Aryl cyclopropyl-amino-isoquinolinyl amide compounds

Patent metadata

Field	Value
Publication number	US-2023227430-A1
Application number	US-202217895436-A
Country	US
Kind code	A1
Filing date	Aug 25, 2022
Priority date	Sep 14, 2018
Publication date	Jul 20, 2023
Grant date	—

Abstract

Provided herein are amino isoquinolinyl amide and sulfonamide compounds that affect the function of kinases and other proteins in a cell and that are useful as therapeutic agents. In particular, these compounds are useful in the treatment of eye diseases such as glaucoma and retinal diseases, as anti-inflammatory agents, for the treatment of cardiovascular diseases, and for diseases characterized by abnormal growth, such as cancers.

First claim

What is claimed is:

1 . A method of treating an ocular disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halo, —CN, —C 1-6 alkyl, —C 1-6 alkoxyl, —C 1-6 haloalkyl, —C 1-6 haloalkoxyl;
R 2 is H or halo;
X is —(C 1-5 heteroaryl)-R 3 ; and
R 3 is halo, —C 2-6 heterocyclyl, or —C 1-6 heteroalkyl.

2 . The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof.

3 . The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 , wherein R 1 is H, halo, —CN, —C 1-3 alkyl, —C 1-3 alkoxyl, —C 1-3 haloalkyl, —C 1-3 haloalkoxyl.

5 . The method of claim 1 , wherein R 1 is H, Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , or —OCF 3 .

6 . The method of claim 1 , wherein R 1 is Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , or —OCF 3 .

7 . The method of claim 1 , wherein R 2 is F, Cl, Br, or I.

8 . The method of claim 1 , wherein R 2 is H or F.

9 . The method of claim 1 , wherein X is —(C 3-5 heteroaryl)-R 3 .

10 . The method of claim 1 , wherein X is

11 . The method of claim 1 , wherein R 3 is —C 2-6 heterocyclyl or —C 1-6 heteroalkyl.

12 . The method of claim 1 , wherein R 3 is —C 3-5 heterocycloalkyl or —C 1-4 heteroalkyl.

13 . The method of claim 1 , wherein R 3 is F,

14 . The method of claim 1 , wherein
R 1 is H, Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , or —OCF 3 ; R 2 is H or F; X is

and
R 3 is F,

15 . The method of claim 1 , wherein
R 1 is Cl, —CN, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CF 3 , or —OCF 3 ; R 2 is H or F; X is

and
R 3 is

16 . The method of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

17 . The method of claim 1 , wherein the ocular disorder is glaucoma, an inflammatory eye disease, a neurodegenerative eye disease, diabetic eye disease, wet age-related macular degeneration, or dry age-related macular degeneration.

18 . The method of claim 1 , wherein the compound is administered topically to an eye of the subject.

19 . The method of claim 1 , wherein the compound is administered topically to an eyelid of the subject.

20 . A method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halo, —CN, —C 1-6 alkyl, —C 1-6 alkoxyl, —C 1-6 haloalkyl, —C 1-6 haloalkoxyl;
R 2 is H or halo;
X is —(C 1-5 heteroaryl)-R 3 ; and
R 3 is halo, —C 2-6 heterocyclyl, or —C 1-6 heteroalkyl.

21 . The method of claim 20 , wherein the compound is administered topically to an eye of the subject

22 . The method of claim 20 , wherein the compound is administered topically to an eyelid of the subject.

23 . The method of claim 20 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

24 . A method of modulating kinase activity in a cell, comprising contacting the cell with an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halo, —CN, —C 1-6 alkyl, —C 1-6 alkoxyl, —C 1-6 haloalkyl, —C 1-6 haloalkoxyl;
R 2 is H or halo;
X is —(C 1-5 heteroaryl)-R 3 ; and
R 3 is halo, —C 2-6 heterocyclyl, or —C 1-6 heteroalkyl.

25 . The method of claim 24 , wherein the cell is in a subject.

26 . The method of claim 24 , wherein the cell is in a human subject.

27 . The method of claim 24 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

28 . A method of treating a disease or disorder associated with kinase activity in a subject in need thereof, comprising contacting the subject with a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
R 1 is H, halo, —CN, —C 1-6 alkyl, —C 1-6 alkoxyl, —C 1-6 haloalkyl, —C 1-6 haloalkoxyl;
R 2 is H or halo;
X is —(C 1-5 heteroaryl)-R 3 ; and
R 3 is halo, —C 2-6 heterocyclyl, or —C 1-6 heteroalkyl.

29 . The method of claim 28 , wherein the kinase activity is a Janus kinase activity.

30 . The method of claim 28 , wherein the kinase activity is a Rho-associated protein kinase activity.

31 . The method of claim 28 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Assignees

• Aerie Pharmaceuticals Inc

Inventors

• Delong Mitchell A
• Sturdivant Jill M
• Lichorowic Cynthia L
• Kornilov Andriy

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P27/06 Primary

  Antiglaucoma agents or miotics · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title