Heteroaryl substituted pyridines and methods of use

Patent metadata

Field	Value
Publication number	US-10138227-B2
Application number	US-201715602892-A
Country	US
Kind code	B2
Filing date	May 23, 2017
Priority date	Jun 3, 2016
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The invention discloses compounds of Formula I,

wherein X 1 , X 2 , R 1 , and R 2 are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.

First claim

What is claimed is:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein
X 1 and X 2 are independently selected
H;
halo;
C 1-4 alkyl optionally substituted with one or more independently selected halo;
C 1-4 alkoxy optionally substituted with one or more independently selected
—OH;
C 1-4 alkoxy; or
—NR 8A R 8B ;

—NR 9A R 8B ;
cyclopropyl optionally substituted with one or more independently selected R 5 groups;
phenoxy optionally substituted with one or more independently selected R 5 groups; or
phenyl optionally substituted with one or more independently selected R 5 groups;

R 1 is
C 1-4 alkyl optionally substituted with one or more independently selected
—OH;
C 1-4 alkoxy; or
4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N;

phenyl optionally substituted with one or more independently selected R 4 groups;
N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups;
N-linked 4-6 membered monocyclic heterocycle comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of N, O, and S, fused to a phenyl, wherein the monocyclic heterocycle and the phenyl are optionally substituted with one or more independently selected R 5 groups;
C 3-7 cycloalkyl optionally substituted with one or more independently selected R 5 groups; or
—NR 6 R 7 ;

R 2 is 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R 3 groups;
each R 3 is independently selected from the group consisting of:
C 1-4 alkyl optionally substituted with one or more independently selected
C 3-7 cycloalkyl; wherein the C 3-7 cycloalkyl is optionally substituted with one or more independently selected R A groups;
4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R A groups;
phenyl; wherein the phenyl is optionally substituted with one or more independently selected R A groups;
C 1-4 alkoxy optionally substituted with one or more independently selected C3-7 cycloalkyl, halo, or —OCH 3 ;
—OR 11
—OH;
halo;
—CN;
—OC(O)R 10 ;
—OS (O) 2 OH;
—NHC(═S)R 11 ; or
—OP(O)(OH)(OH);

—C(O)NH 2 ;
phenyl; wherein the phenyl is optionally substituted with one or more independently selected R A groups;
5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R A groups;
C 3-7 cycloalkyl; wherein the C 3-7 cycloalkyl is optionally substituted with one or more independently selected R A groups; and
4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R A groups;

each R 4 is independently selected from the group consisting of:
halo;
C 1-4 alkyl optionally substituted with one or more independently selected halo; and
C 1-4 alkoxy optionally substituted with one or more independently selected halo;

each R 5 is independently selected from the group consisting of:
—OH;
halo;
C 1-4 alkyl optionally substituted with one or more independently selected C 1-4 alkoxy, halo or —OH; and
C 1-4 alkoxy optionally substituted with one or more independently selected halo;

R 6 is H, C 3-7 alkyl, or C 3-7 cycloalkyl wherein the C 3-7 cycloalkyl is optionally substituted with one or more independently selected R 5 groups;
R 7 is
C 1-4 alkyl optionally substituted with one or more independently selected halo;
phenyl optionally substituted with one or more independently selected halo;
C 1-4 alkyl optionally substituted with one or more independently selected halo; or
C 1-4 alkoxy optionally substituted with one or more independently selected halo;

C 1-4 alkoxy optionally substituted with one or more independently selected halo; or
4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R 5 groups;

each R 8a and R 8b is independently selected from the group consisting of
H; and
C 1-4 alkyl;

R 9a and R 9b are independently selected from the group consisting of
H;
C 1-4 alkyl; and
C 3-7 cycloalkyl; and

each R 10 is independently selected from the group consisting of
C 1-6 alkyl; and
phenyl; wherein phenyl is optionally substituted with one or more independently selected R A groups;

each R 11 is independently selected from the group consisting of
4-6 membered monocyclic heterocycle comprising 1 or 2 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heterocycle is optionally substituted with one or more independently selected R A groups;
5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N; wherein the monocyclic heteroaryl is optionally substituted with one or more independently selected R A groups;
C 3-7 cycloalkyl; wherein the C 3-7 cycloalkyl is optionally substituted with one or more independently selected R A groups; and
phenyl; wherein phenyl is optionally substituted with one or more independently selected R A groups; and

each R A is independently selected from the group consisting of
—CN,
halo;
C 1-4 alkyl optionally substituted with one or more independently selected halo; and
C 1-4 alkoxy optionally substituted with one or more independently selected halo.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl optionally substituted with one independently selected R 4 group.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is phenyl substituted with one —OCF 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 5-6 membered monocyclic heteroaryl comprising 1, 2, or 3 heteroatoms independently selected from the group consisting of O, S, and N, wherein the monocyclic heteroaryl is optionally substituted with one R 3 group.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, or thiazolyl wherein the 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, and thiazolyl are substituted with one independently selected R 3 .

7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-4 alkyl optionally substituted with one or more independently selected
—OH;
halo; or
—OP(O)(OH)(OH).

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-4 alkyl optionally substituted with one or m

Assignees

• Abbvie Sarl
• Galapagos Nv
• Abbvie Sarl

Inventors

• Altenbach Robert J
• Bogdan Andrew
• Coti Ghjuvanni Petru Diunisu
• Cowart Marlon D
• Greszler Stephen N
• Kelgtermans Hans
• Kym Philip R
• Van Der Plas Steven Emiel
• Wang Xueqing

Classifications

• A61P43/00

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title