CFTR regulators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12503447-B2
Application number	US-202117226004-A
Country	US
Kind code	B2
Filing date	Apr 8, 2021
Priority date	Dec 24, 2015
Publication date	Dec 23, 2025
Grant date	Dec 23, 2025

Abstract

Provided herein are compounds that activate CFTR and methods for treating constipation, dry eye disorders, and other diseases and disorders.

First claim

What is claimed is:

1 . A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein,
L 1 is —CH 2 —;
R 20 is substituted or unsubstituted pyridyl, furanyl, or thiophenyl;
n1, n3, n4, n5, n6, n7, n8, and n9 are independently an integer from 0 to 4;
m1, m2, m3, m4, m5, m6, m7, m8, m9, v1, v2, v3, v4, v5, v6, v7, v8, and v9 are independently 1 or 2;
R 1 is hydrogen, —CX 1.1 3 , —CHX 1.1 2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1 3 , —OCHX 1.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is hydrogen, —CHX 2.1 2 , —CH 2 X 2.1 , —CN, —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , C(O)R 2D , —C(O)NR 2B R 2C , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1 3 , —OCHX 2.1 2 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is hydrogen, —CX 3.1 3 , —CHX 3.1 2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NH NR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1 3 , —OCHX 3.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
R 4 is hydrogen, —CX 4.1 3 , —CHX 4.1 2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1 3 , —OCHX 4.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is hydrogen, —CX 5.1 3 , —CHX 5.1 2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1 3 , —OCHX 5.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 1 and R 5 are optionally joined to form, together with the atoms to which they are attached, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 6 is hydrogen, halogen, —CX 6.1 3 , —CHX 6.1 2 , —CH 2 X 6.1 , —CN, —SO n6 R 6A , —SO v6 NR 6B R 6C , —NHNR 6B R 6C , —ONR 6B R 6C , —NHC(O)NHNR 6B R 6C , —NHC(O)NR 6B R 6C , —N(O) m6 , —NR 6B R 6C , —C(O)R 6D , —C(O)OR 6D , —C(O)NR 6B R 6C , —OR 6A , —NR 6B SO 2 R 6A , —NR 6B C(O)R 6D , —NR 6B C(O)OR 6D , —NR 6B OR 6D , —OCX 6.1 3 , —OCHX 6.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 is hydrogen, halogen, —CX 7.1 3 , —CHX 7.1 2 , —CH 2 X 7.1 , —CN, —SO n7 R 7A , —SO v7 NR 7B R 7C , —NHNR 7B R 7C , —ONR 7B R 7C , —NHC(O)NHNR 7B R 7C , —NHC(O)NR 7B R 7C , —N(O) m7 , —NR 7B R 7C , —C(O)R 7D , —C(O)OR 7D , —C(O)NR 7B R 7C , —OR 7A , —NR 7B SO 2 R 7A , —NR 7A C(O)R 7C , —NR 7B C(O)OR 7D , —NR 7B OR 7D , —OCX 7.1 3 , —OCHX 7.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 8 is hydrogen, halogen, —CX 8.1 3 , —CHX 8.1 2 , —CH 2 X 8.1 , —CN, —SO n8 R 8A , —SO v8 NR 8B R 8C , —NHNR 8B R 8C , —ONR 8B R 8C , —NHC(O)NHNR 8B R 8C , —NHC(O)NR 8B R 8C , —N(O) m8 , —NR 8B R 8C , —C(O)R 8D , —C(O)OR 8D , —C(O)NR 8B R 8C , —OR 8A , —NR 8B SO 2 R 8A , —NR 8B C(O)R 8D , —NR 8B C(O)OR 8D , —NR 8B OR 8D , —OCX 8.1 3 , —OCHX 8.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 9 is hydrogen, halogen, —CX 9.1 3 , —CHX 9.1 2 , —CH 2 X 9.1 , —CN, —SO n9 R 9A , —SO v9 NR 9B R 9C , —NHNR 9B R 9C , —ONR 9B R 9C , —NHC(O)NHNR 9B R 9C , —NHC(O)NR 9B R 9C , —N(O) m9 , —NR 9B R 9C , —C(O)R 9D , —C(O)OR 9D , —C(O)NR 9B R 9C , —OR 9A , —NR 9B SO 2 R 9A , —NR 9B C(O)R 9D , —NR 9B C(O)OR 9D , —NR 9B OR 9D , —OCX 9.1 3 , —OCHX 9.1 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 8A , R 8B , R 8C , R 8D , R 9A , R 9B , R 9C and R 9D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —Cl 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O) H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCl 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B , R 5C , R 6B , R 6C , R 7B , R 7C , R 8B , R 8C , R 8B and R 9C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
X 1.1 , X 2.1 , X 3.1 , X 4.1 , X 5.1 , X 6.1 , X 7.1 , X 8.1 , X 9.1 are independently —Cl, —Br, —I or —F, and
wherein at least one of R 1 , R 2 , R 3 , R 4 and R 5 is —NO 2 , with the proviso that, when R 3 is —NO 2 and R 6 , R 7 , R 8 and R 9 are hydrogen, then R 5 is not —NH 2 , or when R 1 is —NO 2 , and R 6 , R 7 , R 8 and R 9 are hydrogen, then R 4 is not NH 2 .

2 . The compound of claim 1 , wherein R 6 , R 7 , R 8 and R 9 are hydrogen.

3 . The compound of claim 1 , wherein: at least two of R 1 , R 2 , R 4 and R 5 are hydr

Assignees

• Univ California

Inventors

• Verkman Alan S
• Levin Marc H
• Cil Onur
• Kurth Mark J

Classifications

• A61K31/498 Primary

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• C07D409/06

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

• C07D405/06

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

• C07D401/06

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

• C07D409/04

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