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CN-122003415-A - Heteroaromatic compounds as positive allosteric modulators of the muscarinic M4 receptor (M4 PAM)

CN122003415ACN 122003415 ACN122003415 ACN 122003415ACN-122003415-A

Abstract

The present invention relates to heteroaromatic compounds of formula (I) or isotopic forms, stereoisomers or pharmaceutically acceptable salts thereof as muscarinic M4 receptor positive allosteric modulators (M4 PAM). The invention is also directed to pharmaceutical compositions comprising such compounds, chemical processes for preparing such compounds, and the use of such compounds in the treatment of psychotic disorders and/or neurological disorders.

Inventors

  • Ramakrishna Niroji
  • Anil Kabari Hinde
  • Abdul Rashid Mohammed
  • Rajesh Kumar Baidanji
  • Slavanti Mancini La
  • Narasimha Tirumara
  • Raghavan Choudley Palachara
  • Lamkuma Subramanian
  • Venkatsvalu Justi

Assignees

  • 苏文生命科学有限公司

Dates

Publication Date
20260508
Application Date
20241018
Priority Date
20231019

Claims (13)

  1. 1. A compound of formula (I), or an isotopic form or a stereoisomer or a pharmaceutically acceptable salt thereof, Wherein, the May each independently be a single bond or a double bond; X 1 is N or C, provided that when X 1 is N, then R 1 is absent; X 2 、X 3 、X 4 、X 5 and X 6 are independently selected from N or C, provided that at least one of X 2 、X 3 、X 4 、X 5 and X 6 is C, and provided that when X 4 、X 5 or X 6 is N, then R 2 、R 3 or R 4 is absent; R 1 when present is selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, or C 1 -C 4 alkoxyalkyl; R 2 when present is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, -CH 2 OH, or C 1 -C 4 alkoxyalkyl; R 3 when present is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, -CH 2 OH, or C 1 -C 4 alkoxyalkyl; R 4 when present is selected from hydrogen, deuterium, halogen, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, -CH 2 OH, or C 1 -C 4 alkoxyalkyl; R 5 is selected from hydrogen, halogen, -NH 2 、-NHCH 3 、C 1 -C 4 alkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 7 cycloalkyl or C 4 -C 10 heterocycloalkyl; R 6 is independently selected from hydrogen or C 1 -C 4 alkyl; A is selected from 3 to 7 membered cycloalkyl or 4 to 10 membered heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 5 substituents independently selected from hydrogen, halogen, deuterium, cyano, -OC 1 -C 4 alkyl and C 1 -C 4 haloalkyl; B is selected from 6-to 10-membered aryl or 5-to 10-membered heteroaryl, wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -NH 2 、NHCH 3 、C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, -OC 1 -C 4 alkyl, -OC 1 -C 4 haloalkyl and C 3 -C 7 cycloalkyl, and N is an integer from 0 to 3.
  2. 2. A compound of formula (I) according to the preceding embodiments, or an isotopic form or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein said compound is selected from: 1- (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- [1- (6-trifluoromethyl-pyridin-3-yl) -azetidin-3-yl ] -ethanone; 1- (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 2- [1- (2-difluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) -ethanone; 1- (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- (1-pyridin-4-yl-azetidin-3-yl) -ethanone; 2- [1- (2-chloro-5-methoxy-pyridin-4-yl) -azetidin-3-yl ] -1- (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) -ethanone; (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) - [1- (2-trifluoromethyl-pyridin-4-yl) -pyrrolidin-3 (R) -yl ] -methanone; (2, 5-dimethyl-6, 8-dihydro-1, 3,7,8 b-tetraaza-asymmetric indacen-7-yl) - (1-pyridin-3-yl-pyrrolidin-3 (R) -yl) -methanone; 1- (4, 7-dimethyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4, 7-dimethyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -2- [1- (6-trifluoromethyl-pyridin-3-yl) -azetidin-3-yl ] -ethanone; 1- (4, 7-dimethyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 1- (4, 7-dimethyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -2- (1-pyridin-4-yl-azetidin-3-yl) -ethanone; 2- [1- (2-difluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (4, 7-dimethyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -ethanone; 1- (4, 7-dimethyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -2- [1- (3-trifluoromethyl-phenyl) -azetidin-3-yl ] -ethanone; (4, 7-dimethyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) - [1- (2-trifluoromethyl-pyridin-4-yl) -pyrrolidin-3 (R) -yl ] -methanone; 