Pharmaceutical Compounds

Abstract

The present invention relates to compounds which are agonists of the muscarinic M1 and M4 receptors and are useful in the treatment of diseases mediated by the muscarinic M1 and / or M4 receptors. Also provided are pharmaceutical compositions containing said compounds and therapeutic uses of said compounds. TIFF2024504252000051.tif3653(1) and salts thereof.

Description

[Technical field]

[0001] The present invention relates to a class of novel heterocyclic compounds, their salts, pharmaceutical compositions containing them, and their use in the treatment of the human body. In particular, the present invention relates to a class of compounds that are agonists of the muscarinic M1 and / or M4 receptors and are therefore useful in the treatment of Alzheimer's disease, schizophrenia, cognitive impairment, and other diseases mediated by the muscarinic M1 / M4 receptors, including, but not limited to, the treatment or alleviation of pain. [Background technology]

[0002] Muscarinic acetylcholine receptors (mAChRs) are members of the G protein-coupled receptor superfamily that mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous systems. Five mAChR subtypes, M1-M5, have been cloned. M1mAChRs are expressed postsynaptically, primarily in the cerebral cortex, hippocampus, striatum, and thalamus; M2mAChRs are present primarily in the brainstem and thalamus, but also in the cerebral cortex, hippocampus, and striatum, and M2mAChRs are present at cholinergic synaptic terminals (Langmead et al., 2008 Br J Pharmacol). However, M2mAChRs are also expressed peripherally on cardiac tissue (where they mediate vagal innervation of the heart) and in smooth muscle and exocrine glands. M3mAChR is expressed at relatively low levels in the CNS, but is widely expressed in smooth muscle and glandular tissues such as sweat and salivary glands (Langmead et al., 2008 Br J Pharmacology). Muscarinic receptors in the central nervous system, especially M1mAChR, play an important role in mediating higher cognitive processing. Diseases associated with cognitive impairment, such as Alzheimer's disease, are associated with loss of cholinergic neurons in the basal forebrain (Whitehouse et al., 1982 Science). Schizophrenia, also characterized by cognitive impairment, also has reduced mAChR density in the prefrontal cortex, hippocampus and caudate putamen of schizophrenic subjects (Dean et al., 2002 Mol Psychiatry). Furthermore, in animal models, blockade or damage of central cholinergic pathways has been shown to cause severe cognitive impairment, and nonselective mAChR antagonists have been shown to induce psychotomimetic effects in psychiatric patients. Cholinergic replacement therapy is primarily based on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown efficacy against symptomatic cognitive decline in the clinic but cause dose-limiting side effects (e.g., gastrointestinal motility disorders, bradycardia, nausea, and vomiting) due to stimulation of peripheral M2 and M3 mAChRs (http: / / www.drugs.com / pro / donepezil.html; http: / / www.drugs.com / pro / rivastigmine.html).

[0003] Furthermore, there has been a search aimed at identifying direct M1mAChR agonists that target increased cognitive function. These efforts have resulted in the identification of various agonists, including compounds such as xanomeline, AF267B, sabcomeline, miramelin, and cevimeline. Many of these compounds have been shown to be highly effective in preclinical models of cognition in both rodents and / or non-human primates. Mirameline has shown efficacy against scopolamine-induced working and spatial memory impairments in rodents, sabcomeline has shown efficacy in a visual object discrimination task in marmosets, and xanomeline has reversed mAChR antagonist-induced impairments in cognitive performance in a passive avoidance paradigm. Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting older adults (26.6 million worldwide in 2006), resulting in severe memory loss and cognitive impairment. The pathogenesis of the disease is complex, but is characterized by two distinctive brain sequelae: the aggregation of amyloid plaques composed mainly of amyloid-β peptides (Aβ), and neurofibrillary tangles formed by hyperphosphorylation of tau protein. The accumulation of Aβ is thought to be a central feature of AD progression, and therefore many putative therapies for the treatment of AD currently target the inhibition of Aβ production. Aβ is derived from the proteolytic cleavage of membrane-bound amyloid precursor protein (APP). APP is processed by two pathways, the nonamyloidogenic pathway and the amyloidogenic pathway. Cleavage of APP by γ-secretase is common to both pathways, whereas in the former, APP is cleaved by α-secretase to produce soluble APPα. The cleavage site is within the Aβ sequence, which prevents the formation of Aβ. However, in the amyloidogenic pathway, APP is also cleaved by β-secretase to produce soluble APPβ and Aβ. In vitro studies have shown that mAChR agonists can promote the processing of APP to the soluble, nonamyloidogenic pathway. In vivo studies have shown that the mAChR agonist AF267B altered disease-like pathology in 3×TgAD transgenic mice, a model of various components of Alzheimer's disease (Caccamo et al., 2006 Neuron). Finally, the mAChR agonist cevimeline has been shown to slightly but significantly reduce cerebrospinal fluid levels of Aβ in patients with Alzheimer's disease, thus demonstrating potential disease modifying efficacy (Nitsch et al., 2000 Neurol).

[0004] Moreover, preclinical studies suggest that mAChR agonists display an atypical antipsychotic-like profile in various preclinical paradigms. The mAChR agonist xanomeline restores many dopamine-driven behaviors (such as amphetamine-induced locomotion in rats, apomorphine-induced climbing in mice, dopamine agonist-driven rotation in unilateral 6-OH-DA-lesioned rats, and amphetamine-induced locomotor anxiety in monkeys) without EPS tendency. Xanomeline has also been shown to inhibit A10, but not A9, dopamine cell firing and conditioned avoidance, and induces c-fos expression in the prefrontal cortex and nucleus accumbens, but not in the striatum, of rats. All these data suggest an atypical antipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev). Muscarinic receptors are also implicated in the neurobiology of addiction. The reinforcing effects of cocaine and other addictive substances are mediated by the mesolimbic dopamine system, where behavioral and neurochemical studies have shown that cholinergic muscarinic receptor subtypes play an important role in regulating dopaminergic neurotransmission. For example, M(4)(- / -) mice exhibited significantly enhanced reward-driven behavior as a result of exposure to cocaine (Schmidt et al Psychopharmacology (2011) Aug;216(3):367-78). Furthermore, xanomeline has been demonstrated to block the effects of cocaine in these models.

[0005] Muscarinic receptors are also involved in the control of movement and may represent novel therapeutic agents for movement disorders such as Parkinson's disease, ADHD, Huntington's disease, Tourette's syndrome, and other syndromes associated with dopaminergic dysfunction as the underlying pathogenic factor-driven disease. Xanomeline, sabcomeline, miramelin and cevimeline are all in various stages of clinical development for the treatment of Alzheimer's disease and / or schizophrenia. Phase II clinical studies of xanomeline have demonstrated its efficacy on various cognitive symptom domains, including behavioral disorders and hallucinations associated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol). The compound has also been evaluated in a small Phase II study of schizophrenia patients, significantly reducing positive and negative symptoms compared to placebo controls (Shekhar et al., 2008 Am J Psych). However, in all clinical studies, xanomeline and other related mAChR agonists have shown unacceptable safety margins with respect to cholinergic side effects, such as nausea, gastrointestinal pain, diarrhea, diaphoresis (excessive sweating), hypersalivation (excessive salivation), syncope and bradycardia.

[0006] Muscarinic receptors are involved in central and peripheral pain. Pain can be divided into three different types: acute, inflammatory, and neuropathic. Acute pain plays an important protective role in keeping the body safe from stimuli that may cause tissue damage, but post-operative pain management is necessary. Inflammatory pain can have many causes, such as tissue damage, autoimmune responses, and pathogen invasion, and is triggered by the action of inflammatory mediators such as neuropeptides and prostaglandins that cause nerve inflammation and pain. Neuropathic pain involves abnormal pain sensations to non-painful stimuli. Neuropathic pain is associated with many different diseases / injuries, such as spinal cord injury, multiple sclerosis, diabetes (diabetic neuropathy), and viral infections (e.g., HIV or herpes). It is also commonly seen in cancer, both as a result of disease or as a side effect of chemotherapy. Activation of muscarinic receptors has been shown to have analgesic effects for many pain conditions through activation of receptors in higher pain centers in the brain and in the spinal cord. Elevation of endogenous levels of acetylcholine by acetylcholinesterase inhibitors, direct activation of muscarinic receptors by agonists or allosteric modulators have been shown to have analgesic activity. In contrast, blocking muscarinic receptors by antagonists or using knockout mice increases pain sensitivity. Evidence for the role of M1 receptors in pain is reviewed in DF Fiorino and M. Garcia-Guzman, 2012. More recently, a small number of compounds have been identified that show improved selectivity for the M1 mAChR subtype compared to peripherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg Med Chem Lett; Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al., 2010 ACS Med Chem Lett). Despite the increased level of selectivity for the M3 mAChR subtype, some of these compounds retain significant agonist activity at both this subtype and the M2 mAChR subtype. Herein, we describe a series of compounds that unexpectedly show a high level of selectivity for the M1 and / or M4 mAChR compared to the M2 and M3 receptor subtypes. Summary of the Invention

