IP Library › Granted Patent US 12,281,115
Granted Patent B2
US 12,281,115 · App. 18/914,975 · Granted Apr 22, 2025

Azaindole rock inhibitors

Inventor: Thomas Maxwell Kaiser (Durham, NC)
Assignee: Avicenna Biosciences, Inc.
C07D471/04A61K9/0019A61K9/08A61K31/437A61K47/20A61K47/38
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Quick Facts
Patent No.
US 12,281,115
App. No.
18/914,975
Granted
Apr 22, 2025
Kind
B2
Abstract

This invention provides rho-associated protein kinase (ROCK) inhibiting compounds for therapeutic applications as described further herein.

Claims (32)

1. A compound of Formula:

wherein:

R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and halogen.

2. The compound of claim 1 , wherein R 1 is hydrogen.

3. The compound of claim 1 , wherein R 1 is C 1 -C 4 alkyl.

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

5. The compound of claim 1 , wherein R 2 is hydrogen.

6. The compound of claim 1 , wherein R 2 is C 1 -C 4 alkyl.

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

8. The compound of claim 1 , wherein the compound is of Formula:

9. The compound of claim 8 , wherein R 2 is hydrogen or C 1 -C 4 alkyl.

10. The compound of claim 8 , wherein R 2 is hydrogen or methyl.

11. The compound of claim 1 , wherein the compound is of structure:

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition of claim 12 , wherein the compound of claim 1 is of structure:

14. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is in the form of a tablet.

15. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is in the form of a capsule.

16. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is in the form of an injection or infusion solution.

17. A method of treating a ROCK1 or ROCK2 mediated disorder selected from amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and dementia in a human in need thereof comprising administering an effective amount of a compound of claim 1 , optionally in a pharmaceutical composition, to the human in need thereof.