1- (4-methyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 1- (4-methyl-1, 3-dihydro-2, 6,8 a-triaza-asymmetric indacen-2-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4-methyl-1, 3-dihydro-2, 7,8 a-triaza-asymmetric indacen-2-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-2, 3a, 7-triaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-2, 3a, 7-triaza-asymmetric indacen-7-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 2- [1- (2-difluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (4, 5-dimethyl-6, 8-dihydro-2, 3a, 7-triaza-asymmetric indacen-7-yl) -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-1, 2,3a, 7-tetraaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-1, 2,3a, 7-tetraaza-asymmetric indacen-7-yl) -2- [1- (6-trifluoromethyl-pyridin-3-yl) -azetidin-3-yl ] -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-1, 2,3a, 7-tetraaza-asymmetric indacen-7-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (3, 4, 5-trimethyl-6, 8-dihydro-1, 2,3a, 7-tetraaza-asymmetric indacen-7-yl) -ethanone; 1- (5, 6-dimethyl-7, 9-dihydro-pyrrolo [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (5, 6-dimethyl-7, 9-dihydro-pyrrolo [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 2- [1- (2-difluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (5, 6-dimethyl-7, 9-dihydro-pyrrolo [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -ethanone; 2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (2, 5, 6-trimethyl-7, 9-dihydro-pyrrolo [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -ethanone; 2- (1-pyridin-3-yl-azetidin-3-yl) -1- (2, 5, 6-trimethyl-7, 9-dihydro-pyrrolo [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -ethanone; 2- [1- (2-difluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (2, 5, 6-trimethyl-7, 9-dihydro-pyrrolo [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-8-yl) -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-1, 3a, 7-triaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-1, 3a, 7-triaza-asymmetric indacen-7-yl) -2- [1- (6-trifluoromethyl-pyridin-3-yl) -azetidin-3-yl ] -ethanone; 1- (4, 5-dimethyl-6, 8-dihydro-1, 3a, 7-triaza-asymmetric indacen-7-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 2- [1- (2-difluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -1- (4, 5-dimethyl-6, 8-dihydro-1, 3a, 7-triaza-asymmetric indacen-7-yl) -ethanone; (4, 5-dimethyl-6, 8-dihydro-1, 3a, 7-triaza-asymmetric indacen-7-yl) - [1- (2-trifluoromethyl-pyridin-4-yl) -pyrrolidin-3 (R) -yl ] -methanone; 1- (5-methyl-6, 8-dihydro-2, 3,4,7,8 b-pentaaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (5-azetidin-1-yl-6, 8-dihydro-2, 3,4,7,8 b-pentaaza-asymmetric indacen-7-yl) -2- [1- (6-trifluoromethyl-pyridin-3-yl) -azetidin-3-yl ] -ethanone; 1- (5-azetidin-1-yl-6, 8-dihydro-2, 3,4,7,8 b-pentaaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (5-azetidin-1-yl-6, 8-dihydro-2, 3,4,7,8 b-pentaaza-asymmetric indacen-7-yl) -2- [1- (2-difluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (2-methyl-6, 8-dihydro-1, 4,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (2-methyl-6, 8-dihydro-1, 4,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 1- (2, 5-dimethyl-6, 8-dihydro-1, 4,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 1- (2, 5-dimethyl-6, 8-dihydro-1, 4,7,8 b-tetraaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4-methyl-1, 3-dihydro-2, 5,6,8 a-tetraaza-asymmetric indacen-2-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone; 1- (4-methyl-1, 3-dihydro-2, 5,6,8 a-tetraaza-asymmetric indacen-2-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone; 1- (1, 5-dimethyl-6, 8-dihydro-2, 3,4,7,8 b-pentaaza-asymmetric indacen-7-yl) -2- [1- (2-trifluoromethyl-pyridin-4-yl) -azetidin-3-yl ] -ethanone, or 1- (1, 5-Dimethyl-6, 8-dihydro-2, 3,4,7,8 b-pentaaza-asymmetric indacen-7-yl) -2- (1-pyridin-3-yl-azetidin-3-yl) -ethanone.
  3. 3. A compound of formula (I) according to claim 1 or claim 2, or an isotopic form, stereoisomer or pharmaceutically acceptable salt thereof, for use as a positive allosteric modulator (M4 PAM) of the muscarinic M4 receptor.
  4. 4. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or claim 2, or an isotopic form, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  5. 5. The pharmaceutical composition according to claim 4 for use in the treatment of a disease or disorder mediated by a muscarinic M4 receptor, wherein the disease or disorder is selected from a psychotic disorder, a neurological disorder, a pain disorder, a sleep disorder or a cognitive disorder.
