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CN-121991063-A - Substituted tetrahydropyrrolo-pyridone compounds and their use in the treatment of medical conditions

CN121991063ACN 121991063 ACN121991063 ACN 121991063ACN-121991063-A

Abstract

The present invention provides substituted tetrahydropyrrolo-pyridone compounds, pharmaceutical compositions and their use in the treatment of muscarinic acetylcholine receptor mediated conditions.

Inventors

  • K. M. Gardiner
  • E. A. Skidmore
  • JAMES EDMUND AUDIA
  • J.Meng
  • J. Miles
  • Ahmed, N.M.
  • E. Gancia
  • WAGSTAFF NIGEL
  • D. G. Evans
  • Russell, F.J.G.

Assignees

  • 卡鲁娜治疗学有限公司

Dates

Publication Date
20260508
Application Date
20231215
Priority Date
20221216

Claims (10)

  1. 1. A compound represented by formula I: (I) Or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, - (C 1-6 alkylene) - (C 3-6 cycloalkyl) or hydrogen; R 2 is halo, C 1-4 alkyl, C 1-4 haloalkyl, or hydrogen; R 3 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -S- (C 1-4 alkyl) or halogen; R 4 independently at each occurrence represents C 1-4 alkyl, C 1-4 haloalkyl or halo; R 5 independently for each occurrence represents C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 3-6 cycloalkyl, hydroxy, C 1-6 alkoxy, - (C 1-6 alkylene) - (C 1-6 alkoxy), - (C 1-6 alkylene) - (C 3-6 cycloalkyl), - (C 1-6 haloalkylene) - (C 3-6 cycloalkyl) or- (C 1-6 alkylene) - (C 3-6 halocycloalkyl), or two occurrences of R 5 together with the intervening atoms thereof form a 4-7 membered ring containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; R 6 is (i) - (C 0-4 alkylene) - (3-to 7-membered saturated or unsaturated heterocyclyl containing 1,2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), (ii) - (C 0-4 alkylene) - (5-to 6-membered heteroaryl containing 1,2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or (iii) - (C 0-4 alkylene) -phenyl, wherein the heterocyclyl, heteroaryl, and phenyl are substituted with 0,1, 2, or 3 occurrences of R 7 ; R 7 independently for each occurrence represents C 1-6 alkyl, halo, C 1-6 haloalkyl, C 3-6 cycloalkyl, hydroxy or C 1-6 alkoxy; A 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or phenyl, wherein the heteroaryl and phenyl are substituted with n occurrences of R 5 and t occurrences of R 6 ; m is 0, 1, 2 or 3; n is 0, 1 or 2, and T is 0 or 1.
  2. 2. The compound of claim 1, wherein the compound is a compound of formula I.
  3. 3. The compound of claim 1 or 2, wherein m is 0.
  4. 4. The compound of claim 1 or 2, wherein m is 1.
  5. 5. The compound of claim 1, wherein the compound is a compound of formula Ia or a pharmaceutically acceptable salt thereof: Ia。
  6. 6. The compound of any one of claims 1-5, wherein a 1 is a 5-6 membered monocyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl is substituted with n occurrences of R 5 and t occurrences of R 6 .
  7. 7. The compound of any one of claims 1-5, wherein a 1 is a 5-membered monocyclic heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heteroaryl is substituted with n occurrences of R 5 and t occurrences of R 6 .
  8. 8. The compound of any one of claims 1-5, wherein a 1 is pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, thiophenyl, or pyridinyl, each substituted with n occurrences of R 5 and t occurrences of R 6 .
  9. 9. The compound of any one of claims 1-5, wherein a 1 is pyrazolyl, imidazolyl, oxazolyl, or isoxazolyl, each substituted with n occurrences of R 5 and t occurrences of R 6 .
  10. 10. The compound of any one of claims 1-5, wherein a 1 is pyrazolyl substituted with n occurrences of R 5 and t occurrences of R 6 .

Description

Substituted tetrahydropyrrolo-pyridone compounds and their use in the treatment of medical conditions The present application is a divisional application of China patent application No. 202380091334.1 (application day: 2023, 12, 15, title of application: substituted tetrahydropyrrolo-pyridone compounds and their use in the treatment of medical conditions). Cross Reference to Related Applications The present application claims the benefit and priority of U.S. provisional patent application serial No. 63/433,156 filed on 12 months 16 of 2022, the contents of which are hereby incorporated by reference in their entirety. Technical Field The present invention provides substituted tetrahydropyrrolo-pyridone compounds, pharmaceutical compositions and their use in the treatment of muscarinic acetylcholine receptor mediated conditions. Background Muscarinic acetylcholine receptor mediated conditions such as Major Depressive Disorder (MDD), bipolar disorder (BPD) and schizophrenia are mental diseases and remain a significant public health problem. Antidepressants, mood stabilizers and antipsychotics currently available to patients can alleviate some of the symptoms of mood disorders in some patients, but are only partially effective in a large number of patients, many of whom are refractory to the currently available medications. Patients suffering from major depressive disorder often exhibit at least two weeks of generalized mood swings, low self-esteem, and lost interest or enjoyment in the generally pleasant activities. Patients with bipolar disorder often exhibit periods of depression and abnormally elevated mood, each lasting from days to weeks. Schizophrenic patients often exhibit active social avoidance, passive social withdrawal, emotional withdrawal, and anxiety. In some cases, supportive therapy may be used to help alleviate symptoms of muscarinic acetylcholine receptor mediated conditions, however, supportive therapy cannot treat the condition directly, nor is it a long term good solution to meet the medical needs of the patient. Compounds that modulate muscarinic acetylcholine receptors may be used in the treatment of diseases associated with muscarinic acetylcholine receptor activity, such as major depressive disorder, bipolar disorder, and schizophrenia. The muscarinic acetylcholine receptor is an acetylcholine receptor that forms G protein-coupled receptor complexes on the cell membranes of certain neurons and other cells. U.S. patent 10,604,519 describes that certain compounds are active at the M4 muscarinic acetylcholine receptor. However, there is a need for new compounds with good classes of drugs to treat muscarinic acetylcholine receptor mediated conditions. The present invention meets the foregoing needs and provides other related advantages. Disclosure of Invention The present invention provides substituted tetrahydropyrrolo-pyridone compounds, pharmaceutical compositions and their use in the treatment of muscarinic acetylcholine receptor mediated conditions. In particular, one aspect of the invention provides a collection of substituted tetrahydropyrrolo-pyridone compounds, such as the compounds represented by formula I: (I) Or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of other collections of substituted tetrahydropyrrolo-pyridone compounds are found in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In another aspect, the invention provides a method of treating a muscarinic acetylcholine receptor mediated condition. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of formula I, to treat a muscarinic acetylcholine receptor mediated condition, as further described in the detailed description. In another aspect of the invention, methods of activating a muscarinic acetylcholine receptor are provided. The method comprises contacting a muscarinic acetylcholine receptor with an effective amount of a compound described herein, such as a compound of formula I, to activate the muscarinic acetylcholine receptor, as further described in the detailed description. Detailed Description The present invention provides substituted tetrahydropyrrolo-pyridone compounds, pharmaceutical compositions and their use in the treatment of muscarinic acetylcholine receptor mediated conditions. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry and immunology. Such techniques are explained in the literature, such as "Comprehensive Organic Synthesis" (B.M. Trost and I.Fleming, editions, 1991-1992), "Handbook of experimental immunology" (D.M. Weir and C.C. Blackwell, editions), "Current proto