Compounds and pharmaceutical compositions thereof for the treatment of cystic fibrosis

Patent metadata

Field	Value
Publication number	US-9382254-B2
Application number	US-201414271080-A
Country	US
Kind code	B2
Filing date	May 6, 2014
Priority date	May 7, 2013
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

The present invention discloses compounds according to Formula I:

wherein R 1 , R 2 , R 3 , L, and the subscript m 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, and methods of treatment using the same, for the treatment of cystic fibrosis by administering a compound of the invention.

First claim

The invention claimed is:

1. A compound according to Formula I

wherein
R 1 is H, —CH 3 , —CF 3 , or cyclopropyl;
L is —NR 4 —;
the subscript m is 0, or 1;
R 2 is
C 1-4 alkyl or C 1-4 alkyl substituted with one or more independently selected R 5 groups,
C 3-7 cycloalkyl,
4-10 membered monocyclic, bridged-, spiro-, or fused bicyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R a groups,
5-6 membered monocyclic heterocycloalkenyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R a groups,
C 6-10 mono or bicyclic aryl optionally substituted with one or more independently selected R b , or
5-10 membered monocyclic or fused bicyclic heteroaryl, comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R b;

R 3 is
C 3-7 cycloalkyl optionally substituted with one or more independently selected R c groups,
4-7 membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from O, and S, and optionally substituted with R c ,
C 6-10 mono or bicyclic aryl optionally substituted with one or more independently selected R d groups,
phenyl fused to a 5-6 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R d groups,
phenyl fused to a C 5-6 cycloalkyl, optionally substituted with one or more independently selected R d groups,
5-10 membered mono or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R d groups,
5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, fused to a 5-6 membered heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R d groups,
5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, fused to a C 5-6 cycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, and optionally substituted with one or more independently selected R d groups,
C 2-6 alkenyl,
C 3-6 alkyl, or
C 1-6 alkyl substituted with one or more independently selected R e groups;

R 4 is
C 1-6 alkyl or C 1-6 alkyl substituted with one or more independently selected R 6 groups, or
C 3-7 cycloalkyl;

each R 5 is independently selected from
halo,
OH,
—CN,
C 1-4 alkoxy,
—NR 8e R 8f ,
C 3-7 cycloalkyl,
6 membered mono or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, and
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;

each R 6 , is independently selected from
halo,
OH,
—CN,
—NR 8g R 8h , and
C 1-4 alkoxy;

each R a is selected from
halo,
CN,
oxo,
C 1-4 alkyl or C 1-4 alkyl substituted with one or more independently selected R 7a ,
C 1-4 alkoxy or C 14 alkoxy substituted with one or more independently selected R 7a ,
—C(═O)O—C 1-4 alkyl,
phenyl,
5-10 membered mono, or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, and optionally substituted with one or more independently selected C 1-4 alkyl, and
—NR 8a R 8b ;

each R b is selected from
halo,
—CN,
C 1-4 alkyl or C 1-4 alkyl substituted with one or more independently selected R 7b ,
C 1-4 alkoxy or C 1-4 alkoxy substituted with one or more independently selected R 7b ,
—OC(═O)C 1-4 alkyl, and
—NR 8c R 8d ;

each R c is selected from
halo,
OH,
—CN,
oxo,
C 1-4 alkyl or C 1-4 alkyl substituted with one or more independently selected R 7c ),
C 1-4 alkoxy or C 1-4 alkoxy substituted with one or more independently selected R 7c ),
phenyl or phenyl substituted with one or more independently selected halo, C 1-4 alkyl,
C 1-4 alkoxy, —CN, or —NR 9a R 9b ), and
5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S or N, O, or S substituted with one or more independently selected halo, C 1-4 alkyl, C 1-4 alkoxy, CN, —NR 9c R 9d ;

each R d is selected from
halo,
—CN,
—OH,
C 1-4 alkyl or C 1-4 alkyl substituted with one or more independently selected R 7d ,
C 1-4 alkoxy or C 1-4 alkoxy substituted with one or more independently selected R 7d ,
C 3-7 cycloalkyl,
5-10 membered mono or fused bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, or S, and
—NH-Phenyl;

each R e is selected from
halo,
OH,
—CN,
C 1-4 alkoxy or C 1-4 alkoxy substituted with one or more independently selected R 7e ,
C 3-7 cycloalkyl,
phenyl or phenyl with one or more independently selected halo, C 1-4 alkyl, C 1-4 alkoxy, CN, and —NR 9e R 9f , and
5-6 membered monocyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S or N, O, and S substituted with one or more independently selected halo, C 1-4 alkyl, C 1-4 alkoxy, CN, and —NR 9g R 9h ;

each R 7a , R 7b , R 7c , R 7d , and R 7e is independently selected from
halo,
OH,
—CN,
—NR 8i R 8j , and
C 1-4 alkoxy;

each R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 8g , R 8h , R 8i , or R 8j is independently selected from H, and C 1-4 alkyl;
each R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9g , or R 9h is independently selected from H, and C 1-4 alkyl;
or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.

2. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula II:

wherein R 1 , R 2 , R 3 , and R 4 are as described in claim 1 .

3. A compound or pharmaceutically acceptable salt thereof, according to claim 2 , wherein R 4 is C 1-6 alkyl.

4. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula III:

wherein R 1 , R 2 , and R 3 are as described in claim 1 .

5. A compound or pharmaceutically acceptable salt thereof, according to claim 4 , wherein R 2 is phenyl substituted with one or more independently selected R b .

6. A compound or pharmaceutically acceptable salt thereof, according to claim 5 , wherein R b is F, Cl, or CN.

7. A compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is according to Formula IV:

wherein Cy is 4-10 membered monocyclic or fused bicyclical heterocycloalkyl comprising one or more heteroatoms independently selected from N, O, and S, R a is as described in claim 1 , and the subscript n is 0, 1 or 2.

8. A compo

Assignees

• Galapagos Nv

Inventors

• De Blieck Ann
• De Munck Tom Roger Lisette
• Joannesse Caroline Martine Andrée Marie
• Kelgtermans Hans
• Mammoliti Oscar
• Menet Christel Jeanne Marie
• Tricarico Giovanni Alessandro
• Van Der Plas Steven Emiel

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

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K31/538

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• A61K31/381 Primary

  having five-membered rings · CPC title