S(O) 2 (C 1-3 )alkyl;

R 6 is
(1) hydrogen,
(2) (C 1-6 )alkyl, or
(3) (C 3-7 )cycloalkyl;

n is 0, 1, 2, or 3;
m is 0 or 1;
k is 0, 1, 2 or 3; and
q is 0, 1, 2, or 3.

6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein X is a bond, —O—, —N(H)—, —(CH 2 ) 3 —NH—, —(CH 2 ) 2 —NH—, —CH 2 —N(H)—, —(CH 2 ) 4 —O—, —(CH 2 ) 3 —O—, —(CH 2 ) 2 —O—, —CH 2 —O— or —O—(CH 2 ) 3 —O—.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein ring A is 1H-pyrazolo[4,3-b]pyridinyl, thiazolo[4,5-b]pyridinyl, or 1H-pyrrolo[2,3-b]pyridinyl.

8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

9. A compound of structural formula I-A:

or a pharmaceutically acceptable salt thereof, wherein
X is
(1) a bond,
(2) —O—,
(3) —(C 1-6 )alkyl-O—, wherein the alkyl or oxygen attaches to ring A
(4) —O—(C 1-6 )alkyl-O—, or
(5) —(C 1-6 )alkyl-N(H)—, wherein the alkyl or nitrogen attaches to ring A;

R 1 is
(1) (C 3-7 )cycloalkyl,
(2) heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, S, and O,
(3) heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S,
(4) —S(O) 2 (C 1-3 )alkyl, or
(5) —(CH 2 )q-aryl,

wherein each heterocycloalkyl, heteroaryl, aryl, or cycloalkyl groups are unsubstituted or substituted with 1 to 2 substitutents each independently R 5 ;
R 2 is
(1) (C 1-6 )alkyl,
(2) halo(C 1-6 )alkyl, or
(3) hydroxy(C 1-6 )alkyl;

R 3 is
(1) (C 1-6 )alkyl, or
(2) halo;

R 4 is
(1) hydrogen, or
(2) (C 1-3 )alkyl;

R 5 is
(1) oxo,
(2) hydroxy,
(3) (C 1-6 )alkyl,
(4) halo(C 1-6 )alkyl,
(5) hydroxy(C 1-6 )alkyl,
(6) cyano,
(7) phenyl,
(8) —S(O) 2 (C 1-3 )alkyl,
(9) —(C 1-3 )alkyl-S(O) 2 (C 1-3 )alkyl, or
(10) —(C 1-3 )alkyl-N(H)—S(O) 2 (C 1-3 )alkyl;

n is 0, 1, 2, or 3;
m is 0 or 1;
k is 0, 1, 2 or 3, and
q is 0, 1, 2, or 3.

10. A compound selected from

or a pharmaceutically acceptable salt, thereof.

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

12. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising
(1) a compound of claim 1 or a pharmaceutically acceptable salt thereof;
(2) one or more compounds selected from the group consisting of:
(a) PPAR gamma agonists and partial agonists;
(b) biguanides;
(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;
(d) dipeptidyl peptidase IV (DP-IV) inhibitors;
(e) insulin or an i

Assignees

• Merck Sharp & Dohme

Inventors

• Hagmann William K
• Li Bing
• Szewczyk Jason W
• Wang Bowei
• Parker Dann
• BLIZZARD Timothy
• Josien Hubert
• Biju Purakkattle
• Chobanian Harry
• Gude Candido
• Nargund Ravi P
• Pio Barbara
• Dang Qun
• Lin Linus S
• Hu Bin
• Cui Mingxiang
• Chen Zhengxia
• Dai Meibi
• Zhang Zaihong
• Lv Ying
• Tian Lili

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• C07D451/06

  Oxygen atoms · CPC title

• C07D221/20

  Spiro-condensed ring systems · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title