Piperidine-substituted compounds as muscarinic M4 receptor positive allosteric modulators (M4 PAMs)

Abstract

The present invention relates to piperidine-substituted compounds of Formula (I), or an isotopically-substituted form, a stereoisomer, or a pharmaceutically acceptable salt thereof, as muscarinic M4 receptor positive allosteric modulators (M4 PAMs). The present invention also relates to pharmaceutical compositions comprising such compounds, chemical processes for making such compounds, and uses of such compounds in the treatment of psychiatric and / or neurological disorders.

Description

Technical Field

[0001] This invention relates to piperidine-substituted compounds of formula (I) as muscarinic M4 receptor positive allosteric modulators (M4 PAM), or their isotopic forms, stereoisomers, or pharmaceutically acceptable salts. The invention also describes methods for preparing such compounds, pharmaceutical compositions comprising such compounds, and their use in the treatment of mental disorders and / or neurological disorders. Background Technology

[0002] Currently, available pharmacological treatments for mental and / or neurological disorders (such as schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression) have shown modest improvements in dose-limiting side effects that lead to non-compliance and partial response.

[0003] Targeting muscarinic acetylcholine receptors (mAChRs) is a promising approach for the treatment of mental and / or neurological disorders because it offers a novel and improved pharmacological option. mAChRs are G protein-coupled receptors (GPCRs) that are widely expressed throughout the body. To date, five subtypes, designated M1 through M5, have been identified that respond to the endogenous neurotransmitter acetylcholine (ACh). They play key roles in the activity of regulating many important functions of the central and peripheral nervous systems. The M1, M3, and M5 receptor subtypes are generally coupled to the G protein Gq / G11, while the M2 and M4 receptor subtypes are primarily 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).

[0004] The M4 mAChR subtype has significant therapeutic implications because it is expressed in brain regions rich in dopamine and dopamine receptors, in which it regulates dopaminergic neurons associated with cognition, schizophrenia, psychosis, and addiction (Kentaro et al., 2018, Chem. Pharm. Bull. 66(1), 37–44; Daniel et al., 2019, DrugDiscov Today;24(12):2307-2314).

[0005] Zanomeprazole is an M1 / M4-biased 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 have led to high dropout rates in clinical trials. In a separate study, zanomeprazole was shown to be effective against both positive and negative symptoms of schizophrenia (Shekhar et al., 2008, Am J Psychiatry;165(8):1033-9). Zanomeprazole has shown antipsychotic-like activity in various preclinical behavioral models (Mirza et al., 2003, CNS Drug Rev.;9(2):159-86). Subsequent studies have shown that zanomeprazole does not have antipsychotic-like activity in M4-KO mice (Woolley et al., 2009 Eur J Pharmacol;603(1-3):147-9). The high conservation of ortho-acetylcholine ligand binding sites among muscarinic receptor subtypes makes it difficult to identify selective agonists for muscarinic subtypes. To avoid agonist selectivity and safety issues, an alternative approach is to develop selective muscarinic M4 receptor PAMs that act on less conserved allosteric binding sites.

[0006] In this regard, numerous muscarinic M4 receptor PAMs have been described in the literature, demonstrating cognitive enhancement and antipsychotic drug-like activity. For example, VU0467154 showed antipsychotic drug-like activity in rodent assays predicting antipsychotic effects (Gould et al., 2018, Neuropharmacology;128:492-502). Furthermore, muscarinic M4 receptor PAMs have shown cognitive benefits in rodent models of learning and memory (Bubser et al., 2014 ACS ChemNeurosci.;5(10):920-42).

[0007] Patent publications WO2018 / 118736, WO2018 / 002760, WO2018 / 234953, WO2021 / 099527, WO2023 / 064584, and US20180028501 disclose compounds as muscarinic M4 receptor PAMs. Although several muscarinic M4 receptor PAMs have been disclosed in the literature to date, there are no commercially available muscarinic M4 receptor PAM compounds for the treatment of M4-mediated diseases or disorders, such as schizophrenia, Alzheimer's disease, psychosis, Parkinson's disease, pain, addiction, and Huntington's disease. Therefore, there remains an unmet need for developing novel and more effective muscarinic M4 receptor PAMs for the treatment of disorders affected by muscarinic M4 receptors.

[0008] Literature indicates that compounds acting on muscarinic M2 receptors mediate cholinergic side effects such as bradycardia and hypotension (Grauer et al., 2020 Brain Research; 1737:146814; Sundaram et al., 1989 Brainresearch, 477(1-2), 358-362; Mirza et al., 2003 CNS drug reviews, 9(2), 159-186). Furthermore, the allosteric binding pockets of M4 and M2 muscarinic acetylcholine receptors share similarities, posing a key challenge to developing M4 PAMs with subtype selectivity for M2. Our compound exhibited minimal activity against the muscarinic M2 receptor (Wood et al., 2016 ACS medicinal chemistry letters, 8(2), 233-238; Butler et al., 2024 Journal of medicinal chemistry, 67(13), 10831-10847; Croy et al., 2014 Molecular pharmacology, 86(1), 106-115).

[0009] This invention discloses novel compounds for muscarinic M4 receptors (PAMs) possessing the desired characteristics. The compounds of this invention exhibit strong affinity for muscarinic M4, selectivity relative to muscarinic subtype receptors (such as M1, M2, M3, and M5), acceptable pharmacokinetic properties, good brain penetration, receptor occupancy, and efficacy in animal models. Summary of the Invention

[0010] In a first aspect, the present invention relates to compounds of formula (I),

[0011]

[0012] Or its isotopic form, stereoisomer, or pharmaceutically acceptable salt.

[0013] in,

[0014] Each can be a single bond or a double bond independently;

[0015] X1, X2, X3, and X4 are independently selected from N or C; provided that R2, R3, R4, or R5 does not exist when X1, X2, X3, or X4 is N.

[0016] R1 is selected from halogen, cyano, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -C1-C4 alkoxyalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl;

[0017] When present, R2 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0018] When present, R3 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0019] When present, R4 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0020] When present, R5 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl.

[0021] When present, R6 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl.

[0022] R7 is

[0023] “ "Indicates an attachment point;

[0024] X5 is either N or C;

[0025] R8 and R9 are independently selected from hydrogen, halogen, cyano, -OH, -NH2, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, -OC1-C4 alkoxyalkyl, and -NHC1-C4 alkyl; or alternatively, R8 and R9 together with the carbon atoms to which they are attached form a 5-8 membered heterocycle, wherein the heterocycle is optionally substituted by one to five substituents independently selected from hydrogen, oxo, deuterium, halogen, cyano, -OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, and -C1-C4 alkoxyalkyl; and

[0026] m can be 0, 1, or 2.

[0027] In another aspect, the present invention relates to a method for preparing a compound of formula (I) or its isotopic form or stereoisomer or pharmaceutically acceptable salt thereof.

[0028] In another aspect, the present invention relates to compounds of formula (I) used as positive allosteric modulators of muscarinic M4 receptors, or isotopic forms, stereoisomers, or pharmaceutically acceptable salts thereof.

[0029] In another aspect, the present invention relates to a method for treating muscarinic M4 receptor-mediated diseases or disorders, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I), or an isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof.

[0030] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), or an isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Detailed Implementation

[0031] This article discloses muscarinic M4 receptors (PAM), methods for preparing such compounds, pharmaceutical compositions comprising such compounds, and methods for treating diseases or disorders mediated by muscarinic M4 receptors (such as mental disorders and / or neurological disorders).

[0032] Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings:

[0033] As used herein, the term "-C1-C4 alkyl" refers to a branched or straight-chain aliphatic hydrocarbon containing one to four carbon atoms. Examples of -C1-C4 alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0034] As used herein, the term "-C1-C4 haloalkyl" refers to a -C1-C4 alkyl group as defined above, wherein one or more hydrogen atoms of the same or different carbon atoms are substituted with halogen atoms. Examples of -C1-C4 haloalkyl groups include, but are not limited to, fluoromethyl, 2-fluoroethyl, difluoromethyl, and trifluoromethyl.

[0035] As used herein, the term "-C3-C7 cycloalkyl" refers to a saturated monocyclic hydrocarbon ring containing three to seven carbon atoms. Examples of -C3-C7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0036] As used herein, the term "-C1-C4 alkoxyalkyl" refers to a -C1-C4 alkyl group as defined above, wherein one or more hydrogen atoms having the same or different carbon atoms are substituted by the -C1-C4 alkyl group. Examples of -C1-C4 alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, and butoxymethyl.