[0007] The present invention provides compounds that have activity as muscarinic M1 and / or M4 receptor agonists. More specifically, the present invention provides compounds that exhibit selectivity for the M1 and / or M4 receptors over the M2 and M3 receptor subtypes. Thus, the present invention relates to a compound of formula (1): [ka] (1) or a salt thereof. The present invention relates to a compound of formula (1a): [ka] (1a) The present invention further provides a compound of the formula (wherein X represents a salt). The present invention relates to a compound represented by formula (1b): [ka] (1b) The present invention further provides a compound of the formula:

[0008] The present invention relates to a compound represented by formula (2): [ka] (2) or a salt thereof. The present invention relates to a compound of formula (2a): [ka] (2a) The present invention further provides a compound of the formula (wherein X represents a salt).

[0009] The present invention relates to a compound represented by formula (2b): [ka] (2b) The present invention further provides a compound of the formula: The present invention relates to a compound of formula (2c): [ka] (2c) The present invention further provides a compound of the formula:

[0010] The compound of formula (1) or formula (2) may be a pharma- ceutically acceptable salt. The compounds of formula (1) or formula (2) may be acid addition salts. The compound of formula (1) or formula (2) may be a hydrochloride salt. The compound of formula (1) or formula (2) may be a hydrochloride salt. The compound of formula (1) or formula (2) may be the monohydrochloride monohydrate. In the compounds of formula (1a) or formula (2a), X can be a pharma- ceutically acceptable salt. In the compound of formula (1a) or formula (2a), X may be an acid addition salt. In the compound of formula (1a) or formula (2a), X may be a hydrochloride salt. In the compound of formula (1a) or formula (2a), X may be a monohydrochloride salt. The compound of formula (1) or formula (2) may be a hydrochloride salt. X can be the hydrochloride salt. X can be the monohydrochloride salt. X can be the monohydrochloride monohydrate. The compound can be N-tert-butyl-1-{8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide. The compound can be N-tert-butyl-1-{(1R,3r,5S)-8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide. The compound can be a salt of N-tert-butyl-1-{8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide. The compound can be a salt of N-tert-butyl-1-{(1R,3r,5S)-8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide.

[0011] The compound can be a pharma- ceutically acceptable salt of N-tert-butyl-1-{8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide. The compound can be a pharma- ceutically acceptable salt of N-tert-butyl-1-{(1R,3r,5S)-8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide. The compound can be N-tert-butyl-1-{8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide hydrochloride. The compound can be N-tert-butyl-1-{(1R,3r,5S)-8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide hydrochloride. The compound can be N-tert-butyl-1-{8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide monohydrochloride. The compound can be N-tert-butyl-1-{(1R,3r,5S)-8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide monohydrochloride. The compound can be N-tert-butyl-1-{8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide monohydrochloride monohydrate. The compound can be N-tert-butyl-1-{(1R,3r,5S)-8-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]-8-azabicyclo[3.2.1]octan-3-yl}piperidine-4-carboxamide monohydrochloride monohydrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition As used herein, the following definitions apply unless otherwise stated. The term "treatment" with respect to the use of a compound of Formula (1), Formula (1a), Formula (1b), Formula (2), Formula (2a), Formula (2b) or Formula (2c) is used to describe any form of intervention in which a compound is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from, the disease or disorder in question. Thus, the term "treatment" encompasses both prophylactic treatment and treatment exhibiting measurable or detectable symptoms of the disease or disorder. The term "therapeutically effective amount" as used herein (e.g., with respect to a method of treating a disease or condition) refers to an amount of a compound that is effective to produce a desired therapeutic effect. For example, when the condition is pain, a therapeutically effective amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain or a reduction in the severity of pain.

[0013] salt The compounds described herein can exist in the form of salts, such as acid addition salts, and in some cases salts of organic and inorganic bases, such as carboxylates, sulfonates and phosphates. All such salts are within the scope of the present invention, and references to compounds of formula (1) and formula (2) include salt forms of the compounds defined herein. The salts are typically acid addition salts. The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods, such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with the appropriate base or acid in water or an organic solvent, or in a mixture of both, generally using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

[0014] Acid addition salts can be formed with a wide variety of acids, both organic and inorganic. Examples of acid addition salts within the scope of the invention include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, and the like. , citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrohalic acids (e.g., dibromoacetic acid, acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, Examples of suitable salts include mono- or di-salts formed with acids selected from the group consisting of mitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as mono- or di-salts formed with acylated amino acids and cation exchange resins.

[0015] Amine functional groups in the compounds described herein may be reacted, for example, with alkylating agents to form quaternary ammonium salts, according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the present invention. The compounds of the present invention may exist as mono- or di-salts depending on the pKa of the salt-forming acid. The salt forms of the compounds of the present invention are typically pharma- ceutically acceptable salts, and examples of pharma- ceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, pharma- ceutical non-acceptable salts can also be prepared as intermediate forms and then converted to pharma- ceutical acceptable salts. Such pharma- ceutical non-acceptable salt forms may be useful, for example, in the purification or separation of the compounds of the present invention, and also form part of the present invention.

[0016] stereoisomer Reference to the compounds of formula (1), (1a) and (1b) includes all possible stereoisomeric forms thereof (e.g., enantiomers, epimers and diastereomers; endo-exo isomers, etc.) either as individual isomers or as mixtures (e.g., racemic mixtures) or as two or more isomers, unless the context requires otherwise. Thus, the present invention provides compounds of formula (1) which contain a chiral centre. Isomers can be characterized in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog. Advanced Organic Chemistry by Jerry March, 4 thEdition, John Wiley & Sons, New York, 1992, pages 109-114, and Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415. Stereoisomers can be separated by a number of techniques, including chiral chromatography (chromatography on a chiral support), and such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, stereoisomers can be separated by forming salts of the diastereoisomers with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, followed by separation of the diastereoisomers by selective crystallization, followed by dissociation of the salts to give the individual enantiomers of the free base.

[0017] When a compound of the invention exists in two or more stereoisomeric forms, one diastereomer of a pair of diastereomers may be superior to the other diastereomer, for example in terms of biological activity, and therefore, in certain circumstances, it may be desirable to use only one of the diastereoisomers as a therapeutic agent. Accordingly, the present invention provides a composition comprising a compound having one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound is present as a single isomer (e.g., a diastereomer). In one typical embodiment, 99% or more (eg, substantially all) of the total amount of the compound (or compound for use) is present as a single isomer. For example, in one embodiment, the compound exists as a single diastereomer, and the compound has a plane of symmetry.

[0018] Isotopes The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope all isotopes of that element. 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their respective scopes. 12 C. 13 C and 14 C and 16 O and 18 Contains O. Similarly, when referring to a particular functional group, isotopic variations are also included within the scope unless the context indicates otherwise. For example, when referring to an alkyl group such as a tert-butyl group, reference is made to variations in which one or more of the hydrogen atoms in the group are in the form of deuterium or tritium (tritium) isotopes, such as a tert-butyl group in which all nine hydrogen atoms are in the form of deuterium isotopes (perdeuterium-tert-butyl group). The isotope may be radioactive or non-radioactive. The compound may not contain a radioisotope. Such a compound is preferred for therapeutic use. However, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in diagnostic situations.

[0019] solvate The compounds of the present invention can form solvates. Preferred solvates are those formed by incorporating molecules of a non-toxic pharma- ceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid structure (e.g., crystalline structure) of the compounds of the present invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compounds of the present invention with a solvent or a mixture of solvents containing a solvating solvent. In any case, whether or not a solvate has been formed can be determined by analyzing the crystals of the compounds using well-known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography. The solvates may be stoichiometric or nonstoichiometric solvates. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. Thus, the present invention provides the compound in the form of a solvate; Compounds wherein the solvate is a hydrate, The compound is provided wherein the solvate is a monohydrate. For a more detailed discussion of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition (ISBN 0-967-06710-3), published by SSCI, Inc of West Lafayette, IN, USA, 1999. Alternatively, the compounds of the invention may be anhydrous, rather than existing as hydrates.Accordingly, the invention provides compounds of the invention in anhydrous form (e.g., anhydrous crystalline form).

