CFTR regulators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11230535-B2
Application number	US-202016785417-A
Country	US
Kind code	B2
Filing date	Feb 7, 2020
Priority date	Dec 24, 2015
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

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 method of treating constipation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
X is —O—, —NH— or —S—;
n1, n2, n6, n7, n8, and n9 are independently an integer from 0 to 4;
m1, m6, m7, m8, m9, v1, v6, v7, v8, and v9 are each independently 1 or 2;
R 1 is hydrogen, halogen, —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, —CX 2.1 3 , CHX 2.1 2 , —(CH 2 ) n2 CX 2.1 3 , —OR 2A , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or haloalkyl;
R 3 is hydrogen, —C(O)R 3D , —C(O)NHNR 3B R 3C , —C(O)OR 3D , —SO 2 R 3A , C(O)NR 3B R 3C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R 4 is hydrogen, —C(O)R 4D , —C(O)NHNR 4B R 4C , —C(O)OR 4D , —SO 2 R 4A , C(O)NR 4B R 4C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R 3 and R 4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R 3 and R 4 are optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is hydrogen, —C(O)R 5D , —C(O)NHNR 5B R 5C , —C(O)OR 5D , —SO 2 R 5A , C(O)NR 5B R 5C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R 3 and R 4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl 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 1 and R 6 , R 6 and R 7 , R 1 and R 9 , or R 8 , and R 9 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 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 , —CI 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 , —OCI 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 9B and R 9C substituents bonded to the same nitrogen atom may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X 1.1 , X 2.1 , X 6.1 , X 7.1 , X 8.1 and X 9.1 are independently —Cl, —Br, —I or —F;
with the proviso that when X is —O—; R 2 is —(CH 2 ) n2 CX 2.1 3 ; n2 is 1; X 2.1 is fluorine; R 3 is hydrogen; and R 4 is substituted or unsubstituted C 1 -C 3 alkyl, then R 6 is not —NO 2 ; and when X is —O—; R 2 is —(CH 2 ) n2 CX 2.1 3 ; n2 is 1; X 2.1 is fluorine; R 3 is hydrogen; and R 4 is substituted or unsubstituted C 1 -C 3 alkyl, then R 9 is not —NO 2 .

2. The method of claim 1 , further comprising administering to the subject an anti-constipation agent.

3. The method of claim 1 , wherein the compound is administered orally.

4. The method of claim 1 , wherein the constipation is opioid-induce

Assignees

• Univ California

Inventors

• Verkman Alan S
• Levin Marc H
• Cil Onur
• Lee Sujin

Classifications

• A61P27/04

  Artificial tears; Irrigation solutions · CPC title

• A61P1/10

  Laxatives · CPC title

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title