[0037] As used herein, the term "-OC1-C4 alkyl" refers to a -C1-C4 alkyl group as defined above, which is partially attached to the parent molecule via an oxygen atom. Examples of -OC1-C4 alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0038] As used herein, the term "-NHC1-C4 alkyl" refers to a -C1-C4 alkyl group as defined above, which is partially attached to the parent molecule via a nitrogen atom. Examples of -NHC1-C4 alkyl groups include, but are not limited to, methylamine, ethylamine, propylamine, and butylamine.

[0039] As used herein, the term "-OC1-C4 haloalkyl" refers to a -C1-C4 haloalkyl group as defined above that is bonded to an oxygen atom. Examples of -OC1-C4 haloalkyl groups include, but are not limited to, -OCH2F, -OCHF2, and -OCF3.

[0040] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. Preferably, the halogen is fluorine, chlorine, or bromine.

[0041] As used herein, the phrase “5-8 membered heterocycle” refers to a saturated or unsaturated ring containing 5 to 8 carbon atoms, wherein at least one carbon atom is independently substituted by a heteroatom selected from oxygen, nitrogen, or sulfur. Non-limiting examples of 5-8 membered heterocycles include 1H-pyrazolyl, 1-methyl-1H-pyrazolyl, 1H-pyrroleyl, 1-methyl-1H-pyrroleyl, oxazolyl, isoxazolyl, 2-methyloxazolyl, thiazolyl, 1H-imidazolyl, 1,4-dioxalkyl, 1,3-dioxalkyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and piperazineyl.

[0042] As used herein, the phrase "isotopic form" refers to a compound of formula (I) in which one or more atoms of the compound of formula (I) are substituted with their respective isotopes. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as... 2 H (deuterium or D) and 3 H (tritium or T), carbon such as 11 C 13 C and 14 C, nitrogen 13 N and 15 N, oxygen 15 O、 17 O and 18 O, chlorine 36 Cl, fluorine 18 F, iodine 123 I, 124 I, 125 I and 131 I, and sulfur 35 S. Substitution with a heavier isotope, such as replacing one or more key carbon-hydrogen bonds with carbon-deuterium bonds, can demonstrate certain therapeutic advantages resulting from longer metabolic cycles (e.g., increased in vivo half-life or reduced dose requirements), improved safety, or greater efficacy, and may therefore be preferred in some cases.

[0043] Representative examples of isotopic forms of compounds of formula (I) may include, but are not limited to, deuterated compounds of formula (I). The term “deuterated” as used herein, either by itself or when used to modify a compound or group, refers to the substitution of one or more hydrogen atoms attached to one or more carbon atoms with a deuterium atom. For example, compounds of formula (I) may, where applicable, include deuterium, deuterated alkyl, deuterated alkoxy, deuterated cycloalkyl, deuterated heterocyclic, deuterated aryl, deuterated heteroaryl, etc., in one or more of its various variables. The term “deuterated alkyl” refers to a -C1-C4 alkyl group as defined above, wherein at least one hydrogen atom bonded to a carbon atom is replaced by deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bonded to deuterium. In a deuterated alkyl group, a carbon atom may be bonded to more than one deuterium atom; more than one carbon atom in an alkyl group may be bonded to deuterium. Similarly, the term "deuterated" and the terms deuterated heterocyclic, deuterated heteroaryl, deuterated cycloalkyl, deuterated aryl, and deuterated alkoxy each refer to the corresponding chemical moiety in which at least one carbon atom is bonded to deuterium.

[0044] As used herein, the term "stereoisomer" refers to isomers of a compound of formula (I) whose atoms are arranged differently in space. The compounds disclosed herein may exist as single stereoisomers, racemates, and / or mixtures of enantiomers and / or diastereomers. All such pure stereoisomers, racemates, and mixtures thereof are intended to be within the scope of this invention.

[0045] As used herein, the phrase “pharmaceutically acceptable salt” refers to a salt of an active compound, i.e., a compound of formula (I), and is prepared by reaction with a suitable acid or base, depending on the specific substituents found on the compound described herein.

[0046] As used herein, the phrase “therapeutic effective amount” refers to an amount of the compound of the present invention that (i) treats a particular disease, symptom, or disorder, (ii) eliminates one or more symptoms of a particular disease, symptom, or disorder, and / or (iii) delays the onset of one or more symptoms of a particular disease, symptom, or disorder described herein.

[0047] As used herein, the phrase "M4 receptor positive allosteric modulator (PAM)" refers to a ligand that interacts with an allosteric site of the receptor to enhance the response generated by an endogenous ligand at the orosteric binding site. The compounds of this invention are allosteric modulators of the M4 muscarinic acetylcholine receptor, including both positive and silencing allosteric modulators of the M4 muscarinic acetylcholine receptor.

[0048] As used in this article, “mental disorder” refers to an illness or disorder such as anxiety, personality disorder, depression, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), bipolar disorder, attention deficit / hyperactivity disorder (ADHD), schizophrenia, substance use disorder, and other mental disorders.

[0049] As used in this article, “neurological disease or disorder” refers to a disease or disorder such as Alzheimer’s disease, Rett syndrome, Huntington’s disease, vascular dementia, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS).

[0050] As used in this article, “cognitive impairment” refers to diseases or disorders such as amnesia, dementia, forgetfulness, dementia caused by Alzheimer’s disease, dementia caused by human immunodeficiency virus (HIV) disease, dementia caused by Huntington’s disease, dementia caused by Parkinson’s disease, Lewy body dementia, vascular dementia, frontotemporal dementia (FTD), senile dementia, dementia associated with Down syndrome, dementia associated with Tourette syndrome, dementia associated with postmenopausal syndrome, Creutzfeldt-Jakob disease dementia, substance-induced persistent dementia, Pick’s disease dementia, Huntington’s disease dementia, traumatic brain injury, prions, and HIV-related neurocognitive impairment and mild cognitive impairment.

[0051] As used herein, the term "patient" refers to an animal. Preferably, the term "patient" refers to a mammal. The term mammal includes mice, rats, dogs, rabbits, pigs, monkeys, horses, guinea pigs, and humans. More preferably, the patient is a human.

[0052] Implementation Plan

[0053] This invention covers, without any limitation, all compounds described by compounds of formula (I), however preferred aspects and elements of the invention are discussed below in the embodiments.

[0054] In one embodiment, the present invention relates to compounds of formula (I),

[0055]

[0056] Or its isotopic form, stereoisomer, or pharmaceutically acceptable salt.

[0057] in,

[0058] Each can be a single bond or a double bond independently;

[0059] X1, X2, X3, and X4 are independently selected from N or C; provided that R2, R3, R4, or R5 does not exist when X1, X2, X3, or X4 is N.

[0060] R1 is selected from halogen, cyano, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -C1-C4 alkoxyalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl;

[0061] When present, R2 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0062] When present, R3 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0063] When present, R4 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0064] When present, R5 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl.

[0065] When present, R6 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl.

[0066] R7 is

[0067] “ "Indicates an attachment point;

[0068] X5 is either N or C;

[0069] R8 and R9 are independently hydrogen, halogen, cyano, -OH, -NH2, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, -OC1-C4 alkoxyalkyl, -NHC1-C4 alkyl; or alternatively, R8 and R9 together with the carbon atoms to which they are attached form a 5-8 membered heterocycle, wherein the heterocycle is optionally substituted by one to five substituents independently selected from hydrogen, oxo, deuterium, halogen, cyano, -OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, and -C1-C4 alkoxyalkyl; and

[0070] m can be 0, 1, or 2.

[0071] In another implementation scheme, ring

[0072] Selected from:

[0073]

[0074] In another implementation scheme, ring Selected from:

[0075]

[0076] In another embodiment, the present invention relates to a method for treating or preventing diseases or disorders mediated by muscarinic M4 receptors, the method comprising administering a compound of formula (I) to a patient in need.

[0077]

[0078] Or its isotopic form, stereoisomer, or pharmaceutically acceptable salt.

[0079] in,

[0080] Each can be a single bond or a double bond independently;

[0081] X1, X2, X3, and X4 are independently selected from N or C; provided that R2, R3, R4, or R5 does not exist when X1, X2, X3, or X4 is N.

[0082] R1 is selected from halogen, cyano, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -C1-C4 alkoxyalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl;

[0083] When present, R2 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0084] When present, R3 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0085] When present, R4 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl;

[0086] When present, R5 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl.

[0087] When present, R6 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl.

[0088] R7 is

[0089] “ "Indicates an attachment point;

[0090] X5 is either N or C;

[0091] R8 and R9 are independently hydrogen, halogen, cyano, -OH, -NH2, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, -OC1-C4 alkoxyalkyl, -NHC1-C4 alkyl; or alternatively, R8 and R9 together with the carbon atoms to which they are attached form a 5-8 membered heterocycle, wherein the heterocycle is optionally substituted by one to five substituents independently selected from hydrogen, oxo, deuterium, halogen, cyano, -OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, and -C1-C4 alkoxyalkyl; and

[0092] m can be 0, 1, or 2.

