Alkoxy-substituted pyridinyl derivatives as LPA1 receptor antagonists and their use in the treatment of fibrosis

Patent metadata

Field	Value
Publication number	US-12344597-B2
Application number	US-201916972878-A
Country	US
Kind code	B2
Filing date	Jun 5, 2019
Priority date	Jun 7, 2018
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

The present invention relates to pyridinyl derivatives of Formula (I) Formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Ar 1 , L, W, Z, m and n are as described in the description, their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of Formula (I), and especially to their use as LPA1 receptor modulators.

First claim

The invention claimed is:

1. A compound of Formula (I),

wherein
W represents N, and Z represents CH; or
Z represents N, and W represents CH;

R 1 is hydrogen or fluoro;
R 2 is hydrogen, halogen, methyl, ethyl, methoxy or ethoxy;
R 3 is C 1-3 -fluoroalkoxy;
Ar 1 represents phenyl, wherein said group Ar 1 is substituted with R 4 and R 5 , wherein
R 4 is n-propyl, isopropyl, C 3-6 -cycloalkyl optionally containing a ring oxygen atom, or cyclopent-1-en-1-yl; and
R 5 represents one substituent independently selected from hydrogen, fluoro, methyl or methoxy;

m and n represent the integer 1; and
the group -L—R 6 represents
-L 1 -COOH; wherein
-L 1 - represents
-C 1-6 -alkylene-, —CO—C 1-6 -alkylene-, —SO 2 -C 1-6 -alkylene-, —CO—O-C 1-6 -alkylene-, —CO—NH-C 1-6 -alkylene-, or —SO 2 —NH-C 1-6 -alkylene-;
—CO-C 1-6 -alkylene-; wherein said C 1-6 -alkylene is mono-substituted with hydroxy;
-C 0-4 -alkylene-C 3-8 -cycloalkylene-C 0-4 -alkylene-, —CO-C 0-4 -alkylene-C 3-8 -cycloalkylene-C 0-4 -alkylene-, —SO 2 -C 0-4 -alkylene-C 3-8 -cycloalkylene-C 0-4 -alkylene-, or —CO-O-C 0-4 -alkylene-C 3-8 -cycloalkylene-C 0-4 -alkylene-;
—CO-C 0-4 -alkylene-Cy 1 -C 0-4 -alkylene-; wherein Cy 1 independently represents a C 3-6 -heterocycloalkylene containing one ring oxygen atom;
—CO-C 1-4 -alkylene-X 12 -C 1-4 -alkylene-; wherein X 12 independently represents a nitrogen atom which is unsubstituted, or mono-substituted with C 1-4 -alkyl;
—CO-C 2-6 -alkenylene- or —SO 2 -C 2-6 -alkenylene-; or
—CO-C 2-6 -fluoroalkylene-;

-L 2 -hydroxy; wherein -L 2 - represents
-C 2-6 -alkylene-, wherein the C 2-6 -alkylene is unsubstituted, or mono-substituted with hydroxy; or
—CO-C 1-4 -alkylene-X 22 -C 2-4 -alkylene-; wherein X 22 represents a nitrogen atom which is independently unsubstituted, or mono-substituted with C 1-4 -alkyl or C 3-6 -cycloalkyl; or

-L 9 -HET 1 , wherein HET 1 represents 5- or 6-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; wherein said HET 1 independently is unsubstituted or mono-, or di-substituted wherein the substituents are independently selected from C 1-4 -alkyl; halogen; cyano; hydroxy; hydroxymethyl; -C 0-2 -alkylene-Cy 91 -COOR O91 wherein R O91 is hydrogen or C 1-4 -alkyl, and wherein Cy 91 represents a C 3-6 -cycloalkylene group; or -C 0-2 -alkylene-COOR O92 wherein R O92 is hydrogen or C 1-4 -alkyl; and
-L 9 - independently represents
-C 0-6 -alkylene-, or —CO-C 0-6 -alkylene-;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein
W represents N, Z represents CH; and R 2 is hydrogen, methyl, methoxy or ethoxy;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , wherein R 3 represents difluoromethoxy;
or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 , wherein the fragment:

represents:

wherein R 1 is hydrogen or fluoro; R 2 is hydrogen, chloro, methyl, ethyl, methoxy or ethoxy; and R3 is -C1 3-alkoxy or C1-3-fluoroalkoxy; or

wherein R 1 is hydrogen; R 2 is halogen, methyl, or methoxy; and R 3 is C 1-3 -fluoroalkoxy;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 , wherein the fragment:

represents a ring independently selected from the following groups A) or B):

