N-substituted-dioxocyclobutenylamino-3-hydroxy-picolinamides useful as CCR6 inhibitors

Patent metadata

Field	Value
Publication number	US-10975065-B2
Application number	US-201916576997-A
Country	US
Kind code	B2
Filing date	Sep 20, 2019
Priority date	Sep 21, 2018
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The present invention relates to N-substituted-dioxocyclobutenylamino-3-hydroxy-picolinamide compounds of Formulae (IA and 1B)

or a pharmaceutically acceptable salt or hydrate thereof, that inhibit CC chemokine receptor 6 (CCR6), pharmaceutical compositions containing these compounds, and the use of these compounds for treating or preventing diseases, conditions, or disorders ameliorated by inhibition of CCR6.

First claim

We claim:

1. A compound of Formula (IA) or (IB)

or a pharmaceutically acceptable salt thereof, wherein
R 1 is methyl;
R 2 is methyl, ethyl, or isopropyl;
or R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, wherein the heterocycle is optionally substituted with 1, 2, or 3 (C 1 -C 4 )alkyl groups;
R 3 is H;
A is

R 4 is methyl;
R 5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl;
R 6 is H;
B is

R 7 is methyl; and
n is 0.

2. The compound according to claim 1 of Formula (IIA)

or a pharmaceutically acceptable salt thereof, wherein
R 1 is methyl;
R 2 is methyl, ethyl, or isopropyl;
or R 1 and R 2 taken together with the nitrogen atom to which they are attached form a 4-, 5-, or 6-membered heterocycle containing one N heteroatom and optionally 1 or 2 additional heteroatoms selected from the group consisting of O, N, and S, optionally substituted with (C 1 -C 4 )alkyl;
R 3 is H;
R 4 is methyl;
R 5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl;
R 6 is H;
B is

R 7 is methyl; and
n is 0.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 1 and R 2 taken together with the nitrogen atom to which they are attached form morpholine or 4-methylpiperazine;
R 3 is H;
R 4 is methyl;
R 5 is methyl, ethyl, methoxy, Cl, difluoromethoxy, cyano, or cyclopropyl;
R 6 is H;
B is

R 7 is methyl; and
n is 0.

4. A compound selected from the group consisting of
(R)-4-((2-(((4-Chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide;
(R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(5-methylspiro[2.3]hexan-5-yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
4-((2-(((S)-((S)-4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(4-ethyl-1-methyl-1H-pyrazol-3-yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1-methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(S)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide;
(S)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide;
(R)-3-(((1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(morpholine-4-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-1,2-dione;
(R)-3-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-4-((3-hydroxy-2-(4-methylpiperazine-1-carbonyl)pyridin-4-yl)amino)cyclobut-3-ene-12-dione;
(S)-4-((2-(((4-Chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((4-Chloro-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide;
(R)-3-Hydroxy-N-isopropyl-4-((2-(((4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-methylpicolinamide;
(R)-3-Hydroxy-4-((2-(((4-methoxy-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N,N-dimethylpicolinamide;
(R)-3-Hydroxy-4-((2-((1-(4-methoxy-1-methyl-1H-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N,N-dimethylpicolinamide;
(R)-3-Hydroxy-N-isopropyl-4-((2-((1-(4-methoxy-1-methyl-1H-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-methylpicolinamide;
(R)-4-((2-(((4-(Difluoromethoxy)-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((4-Cyano-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1-methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((4-Ethyl-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopropyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-((1-(1,4-Dimethyl-1H-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-((1-(2,5-Dimethylthiazol-4-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((4-Ethyl-1-methyl-1H-pyrazol-3-yl)(1-methylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-((1-(4-Ethyl-1-methyl-1H-pyrazol-3-yl)-2,2-dimethylpropyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-3-Hydroxy-4-((2-((2-(hydroxymethyl)-5-methyIthiazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N,N-dimethylpicolinamide;
(R)-4-((2-(((4-Cyclopropyl-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((4-Cyano-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N-ethyl-3-hydroxy-N-methylpicolinamide;
(R)-4-((2-(((4-cyano-1-methyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N-isopropyl-N-methylpicolinamide;
(R)-4-((2-(((2,5-Dimethylthiazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-3-Hydroxy-4-((2-(((5-methoxy-2-methylthiazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-N,N-dimethylpicolinamide;
(R)-4-((2-(((2,5-Dimethyloxazol-4-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
(R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-ethylcyclobutyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;
4-((2-(((S)-((S)-4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(1,4-dimethyl-1H-pyrazol-3-yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethyl

Assignees

• Pfizer

Inventors

• Gerstenberger Brian Stephen
• Flick Andrew Christopher
• Lombardo Vincent Michael
• Mousseau James John
• Nuhant Philippe Marcel
• Robinson Jr Ralph Pelton
• Schnute Mark Edward
• Kung Daniel Wei-Shung
• Schmitt Daniel Copley
• Thorarensen Atli
• Trujillo John Isidro
• Unwalla Rayomand Jal
• Wu Huixian

Classifications

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• C07D417/08

  linked by a carbon chain containing alicyclic rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/08

  linked by a carbon chain containing alicyclic rings · CPC title

• C07D401/08 Primary

  linked by a carbon chain containing alicyclic rings · CPC title