[0093] In another embodiment, the present invention relates to compounds selected from formula (I) below, or their isotopic forms, stereoisomers, or pharmaceutically acceptable salts:

[0094] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0095] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0096] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0097] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0098] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0099] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0100] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0101] 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0102] 3-[1-(7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile;

[0103] 6-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0104] 6-[4-(6-fluoro-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0105] 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0106] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0107] 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0108] 6-[4-(6-fluoro-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0109] 7-Methyl-6-[4-(6-methylpyridin-3-yloxy)piperidin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine;

[0110] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0111] 3-[1-(7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile;

[0112] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0113] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0114] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0115] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0116] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0117] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0118] 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0119] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0120] 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0121] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0122] 3-[1-(3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile;

[0123] 6-[4-(2-methoxy-pyridin-4-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0124] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0125] 6-[3-fluoro-4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0126] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0127] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0128] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0129] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0130] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0131] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0132] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0133] 3-[1-(3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile;

[0134] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0135] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0136] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0137] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0138] 6-[4-(2-methoxy-pyridin-4-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0139] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0140] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0141] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0142] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0143] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0144] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0145] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0146] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0147] 3-Difluoromethyl-6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0148] 3-Difluoromethyl-6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0149] 3-Difluoromethyl-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0150] 3-Difluoromethyl-6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0151] 3-Difluoromethyl-6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0152] 3-Difluoromethyl-6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0153] 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0154] 3-[1-(3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile;

[0155] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0156] 3-Methoxymethyl-6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0157] 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0158] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0159] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0160] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0161] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0162] 3-Methoxymethyl-6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0163] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0164] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0165] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0166] 3-Difluoromethyl-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0167] 3-Difluoromethyl-6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0168] 3-Difluoromethyl-6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0169] 3-Difluoromethyl-6-[4-(6-methoxy-pyridin-3-yloxy)piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0170] 3-Difluoromethyl-6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine;

[0171] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0172] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0173] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0174] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0175] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0176] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0177] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0178] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0179] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0180] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0181] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0182] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0183] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0184] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0185] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0186] 6-[4-(2-methoxy-pyridin-4-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0187] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0188] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0189] 3-[1-(2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile;

[0190] 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0191] 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0192] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0193] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0194] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0195] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0196] 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0197] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0198] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine;

[0199] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7-dimethyl-imidazo[1,2-b]pyridazine;

[0200] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-imidazo[1,2-b]pyridazine;

[0201] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-imidazo[1,2-b]pyridazine;

[0202] 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-imidazo[1,2-b]pyridazine;

[0203] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2-fluoromethyl-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0204] 2-Fluoromethyl-6-[4-(6-methoxy-pyridin-3-yloxy)piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0205] 2-Fluoromethyl-6-[4-(2-methoxy-pyridin-4-yloxy)piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0206] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2-fluoromethyl-7-methyl-imidazo[1,2-b]pyridazine;

[0207] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,3,7-trimethyl-imidazo[1,2-b]pyridazine;

[0208] 2-Chloro-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0209] 2-Chloro-6-[4-(6-methoxy-pyridin-3-yloxy)piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0210] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine;

[0211] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine;

[0212] 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine;

[0213] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine;

[0214] 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine;

[0215] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine;

[0216] 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0217] 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine;

[0218] 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; or

[0219] 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine.

[0220] Experimental Procedure

[0221] The following scheme describes a general method for preparing compounds of formula (I), wherein X1, X2, X3, X4, R1, R2, R3, R4, R5, R6, R7 and m are as defined above. Furthermore, Z is selected from halogens, methanesulfonates, trifluoromethanesulfonates, toluenesulfonates, etc.

[0222] plan:

[0223]

[0224] Method-I: Preparation of compounds of formula (I)

[0225] The compound of formula-1, the compound of formula-2, cesium fluoride, and triethylamine are added to a solvent selected from DMF or DMSO, and the mixture is heated to 100ºC–120ºC for 8–24 h. The resulting reaction mixture is extracted with a suitable organic solvent, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which is then purified by column chromatography to give the compound of formula (I).

[0226] Method II: Preparation of compounds of formula (I)

[0227] In palladium-catalyzed cross-coupling reactions, suitable palladium metal catalysts (such as Pd2(dba)3), phosphine ligands (such as xantphos or BINAP), and bases (such as NaO) are used. t Bu, KO t (Bu or Cs2CO3), reacting the compound of formula-1 with the compound of formula-2 in a suitable solvent selected from toluene or 1,4-dioxane at reflux temperature for 10 to 24 h. The resulting reaction mixture is extracted with a suitable organic solvent, washed with brine, washed with Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which is purified by column chromatography to give the compound of formula (I).

[0228] Preparation of pharmaceutically acceptable salts of compounds of formula (I)

[0229] Compounds of formula (I) may optionally be converted into their pharmaceutically acceptable salts by reaction with a suitable acid or base. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. The salts are formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid) or organic acids (e.g., oxalic acid, succinic acid, maleic acid, acetic acid, citric acid, malic acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid).

[0230] Preparation of stereoisomers of the compound of formula (I)

[0231] Stereoisomers of the compound of formula (I) can be prepared by one or more conventional methods as presented below:

[0232] a. One or more reagents may be used in their optically active form.

[0233] b. Optically pure catalysts or chiral ligands, as well as metal catalysts, can be used in the reduction process. Metal catalysts can be rhodium, ruthenium, indium, etc. Chiral ligands are preferably chiral phosphine.

[0234] c. The mixture of stereoisomers can be resolved by conventional methods, such as forming diastereomer salts with chiral acids, chiral amines, chiral amino alcohols, or chiral amino acids. The resulting diastereomer mixture can then be separated by methods such as fractional crystallization or chromatography, followed by additional steps to separate the optically active product from the resolved salt.

[0235] d. Mixtures of stereoisomers can be resolved by conventional methods, such as microbial resolution or resolution of diastereomeric salts formed with chiral acids or chiral bases. Chiral acids that can be used include tartaric acid, mandelic acid, lactic acid, camphor sulfonic acid, and amino acids. Chiral bases that can be used include cinchona alkaloids, strychnine, or basic amino acids (such as lysine and arginine).

[0236] In another embodiment, suitable pharmaceutically acceptable salts include acetates, hydrochlorides, hydrobromides, oxalates, fumarates, tartrates, maleates, benzoates, methanesulfonates, and succinates.

[0237] In another embodiment of the invention, a compound of formula (I), or its isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, is used as a positive allosteric modulator (PAM) of the muscarinic M4 receptor.

[0238] In another embodiment of the invention, a compound of formula (I), or its isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, is used to prepare a medicament for treating or preventing diseases or disorders mediated by muscarinic M4 receptors.

[0239] In another embodiment, the present invention relates to a method for treating or preventing a disease or disorder mediated by a muscarinic M4 receptor in a patient, the method comprising administering to a patient in need a therapeutically effective amount of a compound of formula (I), or an isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof.

[0240] In another embodiment, the present invention relates to a method for treating or preventing diseases or disorders mediated by muscarinic M4 receptors, said diseases or disorders being selected from mental disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0241] In another embodiment, the present invention relates to a compound of formula (I), or an isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder selected from mental disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0242] In another embodiment, the present invention relates to the use of a compound of formula (I), or its isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder selected from mental disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0243] In another embodiment, the present invention relates to the use of a compound of formula (I), or its isotopic form, stereoisomer, or pharmaceutically acceptable salt, in the preparation of a medicament for treating a disease or disorder selected from mental disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

[0244] In some implementation schemes, mental disorders are selected from anxiety, personality disorders, depression, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), bipolar disorder, attention deficit / hyperactivity disorder (ADHD), schizophrenia, substance use disorder, and other mental disorders.

[0245] In some implementations, other mental disorders include 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 persistent delirium, or any other illness with psychotic features.

[0246] In some implementations, the neurological disease or disorder is selected from Alzheimer's disease, Rett syndrome, Huntington's disease, vascular dementia, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).

[0247] In some implementations, cognitive impairment is selected from amnesia, dementia, forgetfulness, dementia caused by Alzheimer's disease, dementia caused by HIV disease, dementia caused by Huntington's disease, dementia caused by Parkinson's disease, Lewy body dementia, vascular dementia, frontotemporal dementia (FTD), senile dementia, dementia associated with Down syndrome, dementia associated with Tourette syndrome, dementia associated with postmenopausal syndrome, Creutzfeldt-Jakob disease dementia, substance-induced persistent dementia, Pick's disease dementia, Huntington's disease dementia, traumatic brain injury, prions, HIV-related neurocognitive impairment, mild cognitive impairment, or any other disease with cognitive symptoms.