  6. 6. A compound of formula (I) or an isotopic form, stereoisomer or pharmaceutically acceptable salt thereof as claimed in claim 1 or claim 2 for use in the treatment of a disease or disorder mediated by muscarinic M4 receptors, wherein the disease or disorder is selected from a psychotic disorder, a neurological disorder, a pain disorder, a sleep disorder or a cognitive disorder.
  7. 7. A compound for use according to claim 6, wherein the psychotic disorder is selected from anxiety, personality disorder, depression, post Traumatic Stress Disorder (PTSD), obsessive-compulsive disorder (OCD), bipolar disorders, attention deficit/hyperactivity disorder (ADHD), psychosis, schizophrenia, substance use disorders and psychotic disorders.
  8. 8. The compound for use according to claim 6, wherein the neurological disease or disorder is selected from the group consisting of alzheimer's disease, rett syndrome, huntington's disease, vascular dementia, parkinson's disease and Amyotrophic Lateral Sclerosis (ALS).
  9. 9. The compound for use according to claim 6, wherein the cognitive disorder is selected from amnesia, dementia, amnesia disorder, dementia due to alzheimer's disease, dementia due to HIV disease, dementia due to huntington's disease, dementia due to parkinson's disease, dementia with lewy bodies, vascular dementia, frontotemporal dementia, senile dementia, dementia associated with down's syndrome, dementia associated with tourette's syndrome, dementia associated with postmenopausal, creutzfeldt-jakob disease dementia, substance-induced persisting dementia, pick's dementia, huntington's disease dementia, traumatic brain injury, prion disease, HIV-related neurocognitive disorder, mild cognitive impairment and any other disease with cognitive symptoms.
  10. 10. A compound for use according to claim 7, wherein the schizophrenia is selected from schizophrenic cognitive impairment, positive symptoms of schizophrenia and/or negative symptoms of schizophrenia.
  11. 11. The compound for use according to claim 7, wherein the psychotic disorder is selected from the group consisting of psychosis associated with alzheimer's disease, psychosis associated with parkinson's disease, psychotic depression, psychosis associated with stroke, psychosis associated with epilepsy, psychosis associated with multiple sclerosis, psychosis associated with traumatic brain injury, substance-induced persisting delirium, or any other disorder with psychotic features.
  12. 12. A compound of formula (II): Wherein, the May each independently be a single bond or a double bond; X 1 is selected from C or N; X 2 is selected from C or N; x 3 is selected from C or N; X 4 is selected from C or N; x 5 is selected from C or N; X 6 is selected from C or N; provided that at least one of X 1 、X 2 、X 3 、X 4 、X 5 and X 6 is C, provided that when X 1 、X 2 、X 3 、X 4 、X 5 or X 6 is N, then R 1 、R 2 、R 3 or R 4 is absent; R 1 when present is selected from hydrogen, halogen, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl or C 4 -C 10 heterocycloalkyl; R 2 when present is selected from hydrogen, halogen, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl or C 4 -C 10 heterocycloalkyl; R 3 when present is selected from hydrogen, halogen, C 1 -C 4 alkyl, -OC 1- C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 4 cycloalkyl or C 4 -C 10 heterocycloalkyl; R 4 when present is selected from hydrogen, halogen, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl or C 4 -C 10 heterocycloalkyl; R 5 is selected from hydrogen, halogen, C 1 -C 4 alkyl, -OC 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl or C 4 -C 10 heterocycloalkyl, and R 6 is selected from hydrogen or C 1 -C 4 alkyl.
  13. 13. The compound of formula (II) or a pharmaceutically acceptable salt thereof according to claim 12, wherein R 1 is selected from hydrogen, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, CHF 2 , or CF 3 , wherein R 2 is selected from hydrogen, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, CHF 2 , or CF 3 , wherein R 3 is selected from hydrogen, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, CHF 2 , or CF 3 , wherein R 4 is selected from hydrogen, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, CHF 2 , or CF 3 , and wherein R 5 is selected from hydrogen, chloro, fluoro, methyl, ethyl, methoxy, ethoxy, CHF 2 、CF 3 , or CF 3 Wherein R 6 is selected from hydrogen, methyl or ethyl.