[0020] Crystalline and amorphous forms Compounds may exist in a crystalline or non-crystalline (e.g., amorphous) state. Whether a compound exists in a crystalline state can be readily determined by standard techniques such as X-ray powder diffraction (XRPD). Crystals and their crystalline structures can be characterized using a number of techniques, including single crystal X-ray crystallography, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and infrared spectroscopy (e.g., Fourier transform infrared spectroscopy (FTIR)). The behavior of crystals under varying humidity conditions can also be analyzed by XRPD through gravimetric vapour sorption studies. The crystal structure of a compound can be determined by X-ray crystallography, which can be carried out according to conventional methods, for example, as described herein and in Fundamentals of Crystallography, C. Giacovazzo, HL Monaco, D. Viterbo, F. Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union of Crystallography / Oxford University Press, 1992 ISBN 0-19-855578-4 (p / b), 0-19-85579-2 (h / b)). This technique involves the analysis and interpretation of X-ray diffraction of a single crystal. In amorphous solids, the three-dimensional structure that is usually present in crystalline forms does not exist, and the relative positions of molecules in amorphous forms are essentially random. See, for example, Hancock et al. J. Pharm. Sci. (1997), 86, 1). Thus, the present invention provides A compound in crystalline form, (a) a compound that is 50% to 100% crystalline, more specifically, at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, e.g., 100% crystalline; The compound is provided in an amorphous form.

[0021] Complexes and clathrates The compounds of the invention also include complexes (eg, inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals). Thus, the present invention provides compounds in the form of complexes or clathrates. Biological Activity and Therapeutic Uses The compounds of the present invention have activity as muscarinic M1 and M4 receptor agonists. The muscarinic activity of the compounds can be determined using the phosphorylation-ERK1 / 2 assay described in Example A below. A major advantage of the compounds of the invention is that they are highly selective for the M1 and / or M4 receptors compared to the M2 and M3 receptor subtypes. The compounds of the invention are not agonists of the M2 and M3 receptor subtypes. For example, the compounds of the invention typically have a pEC50 of at least 6 (preferably at least 6.5) for the M1 receptor in the functional assay described in Example A. 50 value and E of more than 80 (preferably more than 90) max values, while having a pEC value of less than 5 when tested against M2 and M3 subtypes in the functional assay of Example A. 50 value and E less than 20% max It may have a value.

[0022] With respect to the compounds of the invention, the invention further provides: Compounds for use in medicine, Compounds for use as muscarinic M1 and / or M4 receptor agonists, A pEC50 of greater than 6.9 for the M1 receptor in the assay of Example A herein or a substantially similar assay. 50 and at least 80 E max a compound which is a muscarinic M1 receptor agonist having the formula: pEC > 7.0 50 a compound which is a muscarinic M1 receptor agonist having the formula: At least 90 E max A compound having the formula A pEC50 of greater than 6.0 for the M4 receptor in the assay of Example A herein or a substantially similar assay. 50 a compound which is a muscarinic M1 and M4 receptor agonist having the formula: Compounds that are selective for muscarinic M1 and M4 receptors relative to M2 and M3 receptors; pEC50 < 5 for muscarinic M2 and M3 receptor subtypes 50 and E below 30 max A compound having the formula A compound for use in the treatment of a disease or condition mediated by muscarinic M1 and / or M4 receptors. Due to their muscarinic M1 and M4 receptor agonist activity, the compounds of the present invention can be used in the treatment of Alzheimer's disease, dementia with Lewy bodies, schizophrenia, and other psychiatric disorders, cognitive disorders, and other diseases mediated by the muscarinic M1 and / or M4 receptors, and can also be used in the treatment of various types of pain.

[0023] Thus, with respect to the compounds of the invention, the invention further provides: A compound for use in the treatment of a cognitive or psychiatric disorder, 1. A compound for use in the treatment of a cognitive or psychiatric disorder, wherein the cognitive or psychiatric disorder comprises, results from, or is associated with a condition selected from the following: cognitive impairment, mild cognitive impairment (MCI) (including mild cognitive impairment due to Alzheimer's disease and / or prodromal Alzheimer's disease, such as amnesic MCI and non-amnesic MCI), frontotemporal dementia, vascular dementia, dementia with Lewy bodies, presenile dementia, senile dementia, Friedreich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia, mania, Tourette's syndrome, Alzheimer's disease (including prodromal Alzheimer's disease, as well as conditions listed in the U.S. Food and Drug Administration's "Early Alzheimer's disease: Developing Drugs for Treatment" at fda.gov / downloads / Drugs / GuidanceComplianceRegulatoryInformation / Guidances / UCM596728.pdf available), progressive supranuclear palsy, cognitive impairment (such as attention, orientation, learning disabilities, memory (i.e. memory impairment, amnesia, amnesic disorder, transient global amnesia and age-related memory impairment), and language functions); cognitive impairment as a result of stroke, Huntington's disease, Pick's disease, AIDS-related dementia or other dementia conditions, e.g. multi-infarct dementia, alcoholic dementia, hypothyroidism-related dementia, and dementias associated with other degenerative disorders such as cerebellar atrophy and amyotrophic lateral sclerosis; other acute or subacute conditions that may cause cognitive decline, such as delirium or depression (pseudo-dementia states), trauma, head injury, age-related cognitive decline, stroke, neurodegeneration, drug-induced conditions, Neurotoxic drugs, age-related cognitive impairment, autism-related cognitive impairment, Down's syndrome, psychosis-related cognitive impairment, and post-electroconvulsive therapy-related cognitive impairment; cognitive impairment due to drug abuse or withdrawal (drugs such as nicotine, cannabis, amphetamines, cocaine), attention deficit hyperactivity disorder (ADHD) and movement disorders (e.g. Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesia), schizophrenia, schizophreniform disorders, psychotic depression, mania, acute mania, paranoid disorder, hallucinatory and delusional disorders, personality disorders, obsessive-compulsive disorder, schizotypal disorder, delusional disorder, psychosis due to malignancy, or metabolic disorders, or endocrine disorders or narcolepsy, psychosis due to drug abuse or withdrawal, bipolar disorder and schizoaffective disorder.

[0024] A compound for use in the treatment of Alzheimer's disease, A compound for use in the treatment of dementia with Lewy bodies, A compound for use in the treatment of schizophrenia, A method of treating a cognitive disorder in a subject (e.g., a mammalian patient, such as a human (e.g., a human in need of treatment)), comprising administering a therapeutically effective amount of a compound of the invention; A method of treating a cognitive impairment in a subject (e.g., a mammalian patient, such as a human (e.g., a human in need of treatment)), comprising administering a therapeutically effective amount of a compound of the invention, wherein the cognitive impairment comprises, results from, or is associated with a condition as defined above; A method of treating cognitive impairment in a subject (e.g., a mammalian patient, such as a human (e.g., a human in need of treatment)), comprising administering a therapeutically effective amount of a compound of the invention, wherein the cognitive impairment results from or is associated with Alzheimer's disease; A method of treating a cognitive disorder in a subject (e.g., a mammalian patient, such as a human (e.g., a human in need of treatment)), comprising administering a therapeutically effective amount of a compound of the invention, wherein the cognitive disorder is dementia with Lewy bodies; a method of treating a cognitive disorder in a subject (e.g., a mammalian patient, such as a human (e.g., a human in need of treatment)), comprising administering a therapeutically effective amount of a compound of the invention, wherein the cognitive disorder is schizophrenia;

[0025] Use of a compound of the present invention for the manufacture of a medicament for the treatment of cognitive disorders; Use of a compound of the invention for the manufacture of a medicament for the treatment of a cognitive disorder, wherein the cognitive disorder comprises, results from or is associated with a condition as defined above. Use of a compound of the present invention for the manufacture of a medicament for the treatment of a cognitive disorder, wherein the cognitive disorder includes, results from, or is associated with Alzheimer's disease. Use of a compound of the invention for the manufacture of a medicament for the treatment of a cognitive disorder, wherein the cognitive disorder includes, results from, or is associated with dementia with Lewy bodies. Use of a compound of the present invention for the manufacture of a medicament for the treatment of a cognitive disorder, wherein the cognitive disorder comprises, results from, or is associated with schizophrenia. Compounds for the treatment or reduction of severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain,