[0248] In some embodiments, the present invention relates to a method for treating or preventing a muscarinic M4 receptor-mediated disease or disorder selected from schizophrenia.

[0249] In some implementations, treatment for schizophrenia includes treatment of cognitive impairment, positive symptoms, and / or negative symptoms of schizophrenia.

[0250] In some implementation schemes, cognitive impairment in schizophrenia includes, but is not limited to, attention and alertness, focus, executive function, processing speed, verbal learning, working memory, problem-solving, and / or social cognition.

[0251] In some implementation schemes, positive symptoms of schizophrenia include, but are not limited to, hallucinations, delusions, conceptual confusion, excitement, grandiosity, suspicion / persecution, and hostility.

[0252] In some implementation schemes, negative symptoms of schizophrenia include, but are not limited to, emotional blunting, emotional withdrawal, interpersonal dysfunction, passive / apathetic social withdrawal, difficulty with abstract thinking, lack of spontaneity and fluency of conversation, and stereotyped thinking.

[0253] In another embodiment, the invention includes pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of formula (I) of the invention, or an isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, presented with a pharmaceutically acceptable carrier. The carrier may be solid, liquid, or both, and may be formulated with the compound into a unit-dose composition, such as pills, tablets, coated tablets, capsules, powders, granules, patches, implants, films, liquids, semi-solids, gels, aerosols, emulsions, elixirs, etc.

[0254] The compounds of the present invention can be administered via any suitable route, preferably in the form of a pharmaceutical composition suitable for such route, and at a dose effective for the intended treatment. The active compounds and compositions can be administered, for example, orally, rectally, parenterally, or topically.

[0255] The dosage of the active compound can vary depending on a variety of factors, such as the patient's age and weight, the nature and severity of the disease being treated, and other factors. Therefore, any reference to the therapeutically effective amount of the stereoisomers and pharmaceutically acceptable salts of compounds of formula (I) refers to the aforementioned factors.

[0256] The following abbreviations are used in this article:

[0257] AMP: Adenosine monophosphate

[0258] BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0259] CDCl3: Deuterated chloroform

[0260] Cs2CO3: Cesium carbonate

[0261] DCM: Dichloromethane

[0262] DIAD: Diisopropyl azodicarbonate

[0263] DMA.DMA: N,N-dimethylacetamide dimethyl acetal

[0264] DMF.DMA: N,N-Dimethylformamide dimethyl acetal

[0265] DMAP: 4-(dimethylamino)pyridine

[0266] DMF: N,N-dimethylformamide

[0267] DMSO: Dimethyl sulfoxide

[0268] EC 50 : half of the maximum effective concentration

[0269] EtOAc: Ethyl acetate

[0270] g: grams

[0271] h: hours

[0272] hM4 PAM: Human muscarinic M4 positive allosteric modifier

[0273] IPA: Isopropyl alcohol

[0274] KO t Bu: Potassium tert-Butoxide

[0275] MeOH: Methanol

[0276] mL: milliliters

[0277] mmol: millimole

[0278] Na2SO4: Sodium sulfate

[0279] NaO t Bu: Sodium tert-butoxide

[0280] ppm (parts per million)

[0281] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride

[0282] Pd2(dba3): Tris(dibenzylacetone)dipalladium

[0283] Ph3P: Triphenylphosphine

[0284] RT: Room temperature

[0285] THF: Tetrahydrofuran

[0286] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium

[0287] Example

[0288] The compounds of the present invention were prepared using appropriate materials and conditions according to the following experimental procedure. The following examples are provided by way of illustration only and are not intended to limit the scope of the invention.

[0289] Preparation of intermediates:

[0290] Intermediate-1: 6-chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0291] Formylhydrazine (2 g, 33.90 mmol) was added to a stirred solution of 3,6-dichloro-4,5-dimethylpyridazine (2 g, 11.29 mmol) in 1-butanol (20 mL) at room temperature, and the reaction mixture was refluxed for 16 h. Volatiles were removed under reduced pressure, and the resulting solid was purified by silica gel column chromatography using 1%–2% MeOH in DCM to obtain the target compound. Yield: 1.2 g (60%); 1 H-NMR (CDCl) 3, 400 MHz) δ ppm: 2.43 (s, 3H), 2.74 (s, 3H), 8.96 (s, 1H); mass (m / z): 183.0, 185.1 (M+H) + .

[0292] Intermediate-2: 6-Chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0293] Formylhydrazine (1.8 g, 30.67 mmol) was added to a stirred solution of 3,6-dichloro-4-methylpyridazine (2.0 g, 12.26 mmol) in 1-butanol (30 mL) at room temperature, and the reaction mixture was refluxed for 16 h. Volatiles were removed under reduced pressure, and the resulting mixture of methyl regioisomers (1:1) was purified by column chromatography. The target compound was obtained using 60%–80% EtOAc in n-hexane. Yield: 0.3 g (18%); 1 H-NMR (CDCl) 3, 400 MHz) δ ppm: 2.50 (s, 3H), 7.95 (s, 1H), 8.99 (s, 1H); mass (m / z): 168.6, 170.4 (M+H) + .

[0294] Intermediate-3: 6-Chloro-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0295] Intermediate-3 was obtained by using 3,6-dichloro-4,5-dimethylpyridazine and acetylhydrazine as starting materials and employing some non-critical variations, according to the following procedure given for intermediate-1. 1 H-NMR (CDCl) 3, δppm (400 MHz): 2.41 (s, 3H), 2.71 (s, 3H), 2.77 (s, 3H); mass (m / z): 196.9, 198.8 (M+H) + .

[0296] Intermediate-4: 6-chloro-7,8-dimethyl-3-trifluoromethyl[1,2,4]triazolo[4,3b]pyridazine

[0297] Step 1: (6-chloro-4,5-dimethyl-pyridazin-3-yl)-hydrazine

[0298] Hydrazine hydrate (0.42 mL, 8.4 mmol) was added to a stirred solution of 3,6-dichloro-4,5-dimethylpyridazine (0.1 g, 5.6 mmol) in 1,4-dioxane (10 mL), and the reaction mixture was refluxed for 7 h, during which time a solid precipitated. These solids were filtered and dried under vacuum to obtain the target compound. Yield: 0.78 g (80%); mass (m / z): 172.8, 174.8 (M+H) +

[0299] Step 2: 6-Chloro-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0300] A stirred suspension of (6-chloro-4,5-dimethyl-pyridazin-3-yl)hydrazine (0.3 g, 1.7 mmol) in trifluoroacetic acid (0.71 mL, 8.7 mmol) was heated at 120ºC for 2 h in a sealed tube. Water (20 mL) was added to the reaction mixture and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with a brine solution (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the target compound. Yield: 0.19 g (44%); 1 H-NMR (CDCl) 3, δppm (400 MHz): 2.48 (s, 3H), 2.79 (s, 3H); mass (m / z): 250.7, 252.7 (M+H) + .

[0301] Intermediate-5: 6-Chloro-3-difluoromethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0302] Intermediate-5 was obtained by using (6-chloro-4,5-dimethyl-pyridazin-3-yl)-hydrazine (step 1 of intermediate-4) and difluoroacetic acid as starting materials, with some non-critical variations, according to the given procedure for intermediate-4. 1 H-NMR (CDCl) 3,400 MHz) δ ppm: 2.47 (s, 3H), 2.77 (s, 3H), 7.07 – 7.33 (m, 1H); mass (m / z): 233.8, 235.7 (M+H) + .

[0303] Intermediate-6: 6-chloro-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0304] Intermediate-6 was obtained by using 3,6-dichloro-4-methylpyridazine and acetylhydrazine as starting materials and employing some non-critical variations, following the procedure given for intermediate-2. 1 H-NMR (CDCl) 3, 400 MHz) δ ppm: 2.47 (s, 3H), 2.79 (s, 3H), 7.87 (s, 1H); mass (m / z): 182.9, 184.8 (M+H) + .

[0305] Intermediate-7: 6-Chloro-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0306] Step 1: (6-chloro-5-methyl-pyridazin-3-yl)-hydrazine

[0307] Hydrazine hydrate (6.6 mL, 13.5 mmol) was added to a stirred solution of 3,6-dichloro-4-methylpyridazine (20 g, 12.3 mmol) in 1,4-dioxane (100 mL), and the reaction mixture was refluxed for 7 h, during which time a solid precipitated. These solids were filtered and dried under vacuum to obtain the target compound. Yield: 18.0 g (91%); mass (m / z): 158.8, 160.8 (M+H) + .

