2-amino-pyridine and 2-amino-pyrimidine derivatives and medicinal use thereof

Patent metadata

Field	Value
Publication number	US-9783522-B2
Application number	US-201515306312-A
Country	US
Kind code	B2
Filing date	Apr 24, 2015
Priority date	Apr 24, 2014
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

Provided is a compound superior in an autotaxin inhibitory action and the like, effective as a prophylactic or therapeutic drug for diseases involving ATX. The present invention relates to a compound represented by the following formula (I):

[wherein each symbol is as described in the DESCRIPTION], which has a superior autotaxin inhibitory action and is useful as a prophylactic or therapeutic drug for diseases involving ATX.

First claim

The invention claimed is:

1. A compound of formula (1) or a pharmacologically acceptable salt thereof:

wherein
A is cycloalkyl, a heterocyclic group, aryl or heteroaryl;
Z 1 , Z 2 and Z 3 are one of A)-D):

A) all of Z 1 , Z 2 and Z 3 are carbons;
B) Z 1 is nitrogen, and Z 2 and Z 3 are carbons;
C) Z 2 is nitrogen, and Z 1 and Z 3 are carbons;
D) Z 1 and Z 2 are nitrogens, and Z 3 is carbon;
Z 4 is carbon or nitrogen;
R 1 is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, a heterocyclic group, aryl or heteroaryl where the heteroaryl optionally further has at least one substituent selected from alkyl;
R 2 and R 3 are the same or different and each is hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or aryl;
R 4 is hydrogen, alkyl or halogen;
R 5 and R 6 are the same or different and each is —X 1 —R 7a where X 1 is a single bond, linear alkylene, cyclic alkylene, —O—, —O-alkylene- or —CO—, and the linear alkylene, cyclic alkylene or —O-alkylene- for X 1 optionally further has at least one substituent selected from hydroxy, halogen, alkyl, hydroxyalkyl and alkoxy;
R 7a is hydrogen, hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, carboxyl, —NR 7b R 7c , alkyleneoxide, cyano, dialkylcarbamoyl, alkylsulfonyl, a heterocyclic group or heteroaryl where R 7b and R 7c are the same or different and each is hydrogen, hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl, and the heterocyclic group or heteroaryl for R 7a optionally further has at least one substituent selected from hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl and aminoalkyl; and
L 1 is a group selected from 1)-6):

1) —X 2 —;
2) —X 2 —(CH 2 ) n —;
3) —O—X 3 —,
4) —O—(CH 2 ) n—X 3 —;
5) —CO—X 3 —; and
6) —CO—NH—X 3 —
where X 2 is a single bond, linear alkylene, cyclic alkylene, alkenylene, alkynylene, heterocycloalkylene or heteroarylene, X 3 is linear alkylene, cyclic alkylene, alkenylene, alkynylene, heterocycloalkylene or heteroarylene, the linear alkylene, cyclic alkylene, alkenylene or alkynylene for X 2 or X 3 optionally further has at least one substituent selected from alkyl, cycloalkyl, hydroxyalkyl, haloalkyl and alkyleneoxide, the alkyl optionally has at least one substituent selected from aryl and heteroaryl, and n is an integer of 1-3.

2. The compound according to claim 1 , wherein A is aryl or heteroaryl, or a pharmacologically acceptable salt thereof.

3. The compound according to claim 1 , wherein A is a heterocyclic group, or a pharmacologically acceptable salt thereof.

4. The compound according to claim 1 , wherein all of Z 1 , Z 2 and Z 3 are carbons, or a pharmacologically acceptable salt thereof.

5. The compound according to claim 1 , wherein R 1 is halogen, haloalkyl or haloalkoxy, or a pharmacologically acceptable salt thereof.

6. The compound according to claim 5 , wherein R 1 is haloalkoxy, or a pharmacologically acceptable salt thereof.

7. The compound according to claim 1 , wherein R 1 is substituted at the 3-position of the 6-membered ring, or a pharmacologically acceptable salt thereof.

8. The compound according to claim 1 , wherein R 5 and R 6 are the same or different and each is one of
—X 1 —R 7a where X 1 is —O—, and R 7a is alkyl,
—X 1 —R 7a where X 1 is linear alkylene or cyclic alkylene, and R 7a is hydrogen, and
—X 1 —R 7a where X 1 is a single bond, and R 7a is halogen or cyano, or a pharmacologically acceptable salt thereof.

