Rho kinase inhibitors and compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12428413-B2
Application number	US-202017621567-A
Country	US
Kind code	B2
Filing date	Jun 26, 2020
Priority date	Jun 28, 2019
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

Provided herein are certain inhibitors of ROCK (rho-kinases or rho-associated kinases), which are useful as medicament, for the treatment Huntington's disease in particular.

First claim

The invention claimed is:

1. A compound of formula I:

or a deuterated analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof, wherein:
ring B is a 6-10 membered aryl or 6-10 membered heteroaryl ring, wherein ring B is optionally substituted with 1-5 R 4 ;
X is —O— or —N(R 3 )—;
R 1 is H or optionally substituted C 1-3 alkyl;
each R 2 is independently oxo, halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, or C 1-3 alkoxy;
R 3 is H or C 1-3 alkyl;
each R 4 is independently halo, C 1-3 alkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
and
n is 0, 1, or 2.

2. The compound of claim 1 , wherein the compound is a compound of formula II:

3. The compound of claim 1 , wherein n is 0.

4. The compound of claim 1 , wherein n is 2, and each R 2 is methyl.

5. The compound of claim 1 , wherein the compound is a compound of formula III:

6. The compound of claim 5 , wherein the compound is a compound of formula III(a):

7. The compound of claim 5 , wherein the compound is a compound of formula III(b):

8. The compound of claim 6 , wherein the compound is a compound of formula IV(a):

and R 1 is optionally substituted C 1-3 alkyl, or
the compound is a compound of formula IV(b):

and R 1 is optionally substituted C 1-3 alkyl.

9. The compound of claim 7 , wherein the compound is a compound of formula IV(c):

and R 1 is optionally substituted C 1-3 alkyl, or
the compound is a compound of formula IV(d):

and R 1 is optionally substituted C 1-3 alkyl.

10. The compound of claim 1 , wherein X is —N(R 3 )—.

11. The compound of claim 10 , wherein R 3 is H.

12. The compound of claim 1 , wherein R 1 is methyl.

13. The compound of claim 1 , wherein R 2 is methyl.

14. The compound of claim 1 , wherein ring B is a 6-10 membered aryl optionally substituted with 1 to 3 substituents selected from halo, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.

15. The compound of claim 1 , wherein ring B is a 6-10 membered heteroaryl optionally substituted with 1 to 3 substituents selected from halo, C 1-3 alkyl, C 1-3 alkoxy, and C 1-3 haloalkoxy.

16. A compound selected from:

or a deuterated analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

18. A method of inhibiting rho-kinase in a patient having a condition or disorder, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , wherein the condition or disorder is selected from Huntington's disease (HD), spinal cord and/or brain injury, chronic pulmonary hypertension, Parkinson's disease, amyotrophic lateral sclerosis, cerebral cavernous malformation, cardiovascular disease, Alzheimer's disease (AD), glaucoma, multiple sclerosis (MS), corneal lesions, diabetes, chronic and/or neuropathic pain, stroke, ischemia, retinopathy, spinal muscular atrophy (SMA), erectile dysfunction, non-hypertensive nephropathy, hypertensive nephropathy, hypertension, optic nerve lesion, hepatic fibrosis, lupus, liver failure after transplant, encephalomyelitis, epilepsy, and glioblastoma.

19. The method of claim 18 , wherein the condition or disorder is Huntington's disease.

Assignees

• Chdi Foundation Inc

Inventors

• Maillard Michel C
• Lee Matthew R
• Dominguez Celia
• Barnes Michael
• Haughan Alan F
• Ladduwahetty Tammy
• Luckhurst Christopher A
• Stott Andrew J
• Tierney Jason

Classifications

• C07D487/08

  Bridged systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

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