[0308] Step 2: 6-Chloro-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0309] A stirred suspension of (6-chloro-5-methylpyridazin-3-yl)hydrazine (4.0 g, 2.5 mmol) in trifluoroacetic acid (10.3 mL, 12.6 mmol) was heated in a sealed tube at 120ºC for 4 h. Water (20 mL) was added to the reaction mixture and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with a brine solution (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give a mixture of methyl regioisomers (1:1). The target compound was obtained using 40% EtOAc in n-hexane. Yield: 1.8 g (30.5%); 1 H-NMR (CDCl) 3, δ ppm (400 MHz): 2.56 (s, 3H), 8.04 (s, 1H); mass (m / z): 236.8, 238.9 (M+H) +

[0310] Intermediate-8: 6-chloro-3-difluoromethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0311] Intermediate-8 was obtained by using (6-chloro-5-methyl-pyridazin-3-yl)-hydrazine (step 1 of intermediate-7) and difluoroacetic acid as starting materials, with some non-critical variations, according to the procedure given for intermediate-7. 1 H-NMR (CDCl) 3, 400 MHz) δ ppm: 2.54 (s, 3H), 7.21 – 7.34 (m, 1H), 8.01 (s, 1H); mass (m / z): 218.6, 220.7 (M+H) + .

[0312] Intermediate-9: 6-chloro-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine

[0313] Intermediate-9 was obtained by using (6-chloro-4,5-dimethyl-pyridazin-3-yl)-hydrazine (step 1 of intermediate-4) and 2-methoxyacetyl chloride as starting materials, with some non-critical variations, according to the given procedure for intermediate-4. 1 H-NMR (CDCl) 3, 400 MHz) δ ppm: 2.57 (s, 3H), 2.98 (s, 3H), 3.50 (s, 3H), 5.04 (s, 2H); mass (m / z): 226.8, 228.7 (M+H) + .

[0314] Intermediate-10: 6-chloro-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0315] Intermediate-10 was obtained by using (6-chloro-5-methyl-pyridazin-3-yl)-hydrazine (step 1 of intermediate-7) and 2-methoxyacetyl chloride as starting materials and with some non-critical variations, according to the given procedure for intermediate-7. 1 H– NMR (CDCl 3, δ ppm (400 MHz): 2.50 (s, 3H), 3.48 (s, 3H), 4.99 (s, 2H), 7.94 (s, 1H); mass (m / z): 213.1, 216.0 (M+H) + .

[0316] Intermediate-11: 6-chloro-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine

[0317] DMF-DMA (0.46 g, 4.14 mmol) was added to a stirred solution of 6-chloro-4,5-dimethylpyridazin-3-ylamine (0.5 g, 31.84 mmol) in 2-propanol (15 mL), and the mixture was heated at 90ºC for 3 h. The reaction mixture was then cooled to 55ºC–60ºC, and hydroxylamine hydrochloride (0.27 g, 4.14 mmol) was added, followed by further stirring at 55ºC–60ºC for 2 h. Volatiles were removed under reduced pressure, and polyphosphoric acid (5 g) was added at room temperature. The reaction mixture was further heated at 110ºC for 3 h. The reaction mixture was then cooled to room temperature, and ammonia was slowly added to the reaction mixture, during which solids precipitated. These solids were filtered and dried under reduced pressure to obtain the target compound. Yield: 0.5 g (32%); 1 H₂ – NMR (CDCl₃, 400 MHz) δ ppm: 2.49 (s, 3H), 2.71 (s, 3H), 8.38 (s, 1H); mass (m / z): 182.9, 184.7 (M+H) + .

[0318] Intermediate-12: 6-chloro-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine

[0319] Intermediate-12 was obtained by using 6-chloro-5-methylpyridazine-3-ylamine and DMF-DMA as starting materials and employing some non-critical variations, according to the following procedure given for intermediate-11. 1 H-NMR (CDCl) 3, δ ppm (400 MHz): 2.47 (s, 3H), 7.52 (s, 1H), 7.87 (s, 1H); mass (m / z): 168.9, 170.8 (M+H) + .

[0320] Intermediate-13: 6-chloro-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine

[0321] Intermediate-13 was obtained by using 6-chloro-4,5-dimethyl-pyridazine-3-ylamine and DMA-DMA as starting materials and employing some non-critical variations, according to the following procedure given for intermediate-11. 1 H-NMR (CDCl) 3, (400MHz) δ ppm: 2.46 (s, 3H), 2.62 (s, 3H), 2.66 (s, 3H); mass (m / z): 196.9, 198.8 (M+H) + .

[0322] Intermediate-14: 6-chloro-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine

[0323] Intermediate-14 was obtained by using 6-chloro-5-methylpyridazine-3-ylamine and DMA-DMA as starting materials and employing some non-critical variations, following the given procedure for intermediate-11. 1 H-NMR (CDCl) 3, 400 MHz) δppm: 2.52 (s, 3H), 2.63 (s, 3H), 7.82 (s, 1H); mass (m / z): 182.9, 184.8 (M+H)+.

[0324] Intermediate-15: 6-chloro-2,7-dimethyl-imidazo[1,2-b]pyridazine

[0325] Chloroacetone (2 g, 10.65 mmol) was added to a stirred solution of 6-chloro-5-methylpyridazin-3-ylamine (0.42 g, 2.60 mmol) in 1-butanol (10 mL) at room temperature, and the reaction mixture was refluxed for 8 h. Volatiles were removed under reduced pressure, and the resulting solid was purified by silica gel column chromatography using 1%–2% MeOH in DCM to obtain the target compound. Yield: 0.15 g (38%); 1 H-NMR (CDCl) 3, δ ppm (400 MHz): 2.43 (s, 3H), 2.47 (s, 3H), 7.64 (m, 2H); mass (m / z): 181.7, 182.8 (M+H) + .

[0326] Intermediate-16: 6-chloro-2,7,8-trimethyl-imidazo[1,2-b]pyridazine

[0327] Intermediate-16 was obtained by using 6-chloro-4,5-dimethyl-pyridazine-3-ylamine and chloroacetone as starting materials and employing some non-critical variations, according to the following procedure given for intermediate-15. 1 H-NMR (CDCl) 3, (400MHz) δ ppm: 2.38 (s, 3H), 2.47 (s, 3H), 2.63 (s, 3H), 7.59 (s, 1H); mass (m / z): 196.0, 197.8 (M+H) +

[0328] Intermediate-17: 6-chloro-2-fluoromethyl-7,8-dimethyl-imidazo[1,2-b]pyridazine

[0329] 1,3-Difluoroacetone (0.5 mL, 6.3 mmol) was added to a stirred solution of 6-chloro-4,5-dimethylpyridazin-3-ylamine (0.5 g, 3.1 mmol) in ethanol (20 mL), and the reaction mixture was refluxed for 16 h. Volatiles were removed under reduced pressure, and the resulting solid was purified by silica gel column chromatography using 30%–40% EtOAc in n-hexane to obtain the target compound. Yield: 0.25 g (36.8%); 1 H-NMR (DMSO-d) 6,400 MHz) δ ppm: 2.36 (s, 3H), 2.59 (s, 3H), 5.43 (s, 1H), 5.55 (s, 1H), 8.36 (s, 1H); mass (m / z): 213.8, 215.8 (M+H) +

[0330] Intermediate-18: 6-chloro-2-fluoromethyl-7-methyl-imidazo[1,2-b]pyridazine

[0331] Intermediate-18 was obtained by using 6-chloro-5-methylpyridazine-3-ylamine and 1,3-difluoroacetone as starting materials and employing some non-critical variations, following the procedure given for intermediate-17. 1 H-NMR (DMSO-d) 6, (400MHz) δ ppm: 2.38 (s, 3H), 5.43 (s, 1H), 5.55 (s, 1H), 7.96 (s, 1H), 8.36 (s, 1H); mass (m / z): 199.8, 201.7 (M+H) +

[0332] Intermediate-19: 6-chloro-2,3,7-trimethyl-imidazo[1,2-b]pyridazine

[0333] 3-Bromo-2-butanone (0.6 g, 2.49 mmol) was added to a stirred solution of 6-chloro-5-methylpyridazin-3-ylamine (0.3 g, 2.08 mmol) in ethanol (10 mL) at room temperature, and the reaction mixture was refluxed for 16 h. Volatiles were removed under reduced pressure, and the resulting solid was purified by silica gel column chromatography using 1%–2% MeOH in DCM to obtain the target compound. Yield: 0.2 g (75%); 1 H-NMR (CDCl) 3, δ ppm (400 MHz): 2.42 (s, 3H), 2.43 (s, 3H), 2.47 (s, 3H), 7.63 (m, 1H); mass (m / z): 196.0, 197.8 (M+H) + .