9. The compound according to claim 1 , wherein L 1 is —X 2 — where X 2 is straight chain alkylene or cyclic alkylene, or a pharmacologically acceptable salt thereof.

10. The compound according to claim 9 , wherein L 1 is —X 2 — where X 2 is C1-2 straight chain alkylene or C3-6 cyclic alkylene, or a pharmacologically acceptable salt thereof.

11. The compound according to claim 1 , wherein the cycloalkyl for A is a group selected from:

the heterocyclic group for A is a group selected from:

the aryl for A is:

 and
the heteroaryl for A is a group selected from:

or a pharmacologically acceptable salt thereof.

12. The compound according to claim 2 , wherein A is

or a pharmacologically acceptable salt thereof.

13. The compound according to claim 3 , wherein A is

or a pharmacologically acceptable salt thereof.

14. A compound or a pharmacologically acceptable salt thereof, wherein the compound is one of
2-[6-(3 trifluoromethoxy-benzylamino)-pyridin-3-yl]-3H-benzimidazole-4-carboxylic acid,
2-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-benzoxazole-6-carboxylic acid,
1-methyl-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-1H-indazole-3-carboxylic acid,
5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-1H-indazole-3-carboxylic acid,
3-{3-cyano-2-methoxy-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-phenyl}-propionic acid,
3-{2-chloro-5-[2-(3-trifluoromethoxy-benzylamino)-pyrimidin-5-yl]-phenyl}-propionic acid,
3-{3-cyano-2-methoxy-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-phenyl}-2-methyl-propionic acid,
2-{2-methoxy-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-phenyl}-cyclopropanecarboxylic acid,
(1S,2S)-2-{2-methoxy-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-phenyl}-cyclopropanecarboxylic acid,
2-[5-methoxy-6′-(3-trifluoromethoxy-benzylamino)-[2,3′]bipyridinyl-6-yl]-cyclopropanecarboxylic acid,
(1S,2S)-2-[5-methoxy-6′-(3-trifluoromethoxy-benzylamino)-[2,3′]bipyridinyl-6-yl]-cyclopropanecarboxylic acid,
(1S,2S)-2-{3-methoxy-6-[2-(3-trifluoromethoxy-benzylamino)-pyrimidin-5-yl]-pyridin-2-yl}-cyclopropanecarboxylic acid,
(1S,2S)-2-[5-chloro-6′-(3-trifluoromethoxy-benzylamino)-[2,3′]bipyridinyl-6-yl]-cyclopropanecarboxylic acid,
(1S,2S)-2-[5-ethoxy-6′-(3-trifluoromethoxy-benzylamino)-[2,3′]bipyridinyl-6-yl]-cyclopropanecarboxylic acid,
(1S,2S)-2-[5-methyl-6′-(3-trifluoromethoxy-benzylamino)-[2,3′]bipyridinyl-6-yl]-cyclopropanecarboxylic acid,
3-{2-methoxy-5-[2-(3-trifluoromethoxy-benzylamino)-pyrimidin-5-yl]-phenyl}-propionic acid,
3-{2-methoxy-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-phenyl}-propionic acid,
2-{2-methoxy-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-phenyl}-2-methyl-propionic acid,
2-{3-cyano-2-methoxy-5-[6-(3-trifluoromethoxy-benzylamino)-pyridin-3-yl]-phenyl}-2-methyl-propionic acid,
2-chloro-3-(1-methyl-pyrrolidin-3-yloxy)-5-[2-(3-trifluoromethoxy-benzylamino)-pyrimidin-5-yl]-benzoic acid,
2-chloro-3-(pyrrolidin-3-yloxy)-5-[2-(3-trifluoromethoxy-benzylamino)-pyrimidin-5-yl]-benzoic acid,
3-(azetidin-3-yloxy)-2-chloro-5-[2-(3-trifluoromethoxy-benzylamino)-pyrimidin-5-yl]-benzoic acid,
2-chloro-3-(1-methyl-azetidin-3-yloxy)-5-[2-(3-trifluoromethoxy-benzylamino)-pyrimidin-5-yl]-benzoic acid,
2-methoxy-3-pyridin-

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

• Takahashi Taichi
• Umino Akinori
• Iijima Daisuke
• Takamatsu Hisayuki

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title