Modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use

Patent metadata

Field	Value
Publication number	US-10428017-B2
Application number	US-201815902802-A
Country	US
Kind code	B2
Filing date	Feb 22, 2018
Priority date	Feb 24, 2017
Publication date	Oct 1, 2019
Grant date	Oct 1, 2019

Abstract

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:

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

wherein
A 1 is selected from the group consisting of

R 1 is selected from the group consisting of hydrogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 1 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of R 7 , OR 7 , SR 7 , NHR 7 , N(R 7 ) 2 , NH 2 , C(O)OH, OH, CN, NO 2 , F, Cl, Br and I; wherein the R 1 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C(O)OH, OH, oxo, CN, NO 2 , F, Cl, Br and I;
one of R 2A , R 2B , R 2C and R 2D is hydrogen, and the remaining are independently selected from the group consisting of hydrogen, R 8 , OR 8 , C(O)R 8 , C(O)OR 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , NH 2 , C(O)OH, OH, CN, NO 2 , F, Cl, Br and I; or
two of R 2A , R 2B , R 2C , and R 2D a on adjacent carbons form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are independently selected from the group consisting of hydrogen, R 8 , OR 8 , C(O)R 8 , OC(O)R 8 , C(O)OR 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , NH 2 , C(O)OH, OH, CN, NO 2 , F, Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkenyl, and 4-7 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R 8 , OR 8 , C(O)R 8 , OC(O)R 8 , C(O)OR 8 , SO 2 R 8 , NHR 8 , N(R 8 ) 2 , NH 2 , C(O)OH, OH, CN, NO 2 , F, Cl, Br and I;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 3 C 2 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkoxy, phenyl, OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein the R 3 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of R 9 , OR 9 , C(O)R 9 , OC(O)R 9 , C(O)OR 9 , SO 2 R 9 , C(O)NH 2 , C(O)NHR 9 , C(O)N(R 9 ) 2 , NHC(O)R 9 , NHR 9 , N(R 9 ) 2 , NH 2 , C(O)OH, OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; wherein the R 4 C 1 -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of R 10 , OR 10 , SR 10 , NHR 10 , N(R 10 ) 2 , NH 2 , C(O)OH, OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 5A , R 5B , R 5C , and R 5D are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 5A , R 5B , R 5C , and R 5D C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, 4-12 membered heterocyclyl, C 1 -C 6 thioalkyl, OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein the R 5A , R 5B , R 5C , and R 5D 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C(O)OH, NH 2 , OH, oxo, CN, NO 2 , F, Cl, Br and I; or
R 5A and R 5B , together with the carbon atom to which they are attached, form a C 3 -C 7 monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C 3 -C 7 monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C(O)OH, NH 2 , OH, oxo, CN, NO 2 , F, Cl, Br and I; and
R 5C and R 5D are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 5C and R 5D C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, 4-12 membered heterocyclyl, C 1 -C 6 thioalkyl, OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein the R 5C and R 5D 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C(O)OH, NH 2 , OH, oxo, CN, NO 2 , F, Cl, Br and I; or
R 5C and R 5D , together with the carbon atom to which they are attached, form a C 3 -C 7 monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle; wherein the C 3 -C 7 monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle are each optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C(O)OH, NH 2 , OH, oxo, CN, NO 2 , F, Cl, Br and I; and
R 5A and R 5B are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R 5A and R 5B C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 1 -C 6 alkoxy are optionally substituted with one or more substituents independently selected from the group consisting of 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, 4-12 membered heterocyclyl, C 1 -C 6 thioalkyl, OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein the R 5A and R 5B 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C(O)OH, NH 2 , OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 6A , R 6B , R 6C , and R 6D are each independently hydrogen;
R 7 , at each occurrence, is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R 7 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2

Assignees

• Abbvie Sarl
• Galapagos Nv

Inventors

• Altenbach Robert J
• Bogdan Andrew
• Desroy Nicolas
• Gfesser Gregory A
• Greszler Stephen N
• Kym Philip R
• Liu Bo
• Malagu Karine Fabienne
• Merayo Merayo Nuria
• Pizzonero Mathieu Rafaël
• Searle Xenia B
• Van Der Plas Steven Emiel
• Wang Xueqing
• Yeung Ming C
• Zhao Gang

Classifications

• C07C2601/14

  The ring being saturated · CPC title

• C07D311/76

  Benzo[c]pyrans · CPC title

• C07D311/04

  Benzo[b]pyrans, not hydrogenated in the carbocyclic ring · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07C317/14

  having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings · CPC title