[0334] Intermediate-20: 2,6-Dichloro-7,8-dimethyl-imidazo[1,2-b]pyridazine

[0335] 0.43 g (63.0 mmol) of chloroacetic acid and 0.6 mL (4.90 mmol) of triethylamine were sequentially added to a stirred solution of 6-chloro-4,5-dimethylpyridazin-3-ylamine (0.77 g, 4.90 mmol) in ethanol:water (1:1 mL). The reaction mixture was heated at 110ºC for 10–12 h, followed by cooling to room temperature. Water (50 mL) was added to the reaction mixture and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with 100 mL of saline solution, dried over Na₂SO₄, and concentrated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography using 2%–4% MeOH in DCM to give the target compound. Yield: 0.34 g (38%); mass (m / z): 217.2, 219.5 (M+H) + .

[0336] Intermediate-21: 6-chloro-7-methyl-imidazo[1,2-b]pyridazine

[0337] Chloroacetaldehyde (2 g, 10.65 mmol) was added to a stirred solution of 6-chloro-5-methylpyridazin-3-ylamine (0.42 g, 2.60 mmol) in 1-butanol (10 mL) at room temperature, and the reaction mixture was refluxed for 16 h. Volatiles were removed under reduced pressure, and the resulting solid was purified by silica gel column chromatography using 1%–2% MeOH in DCM to obtain the target compound. Yield: 0.4 (88%); 1 H-NMR (CDCl) 3, 400 MHz) δ ppm: 2.45 (s, 3H), 7.71 (s, 1H), 7.77 (s, 1H), 7.87 (s, 1H); mass (m / z): 167.6, 170.0 (M+H) + .

[0338] Intermediate-22: 6-chloro-7,8-dimethyl-imidazo[1,2-b]pyridazine

[0339] Intermediate-22 was obtained by using 6-chloro-4,5-dimethyl-pyridazine-3-ylamine and chloroacetaldehyde as starting materials and employing some non-critical variations, according to the following procedure given for intermediate-21. 1 H-NMR (CDCl) 3,(400MHz) δ ppm: 2.44 (s, 3H), 2.67 (s, 3H), 8.17 (s, 1H), 8.52 (s, 1H); mass (m / z): 181.8, 184.2 (M+H) + .

[0340] Intermediate-23: 4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidine hydrochloride

[0341] Step 1: 4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

[0342] 2,3-Dihydro-benzo[1,4]dioxin-6-ol (12 g, 78.94 mmol) and Ph3P (25 g, 94.73 mmol) were sequentially added to a stirred solution of tert-butyl 4-hydroxypiperidin-1-carboxylate (15.86 g, 78.94 mmol) in 120 mL of THF aqueous solution. The mixture was cooled to 0–5°C, DIAD (32 g, 157.8 mmol) was added, and the reaction mixture was restored to room temperature and stirred further at room temperature for 16 h. Volatiles were removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography using 10%–12% EtOAc in n-hexane to give the target compound. Yield: 12.6 g (48%); 1 H – NMR (CDCl3, 400 MHz) δ ppm: 1.42 – 1.46 (s, 9H), 1.69 – 1.72 (m,2H), 1.85 – 1.87 (m, 2H), 3.25 – 3.31 (m, 2H), 3.66 – 3.72 (m, 2H), 4.20 – 4.23 (m, 4H), 4.24 – 4.31 (m, 1H), 6.41 – 6.46 (m, 2H), 6.74 – 6.77 (d, J =8.8 Hz, 1H); mass (m / z): 336.2 (M+H) + .

[0343] Step 2: 4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidine hydrochloride

[0344] IPA·HCl (30 mL, 10 vol., 12% w / v solution) was added to a stirred solution of tert-butyl 4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidine-1-carboxylate (12.6 g, 37.61 mmol) in MeOH (10 mL), and the reaction mixture was maintained at room temperature for 4 h. Volatiles were removed under reduced pressure to give the target compound. Yield: 9.2 g (90%); 1 H-NMR (DMSO-d) 6, 400 MHz) δ ppm: 1.74 – 1.77 (m, 2H), 2.01 – 2.06 (m,2H), 3.01 – 3.02 (m, 2H), 3.17 (m, 2H), 4.16 – 4.20 (m, 4H), 4.46 – 4.49 (m,1H), 6.45 – 6.46 (m, 1H), 6.54 – 6.55 (d, J = 2.8 Hz, 1H), 6.75 – 6.77 (d, J= 8.8 Hz, 1H), 8.87 (bs, 2H); mass (m / z): 236.0 (M+H) + .

[0345] Intermediates 24 to 35 were prepared using the appropriate starting materials given in the table below, following the experimental procedures given in steps 1 and 2 of intermediate-23 and with some non-critical variations.

[0346]

[0347]

[0348]

[0349] Method-I

[0350] Example 1: 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine

[0351]

[0352] Cesium fluoride (1.4 g, 9.43 mmol), triethylamine (1.8 mL, 12.58 mmol), and piperidine hydrochloride (0.85 g, 3.14 mmol, intermediate-23) were sequentially added to a stirred solution of 4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidine hydrochloride (0.85 g, 3.14 mmol, intermediate-23) and 6-chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine (0.53 g, 3.14 mmol, intermediate-2) in DMSO (15 mL). The reaction mixture was heated at 110ºC for 10–12 h, followed by cooling to room temperature. Water (50 mL) was added to the reaction mixture and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with a saline solution (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure to obtain the crude compound, which was purified by silica gel column chromatography using 2%–4% MeOH in DCM to obtain the target compound. Yield: 0.54 g (50%). 1 H-NMR (CDCl) 3, 400 MHz) δppm: 1.92 – 1.99 (m, 2H), 2.08 – 2.13 (m, 2H), 2.40 (s, 3H), 3.08 – 3.13 (m,2H), 3.43 – 3.49 (m, 2H), 4.21 – 4.25 (m, 4H), 4.37 – 4.41 (m, 1H), 6.45 –6.48 (m, 1H), 6.50 – 6.51 (d, J = 2.4 Hz, 1H), 6.77 – 6.79 (d, J = 8.4 Hz,1H), 7.74 (s, 1H), 8.83 (s, 1H); mass (m / z): 368.0 (M+H) + .

[0353] Method II

[0354] Example-2: 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine

[0355]

[0356] Pd2dba3 (0.02 g, 0.02 mmol), BINAP (0.013 g, 0.02 mmol), followed by NaOtBu (0.84 g, 0.8 mmol) were sequentially added to a stirred solution of 4-(2,3-dihydro-benzofuran-6-yloxy)-piperidine hydrochloride (0.05 g, 0.2 mmol, intermediate-25) and 6-chloro-7,8-dimethyl-imidazo[1,2-b]pyridazine (0.04 g, 0.2 mmol, intermediate-22) in toluene (20 mL). The reaction mixture was then refluxed under N2 atmosphere for 16 h. The reaction mixture was cooled to room temperature and poured into water (30 mL), and the product was extracted using EtOAc (100 mL x 3). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, which was purified by column chromatography using 2%–4% MeOH in DCM to obtain the target compound. Yield: 0.05 g (62.5%). 1 H-NMR (CDCl) 3, 400 MHz) δ ppm: 1.92 – 1.98 (m, 2H), 2.08 – 2.13 (m, 2H), 2.28 (s,3H), 2.28 (s, 3H), 2.95 – 3.02 (m, 2H), 3.17 – 3.21 (t, J = 8.8Hz, 2H), 3.35– 3.41 (m,2H), 4.31– 4.33 (m, 1H), 4.53 – 4.57 (t, J = 8.4 Hz, 2H), 6.82 –6.71 (m, 2H), 6.85 – 6.85 (d, J = 1.2 Hz, 1H), 7.53 – 7.54 (d, J = 1.2 Hz, 1H), 7.69 – 7.69 (d, J = 1.2 Hz, 1H); mass (m / z): 365.2 (M+H) + .

[0357] Examples 3 through 126 were prepared using suitable intermediates (synthesized above) and with some non-critical variations, following the experimental procedures provided in Examples 1 or 2.

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387] Example 127: Allosteric Power of Muscarinic M4 Receptor EC 50 Determining the value

[0388] The ability of the compound to activate the muscarinic M4 receptor was tested. The experimental procedure and results are provided below.