[0026] 1. A method of treating or reducing the severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain, which method comprises administering a therapeutically effective amount of a compound of the invention; Compounds for the treatment of peripheral disorders such as reducing intraocular pressure in glaucoma, and for the treatment of dry eye and dry mouth such as in Sjogren's syndrome; a method for treating extremity disorders, such as reducing intraocular pressure in glaucoma, and dry eye and dry mouth, such as Sjogren's syndrome, comprising administering a therapeutically effective amount of a compound of the present invention; Use of a compound of the invention for the manufacture of a medicament for the treatment or reduction of severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain, or for the treatment of extremity disorders such as reducing intraocular pressure in glaucoma, and dry eye and dry mouth such as in Sjogren's syndrome,

[0027] Use of the compounds of the present invention to treat skin lesions, such as those resulting from pemphigus vulgaris, dermatitis herpetiformis, pemphigoid and other blistering skin conditions; Use of the compounds of the present invention for treating, preventing, ameliorating or reversing conditions associated with altered gastrointestinal function and motility, such as symptoms of functional dyspepsia, irritable bowel syndrome, gastroesophageal acid reflux (GER) and esophageal hypoperistalsis, gastroparesis and chronic diarrhea; Use of the compounds of the present invention to treat olfactory dysfunction such as Bosma-Henkin-Christiansen syndrome, chemical poisoning (e.g., selenium and silver), hypopituitarism, Kallmann syndrome, skull fractures, tumor treatment, and hypothyroidism; Use of the compounds of the present invention for treating addiction; Use of the compounds of the present invention for treating movement disorders such as Parkinson's disease, ADHD, Huntington's disease, Tourette's syndrome and other syndromes associated with dopaminergic dysfunction as the underlying pathogenic factor driving the disease; Use of the compounds of the present invention to treat behavioral and psychological symptoms of dementia (BPSD; including agitation, verbal aggression, physical aggression, depression, anxiety, abnormal motor behavior, elevated mood, irritability, blunted affect, disinhibition, impulsivity, delusions, hallucinations, sleep changes, and appetite changes).

[0028] Compounds of the present invention include Example 1, Example 1-1, and Example 1-2 shown below. [Table 1]

[0029] Methods for preparing the compounds of the present invention The compounds of the invention can be prepared according to synthetic methods well known to those skilled in the art and described herein. Also provided is a process for preparing the compound defined above, said process comprising any of A, B or C: (A) Formula (10): [ka] is reacted under reductive amination conditions to give a compound of formula (11): [ka] or (B) Equation (12): [ka] with an amine of formula (CH3)3CNH2, where R represents a suitable group such as methyl or ethyl; or (C) Formula (13): [ka] reacting the compound of formula (CH3)3CNH2 with an amine of formula (CH3)3CNH2.

[0030] Such methods are well known to those skilled in the art. Examples of synthetic procedures for converting one functional group to another are described in standard texts, such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, Michael B. Smith, John Wiley, 2013, (ISBN: 978-0-470-46259-1), Organic Syntheses, Online Edition, www.orgsyn.org, (ISSN 2333-3553), and Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2). In the reactions mentioned above, it may be necessary to protect one or more groups to prevent reaction from occurring at undesired locations on the molecule. Examples of protecting groups, as well as methods for protecting and deprotecting functional groups, can be found in Greene's Protective Groups in Organic Synthesis, Fifth Edition, Editor: Peter GM Wuts, John Wiley, 2014, (ISBN: 9781118057483). The compounds prepared by the methods described above can be isolated and purified by any of a variety of methods well known to those of skill in the art, including recrystallization, and chromatographic techniques such as column chromatography (e.g., flash chromatography), HPLC, and SFC.

[0031] Pharmaceutical preparations While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation). Thus, there is provided a pharmaceutical composition comprising at least one compound of the invention as defined above, together with at least one pharma- ceutically acceptable excipient. The composition may be a tablet composition. The composition may be a capsule composition. The one or more pharma- ceutically acceptable excipients can be selected, for example, from carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents, such as fillers or bulking agents; and liquid diluents, such as solvents and cosolvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g., polymers or waxes that slow or retard release), binding agents, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity-adjusting agents, thickeners, flavors, sweeteners, dyes, plasticizers, taste-masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions. As used herein, the term "pharmaceutical acceptable" means a compound, material, composition, and / or dosage form that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human subject) without undue toxicity, irritation, allergic response, or other problem or complication, and is commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. Pharmaceutical compositions containing the compounds of the present invention can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, optic, rectal, vaginal, or transdermal administration.

[0032] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, liquids, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches (e.g., buccal patches). The tablet composition may contain a unit dose of the active compound together with an inert diluent or carrier, such as a sugar or sugar alcohol (e.g., lactose, sucrose, sorbitol or mannitol); and / or a non-sugar-based diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch, such as corn starch. Tablets may also contain standard ingredients, such as binders and granulating agents (e.g., polyvinylpyrrolidone), disintegrants (e.g., swellable cross-linked polymers, such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate buffers or citrate buffers), and effervescent agents (e.g., citrate / bicarbonate mixtures). Such excipients are well known and need not be discussed in detail here. Tablets may be designed to release the drug upon contact with gastric fluids (immediate release tablets) or they may be designed to release in a controlled manner over an extended period of time or in specific areas of the GI tract (controlled release tablets).

[0033] A pharmaceutical composition typically comprises approximately 1% (w / w) to approximately 95% (preferably % (w / w)) of an active ingredient and 99% (w / w) to 5% (w / w) of a pharma- ceutically acceptable excipient (e.g., as defined above) or a combination of excipients. Preferably, the composition comprises approximately 20% (w / w) to approximately 90% (w / w) of an active ingredient and 80% (w / w) to 10% of a pharmaceutical excipient or a combination of excipients. A pharmaceutical composition comprises approximately 1% to approximately 95%, preferably approximately 20% to approximately 90%, of an active ingredient. The pharmaceutical composition of the present invention may be in unit dose form, such as in the form of an ampoule, a vial, a suppository, a pre-filled syringe, a dragee, a powder, a tablet or a capsule. Tablets and capsules may, for example, contain 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid, and / or 0-99% (w / w) filler / or extender (depending on the drug dose). Tablets and capsules may also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, 0-5% (w / w) dye. Extended release tablets further typically contain 0-99% (w / w) release-controlling (e.g., retarding) polymer (depending on the dose). Film coats for tablets or capsules typically contain 0-10% (w / w) polymer, 0-3% (w / w) dye, and / or 0-2% (w / w) plasticizer. Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) co-solvent, and / or 0-99% (w / w) water for injection (WFI) (depending on dose and whether lyophilized), and intramuscular depot formulations may contain 0-99% (w / w) oil.

[0034] Pharmaceutical formulations may be provided to the patient in "patient packs" which contain an entire course of treatment in a single package, typically a blister pack. The compounds of the invention are generally provided in unit dosage form and thus typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram to 2 milligrams of active ingredient. Within these ranges, certain narrower ranges of compound are 0.1 milligrams to 2 grams of active ingredient (more generally, 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g., 1 microgram to 10 milligrams, e.g., 0.1 milligram to 2 milligrams of active ingredient). For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example, 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram of active compound. The active compound is administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect (an effective amount). The exact amount of compound to be administered can be determined by the attending physician according to standard procedures. EXAMPLES

[0035] General Procedure Unless a preparative route is described, the relevant intermediates are commercially available. Commercially available reagents were used without further purification. Room temperature (rt) refers to approximately 22-30°C. 1 H NMR spectra were recorded on a Bruker instrument at 400 MHz. Chemical shift values ​​are expressed in parts per million (ppm) (i.e., (δ) values). The following abbreviations are used for the multiplicity of the NMR signals: s = singlet, br = broad, d = doublet, t = triplet, q = quartet, quint = quintet, td = triplet of doublets, tt = triplet of triplets, qd = quartet of doublets, ddd = doublet of doublets of doublets, ddt = doublet of doublets of triplets, m = multiplet. Coupling constants were reported as J values ​​measured in Hz. NMR and mass spectrometry results were corrected to take into account background peaks. LCMS analysis LCMS analysis of compounds was performed under electrospray conditions using the equipment and methods shown in the table below. [Table 2]

[0036] [Table 3]