Description

Heteroaromatic compounds as positive allosteric modulators of the muscarinic M4 receptor (M4 PAM) Technical Field The present invention relates to heteroaromatic compounds of formula (I) or isotopic forms, stereoisomers or pharmaceutically acceptable salts thereof as modulators of the positive allosteric modulators of the muscarinic M4 receptor (M4 receptor positive allosteric modulator, M4 PAM). The invention also describes methods of preparing such compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds in the treatment of psychotic disorders and/or neurological disorders. Background Currently, available drug treatments for psychotic disorders and/or neurological disorders such as schizophrenia, alzheimer's disease, parkinson's disease, huntington's disease, depression show modest improvements but have dose-limiting side effects leading to non-compliance and partial response. Targeting muscarinic acetylcholine receptors (muscarinic acetylcholine receptor, mAChR) is a promising approach for the treatment of psychotic and/or neurological disorders, as it provides a new and improved drug choice. mAChR is a G protein-coupled receptor (GPCR), which is widely expressed throughout the body. To date, five subtypes have been identified that are responsive to the endogenous neurotransmitter acetylcholine (acetylcholine, ACh), designated M1 through M5. They play a key role in the activity of regulating many important functions of the central and peripheral nervous systems. The M1, M3 and M5 receptor subtypes are usually coupled to the G protein Gq/G11, while the M2 and M4 receptor subtypes are predominantly coupled to the Gi/Go protein (Wess et al, 1996, crit Rev neurobiol.;10 (1): 69-99; langmead et al, 2008, pharmacol Ther.;117 (2): 232-243). The M4 mAChR subtype has important therapeutic implications because it is expressed in regions of the brain that are rich in dopamine and dopamine receptors, where it modulates dopaminergic neurons associated with cognition, schizophrenia, psychosis and addiction (Kentaro et al, 2018, chem. Pharm. Bull. 66 (1), 37-44; daniel et al, 2019, drug Discov Today;24 (12): 2307-2314). Acetamine (Xanomeline) is an M1/M4-preferential mAChR agonist that has been shown to significantly reduce behavioral symptoms in patients with Alzheimer's disease (Bodick et al, 1997, arch neurol.;54 (4): 465-73), but gastrointestinal side effects lead to high withdrawal rates (drop-out rates) in clinical trials. In a separate study, the Neumeine showed efficacy against positive and negative symptoms of schizophrenia (Shekhar et al, 2008, am J Psychiary; 165 (8): 1033-9). The xanomeline showed antipsychotic-like activity in various preclinical behavioral models (Mirza et al 2003, CNS Drug Rev.;9 (2): 159-86). Subsequent studies showed that the antipsychotic effect of the penomelin was absent in M4-KO mice (Woolley et al 2009 Eur J Pharmacol;603 (1-3): 147-9). There is a high degree of conservation between the muscarinic receptor subtypes at their normal acetylcholine ligand binding sites, which makes it difficult to identify muscarinic subtype selective agonists. To circumvent the problem of agonist selectivity and safety, an alternative approach is to develop selective muscarinic M4 receptor PAM, which acts on less conserved allosteric binding sites. In this regard, many muscarinic M4 receptor PAMs have been described in the literature, exhibiting cognitive enhancing and antipsychotic-like activity. For example, in rodent assays that predict antipsychotic effects, VU0467154 exhibits antipsychotic-like activity (Gould et al, 2018, neuropharmacology; 128:492-502). In addition, muscarinic M4 receptor PAM exhibits pro-cognitive benefits in rodent models of learning and memory (Bubser et al, 2014 ACS Chem Neurosci; 5 (10): 920-42). Patent publications WO2018/002760, WO2018/234953, WO2021/099527, WO2023/064584 and US20180028501 disclose compounds as muscarinic M4 receptor PAM. Although several muscarinic M4 receptor PAM have been disclosed in the literature to date, muscarinic M4 receptor PAM compounds have not been proposed on the market for use in the treatment of M4 mediated diseases or disorders such as schizophrenia, alzheimer's disease, psychosis, parkinson's disease, pain, addiction and huntington's disease. Thus, there remains an unmet need for developing new and more effective muscarinic M4 receptor PAM for use in the treatment of disorders affected by muscarinic M4 receptors. The present invention discloses novel compounds as muscarinic M4 receptor PAM having desirable characteristics. The compounds of the invention have potent affinity, selectivity, acceptable pharmacokinetic properties, good brain penetration and efficacy in animal models. Disclosure of Invention In a first aspect, the present invention relates to a compound of formula (I), or an isotopic form or stereoisomer or pharmaceutically acceptable salt thereof, Wherein, the May each independently be