Inhibitors of TRPC6

Patent metadata

Field	Value
Publication number	US-RE49699-E
Application number	US-202117334097-A
Country	US
Kind code	E1
Filing date	May 28, 2021
Priority date	Oct 27, 2017
Publication date	Oct 17, 2023
Grant date	Oct 17, 2023

Abstract

The invention related to compounds of formula (I),

and pharmaceutically acceptable salts thereof, wherein R 1 to R 2 , A, Y and L are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

First claim

What is claimed is:

1. A compound of formula (I)

wherein
L is absent or is methylene or ethylene;
Y is CH or N;
A is CH or N;
R 1 is selected from the group consisting of:
C 1-6 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, C 3-6 cycloalkyl and OC 3-6 cycloalkyl;
phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF 3 , halo, C 3-6 cycloalkyl, OC 3-6 cycloalkyl, and OC 1-6 alkyl; wherein said OC 1-6 alkyl may be optionally substituted with one to three halo; and
C 3-6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo and C 1-6 alkyl optionally substituted with 1 to 3 halo;
R 2 is selected from the group consisting of H, C 1-6 alkyl, OCF 3 , C 3-6 cycloalkyl, OC 3-6 alkyl, and OC 3-6 cycloalkyl;
R 3 is selected from the group consisting of H; C_alkyl, C 3-6 cycloalkyl, and OC 3-6 cycloalkyl; wherein each of the C 1-6 alkyl, C 3-6 cycloalkyl, or OC 3-6 cycltoalkyl of the R 3 group may independently be optionally substituted with one to three groups each independently selected from the group consisting of halo, OH, OC 1-6 alkyl, SC 1-6 alkyl, and N(C 1-6 alky) 2 ; and wherein one to three carbon atoms of the C 1-6 alkyl of the R 3 group may optionally be replaced one or two moieties selected from the group consisting of NH, N(C 1-6 alkyl), O, and S;
R 4 and R 5 are each independently selected from the group consisting of H and C 1-6 ,alkyl; or
R 3 and R 4 together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or
R 3 and R 5 together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N, O, and S;
R 6 is selected from the group consisting of H, C 1-6 alkyl, CN, CF 3 , OCF 3 , C 3-6 cycloalkyl, OC 1-6 alkyl, and OC 3-6 cycloalkyl;
R 7 is selected from the group consisting of H and OC 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein
R 1 is selected from the group consisting of:
C 1-6 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo and C 3-6 cycloalkyl;
phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of CF 3 , halo, OC 3-6 cycloalkyl, and OC 1-6 alkyl; wherein said OC 1-6 alkyl may be optionally substituted with one to three halo; and
C 3-6 cycloalkyl optionally substituted with 1 to 3 halo groups;
R 2 is OC 1-6 alkyl;
R 3 is selected from the group consisting of H and C 1-6 alkyl, optionally substituted with OH or OC 1-6 alkyl;
R 4 is H;
R 5 is H; or
R 3 and R 4 together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; and R
R 3 and R 5 together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N and O;
R 6 is selected from the group consisting of H; C 1-6 alkyl, OC 1-6 alkyl, and OC 3-6 cycloalkyl; and
R 7 is selected from the group consisting of H and OC 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein
A is CH and Y is N; or
A is CH and Y is CH; or
A is N and Y is CH;

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein
1 is phenyl optionally substituted with a group selected from the group consisting of CF 3 , halo, OC 3-6 cycloalkyl, and OC 1-6 alkyl; wherein the OC 3-6 alkyl may be optionally substituted with one to three halo;
R 2 is OC 1-6 alkyl;
R 3 is selected from the group consisting of H and C 1-6 alkyl optionally substituted with OH or OC 1-6 alkyl;
R 4 is H;
R 5 is H; or
R 3 and R 4 can together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or
R 3 and R 5 together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N and O;
R 6 is selected from the group consisting of H, C 1-6 alky, OC 1-6 alkyl, and OC 3-6 cycloalkyl;
R 7 is selected from the group consisting of H and OC 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein
R 1 is phenyl optionally substituted with a group selected from the group consisting of CF 3 , OCF 3 , F, and methoxy;
R 2 is selected from the group consisting of methoxy or ethoxy;
R 3 is selected from the group consisting of H, C 1-6 alkyl, 2-hydroxymethyl, methoxymethyl, and 1-hydroxyethyl;
R 4 is H;
R 5 is H; or
R 3 and R 4 together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or
R 3 and R 5 together with the atoms to which they are attached may join to form a 3- to 9-membered bicyclic ring, wherein said 3- to 9-membered bicyclic ring may optionally contain one to three heteroatoms selected from the group consisting of N, O, and S;
R 6 is selected from the group consisting of H, methyl, methoxy, ethoxy, propoxy, and cyclopropyloxy; and
R 7 is selected from the group consisting of H and methoxy;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein
R 1 together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethyiphenyl, 4-difluoromethoxyphenyl 4-cyclopropyloxyphenyl, cyclopropyl, cyclopentyl, cyclohexyl, benzyl, 2-fluorobenzyl, and phenylethyl; and
R 2 is methoxy or ethoxy;

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein
Y is CH and A is N;
R 1 together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-trifluoromethylphenyl, 4difluoromethoxyphenyl, 4-cyclopropoxyphenyl, benzyl, 2-fluorobenzyl, and phenylethyl;
R 2 is methoxy or ethoxy;
R 3 , R 4 and R 5 are each H;
R 6 is H, methyl, methoxy, or ethoxy; and
R 7 is H;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein
Y is CH and A is CH;
R 1 together with L represent a group selected from the group consisting of phenyl, 4-chlorophenyi, 4-fluorophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, cyclopentyl, cyclohexyl, benzyl, 2-fluorobenzyl, and phenylethyl;
R 2 is methoxy or ethoxy;
R 3 , R 4 and R 5 are each H;
R 6 is H, methyl, methoxy or ethoxy; and
R 7 is H;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein
Y is N and A is CH;
R 1 together with L represent a group selected from the group consisting of phenyl, and 4-fluorophenyl;
R 2 is methoxy;
R 3 is selected from the group consisting of H, 2-hydroxymethyl, and hydroxyethyl;
R 4 is H;
R 5 is H; or
R 3 and R 4 together with the atom to which they are attached may join to form a 3-membered carbocyclyl ring; or
R 3 and R 5 together wit

Assignees

• Boehringer Ingelheim Int
• Hydra Biosciences Llc

Inventors

• Bouyssou Thierry
• Gottschling Dirk
• Heine Niklas
• Keenan Lana Louise Smith
• Lowe Michael D
• Razavi Hossein
• Sarko Christopher Ronald
• Surprenant Simon
• Takahashi Hidenori
• Turner Michael Robert
• Wu Xinyuan

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/45

  having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title

• C07D213/04

  having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom · CPC title

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title