[0037] Preparative HPLC purification Preparative HPLC purification was performed using a Shimadzu LC-20AP binary system with an SPD-20A UV detector. Purification technique: [phase (column description, column length x inner diameter, particle size), solvent flow rate, gradient - mobile phase B in mobile phase A (over time) expressed as % mobile phase (A), mobile phase (B)]. Preparative HPLC method A Preparative HPLC: [Reverse phase (X-BRIDGE C-18, 250 × 50 mm, 5 μm), 85 mL / min, gradient: 35% to 70% (26 min), 100% (2 min), 100% to 35% (6 min), mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonia in water, (B): 100% acetonitrile] Preparative HPLC method B Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 50 mm, 5 μm), 85 mL / min, gradient: 40% to 60% (26 min), 60% (4 min), 100% (2 min), 100% to 40% (7 min), mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonia in water, (B): 100% acetonitrile]

[0038] Abbreviation AcOH = acetic acid Bn = benzyl t-BuOH = tert-butyl alcohol CPM = cyclopentyl methyl ether DCM = dichloromethane DIPEA = N,N-Diisopropylethylamine DMF = dimethylformamide DMSO = dimethyl sulfoxide ESI = electrospray ionization EtOH = ethanol h = time / second HATU = Hexafluorophosphate azabenzotriazole tetramethyluronium HPLC = High Performance Liquid Chromatography IPA = Propan-2-ol LCMS = Liquid Chromatography Mass Spectrometry MeOH = methanol min = minutes / seconds 2-MTHF = 2-methyltetrahydrofuran nm = nanometers NMO = 4-Methylmorpholine 4-oxide NMR = nuclear magnetic resonance rt = room temperature RT = residence time TEA = triethylamine TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran The prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

[0039] Synthesis of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide hydrochloride (Example 1-1) [ka] [ka]

[0040] Step 1: Synthesis of benzyl cyclopent-3-ene-1-carboxylate (intermediate 2) To a mixture of K2CO3 (61.5 g, 446 mmol) and cyclopent-3-ene-1-carboxylic acid (CAS: 7686-77-3, intermediate 1) (25.0 g, 223 mmol) in acetone (375 mL), (bromomethyl)benzene (CAS: 100-39-0) (29.1 mL, 245 mmol) was added dropwise. The reaction was stirred at 60 °C for 2 h and then cooled to room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude was purified by column chromatography [normal phase (neutral Al2O3), 0-10% (ethyl acetate in hexane)] to give benzyl cyclopent-3-ene-1-carboxylate (intermediate 2) (40.1 g, 89.0%). LCMS (System 1, Method A): (ESI) m / z 203 [M+H] + RT 5.10 min, 254 nm. [ka]

[0041] Step 2: Synthesis of benzyl 3,4-dihydroxycyclopentane-1-carboxylate (Intermediate 3) A mixture of 4-methylmorpholine 4-oxide (30.44 g, 260 mmol), OsO4 (2% in t-BuOH, 12.0 mL, 0.94 mmol), and benzyl cyclopent-3-ene-1-carboxylate (Intermediate 2) (43.8 g, 217 mmol) in acetone (431 mL) was stirred at room temperature for 16 h. The mixture was treated with saturated aqueous Na2SO3 (500 mL) and then extracted with DCM (3 x 400 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography [normal phase (silica), 0-50% (ethyl acetate in hexane)] to give benzyl 3,4-dihydroxycyclopentane-1-carboxylate (Intermediate 3) (30.4 g, 59.4%). LCMS (System 2, Method B): (ESI) m / z 237 [M+H] + RT 2.38 min, 224 nm. [ka]

[0042] Step 3: Synthesis of benzyl 4-oxo-2-(2-oxoethyl)butanoate (Intermediate 4) A mixture of NaIO4 (48.7 g, 229 mmol) and benzyl 3,4-dihydroxycyclopentane-1-carboxylate (Intermediate 3) (36.0 g, 153 mmol) in THF (1800 mL) and water (144 mL) was stirred at room temperature for 2 h. Water (1500 mL) was added until the precipitate dissolved, and then the mixture was extracted with DCM (3 x 500 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give benzyl 4-oxo-2-(2-oxoethyl)butanoate (Intermediate 4) (35.8 g, 100.0%). The crude was used without further purification. LCMS (System 2, Method B): (ESI) m / z 233 [MH] - RT 2.33 min and 2.74 min, 202 nm. [ka]

[0043] Step 4: Synthesis of tert-butyl (1R,3r,5S)-3-(4-((benzyloxy)carbonyl)piperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 6) A solution of benzyl 4-oxo-2-(2-oxoethyl)butanoate (intermediate 4) (35.8 g, 153 mmol) and tert-butyl (1R,3r,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (CAS: 207405-68-3, intermediate 5) (34.6 g, 153 mmol) in EtOH (1400 mL) was stirred at room temperature for 30 min. Then, NaBH3CN (9.64 g, 153 mmol) and AcOH (3.0 mL, 52.5 mmol) were added to the solution and stirring was continued at room temperature for 16 h. The reaction mixture was diluted with water (1000 mL) and extracted with DCM (3 x 500 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography [normal phase (silica), 0-30% (ethyl acetate in hexanes)] to give tert-butyl (1R,3r,5S)-3-(4-((benzyloxy)carbonyl)piperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 6) (41.0 g, 62.6%). LCMS (System 2, Method B): (ESI) m / z 429 [M+H] + RT 4.28 min, 202 nm. [ka]

[0044] Step 5: Synthesis of benzyl 1-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate dihydrochloride (Intermediate 7) To a solution of tert-butyl (1R,3r,5S)-3-(4-((benzyloxy)carbonyl)piperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Intermediate 6) (41.0 g, 96.0 mmol) in 1,4-dioxane (82.0 mL) was added HCl in 1,4-dioxane (4 M, 410 mL, 10 vol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was azeotroped with hexane (2×50 mL) and then triturated with hexane (2×50 mL) to give benzyl 1-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate dihydrochloride (Intermediate 7) (38.4 g, 100.0%). LCMS (System 1, Method B): (ESI) m / z 329 [M+H] + RT 3.10 min, 202 nm. [ka]

[0045] Step 6: Synthesis of benzyl 1-((1R,3r,5S)-8-cyano-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 8) To a solution of benzyl 1-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate dihydrochloride (Intermediate 7) (38.4 g, 96.0 mmol) in DCM (314 mL) was added triethylamine (39.8 mL, 287 mmol) dropwise at -20 °C while maintaining the internal temperature in the range of -20 °C to 0 °C. The reaction was then stirred at this temperature for 30 min. To the reaction was then added cyanogen bromide (15.1 g, 144 mmol) as a solution in DCM (31.0 mL) dropwise while maintaining the internal temperature in the range of -20 °C to 0 °C. The reaction was then allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO3 (700 mL) and extracted with DCM (3 x 300 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by column chromatography [normal phase (neutral Al2O3), 0-30% (ethyl acetate in hexane)] to give benzyl 1-((1R,3r,5S)-8-cyano-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 8) (16.0 g, 47.4%). LCMS (System 2, Method B): (ESI) m / z 354 [M+H] + RT 3.69 min, 202 nm. [ka]

[0046] Step 7: Synthesis of benzyl 1-((1R,3r,5S)-8-((((tert-butoxycarbonyl)amino)oxy)(imino)methyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 10) To a solution of benzyl 1-((1R,3r,5S)-8-cyano-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 8) (16.0 g, 45.3 mmol) in THF (160 mL) was added tert-butyl hydroxycarbamate (CAS: 36016-38-3, Intermediate 9) (6.63 g, 49.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 20 min. Then, to this solution was slowly added zinc chloride in 2-MTHF (1.9 M, 47.7 mL, 90.6 mmol) at 0° C., followed by stirring at room temperature for 16 h. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting crude material was triturated with hexanes (2×50 mL) to give benzyl 1-((1R,3r,5S)-8-((((tert-butoxycarbonyl)amino)oxy)(imino)methyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 10) (22.0 g, 100.0%). The crude material was used without further purification. LCMS (System 2, Method B): (ESI) m / z 487 [M+H] + RT 3.10 min, 202 nm. [ka]

[0047] Step 8: Synthesis of benzyl 1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 11) To a solution of benzyl 1-((1R,3r,5S)-8-((((tert-butoxycarbonyl)amino)oxy)(imino)methyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 10) (22.0 g, 5.3 mmol) in DCM (220 mL) was added TFA (110 mL, 5 vol) dropwise at 0°C-5°C. The reaction mixture was stirred at room temperature for 40 minutes and then cooled to 0°C-5°C. To this was then added TFAA (28.7 mL, 203.7 mmol) dropwise and stirred for 30 minutes before warming to room temperature and stirring for 16 hours. The reaction mixture was diluted with toluene (220 mL) and concentrated under reduced pressure. Saturated NaHCO3 solution (800 mL) was added and the reaction was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography [normal phase (neutral Al2O3), 0-30% (ethyl acetate in hexane)] to give benzyl 1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 11) (12.4 g, 59.0%). LCMS (System 2, Method B): (ESI) m / z 465 [M+H] + RT 4.40 min, 240 nm. [ka]