[0389] A. CRE-Luc Reporter Assay – The CHO-K1 cell line (Chinese hamster ovary (CHO) K1 (ATCC CCL-61) purchased from ATCC) engineered to stably express the recombinant human muscarinic M4 receptor and pCRE-Luc reporter system was used for a cell-based assay. The assay provides a non-radioactive method for determining the binding of compounds to GPCRs. In this specific assay, the level of intracellular cyclic AMP, regulated by receptor activation or inhibition, was measured. The recombinant cells contained a luciferase reporter gene controlled by the cyclic AMP response element.

[0390] The cells were grown in 96-well clear-bottomed white plates in Hams F12 medium containing 10% fetal bovine serum (FBS, Thermo Fisher Scientific). Cells were serum-starved overnight before adding the compound or standard agonist. Gradual increases in concentration of the test compound were added to EC in Opti-MEM medium. 20 Acetylcholine and trichodin (1 µM) were added to the cells together.

[0391] Cells were incubated at 37ºC in a CO2 incubator for 4 h. After removing the culture medium, cells were lysed using lysis buffer, assay reagents were added, and luciferase activity was measured in a photometer. In the presence of tuftin (1 μM), luciferase activity stimulated with a reference agonist (10 μM) was designated as 100%, while basal luciferase activity (i.e., tuftin only (1 μM), in the absence of a reference agonist) was designated as 0%. After correction for basal luciferase activity, the remaining luminescence values ​​of the compounds obtained at various doses were calculated with reference to the stimulated values. The relationship between compound activity (%) and compound concentration was plotted, and the dose-response curves were analyzed using a 4-parameter logistic fitting model in GraphPad Prism software. EC5 of the compounds... 50 The value is defined as existing EC 20 The concentration required to stimulate 50% luciferase activity under acetylcholine conditions was determined, and the results were used as EC50. 50 Provided in Table 1A below.

[0392] Table 1A: Allosteric Power of Muscarinic M4 Receptors (EC) 50 value

[0393]

[0394] B. Glosensor cAMP Assay – HEK293 cell lines (human embryonic kidney cells (HEK-293) (ATCC CRL-1573) purchased from ATCC) engineered to transiently express recombinant human muscarinic M4 receptor and pGloSensor-22F cAMP were used for the Glosensor cAMP assay. The assay provides a non-radioactive method for determining the binding of a compound to a GPCR using a genetically encoded biosensor variant whose cAMP-binding domain is fused to a mutant form of firefly luciferase. Upon binding to cAMP, a conformational change occurs, resulting in a significant increase in light output. Cells transiently or stably expressing the biosensor variant, after substrate preequilibration, can be used to measure GPCR function using a live-cell, non-lytic assay, enabling easy measurement of the kinetics of cAMP accumulation or turnover in live cells.

[0395] The cells were grown overnight in a CO2 incubator at 37ºC in 96-well clear white plates in DuPont modified Eagle medium containing Glutamax and 10% fetal bovine serum (FBS, purchased from Thermo Fisher Scientific). Before adding the compound or standard agonist, the cells were pre-equilibrated with the substrate for 2 h at room temperature in CO2-independent medium containing 10% FBS. Gradual increases in the concentration of the test compound were added to EC in CO2-independent medium containing 10% FBS. 20 Acetylcholine and isoproterenol (0.1 µM) were added to the cells together.

[0396] Incubation was continued for 12 minutes at room temperature. After incubation, luciferase activity was measured in a photometer. In the presence of isoproterenol, the luciferase activity stimulated by a reference agonist (10 μM) was designated as 100%, while the basal luciferase activity (i.e., isoproterenol alone, in the absence of a reference agonist) was designated as 0%. After correction for basal luciferase activity, the remaining luminescence values ​​of the compounds obtained at various doses were calculated with reference to the stimulated values. The relationship between compound activity (%) and compound concentration was plotted, and the dose-response curves were analyzed using a 4-parameter logistic fitting model in GraphPad Prism software. EC50 of the compounds... 50 The value is defined as existing EC 20 The concentration required to stimulate 50% luciferase activity under acetylcholine conditions was determined, and the results were used as EC50. 50 Provided in Table 1B below.

[0397] Table 1B: Allosteric Power of Muscarinic M4 Receptors (EC)50 value

[0398]

[0399] C. Muscarinic M2 CRE-Luc Reporter Assay – The CHO-K1 cell line (Chinese hamster ovary (CHO) K1 (ATCC CCL-61) purchased from ATCC) engineered to stably express the recombinant human muscarinic M2 receptor and pCRE-Luc reporter system was used for a cell-based assay. The assay provides a non-radioactive method for determining the binding of compounds to GPCRs. In this particular assay, the level of intracellular cyclic AMP, regulated by receptor activation or inhibition, was measured. The recombinant cells contained a luciferase reporter gene controlled by the cyclic AMP response element.

[0400] The cells were grown in 96-well clear white plates in Hams F12 medium containing 10% fetal bovine serum (FBS, Thermo Fisher Scientific). Cells were starved of serum overnight before adding the compound or standard agonist. The test compound was gradually increased in concentration and then added to EC in Opti-MEM medium. 20 Acetylcholine and trichodin (1 M) are added to the cells together.

[0401] Cells were incubated at 37ºC in a CO2 incubator for 4 h. After removing the culture medium, cells were lysed using lysis buffer, assay reagents were added, and luciferase activity was measured in a photometer. In the presence of tuftin (1 μM), luciferase activity stimulated with a reference agonist (10 μM) was designated as 100%, while basal luciferase activity (i.e., tuftin only (1 μM), in the absence of a reference agonist) was designated as 0%. After correction for basal luciferase activity, the remaining luminescence values ​​of the compounds obtained at various doses were calculated with reference to the stimulated values. The relationship between compound activity (%) and compound concentration was plotted, and the dose-response curves were analyzed using a 4-parameter logistic fitting model in GraphPad Prism software. EC5 of the compounds... 50 The value is defined as existing EC 20 The concentration required to stimulate 50% luciferase activity under acetylcholine conditions was determined, and the results were used as EC50. 50 Provided in Table 1C below.

[0402] Table 1C: Allosteric Power of Muscarinic M2 Receptors (EC) 50 value

[0403]

[0404] Example 128: Pharmacokinetic Study in Rodents

[0405] Male Wistar rats (250 ± 50 g) were used as experimental animals. Animals were housed individually in polypropylene cages. Two days prior to the study, male Wistar rats were anesthetized with isoflurane for surgical placement of a jugular vein catheter. The test compound was administered to rats at a dose of 5 mg / kg and a volumetric dose of 2 mL / kg. Rats were given free access to food and water during acclimatization, surgical recovery, and the study period.

[0406] Preparations for intraperitoneal administration were prepared using 5% v / v DMSO + 5% v / v Solutol HS15 + 90% v / v water for injection as the medium. Dosage preparations were freshly prepared on the day of administration.

[0407] Following administration, 200 µL of blood was collected via the jugular vein at each time point, and an equal volume of physiological saline was added. The collected blood samples were transferred to labeled Eppendorf tubes containing 10 μL of heparin sodium (1000 IU / mL) as an anticoagulant. Blood samples were collected at 0.08, 0.25, 0.5, 1, 2, 3, 5, 7, and 24 h post-administration. The blood was centrifuged at 4,000 rpm for 10 min. Plasma was separated and stored frozen at -80ºC until analysis. The concentration of the test compound in the plasma was quantified using a qualified LC-MS / MS method with appropriate extraction techniques. The study samples were analyzed using calibration samples from the batch and quality control samples distributed throughout the batch.

