Inhibitors of TRPC6

Patent metadata

Field	Value
Publication number	US-11485740-B2
Application number	US-201916970129-A
Country	US
Kind code	B2
Filing date	Feb 13, 2019
Priority date	Feb 15, 2018
Publication date	Nov 1, 2022
Grant date	Nov 1, 2022

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts therefore, wherein R1 to R6, A, U, V, W, X, Y, and Z 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:
A is CR 7 or N;
U is CH or N;
V is CR 8 or N;
W is CR 9 or N;
X is CH, CC 1-6 alkyl, COC 1-6 alkyl, or N;
Y is CH or N;
Z is CH, COH, COC 1-6 alkyl or N;
R 1 is selected from the group consisting of H and halogen;
R 2 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;
when Z is COH, R 1 may join with the hydroxyl group attached to the Z ring atom to form a central furanyl ring;
R 3 is selected from the group consisting of
H,
C 1-6 alkyl optionally substituted with one to three groups independently selected from the group consisting of halogen, hydroxy or methoxy, and
C 3-6 cycloalkyl;

R 4 is selected from the group consisting of H, C 1-6 alkyl optionally substituted with hydroxyl, C 3-6 cycloalkyl;
R 5 is H or C 1-6 alkyl;
R 3 and R 5 can together form a bicyclic ring;
R 6 is selected from the group consisting of
H,
C 1-6 alkyl,
—CN,
—CF 3 ,
—OCF 3 ,
C 3-6 cycloalkyl, and
OC 1-6 alkyl optionally substituted one to three halogen;

R 7 is selected from the group consisting of H, C 1-6 alkyl, and OC 1-6 alkyl optionally substituted with one to three halogen;
R 8 is selected from the group consisting of
H,
C 1-6 alkyl optionally substituted with C 3-6 cycloalkyl or one to three halogen,
halogen,
—CN,
—CF 3 ,
—NH 2 ,
phenyl,
C 3-6 cycloalkyl,
OC 3-6 cycloalkyl,
OC 1-6 alkyl optionally substituted with one to three halogen or C 3-6 cycloalkyl optionally substituted with one to three halogen; and
1-fluoromethyl-cyclopropylmethoxy;

R 9 is selected from the group consisting of
H,
C 1-6 alkyl optionally substituted with one to three halogen,
halogen,
—CN,
—CF 3 ,
OH,
C 3-6 cycloalkyl,
OC 1-6 alkyl optionally substituted with C 3-6 cycloalkyl or one to three halogen, and
OC 3-6 cycloalkyl;

when V is CR 8 and W is CR 9 , R 8 and R 9 can together form a 5- to 6-membered fused heterocyclic ring;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein
R 2 is selected from the group consisting of H, C 1-6 alkyl, and OC 1-6 alkyl;
R 3 is selected from the group consisting of H and C 1-6 alkyl optionally substituted with one to three groups independently selected from the group consisting of halogen and hydroxyl;
R 4 is selected from the group consisting of H and C 1-6 alkyl optionally substituted with hydroxyl;
R 5 is H;
R 6 is selected from the group consisting of H, C 1-6 alkyl, and OC 1-6 alkyl optionally substituted with one to three halogen;
or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein Z is CH or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein:
U is N, V is CR 8 , and W is CR 9 ,
X is CH or N,
or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein:
A is N,
X is N,
Y is CH,
or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein:
A is N,
X is CH,
Y is CH,
or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein:
A is CR 7 ,
X is N,
Y is N,
or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein
A is CR 7 ,
X is N,
Y is CH,
or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein R 8 is selected from the group consisting H, F, CF 3 , ethyl, methoxy, ethoxy, sec-butoxy, trifluoromethoxy, trifluoroethoxy, cyclopropyl, cyclopropylmethoxy, 1-cyclopropylethoxy, 1-methylcyclopropylmethoxy, 1-fluoromethylcyclopropylmethoxy, 2,2,2-trifluoroethoxy, 2,2,-dimethylcyclopropylmethoxy, 2,2,-diflurocyclopropylmethoxy, cyclopropoxy, and cyclobutoxy,
or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein R 2 is H or OCH3, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 , wherein
R 3 , R 4 , R 5 and R 6 are each H,
or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein R 2 is OCH3, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 , wherein R 8 is selected from the group consisting of H, fluoro, chloro, CF 3 , —CN, methyl, ethyl, isobutyl, tert-butyl, difluoromethyl, methoxy, difluoromethoxy, ethoxy, isopropoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, cyclopropylmethoxy, cyclopropoxy, and cyclopentoxy, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein R 2 is H or OCH 3 , or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 , wherein R 2 is OCH 3 , or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , wherein R 2 is H, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 , selected from the group consisting of:

Cpd No.
Structure
Structure Name

  1

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-biphenyl-4-yl- methanone

  2

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-(4′-ethyl- biphenyl-4-yl)-methanone

  3

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-(4′-methyl- biphenyl-4-yl)-methanone

  4

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-(4′-chloro- biphenyl-4-yl)-methanone

  5

[4-(6-Amino-pyridazin-3-yl)- piperidin-1-yl]-(4′-methoxy- biphenyl-4-yl)-methanone

Assignees

• Boehringer Ingelheim Int
• Hydra Biosciences Llc

Inventors

• Brunette Steven
• Cui Jianwen
• Lowe Michael D
• Sarko Christopher Ronald
• Surprenant Simon
• Turner Michael Robert
• Wu Xinyuan
• Smith Keenan Lana Louise
• Bouyssou Thierry
• Nicklin Paul

Classifications

• C07D401/04

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D487/08 Primary

  Bridged systems · CPC title

• C07D403/04 Primary

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

• C07D405/14

  containing three or more hetero rings · CPC title