[0048] Step 9: Synthesis of 1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylic acid hydrochloride (Intermediate 12) To a solution of benzyl 1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (Intermediate 11) (12.3 g, 26.5 mmol) in THF (123 mL) and water (24.6 mL) was added lithium hydroxide monohydrate (2.78 g, 66.3 mmol) portionwise at room temperature and then stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL), cooled to 0° C.-10° C., and the pH was adjusted to 5-6 using 1 M HCl solution (approximately 70-80 mL). The reaction mixture was stirred for 1 hour, then the aqueous layer was separated and lyophilized to give 1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylic acid hydrochloride (Intermediate 12) (15.1 g, crude), which was used without further purification. LCMS (System 2, Method B): (ESI) m / z 375 [M+H] + RT 2.10 min, 236 nm. [ka]

[0049] Step 10: Synthesis of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide (Intermediate 14) To a solution of 1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylic acid hydrochloride (Intermediate 12) (5.8 g, 14.1 mmol) (8 g of crude material isolated from step 9 was used) in DMF (80.0 mL) was added HATU (12.2 g, 32.0 mmol) portionwise at 0° C.-10° C. The reaction was stirred at 0° C.-10° C. for 40 minutes. To this reaction was then added 2-methylpropan-2-amine (CAS: 75-64-9, Intermediate 13) (6.8 mL, 64.2 mmol) and DIPEA (11.4 mL, 64.2 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 hours. Ice water (500 mL) was added, stirred for 20 min, and the precipitate that formed was collected by filtration. The filter cake was washed with cold water (500 mL) and then with hexanes (500 mL) to give crude product (2.5 g). The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give additional crude product (4.5 g). The crude products were combined and purified by column chromatography [normal phase (silica), 0-50% (ethyl acetate in hexanes)] to give two batches of product with different purity (2.0 g and 3.8 g). Each batch was then taken separately and further purified by preparative HPLC methods A and B, respectively. The resulting products were combined and crystallized using IPA (10 vol) and MeOH (1 vol) and the filter cake was washed with cold IPA (2 vol) to give N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide (Intermediate 14) (1.9 g, 31.4%). LCMS (System 2, Method B): (ESI) m / z 430 [M+H] + RT 3.54 min, 240 nm. 1H NMR (400 MHz, DMSO-d6): δ 7.31 (br. s, 1H), 4.39 - 4.25 (m, 2H), 3.26 - 3.15 (m, 2H), 2.27 - 1.80 (m, 10H), 1.71 - 1.44 (m, 6H), 1.22 (s, 9H). [ka]

[0050] Step 11: Synthesis of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide hydrochloride (Example 1-1) To a solution of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide (Intermediate 14) (1.9 g, 4.4 mmol) in 1,4-dioxane (3.8 mL) was added HCl in 1,4-dioxane (4 M, 19.0 mL, 10 vol) at 0° C. The reaction was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The resulting residue was azeotroped with 1,4-dioxane (2×10 mL) and then triturated with 1,4-dioxane (10 mL). The solid was collected by filtration, and the filter cake was washed with 1,4-dioxane (2×5 mL), n-pentane (10 mL), and dried under reduced pressure. The solid was crystallized using IPA (10 vol) and MeOH (1 vol), and the filter cake was washed with cold IPA (2 vol) to give N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide hydrochloride (Example 1-1) (1.8 g, 87.9%). LCMS (System 2, Method B): (ESI) m / z 430 [M+H] + RT 3.55 min, 240 nm. 1H NMR (400 MHz, DMSO-d6): δ 10.78 - 10.24 (m, 1H), 7.58 - 7.46 (m, 1H), 4.62 - 4.50 (m, 2H), 3.54 - 3.43 (m, 2H), 3.32 - 3.06 (m, 2H), 2.85 - 2.64 (m, 4H), 2.37 - 2.20 (m, 1H), 2.13 - 2.00 (m, 2H), 1.93 - 1.69 (m, 7H), 1.23 (s, 9H).

[0051] Scale-up synthesis of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide monohydrochloride monohydrate (Example 1-2)

change

[0052] Step 1: Synthesis of benzyl cyclopent-3-ene-1-carboxylate (2)

change

[0053] Step 2: Synthesis of benzyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate (15) [ka] A clean and dry 5.0 L 4-neck RB flask equipped with a condenser and thermometer pocket was charged with MTBE (2450 mL) and benzyl cyclopent-3-ene-1-carboxylate (Intermediate 2, 245 g) at room temperature (22-25 °C) under nitrogen atmosphere and the reaction mixture was cooled to 5-10 °C. m-CPBA (362.6 g) was added in five separate lots, causing the color to change from dark brown to yellow. The reaction mixture was slowly warmed to 15-20 °C and continued to stir at 15-20 °C for 16-20 h. The progress of the reaction was monitored by HPLC until completion. 20% aqueous sodium bisulfite solution (3675 mL, 15 V) was added slowly over 15-20 min and stirred at 20-25 °C for 30 min. The organic layer was separated and 10% aqueous Na2CO3 (2450 mL, 10 V) was added and stirred at 20-25 °C for 15 min. The organic layer was separated and 20% aqueous sodium bisulfite (2450 mL, 10 V) was added and stirred until the peroxide content was < 3 mg / L (peroxide strip). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under pressure at 37-40 °C to give benzyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate. Crude mass: 234g, Crude yield: 88%, Crude characteristics: pale yellow liquid The crude material was used directly in the next step without further purification.

[0054] Step 03: Synthesis of benzyl 4-oxo-2-(2-oxoethyl)butanoate (4) [ka] A clean and dry 2.0 L 4-neck RB flask equipped with a condenser and a thermometer pocket was charged with ethyl acetate (380 mL) and periodic acid (87.41 g) at room temperature (22-25 °C) under nitrogen atmosphere, and the white suspension was cooled to 0-10 °C. Benzyl 6-oxabicyclo[3.1.0]hexane-3-carboxylate (Intermediate 15, 76 g in 380 mL ethyl acetate solution) was added, and a color change from dark brown to yellow was observed. The reaction mixture was slowly warmed to 15-20 °C and kept stirring for 3-4 h. The progress of the reaction was monitored by TLC and HPLC until completion of the reaction. Demineralized water (760 mL, 10 V) was added and stirred at 20-25 °C for 15-20 min, repeated three times. The organic layer was separated, washed with brine solution (380 mL, 5 V) and stirred at 20-25 °C for 5-10 min. The organic layer was separated, dried over sodium sulfate, filtered, and the organic layer was evaporated under pressure at 37-40° C. to obtain benzyl-4-oxo-2-(2-oxoethyl)butanoate. Mass of crude product: 82g. Characteristics of crude product: pale yellow liquid. The crude material was used directly in the next step without further purification.

[0055] Step 04: Synthesis of tert-butyl (1R,3R,5S)-3-(4-((benzyloxy)carbonyl)piperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (6) [ka] A clean, dry 2.0 L 4-neck RB flask equipped with a condenser and thermometer pocket was charged with 2-methyl-THF (570 mL) and benzyl-4-oxo-2-(2-oxoethyl)butanoate (Intermediate 4, 57 g (actual crude mass obtained directly from step 3 was 82 g) at room temperature (22-23 °C) under nitrogen atmosphere. Intermediate 5 (endo amine) (49.54 g) was added and the reaction was cooled to 5-10 °C and the reaction was stirred for 30 minutes. Sodium triacetoxyborohydride (56.78 g) and glacial acetic acid (5.7 HCl (1 mL) was added and the reaction mixture was allowed to warm to room temperature (22-23 °C) and stirred for 10-12 h. The reaction progress was monitored by TLC and HPLC and once complete, saturated bicarbonate solution (400 mL, 7 V) was added and stirred at 20-25 °C for 15-20 min. The organic layer was separated, dried over sodium sulfate, filtered and evaporated under pressure at 37-40 °C to give tert-butyl (1R,3R,5S)-3-(4-((benzyloxy)carbonyl)piperidin-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. Mass of crude product: 115g, Characteristics of crude product: Thick liquid, Color: Light chestnut

[0056] Purification with oxalate formation: A clean, dry 500 mL 4-neck RB flask equipped with a thermometer and condenser was charged with the crude material (25 g) and acetone (150 mL, 6 V) and cooled to 5-10°C. Oxalic acid (10 g, 2.0 eq.) was charged and the reaction mass was allowed to warm to room temperature with stirring for 2 h. The reaction mass was evaporated at 40°C to give the crude material (mass: 35 g), which was then charged with 10 Vol of MTBE at 25-30°C and stirred for 30 min. The reaction mass was filtered and a bed wash with MTBE (1.0 vol) was performed to give a wet solid (oxalate salt, 26 g). The solid was suspended in saturated bicarbonate solution (30 vol, 780 mL) and ethyl acetate (25 Vol, 650 mL) and stirred for 15 min. The organic layer was separated, dried over Na2SO4, and evaporated under vacuum at 37-40°C to give the product. Mass of product: 8.0g If necessary, this material can be further purified by column chromatography adsorbed onto neutral alumina (source - SDFCL) using hexane:ethyl acetate. Column gradient: 5->10->12% (ethyl acetate:hexane).

