Pyridinyl derivatives, pharmaceutical compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-9926292-B2
Application number	US-201715588739-A
Country	US
Kind code	B2
Filing date	May 8, 2017
Priority date	May 12, 2016
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

The invention relates to new pyridinyl derivatives of the formula

wherein R 1 and A are as defined in the description and claims, to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is N or CH;
R 1 is selected from the group consisting of C 1-6 -alkyl, C 3-6 -cycloalkyl, heterocyclyl, —O—R 2 , —S—R 2 , —NH—R 2 and —N(R 2 ) 2 ,
wherein each R 2 is independently selected from the group consisting of C 1-6 -alkyl, C 3-6 -cycloalkyl, heterocyclyl, —(C 1-2 -alkyl)-(C 3-6 -cycloalkyl), —(C 1-2 -alkyl)-heterocyclyl, —(C 1-2 -alkyl)-aryl, —(C 1-2 -alkyl)-heteroaryl and —(C 1-2 -alkyl)-C≡CH;
wherein each heterocyclyl of R 1 and R 2 is a 4- to 7-membered saturated carbocyclic group, in which 1 or 2 CH 2 -moieties are independently of each other replaced by an atom or group selected from NH, O, S, —S(═O)—, —S(═O) 2 — or —C(═O)—; and
wherein each aryl is selected from the group consisting of phenyl and naphthyl; and
wherein each heteroaryl is a 5- or 6-membered heteroaromatic ring which contains 1, 2 or 3 heteroatoms independently selected from ═N—, —NH—, —O— and —S—, wherein in heteroaromatic groups containing a —CH═N— unit, this group is optionally replaced by —NH—C(═O)—; and
wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group of R 1 and R 2 is optionally independently substituted with one or more F, Cl, CN, OH, C 1-3 -alkyl, —O—(C 1-3 -alkyl), —C(═O)—(C 1-3 -alkyl) and —C(═O)—(C 3-7 -cycloalkyl);

wherein each of the above-mentioned alkyl groups may be linear or branched and are optionally substituted by one or more F;
or a salt thereof.

2. A compound of formula (I) according to claim 1 , wherein R 1 is C 1-4 -alkyl, C 3-5 -cycloalkyl, heterocyclyl, —O—R 2 , —S—R 2 , —NH—R 2 or —N(R 2 ) 2 ;
wherein each heterocyclyl is a 4- to 6-membered saturated carbocyclic group, in which 1 or 2 CH 2 -moieties are replaced by a heteroatom selected from NH, O or S; and
wherein each alkyl, cycloalkyl or heterocyclyl group is optionally independently substituted with 1 to 5 F and/or 1 to 3 substituents independently selected from the group consisting of Cl, CN, OH, C 1-2 -alkyl, —O—(C 1-2 -alkyl), —C(═O)—(C 1-2 -alkyl) and —C(═O)—(C 3-4 -cycloalkyl);

or a salt thereof.

3. A compound of formula (I) according to claim 2 , wherein R 1 is C 1-2 -alkyl, C 3-4 -cycloalkyl, heterocyclyl, —O—R 2 , —NH—R 2 or —N(R 2 ) 2 ;
wherein each heterocyclyl is selected from the group consisting of azetidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and
wherein each alkyl, cycloalkyl or heterocyclyl group is optionally independently substituted with 1 to 3 F or one substituent selected from the group consisting of CN, OH, CH 3 , —O—CH 3 , —C(═O)—CH 3 and —C(═O)-cyclopropyl;

or a salt thereof.

4. A compound of formula (I) according to claim 1 , wherein R 2 is selected from the group consisting of C 1-4 -alkyl, C 3-5 -cycloalkyl, heterocyclyl, —(C 1-2 -alkyl)-(C 3-5 -cycloalkyl), —(C 1-2 -alkyl)-heterocyclyl, —(C 1-2 -alkyl)-aryl, —(C 1-2 -alkyl)-heteroaryl and —(C 1-2 -alkyl)-C≡CH;
wherein each heterocyclyl is a 4- to 6-membered saturated carbocyclic group, in which 1 or 2 CH 2 -moieties are replaced by a heteroatom selected from NH, O or S; and
wherein each aryl is selected from the group consisting of phenyl and naphthyl; and
wherein each heteroaryl is a 5- or 6-membered heteroaromatic ring which contains 1, 2 or 3 heteroatoms independently selected from ═N—, —NH—, —O— and —S—; and
wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally independently substituted with one or more F, Cl, CN, OH, C 1-2 -alkyl, —O—(C 1-2 -alkyl), —C(═O)—(C 1-2 -alkyl) and —C(═O)—(C 3-7 -cycloalkyl);

or a salt thereof.