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 , wherein Ar 1 represents phenyl;
wherein said phenyl group is substituted with R 4 and R 5 , wherein
R 4 represents n-propyl, isopropyl, or monocyclic C 3-6 -cycloalkyl; and
R 5 represents hydrogen, fluoro, or methyl;

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 , wherein the fragment:

represents a ring independently selected from the following groups:

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 , wherein the group -L—R 6 represents
-L 1 -COOH; and
-L 1 - represents
—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —C(CH 3 ) 2 —CH 2 —, *—CH 2 —CH 2 —C(CH 3 ) 2 —, *—CH 2 —CH 2 —CH 2 —C(CH 3 ) 2 —, *—CO—CH 2 —CH 2 —, *—CO—CH(CH 3 )—CH 2 —, *—CO—CH 2 —C(OH)(CH 3 )—, *—CO—CH 2 —CH 2 —CH 2 —, *—CO—CH 2 —C(CH 3 ) 2 —, *—CO—C(CH 3 ) 2 —CH 2 —, *—SO 2 —CH 2 —, *—SO 2 —CH 2 —CH 2 —, *—SO 2 —CH 2 —CH 2 —CH 2 —, *—SO 2 —CH 2 —C(CH 3 ) 2 —, *—CO—O—CH 2 —, *—CO—O—CH(CH 3 )—, *—CO—O—CH 2 —C(CH 3 ) 2 —, *—CO—NH—C(CH 3 ) 2 —CH 2 —, *—CO—NH—CH 2 —C(CH 3 ) 2 —, *—CO—NH—CH 2 —CH 2 —C(CH 3 ) 2 —, *—SO 2 —NH—CH 2 —; *—CH 2 —CH 2 —CH 2 -cyclopropane-1,1-diyl-, *—CO-cyclopropane-1,2-yl-, *—CO—CH 2 -cyclopropane-1,1-diyl-, *—CO—CH 2 -cyclobutane-1,1-diyl-, *—SO 2 -cyclopropane-1,1-diyl—CH 2 —, *—CO—O-cyclopropane-1,1-diyl-, *—CO—O—CH 2 -cyclopropane-1,1-diyl-;
*—CO—CH 2 —(tetrahydro-2H-pyran-4,4-diyl)-;
*—CO—CH 2 —N(n-butyl)—CH 2 —;
*—SO 2 —CH═CH—, *—CO—C(CH 2 )—CH 2 —; or
*—CO—CF 2 —CH 2 —;

-L 2 -hydroxy; wherein -L 2 - represents
*—CH 2 —CH(OH)—CH 2 —; or
*—CO—CH 2 —NH—CH 2 —CH 2 —, *—CO—CH 2 —NH—CH(CH 3 )—CH 2 —, *—CO—CH 2 —NH—CH 2 —CH(CH 3 )—; or

-L 9 -HET 1 , wherein -L 9 -HET 1 represents

wherein in the above groups the asterisks indicate the bond which is connected to the rest of the molecule;
or a pharmaceutically acceptable salt thereof.

9. A compound, wherein said compound is:
N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
1-(2-aminoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-hydroxyethyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-hydroxypropyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
1-cyano-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
1-(3-(1H-tetrazol-5-yl)propyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(3-hydroxy-3-methylbutyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-1-(2-(1-hydroxycyclopropyl)ethyl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
1-(2-aminopropyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)azetidine-3-carboxamide;
3-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl)carbamoyl)-3-(2-isopropylphenyl)azetidin-1-yl)propanoic acid;
1-(2-cyanoethyl)-N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphe

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Bolli Martin
• Brotschi Christine
• Lescop Cyrille
• Williams Jodi T

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title