[0057] Step 05: Synthesis of benzyl 1-((1R,3R,5S)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate hydrochloride (7) [ka] A clean and dry 5.0 L 4-neck RB flask equipped with a condenser and thermometer pocket was charged with cyclopentyl methyl ether (452 ​​mL, 4.0 V) and intermediate 6 (113 g, 1.0 eq.) under nitrogen atmosphere and the reaction mixture was cooled to 0-5°C. 3M HCl in cyclopentyl methyl ether (904 mL, 8.0 V) was added very slowly at 0-5°C and the reaction mixture was slowly warmed to 22-25°C and stirred for 16 h. The reaction was monitored by HPLC until completion. The reaction mixture was filtered under N2 atmosphere and bed washed with MTBE (2.0 vol.). The product wet cake was removed under N2 and dried under vacuum at 45-47°C to give the crude product which was used directly in the next step without any further purification.

[0058] Step 06: Synthesis of benzyl 1-((1R,3R,5S)-8-cyano-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (8) [ka] A clean and dry 5.0 L 4-neck RB flask equipped with a condenser and thermometer pocket was charged with dichloromethane (1860 mL, 10 vol.), intermediate 7 (186.0 g, 1.0 eq.) and triethylamine (355 mL, 5.0 eq.) under nitrogen atmosphere at 22-25°C over 10-15 min and the reaction mixture was stirred for 30-45 min. The reaction mixture was cooled to 0-5°C and cyanogen bromide (92 g, 1.7 eq.) in DCM (372 mL, 2.0 V) was added at 0-5°C and the reaction mixture was slowly warmed to 22-25°C and stirred at 22-25°C for 3-4 h. The progress of the reaction was monitored by HPLC until completion. The reaction mixture was diluted with DCM (1860 mL, 10 vol.) and basified with saturated NaHCO3 solution (930 mL, 5 V). The organic layer was separated and the aqueous layer was extracted with DCM (1860 mL, 10 vol). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 190 g of crude compound. The crude compound was purified by neutral alumina column chromatography using 15% ethyl acetate in hexane. The pure fractions were collected and concentrated under reduced pressure to give 75 g of pure compound (yield: 46%).

[0059] Step 07: Synthesis of benzyl 1-((1R,3R,5S)-8-((((tertbutoxycarbonyl)amino)oxy)(imino)methyl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (10) [ka] A clean and dry 3.0 L 4-neck RB flask equipped with a condenser and thermometer pocket was charged with 2-methyl-THF (800 mL, 10 vol.) and intermediate 8 (80 g, 1.0 eq.) under nitrogen atmosphere and the reaction mixture was cooled to 0-5 °C. A solution of ZnCl2 (2.2 eq., 1.9 M solution in 2-methyl-THF) was added and the reaction mixture was stirred at 0 °C for 30 min. Then, N-Boc-hydroxylamine (intermediate 9) (1.2 eq.) was added and the reaction mixture was slowly warmed to 23-25 ​​°C and continued to stir for 16 h. The progress of the reaction was monitored by TLC and HPLC until completion. The reaction mixture was quenched with water (800 mL, 10.0 V) and then the product was extracted with ethyl acetate (2 x 800 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 110 g (quantitative yield) of crude compound. This product was used directly in the next step without further purification.

[0060] Step 08: Synthesis of benzyl 1-((1R,3R,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylate (11) [ka] A clean and dry 3.0 L 4-neck RB flask equipped with a condenser and thermometer pocket was charged with DCM (1150 mL, 10.0 vol.) and Intermediate 10 (115.0 g, 1.0 eq.) under nitrogen atmosphere and the reaction mixture was cooled to 0-5 °C. A mixture of trifluoroacetic acid (271 mL, 15.0 eq.) and TFAA (164 mL, 5.0 eq.) was added dropwise in three portions at 0-5 °C with an interval of 3-4 h under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h and then stirred for an additional 16 h until the reaction progress was complete (monitored by TLC and HPLC). After completion of the reaction, the reaction mixture was cooled to 0 °C, the pH was adjusted (7-8) using saturated aqueous NaHCO3, and the reaction mixture was stirred for 15 min. The layers were separated and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 145 g of crude compound. The crude compound was purified by column chromatography on neutral alumina using hexane and ethyl acetate as eluents to give 49 g of pure product.

[0061] Step 09: Synthesis of 1-((1R,3R,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxylic acid (12) [ka] A clean and dry 5.0 L 4-neck RB flask equipped with a condenser and thermometer pocket was charged with THF (2250 mL), demineralized water (450 mL) and intermediate 11 (225 g) at room temperature (22-25 °C) under nitrogen atmosphere. Lithium hydroxide monohydrate (30.5 g, 2.0 eq.) was added at room temperature (22-25 °C) and the reaction mixture was stirred at 60 °C for 4 h. The progress of the reaction was monitored by TLC and HPLC and after completion of the reaction, the reaction mixture was cooled to 0-5 °C. The pH was adjusted to 4-5 using 1N HCl solution and the mixture was stirred for 15 min. The solvent was evaporated and the crude product was purified by adding MTBE (10.0 V) to the crude solid compound at room temperature and stirring at room temperature for 2 h. The solid was filtered and washed with MTBE (10.0 V). The solid compound was dried under vacuum to give 245 g of product (actual compound was 216 g of intermediate 12, remaining approximately 29.0 g was the lithium chloride salt) as an off-white solid.

[0062] Step 10: Synthesis of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide [ka] procedure: A clean, dry 1 L three-necked round bottom flask equipped with a mechanical stirrer and nitrogen inlet was charged with acetonitrile (20.0 V) and intermediate 12 (1.0 eq) in a single lot and the reaction product was stirred for 10 min. The reaction mixture was cooled to 0° C. and then HATU was added followed by tert-butylamine (1.5 eq), DIPEA (4.0 V) was added slowly over 15 min. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and, once complete, excess acetonitrile was distilled off under reduced pressure. The reaction was quenched with demineralized water (40.0 V) to precipitate a solid material and stirred for 60 min. The solid was washed with demineralized water (5.0 V) and dried by suction. The solid compound was dried under vacuum to give 56.0 g of product as an off-white solid.

[0063] Step 11: Synthesis of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide hydrochloride [ka] A flask was taken of the free base of intermediate 14 (56.0 g, 1.0 eq.) in acetone (10.0 V) and the reaction mixture was stirred for 10 min. Then the reaction mixture was cooled to 0° C. and 15% HCl solution in IPA was added dropwise at 0° C. Then the reaction mixture was warmed to 25-30° C. and stirred at 25-30° C. for 2 h. The solvent was evaporated completely under reduced pressure and co-evaporated twice with n-heptane at 10.0 V. The solid compound was dried under vacuum to give 59.0 g of product as an off-white solid.

