Pyrrolo-pyridazine Derivatives as Muscarinic M₁ Receptor Positive Allosteric Modulators

Important Compound Classes

Title

Pyrrolo-pyridazine Derivatives as Muscarinic M₁ Receptor Positive Allosteric Modulators

Patent Application Number

WO 2020/079606A1

Publication Date

April 23, 2020

Priority Application

201841039345IN

Priority Date

October 17, 2018

Inventors

Nirogi, R; Mohammed, A. R.; Shinde, A. K.; Ravella, S. R.; Subramanian, R.; Jasti, V.

Assignee Company

Suven Life Sciences Limited

Disease Area

CNS, neurodegenerative disease

Biological Target

Muscarinic M₁ receptor

Summary

The muscarinic acetylcholine family of receptors are a group of G-protein couple receptors (GPCRs) that are widely expressed throughout the body. There are 5 subtypes which are designated M₁ through M₅, each of which are activated by acetylcholine. M₂ and M₄ are G_i/o coupled, whereas M₁, M₃, and M₅ are G_q coupled. It has been demonstrated that M₁ is predominantly expressed in various brain regions including the cortex, amygdala, and hippocampus, all of which are involved in cognition. This expression pattern has led to interest in the development of novel therapies that activate M₁ as a means of improving cognitive performance. In addition, it has been suggested that compounds capable of activating M₁ could have utility in neurodegenerative diseases such as Alzheimer’s disease, frontotemporal dementia, Lewy body dementia, vascular dementia, as well as dementia associated with Parkinson’s disease and Huntington’s disease. The present patent application describes a series of novel M₁ positive allosteric modulators and their potential therapeutic utility.

Definitions

R¹ is selected from -(C_1–6)-alkyl, -(C_5–7)-cycloalkyl, -(C_5–7)-heterocycloalkyl, or -(C_6–10)-aryl, each of which is optionally substituted with one or more groups selected from halogen, hydroxy, NH₂, CH₂OH, and (C_1–4)-alkyl;

R² is selected from hydrogen, halogen, -(C_1–6)-alkyl, -(C_3–6)-cycloalkyl, or halo(C_1–4)-alkyl;

A¹ is CH₂, CHF, or CF₂;

P is independently selected from CH or N;

Q is independently selected from CH or N;

W is independently selected from CH or N;

Y is independently selected from CH or N;

Z is independently selected from CH or N;

A² is hydrogen, halogen, -OR², -NHR², -NHCOR², -CN, -CONHR², -CON(R²)₂, -(C_1–4)-alkyl, -(C_3–6)-cycloalkyl, -(C_6–10)-aryl, and-(C_5–10)-heteroaryl; wherein each of the -(C_1–4)-alkyl, -(C_3–6)-cycloalkyl, -(C_6–10)-aryl, and-(C_5–10)-heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -OR², -O-(C_1–4)-alkyl, -S-(C_1–4)-alkyl, -N(CH₃)₂, -(C_1–4)-alkyl, -(C_3–6)-cycloalkyl, halo(C_1–4)-alkyl, -NHR², -NHCOR², -CONHR², -CN; wherein R² at each occurrence is independently selected from hydrogen, halogen, -(C_1–6)-alkyl, -(C_3–6)-cycloalkyl, or halo(C_1–4)-alkyl.

Key Structures

Biological Assay

Muscarinic M_l receptor pCRE-Luc luciferase reporter assay

Biological Data

Claims

Twelve total claims, five composition of matter claims, seven method of use claims

Recent Review Articles

• 1.Erskine D.; Taylor J. P.; Bakker G.; Brown A. J. H.; Tasker T.; Nathan P. J.. Cholinergic muscarinic M1 and M4 receptors as therapeutic targets for cognitive, behavioral, and psychological symptoms in psychiatric and neurological disorders Drug Discovery Today 2019, 24, (12), 2307–2314..
• 2.Felder C. C.; Goldsmith P. J.; Jackson K.; Sanger H. E.; Evans D. A.; Mogg A. J.; Broad L. M.. Current status of muscarinic M1 and M4 receptors as drug targets for neurodegenerative diseases Neuropharmacology 2018, 136, 449–458..
• 3.Yohn S. E.; Conn P. J.. Positive allosteric modulation of M1 and M4 muscarinic receptors as potential therapeutic treatments for schizophrenia Neuropharmacology 2018, 136, 438–448..

The author declares no competing financial interest.