IP Library › Granted Patent US 10,975,065
Granted Patent B2
US 10,975,065 · App. 16/576,997 · Granted Apr 13, 2021

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

Inventors: Brian Stephen Gerstenberger (Cambridge, MA); Andrew Christopher Flick (Kirkland, WA); Vincent Michael Lombardo (East Lyme, CT); James John Mousseau (Norwich, CT); Philippe Marcel Nuhant (Dorchester, MA); Ralph Pelton Robinson, Jr. (Gales Ferry, CT); Mark Edward Schnute (Acton, MA); Daniel Wei-Shung Kung (Salem, CT); Daniel Copley Schmitt (Westerli, RI); Atli Thorarensen (Stow, MA); John Isidro Trujillo (Ledyard, CT); Rayomand Jal Unwalla (Bedford, MA); Huixian Wu (East Lyme, CT)
Assignee: Pfizer Inc.
C07D413/14A61P29/00C07D401/12C07D401/14C07D405/14C07D413/12C07D417/12C07D417/14C07F9/65583
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Quick Facts
Patent No.
US 10,975,065
App. No.
16/576,997
Granted
Apr 13, 2021
Kind
B2
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.

Claims (84)

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-dimethylpicolinamide;

(R)-3-hydroxy-N,N-dimethyl-4-((2-(((1-methyl-4-(methyl-d)-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)picolinamide;

4-((2-(((1R)-(1,4-dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl-3,4-d 2 )methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide; and

4-((2-(((S)-((S)-4,4-Difluoro-2-methyltetrahydrofuran-2-yl)(2,5-dimethylthiazol-4-yl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide;

or a pharmaceutically acceptable salt thereof.

5. (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,N-dimethylpicolinamide or a pharmaceutically acceptable salt thereof.

6. A compound of structure

7. Crystalline(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,N-dimethylpicolinamide.

8. Crystalline(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,N-dimethylpicolinamidemonohydrate.

9. Crystalline(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,N-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 18.8±0.2 19.2±0.2, and 20.4±0.2 degrees two theta.

10. Crystalline (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,N-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 17.6±0.2, 18.5±0.2, 18.8±0.2, 19.2±0.2, and 20.4±0.2 degrees two theta.

11. Crystalline (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,N-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern comprising diffraction peaks 11.5±0.2, 15.5±0.2, 17.6±0.2, 18.5±0.2, 18.8±0.2, 19.2±0.2, 20.4±0.2, and 24.5±0.2 degrees two theta.

12. Crystalline (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,N-dimethylpicolinamide monohydrate having an X-ray powder diffraction pattern as depicted in FIG. 4 .

13. (R)-((4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-2-(dimethylcarbamoyl)pyridin-3-yl)oxy)methyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

14. A compound of structure

Assignments (1)
ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023
From: PFIZER INC.
To: PFIZER INC.
Reel/Frame 063119/0087 →