[0408] The pharmacokinetic parameter C was calculated using a standard non-compartmental model with the Phoenix WinNonlin version 8.1 software package. max T max AUC 0-t t 1 / 2 The pharmacokinetic characteristics of the tested compounds are given in Table 2 below:

[0409] Table 2: Pharmacokinetic characteristics of the compounds of the present invention

[0410]

[0411] Example 129: Antagonistic effect on amphetamine-induced excessive motor activity

[0412] Male Wistar rats weighing 230–250 g were used. Rats' weights were recorded. Rats were randomly assigned to groups based on their weight. Animals were brought to the laboratory 1 hour prior to acclimatization. The outdoor arena was a 51 x 51 x 51 cm black arena enclosed by black plastic walls of the same size. Rats were acclimatized to the arena for 30 minutes. Appropriate treatments (mediators or test compounds) were administered to animals based on brain exposure. After the acclimatization period, animals were challenged with amphetamine (0.5 mg / kg, subcutaneously) or the mediator. Animals were then placed in the outdoor arena, and the distance traveled was tracked using Videomotot software for 120 minutes. Data were analyzed using GraphPad Prism. Results for the test compounds are given in Table 3 below:

[0413] Table 3: Antipsychotic drug-like activity of the compounds of the present invention

[0414]

[0415] Example 130: Receptor Occupancy Study in Rats

[0416] Male Wistar rats (250 ± 50 g) were used as experimental animals. Animals were housed individually in polypropylene cages and acclimatized to the experimental conditions for 4 days. On the day of the experiment, the vehicle (10 mL / kg) or the test compound (3, 10, or 30 mg / kg) was administered intraperitoneally to the rats. The test compound was administered at T... max All rats were intravenously administered 3 µg / kg MK-6884 (tracer) via the lateral caudal vein. Five minutes after tracer administration, rats were euthanized by cervical dislocation, and the brain was isolated from the skull, sprayed with ice-cold water, and two brain regions (striatum and cerebellum) were separated and transferred to corresponding pre-labeled / weighed microcentrifuge tubes, stored on dry ice or at -80ºC until processing for tracer extraction and analysis (using LC-MS / MS-based methods). The tracer concentration in the study samples was analyzed using calibration samples from the batch and quality control samples distributed throughout the batch. Receptor occupancy in the striatum was calculated using a ratio method.

[0417] Table 4: Receptor occupancy rate of the test compounds of the present invention

[0418]

[0419] Example 131: Conditioned Memory of Situational Fear

[0420] A rodent fear conditioning chamber (L x W x H, rat: 26 x 30 x 33 cm, Coulburn Instruments, USA) was used, housed in an anechoic chamber. A stainless steel mesh floor (L x W, rat: 26 x 30 cm) connected to an impact scrambler was used to transmit the impact. A ventilation fan provided 60 dB of background noise. A bulb (fixed to the right wall, 27 cm above the chamber floor) provided ambient lighting. The experiment was recorded using a camera mounted on the cabinet ceiling, and the images were analyzed using FreezeFrame 3 software (V3.2.1). The fear conditioning chamber had a transparent acrylic panel.

[0421] On day 0, the rats were randomly divided into groups according to their weight, with two rats in each cage.

[0422] On Day 1, rats were brought to the laboratory at least 1 hour before the experiment. Rats were acclimatized to the fear-conditioned compartment for 2 minutes. After acclimatization, rats received an unavoidable foot shock (unconditioned stimulus (US): 0.7 mA shock for 3 seconds). The shocks were repeated to deliver a total of eight USs, with a 79-second interval between each administration. One minute after the last US, the animals were transferred to their home cages. The compartment was cleaned with 70% ethanol between tests. The test treatment was administered prior to the conditioned phase based on Tmax. Amphetamine 2 mg / kg was subcutaneously injected 25 minutes before the conditioned phase.

[0423] On day 2, rats were brought to the laboratory at least 1 hour before the experiment. Freezing behavior was recorded for 733 seconds (starting from the time the animal was placed in the fear-conditioned compartment). After the 733-second recording, the animal was transferred to its home cage. The duration of freezing was recorded (approximately 3 seconds or more without movement was rated as freezing behavior). The freezing threshold was set to 10 in the movement index used for analysis. The compartment was cleaned with 70% ethanol between tests.

[0424] Table 5: Cognitive-enhancing activities of the compounds of the present invention

[0425]

Claims

1. A compound of formula (I) Or its isotopic form, stereoisomer, or pharmaceutically acceptable salt. in, Each can be a single bond or a double bond independently; X1, X2, X3, and X4 are independently selected from N or C; provided that R2, R3, R4, or R5 does not exist when X1, X2, X3, or X4 is N. R1 is selected from halogen, cyano, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -C1-C4 alkoxyalkyl, -OC1-C4 alkyl or -OC1-C4 haloalkyl; When present, R2 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl; When present, R3 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl; When present, R4 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl; When present, R5 is selected from hydrogen, deuterium, halogen, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl. When present, R6 is selected from hydrogen, deuterium, halogen, cyano, -OH, -CH2OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl or -C1-C4 alkoxyalkyl. R7 is " "Indicates an attachment point; R8 and R9 are independently hydrogen, halogen, cyano, -OH, -NH2, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, -OC1-C4 alkoxyalkyl, -NHC1-C4 alkyl; or alternatively, R8 and R9 together with the carbon atoms to which they are attached form a 5-8 membered heterocycle, wherein the heterocycle is optionally substituted by one to five substituents independently selected from hydrogen, oxo, deuterium, halogen, cyano, -OH, -C1-C4 alkyl, -C1-C4 haloalkyl, -C3-C7 cycloalkyl, -OC1-C4 alkyl, -OC1-C4 haloalkyl, or -C1-C4 alkoxyalkyl; and m can be 0, 1, or 2.

2. A compound of formula (I) according to the foregoing embodiments, or its isotopic form, stereoisomer, or pharmaceutically acceptable salt, wherein the compound is selected from: 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-[1-(7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile; 6-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(6-fluoro-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(6-fluoro-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 7-Methyl-6-[4-(6-methylpyridin-3-yloxy)piperidin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-[1-(7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-[1-(3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile; 6-[4-(2-methoxy-pyridin-4-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[3-fluoro-4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-3,7,8-trimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-[1-(3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2-methoxy-pyridin-4-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3,7-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-[1-(3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Methoxymethyl-6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Methoxymethyl-6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-3-methoxymethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(6-methoxy-pyridin-3-yloxy)piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 3-Difluoromethyl-6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2-methoxy-pyridin-4-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 3-[1-(2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-piperidin-4-yloxy]benzylnitrile; 6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-2,7-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7-dimethyl-imidazo[1,2-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,7,8-trimethyl-imidazo[1,2-b]pyridazine; 6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-2,7,8-trimethyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2-fluoromethyl-7,8-dimethyl-imidazo[1,2-b]pyridazine; 2-Fluoromethyl-6-[4-(6-methoxy-pyridin-3-yloxy)piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; 2-Fluoromethyl-6-[4-(2-methoxy-pyridin-4-yloxy)piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2-fluoromethyl-7-methyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-2,3,7-trimethyl-imidazo[1,2-b]pyridazine; 2-Chloro-6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; 2-Chloro-6-[4-(6-methoxy-pyridin-3-yloxy)piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-5-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine; 6-[4-(4-methoxy-phenoxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7-methyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; 6-[4-(6-methoxy-pyridin-3-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; 6-[4-(2,3-dihydro-benzofuran-6-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine; or 6-[4-(1,3-dihydro-isobenzofuran-5-yloxy)-piperidin-1-yl]-7,8-dimethyl-imidazo[1,2-b]pyridazine.

3. The compound of formula (I) according to claim 1 or claim 2, or its isotopic form, stereoisomer, or pharmaceutically acceptable salt, is used as a positive allosteric modulator of muscarinic M4 receptor (M4 PAM).

4. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or claim 2, or an isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is used to treat a disease or disorder mediated by a muscarinic M4 receptor, wherein the disease or disorder is selected from mental disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

6. A compound of formula (I) according to claim 1 or claim 2, or an isotopic form, stereoisomer, or pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder mediated by a muscarinic M4 receptor, wherein the disease or disorder is selected from mental disorders, neurological disorders, pain disorders, sleep disorders, or cognitive disorders.

7. The compound for the use according to claim 6, wherein the mental disorder is selected from anxiety, personality disorder, depression, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), bipolar disorder, attention deficit / hyperactivity disorder (ADHD), psychosis, schizophrenia, substance use disorder, and other mental disorders.

8. The compound for the use according to claim 6, wherein the neurological disease or disorder is selected from Alzheimer's disease, Rett syndrome, Huntington's disease, vascular dementia, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).

9. The compound for the use according to claim 6, wherein the cognitive impairment is selected from amnesia, dementia, forgetfulness, dementia caused by Alzheimer's disease, dementia caused by HIV disease, dementia caused by Huntington's disease, dementia caused by Parkinson's disease, Lewy body dementia, vascular dementia, frontotemporal dementia, senile dementia, dementia associated with Down syndrome, dementia associated with Tourette syndrome, dementia associated with postmenopausal syndrome, Creutzfeldt-Jakob disease dementia, substance-induced persistent dementia, Pick's disease dementia, Huntington's disease dementia, traumatic brain injury, prions, HIV-related neurocognitive impairment, mild cognitive impairment, and any other disease with cognitive symptoms.

10. The compound for the use according to claim 7, wherein the schizophrenia is selected from cognitive impairment, positive symptoms of schizophrenia, and / or negative symptoms of schizophrenia.

11. The compound for the use according to claim 7, wherein the mental disorder is selected from 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 persistent delirium, or any other disease with psychotic features.

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