Substituted pyrrolidines and methods of use

Patent metadata

Field	Value
Publication number	US-9981910-B2
Application number	US-201715726075-A
Country	US
Kind code	B2
Filing date	Oct 5, 2017
Priority date	Oct 7, 2016
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The invention discloses compounds of Formula (I)

wherein R 1 , R 2 , R 2A , R 3 , R 3A , R 4 , R 4A , and R 5 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:

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

wherein
R 1 is selected from the group consisting of SO 2 R 6 , C(O)R 6 , C(O)OR 6 , and C(O)NR 7 R 8 ;
R 2 is C(O)OH or a bioisostere thereof;
R 2A is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cycloalkyl;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein the R 3 C 1 -C 6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkoxy, OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein the R 3 C 3 -C 6 cycloalkyl, phenyl, and 5-6 membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, OH, oxo, CN, NO 2 , F, Cl, Br and I; and
R 3A is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; or
R 3 and R 3A , together with the carbon to which they are attached, form C 3 -C 6 cycloalkyl; wherein the C 3 -C 6 cycloalkyl formed from R 3 and R 3A and the carbon to which they are attached is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 4 is selected from the group consisting of L 1 -C 6 -C 10 aryl, L 1 -5-11 membered heteroaryl, L-4-12 membered heterocyclyl, L 1 -C 3 -C 11 cycloalkyl, and L 1 -C 4 -C 11 cycloalkenyl; wherein the R 4 C 6 -C 10 aryl, 5-11 membered heteroaryl, 4-12 membered heterocyclyl, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R 9 , OR 9 , C(O)OR 9 , C(O)NR 10 R 11 , SR 9 , NR 10 R 11 , Si(R 9 ) 3 , SF 5 , SO 2 R 9 , OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein L 1 is absent, or is selected from the group consisting of C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, and C 1 -C 6 alkylene-O—; wherein the L 1 C 1 -C 6 alkylene, C 2 -C 6 alkenylene, and C 2 -C 6 alkynylene, alone or as part of a group, are optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkoxy, OH, and oxo; and
R 4A is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; or
R 4 and R 4A , together with the carbon to which they are attached, form 4-12 membered heterocyclyl; wherein the 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 9 , OR 9 , C(O)OR 9 , C(O)NR 10 R 11 , SR 9 , NR 10 R 11 , Si(R 9 ) 3 , SF 5 , SO 2 R 9 , OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 5 is selected from the group consisting of C 6 -C 10 membered aryl, 5-11 membered heteroaryl, 4-6 membered monocyclic heterocycle fused to a phenyl group, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl; wherein the R 5 C 6 -C 10 membered aryl, 5-11 membered heteroaryl, 4-6 membered monocyclic heterocycle fused to a phenyl group, C 3 -C 11 cycloalkyl, and C 4 -C 11 cycloalkenyl are optionally substituted with one or more substituents independently selected from the group consisting of R 12 , OR 12 , NR 13 R 14 , OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 6 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 6 C 1 -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 R 15 , OR 15 , SR 15 , NR 16 R 17 , OH, CN, NO 2 , F, Cl, Br and I; wherein the R 6 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's, OR 18 , C(O)R 18 , OC(O)R 18 , C(O)OR 18 , SO 2 R 18 , NR 19 R 20 , OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 7 and R 8 are each independently hydrogen or C 1 -C 6 alkyl;
R 9 , 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 9 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of R 21 , OR 21 , C(O)R 21 , OC(O)R 21 , C(O)OR 21 , C(O)NR 22 R 23 , SO 2 R 21 , NR 22 R 23 , OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein each R 9 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of R 24 , OR 24 , C(O)R 24 , OC(O)R 24 , C(O)OR 24 , SO 2 R 24 , NR 25 R 26 , OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 10 and R 11 , at each occurrence, are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, phenyl, and 5-6 membered heteroaryl; wherein each R 10 and R 11 phenyl and 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 12 , at each occurrence, is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 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 12 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, N(C 1 -C 6 alkyl) 2 , OH, oxo, CN, NO 2 , F, Cl, Br and I;
R 13 and R 14 , at each occurrence, are each independently hydrogen or C 1 -C 6 alkyl;
R 15 , 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 15 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, oxo, CN, NO 2 , F, Cl, Br and I; wherein each R 15 6-10 membered aryl, 5-11 membered heteroaryl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkenyl, and 4-12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, oxo, OH, CN, NO 2 , F, Cl, Br and I;
R 16 and R 17 , at each occurrence, are each independently hydrogen or C 1 -C 6 alkyl;
R 18 , 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, C 6 -C 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 18 C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 membered aryl, 5-11 membered heteroaryl,

Assignees

• Abbvie Sarl
• Galapagos Nv
• Abbvie Sarl

Inventors

• Altenbach Robert J
• Bogdan Andrew
• Couty Sylvain
• De Lemos Elsa
• Desroy Nicolas
• Duthion Béranger
• Gfesser Gregory A
• Greszler Stephen N
• Housseman Christopher Gaëtan
• Koenig John R
• Kym Philip R
• Liu Bo
• Scanio Marc J
• Searle Xenia
• Wang Xueqing
• Yeung Ming C
• Zhao Gang

Classifications

• C07D207/14 Primary

  Nitrogen atoms not forming part of a nitro radical · CPC title

• C07D207/48

  Sulfur atoms · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title