18. The method of claim 17 , wherein the disorder is mediated by ROCK1.

19. The method of claim 17 , wherein the disorder is mediated by ROCK2.

20. The method of claim 17 , wherein the disorder is amyotrophic lateral sclerosis.

21. The method of claim 17 , wherein the disorder is Parkinson's disease.

22. The method of claim 17 , wherein the disorder is Huntington's disease.

23. The method of claim 17 , wherein the disorder is post-traumatic dementia.

24. The method of claim 17 , wherein the compound of claim 1 is a compound of structure:

25. The method of claim 24 , wherein the disorder is mediated by ROCK1.

26. The method of claim 24 , wherein the disorder is mediated by ROCK2.

27. The method of claim 24 , wherein the disorder is amyotrophic lateral sclerosis.

28. The method of claim 24 , wherein the disorder is Parkinson's disease.

29. The method of claim 24 , wherein the disorder is Huntington's disease.

30. The method of claim 24 , wherein the disorder is post-traumatic dementia.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 3, 2025
From: KAISER, THOMAS MAXWELL
To: AVICENNA BIOSCIENCES, INC.
Reel/Frame 070091/0908 →
Continuity (4)
Continuation 18610041 · Mar 19, 2024
Continuation PCTUS2023086402 · Dec 29, 2023
Provisional Application 63436408 · Dec 30, 2022
Related Publication 20250092038A1 · Mar 20, 2025
References Cited (45)
US 6858638B2 · Damour et al. · 2005 [cited by applicant]
US 10717735B2 · Ibrahim et al. · 2020 [cited by applicant]
US 20090029970A1 · Takeshita · 2009 [cited by applicant]
US 20190002442A1 · Zhao et al. · 2019 [cited by applicant]
US 20190010143A1 · Zhao et al. · 2019 [cited by applicant]
US 20190031654A1 · Ibrahim et al. · 2019 [cited by applicant]
US 20220002266A1 · Zhao et al. · 2022 [cited by applicant]
US 20220273662A1 · Oh et al. · 2022 [cited by applicant]
US 20230257376A1 · Li et al. · 2023 [cited by applicant]
US 20230312530A1 · Zhao et al. · 2023 [cited by applicant]
US 20240246972A1 · Kaiser · 2024 [cited by applicant]
US 20240254124A1 · Kaiser · 2024 [cited by applicant]
WO WO2009023179A2 · 2009 [cited by applicant]
WO WO2009155209A1 · 2009 [cited by applicant]
WO WO2011050245A1 · 2011 [cited by applicant]
WO WO2021214200A1 · 2021 [cited by applicant]
WO WO2023139379A1 · 2023 [cited by applicant]
WO WO2023209692A1 · 2023 [cited by applicant]
U.S. Appl. No. 18/610,041, Thomas Maxwell Kaiser, Jul. 25, 2024. [cited by applicant]
U.S. Appl. No. 18/610,051, Thomas Maxwell Kaiser, Aug. 1, 2024. [cited by applicant]
Bye, Nicole et al. “Rho kinase inhibition following traumatic brain injury in mice promotes functional improvement and acute neuron survival but has little effect on neurogenesis, glial responses or neuroinflammation”, … [cited by applicant]
Chowdhury, Sarwat et al. “Discovery and optimization of indoles and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-I).” [cited by applicant]
Defert, Olivier and Sandro Boland “Rho kinase inhibitors: a patent review (2014-2016).” [cited by applicant]
Duffy, Philip et al. “Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord.” [cited by applicant]
Feng, Yangbo et al. “Discovery of substituted 4-(pyrazol-4-y1)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors.” [cited by applicant]
Feng, Yangbo and Philip V. LoGrasso “Rho kinase inhibitors: a patent review (2012-2013).” [cited by applicant]
Feng, Yangbo et al. “Rho kinase (ROCK) inhibitors and their therapeutic potential.” [cited by applicant]
Glyn, Richard J. and Graham Pattison. “The effects on lipophilicity of replacing oxygenated functionality with their fluorinated bioisosteres”, 2021. [cited by applicant]
International search report and written opinion for PCT/US23/86402, 10 pages, mailed on May 23, 2024. [cited by applicant]
Koch, Jan Christoph et al. “ROCK inhibition in models of neurodegeneration and its potential for clinical translation.” [cited by applicant]
Koch, Jan C. et al. “Compassionate use of the ROCK inhibitor fasudil in three patients with amyotrophic lateral sclerosis.” [cited by applicant]
Li, Xiaohong et al. “PRKX critically regulates endothelial cell proliferation, migration, and vascular-like structure formation.” [cited by applicant]
Lingor, Paul et al. “ROCK-ALS: protocol for a randomized, placebo-controlled, double-blind phase IIa trial of safety, tolerability and efficacy of the rho kinase (ROCK) inhibitor fasudil in amyotrophic lateral sclerosis… [cited by applicant]
Lograsso, Philip V. and Yangbo Feng “Rho kinase (ROCK) inhibitors and their application to inflammatory disorders.” [cited by applicant]
Moskal, Natalia et al. “ROCK inhibitors upregulate the neuroprotective Parkin-mediated mitophagy pathway.” [cited by applicant]
Naseer, Shahmir et al. “Traumatic brain injury leads to alterations in contusional cortical miRNAs involved in dementia”, Biomolecules 12.10, 1457, 2022. [cited by applicant]
Rikitake, Yoshiyuki and James K. Liao “ROCKs as therapeutic targets in cardiovascular diseases.” [cited by applicant]
Roser, Anna-Elisa, Lars Tonges and Paul Lingor “Modulation of microglial activity by Rho-kinase (ROCK) inhibition as therapeutic strategy in Parkinson's disease and amyotrophic lateral sclerosis.” [cited by applicant]
Sessions, E. Hampton et al. “Discovery and optimization of indole and 7-azaindoles as Rho kinase (ROCK) inhibitors (part-II).” [cited by applicant]
Staiger, B. “Pharmaceutical Dosage Forms: A Review”, 2017 first published; 2018 last updated, https://walrus.com/articles/ pharmaceutical-dosage-forms-a-review, 2017. [cited by applicant]
Sun, Shaoyi, and Jianmin Fu “Methyl-containing pharmaceuticals: Methylation in drug design”, Bioorganic & medicinal chemistry letters 28.20, 3283-3289, 2018. [cited by applicant]
Tatenhorst, Lars et al. “Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease.” [cited by applicant]
Wang, Qing et al. “Advantages of Rho-associated kinases and their inhibitor fasudil for the treatment of neurodegenerative diseases.” [cited by applicant]
Weber, Audrey J. and Jeremy H. Herskowitz “Perspectives on ROCK2 as a Therapeutic Target for Alzheimer's Disease.” [cited by applicant]
Yin, Yan et al. “Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors.” [cited by applicant]