Modulators of cystic fibrosis transmembrane conductance regulator protein

Patent metadata

Field	Value
Publication number	US-10118916-B2
Application number	US-201715496094-A
Country	US
Kind code	B2
Filing date	Apr 25, 2017
Priority date	Apr 26, 2016
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

The present invention provides for compounds of formula (I)

wherein R 1 , m, Z, G 1 , R 2 , and R 3 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions mediated and modulated by CFTR, including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

First claim

What is claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein
Z is O;
R 1 groups are optional substituents on the benzo ring, and are each independently halogen, —CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, —OR j , or —SR j ;
m is 0, 1, 2, 3, or 4;
R 2 is hydrogen or C 1 -C 3 alkyl;
R 3 is formula (a)

 wherein
R 3a and R 3b are each independently C 1 -C 3 alkyl; or R 3a and R 3b together with the carbon atom to which they are attached, form a cyclopropyl, a cyclobutyl, or a cyclopentyl; wherein the cyclopropyl, the cyclobutyl, and the cyclopentyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and halogen; and
G 2 is formula (b), phenyl, or —O-phenyl, wherein the phenyl and the phenyl moiety of —O-phenyl are each optionally substituted with 1, 2, 3, or 4 R x groups;

wherein
each R x is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR j , or —SR j ;
X 1 is a bond or O;
Y 1 is O, CH 2 , or —O—CH 2 — wherein the —O—CH 2 — is connected to the benzo ring via the oxygen atom;
Y 2 is O;
R 4 and R 5 are each independently hydrogen or halogen;
R 6 groups are optional substituents on the benzo ring, and are each independently C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, halogen, —CN, —OR j , or —SR j ; and
n is 0, 1, 2, or 3;

G 1 is phenyl, monocyclic heteroaryl, or C 3 -C 6 cycloalkyl; wherein each G 1 is optionally substituted with 1, 2, 3, or 4 R 9 groups;
each R 9 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, C 1 -C 6 haloalkyl, —CN, oxo,
NO 2 , —OR j , —OC(O)R k , —OC(O)N(R j ) 2 , —SR j , —S(O) 2 R j , —S(O) 2 N(R j ) 2 , —C(O)R j , —C(O)OR j , —C(O)N(R j ) 2 , —C(O)N(R j )S(O) 2 R k , —N(R j ) 2 , —N(R j )C(O)R k , —N(R j )S(O) 2 R k , —N(R j )C(O)O(R k ), —N(R j )C(O)N(R j ) 2 , —(C 1 -C 6 alkylenyl)-OR j , —(C 1 -C 6 alkylenyl)-OC(O)R k , —(C 1 -C 6 alkylenyl)-OC(O)N(R j ) 2 , —(C 1 -C 6 alkylenyl)-SR j , —(C 1 -C 6 alkylenyl)-S(O) 2 R j , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R j ) 2 , —(C 1 -C 6 alkylenyl)-C(O)R j , —(C 1 -C 6 alkylenyl)-C(O)OR j , —(C 1 -C 6 alkylenyl)-C(O)N(R j ) 2 , —(C 1 -C 6 alkylenyl)-C(O)N(R j )S(O) 2 R k , —(C 1 -C 6 alkylenyl)-N(R j ) 2 , —(C 1 -C 6 alkylenyl)-N(R j )C(O)R k , —(C 1 -C 6 alkylenyl)-N(R j )S(O) 2 R k , —(C 1 -C 6 alkylenyl)-N(R j )C(O)O(R k ), —(C 1 -C 6 alkylenyl)-N(R j )C(O)N(R j ) 2 , or —(C 1 -C 6 alkylenyl)-CN;

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and
R k , at each occurrence, is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
with the proviso that when R 2 is hydrogen, Z is O, R 3 is formula (a), R 3a and R 3b together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, and G 2 is formula (b) wherein Y 1 is O, R 4 and R 5 are halogen, X 1 is a bond, n is 0 or 1, and R 6 is halogen; then G 1 is optionally substituted pyrimidinyl, optionally substituted pyridazinyl, optionally substituted pyrazinyl, or

 wherein * is the point of connection, R 9 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or halogen; and s is 0, 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
Z is O and R 2 is hydrogen.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
G 1 is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, cyclopropyl, or cyclohexyl; each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 9 groups.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
G 1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R 9 groups; wherein one of the R 9 groups is —OR j or —C(O)OR j , and the other 1, 2, or 3 optional R 9 groups are independently C 1 -C 3 alkyl, halogen, or C 1 -C 3 haloalkyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
Z is O,
R 2 is hydrogen;
G 1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R 9 groups; wherein one of the R 9 groups is —C(O)OR j wherein R j is hydrogen or C 1 -C 6 alkyl, and the other 1, 2, or 3 optional R 9 groups are independently C 1 -C 3 alkyl, halogen, or C 1 -C 3 haloalkyl;
m is 0 or 1; and
R 1 is —OR j wherein R j is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

6. The compound of claim 1 of formula (I-a) or a pharmaceutically acceptable salt thereof

wherein
R 1 , m, Z, G 1 , R 2 , R 3a , and R 3b are as set forth in claim 1 ;
G 2 is formula (b), phenyl, or —O-phenyl, wherein the phenyl and the phenyl moiety of —O-phenyl are each optionally substituted with 1, 2, 3, or 4 R x groups;

wherein
each R x is independently halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR j , or —SR j ;
X 1 is O;
Y 1 is O, CH 2 , or —O—CH 2 — wherein the —O—CH 2 — is connected to the benzo ring via the oxygen atom;
Y 2 is O;
R 4 and R 5 are hydrogen or R 4 and R 5 are halogen;
R 6 groups are optional substituents on the benzo ring, and are each independently C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, halogen, —CN, —OR j , or —SR j ; and
n is 0, 1, 2, or 3; and

R j , at each occurrence, is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G 2 is phenyl or —O-phenyl, wherein the phenyl and the phenyl moiety of —O-phenyl are each optionally substituted with 1, 2, 3, or 4 R x groups.

8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G 2 is phenyl optionally substituted with 1, 2, 3, or 4 R x groups.

9. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G 2 is formula (b) wherein Y 1 is O;
R 4 and R 5 are hydrogen; and
R 3a and R 3b are methyl.

10. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
Z is O;
R 2 is hydrogen; and
R 3a and R 3b are each independently C 1 -C 3 alkyl; or R 3a and R 3b together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl; wherein the cyclopropyl and the cyclobutyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and halogen.

11. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
G 1 is phenyl or cyclohexyl; each of which is substituted with 1, 2, 3, or 4 R 9 groups; wherein one of the R 9 groups is —OR j or —C(O)OR j , and the other 1, 2, or 3 optional R 9 groups are independently C 1 -C 3 alkyl, halogen, or C 1 -C 3 haloalkyl;
m is 0 or 1; and
R 1 is —OR j wherein R j is C 1 -C 6 al

Assignees

• Abbvie Sarl
• Galapagos Nv
• Abbvie Sarl

Inventors

• Altenbach Robert J
• Bogdan Andrew
• Chan Vincent
• Grieme Timothy A
• Koenig John R
• Kym Philip R
• Liu Bo
• Malagu Karine Fabienne
• Patel Sachin V
• Scanio Marc
• Searle Xenia B
• Shekhar Shashank
• Wang Xueqing
• Yeung Ming C

Classifications

• A61P43/00

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

• C07D311/58

  other than with oxygen or sulphur atoms in position 2 or 4 · CPC title

• C07D407/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D311/68

  with nitrogen atoms directly attached in position 4 · CPC title

• C07D311/70

  with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6 · CPC title