5. A compound of formula (I) according to claim 1 , wherein R 2 is selected from the group consisting of: C 1-4 -alkyl, —CH 2 —(C 3-4 -cycloalkyl), —CH 2 -heterocyclyl, —CH 2 -heteroaryl and —CH 2 —CH 2 —C≡CH;
wherein each heterocyclyl is selected from the group consisting of tetrahydrofuranyl and piperidinyl; and
wherein each heteroaryl is selected from the group consisting of isoxazolyl, thiazolyl and thiadiazolyl; and
wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally independently substituted with one or more F, CN, CH 3 , —OCH 3 , —C(═O)—CH 3 and —C(═O)-cyclopropyl;

or a salt thereof.

6. A compound of formula (I) according to claim 1 , wherein
A is N;
or a salt thereof.

7. A compound of formula (I) according to claim 1 , wherein
A is N; and
R 1 is selected from the group consisting of cyclopropyl, heterocyclyl and —O—R 2 ;
wherein R 2 is selected from the group consisting of C 1-6 -alkyl, —(C 1-2 -alkyl)-(C 3-6 -cycloalkyl), —(C 1-2 -alkyl)-heteroaryl and —(C 1-2 -alkyl)-C≡CH;
wherein each heterocyclyl is selected from the group consisting of azetidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and
wherein each heterocyclyl group is optionally independently substituted with one substituent selected from F, CN, OH, CH 3 , —O—CH 3 ; and
wherein each heteroaryl is selected from the group consisting of isoxazolyl, thiazolyl and thiadiazolyl; and
wherein each alkyl, cycloalkyl, heterocyclyl, or heteroaryl group is optionally independently substituted with one or more F, CN, CH 3 , —OCH 3 , —C(═O)—CH 3 and —C(═O)-cyclopropyl;

wherein each of the above-mentioned alkyl groups may be linear or branched and are optionally substituted by one or more F;
or a salt thereof.

8. A compound of formula (I) according to claim 1 , wherein
A is N;
R 1 is selected from the group consisting of cyclopropyl, heterocyclyl and —O—R 2 ;
wherein R 2 is selected from the group consisting of C 1-4 -alkyl, —CH 2 —(C 3-4 -cycloalkyl), —CH 2 -heteroaryl and —CH 2 —CH 2 —C≡CH;
wherein each heteroaryl is selected from the group consisting of isoxazolyl, thiazolyl and thiadiazolyl; and
wherein each alkyl, cycloalkyl, aryl or heteroaryl group is optionally independently substituted with one or more F, CN and —OCH 3 ;
wherein each heterocyclyl is selected from the group consisting of azetidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and
wherein each heterocyclyl group is optionally independently substituted with one substituent selected from F, CN, OH, CH 3 , —O—CH 3 ;

or a salt thereof.

9. A compound of formula (I) according to claim 1 selected from the group consisting of:

or a salt thereof.

10. A pharmaceutically acceptable salt of a compound according to claim 1 .

11. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, for use as a medicament.

12. A method of using a compound according to claim 1 , or pharmaceutically acceptable salt thereof, for treating NASH (non-alcoholic steatohepatitis), pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), retinopathy or nephropathy in a patient in need thereof.

13. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.

14. A pharmaceutical composition comprising one or more compounds according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.

15. The compound according to claim 9 having the structure

Assignees

• Boehringer Ingelheim Int

Inventors

• Blum Andreas
• Godbout Cédrickx
• Hehn Joerg P
• Peters Stefan

Classifications

• 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

• A61P27/02

  Ophthalmic agents · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title