[0064] Step 12 (recrystallization): Synthesis of N-(tert-butyl)-1-((1R,3r,5S)-8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide monohydrochloride monohydrate (Example 1-2) A flask was charged with the hydrochloride salt of intermediate 14 (108.0 g) in IPA (10.0 V) and the reaction mixture was heated to reflux for 1 h, however the solid did not completely dissolve at the reflux temperature. With continued heating for 1 h, MeOH (1.0 V) was added to obtain a solution. The hot solution was passed through filter paper to remove insoluble particles. The solvent (approximately 8 volumes out of 11 volumes of solvent) was removed under reduced pressure. Approximately 3 volumes remained, which was cooled to 0° C. and stirred at the same temperature for 1 h. The solid was then filtered, washed with a minimum amount of chilled IPA and dried by suction. The solid compound was dried under vacuum to obtain 93.5 g of the product as an off-white solid. Analysis was performed to determine the composition of the batch, which was found to be the monohydrochloride monohydrate. Monohydrochloride monohydrate formula: C 20 H 33 N5O3ClF3; molecular weight: 483.96 [Table 4]

[0065] biological activity Example A: Phosphorylation-ERK1 / 2 Assay Functional assays were performed using the Alphascreen Surefire phosphorylation-ERK1 / 2 assay (Crouch & Osmond, Comb. Chem. High Throughput Screen, 2008). ERK1 / 2 phosphorylation is a downstream consequence of Gq / 11 and Gi / o protein-coupled receptor activation and is much more suitable for the assessment of M1, M3 receptors (Gq / 11 coupled) and M2, M4 receptors (Gi / o coupled) than using different assay formats for different receptor subtypes. CHO cells stably expressing human muscarinic M1, M2, M3 or M4 receptors were plated (25K / well) onto 96-well tissue culture plates in MEM-α + 10% dialyzed FBS. Once attached, cells were serum starved overnight. Agonist stimulation was performed by adding 5 μL agonist to the cells for 5 min (37°C). The medium was removed and 50 μL lysis buffer was added. After 15 min, 4 μL of sample was transferred to a 384-well plate and 7 μL of detection mix was added. The plate was incubated for 2 h in the dark with gentle shaking and read on a PHERAstar plate reader. Data obtained for each receptor subtype showed that pEC 50 and E max The results are shown in Table 1 below. [Table 5]

[0066] Example B: CLint (in vitro hepatocytes) (Example 1) Hepatocyte stability assay was performed using pooled cryopreserved hepatocytes (Bioreclamation). Test compounds prepared in DMSO were incubated at 37° C. with hepatocytes at an initial concentration of 1 μM (final: 0.25% DMSO, n=2) and a cell density of 1 million cells / mL. Aliquots were removed at 0.5, 5, 10, 15, 30, 60 and 120 min, the reaction was stopped, and the compound was extracted with acetonitrile containing an internal standard (0.5 μM carbamazepine) for analysis. Samples were centrifuged and the supernatant fractions were analyzed for parent compound by mass spectrometry (LC-MS / MS). The amount of compound remaining (expressed as %) was determined from the MS response of each sample compared to the MS response of the T=0 sample (normalized to the internal standard). Ln plots of the % remaining were used to determine the half-life of compound elimination using the following relationship: Half-life (min) = -0.693 / λ, where λ is the slope of the Ln% remaining vs. time curve. formula: CLint (μL / min / million cells) = (0.693 / half-life (min)) x (1000 / million cells per mL incubation) was used to calculate the in vitro specific clearance (CLint) as μL / min / million cells. Mouse = 7 μL / min / million Rat: 8μL / min / 1 million Dog: 8μL / min / 1 million Monkeys <5μL / min / million Human <5μL / min / million

[0067] Example C: MDCK Permeability / Efflux (Example 1) MDR1-MDCK cells (Solvo Biotechnology) were cultured at 2.35 × 10 per well. 5Cells were seeded on 24-well Transwell plates and used as confluent monolayers after 3 days of incubation at 37°C under 5% CO2. For both apical to basolateral (A to B) and basolateral to apical (B to A) measurements, test and control compounds (propranolol, vinblastine) were added (1 μM, final: 0.1% DMSO, n=2) to the donor compartment of the Transwell plate in assay buffer (Hank's balanced salt solution supplemented with 25 mM HEPES and adjusted to pH 7.4) for each cell type. Incubation was performed at 37°C, and samples were removed from both the donor and acceptor chambers at T=0 and 1 hour to analyze the compounds by mass spectrometry (LC-MS / MS) including internal standards for analysis. The following relation: Papp = (T = end of acceptor compound / (donor compound x donor V) / incubation time) x area of ​​donor V x 60 x 10 -6 cm / s From this, the apparent permeability (Papp) value was determined.

[0068] where V is the volume of each Transwell compartment (125 μL apical, 600 μL basolateral), Concentration is the relative MS response for the compound (normalized to an internal standard) in the donor chamber before incubation and in the acceptor chamber at the end of incubation, Area is the area of ​​the cell exposed to drug translocation (0.33 cm 2 ). Efflux ratios (Papp B to A / Papp A to B) were calculated from the average Papp values ​​in each direction. MDR1-MDCK cell lines were engineered to overexpress the efflux transporter MDR1 (P-glycoprotein). The finding of good permeability from B to A but poor permeability from A to B suggests that the compound is a substrate for this transporter. Lucifer Yellow (LY) was added to the apical buffer in all wells to assess cell layer viability. High levels of LY transport indicate poor cell layer integrity, as LY cannot freely permeate the lipophilic barrier, and LY Papp > 10 × 10 -6Wells with less than 100 cm / s were rejected. Note that compromised integrity in one well does not affect the validity of other wells on the plate. Compound recovery from wells was determined from the MS response (normalized to an internal standard) in the donor and acceptor chambers at the end of incubation compared to the response in the donor chamber pre-incubation. Recovery <50% may suggest problems with compound solubility, stability or binding in the assay, making the results unreliable. A B = 66 × 10 -6 cm / sec BA=77×10 -6 cm / sec BA / AB emission ratio=1.2

[0069] Example D: Solubility Data (Example 1) Water-soluble (thermodynamic)-LCMS / MS method A 10 mM stock solution (in DMSO) for the test sample was prepared. From the 10 mM stock solution, a 1 μM working solution was prepared by diluting the test sample with a mobile phase solution (typically methanol:2 mM ammonium acetate with appropriate internal standard (IS)-, carbamazepine / other appropriate IS-). The working solution was also serially diluted (up to 5-6 linearity points) with the mobile phase solution to prepare standard solutions for plotting the calibration curve. The area for each standard sample was analyzed with LCMS / MS in a single line. The normalized area values ​​were plotted against the concentration to obtain a calibration equation for determining unknown samples. To confirm the hydrothermodynamic (TD) solubility of the test compound, 1 mg (powdered) of the compound was added to 1 mL of each buffer and biorelevant medium listed in the table below to achieve a theoretical concentration equivalent to 1 mg / mL. The test compound was dispersed in the buffer using a vortex mixer.

[0070] [Table 6] The resulting solution was then kept on a RotoSpin (shaker) at 50 rpm for 4 hours for TD solubility at room temperature (25 °C). After the incubation period, the solution was filtered using a 0.45 micron PVDF syringe filter to remove the insoluble fraction of the compound. The filtrate was diluted with mobile phase and then the AUC of the diluted samples was confirmed using LCMS / MS. From the AUC of the test samples, the corresponding concentrations were calculated using a 5-6 point linearity / calibration curve. All numbers reported as μM. [Table 7]

[0071] Example E: HμREL (Example 1) HμREL human Pool™ 96-well hepatocyte co-culture plate (HμREL human Pool TM Upon arrival of the 96-well hepatic co-culture plates, the medium was immediately changed and the cells were allowed to acclimate at 37° C. for approximately 20 hours. The reaction was initiated by adding HμREL® incubation medium (serum-free) and test compounds (final substrate concentration: 1 μM; final DMSO concentration: 0.1%) to the HμREL® 96-well co-culture system (final cell number: 30,000 cells per well). The final incubation volume was 80 μL per time point. Two control compounds were included per assay. All incubations were performed alone for each test compound. Each compound was incubated for 0, 2, 6, 24, 48 and 72 hours (0, 120, 360, 1440, 2880 and 4320 minutes). At the appropriate time points, the reaction was stopped by transferring 60 μL of the incubation to 180 μL acetonitrile containing an internal standard. The termination plate was centrifuged at 3000 rpm for 20 minutes at 4° C. to precipitate any remaining protein. quantitative analysis After protein precipitation, sample supernatants were pooled into cassettes of up to four compounds and analyzed using Cyprotex generic LC-MS / MS conditions. Data analysis The slope of the line was determined from a plot of the ln peak area ratio (compound peak area / internal standard peak area) versus time. The following equation was then used: Elimination rate constant (k) = (-slope) TIFF2024504252000044.tif10166 TIFF2024504252000045.tif10166 (where V = incubation volume (μL) / cell number) CL int <0.143μL / min / million Using the half-life (t 1 / 2 ) and intrinsic clearance (CL int ) was calculated.

[0072] Example F: Predicted Target Engagement for Human Effective Dose (Example 1) The expected requirement for observing efficacy of M1 agonists in humans is the EC 50 Example 1 is predicted to achieve the unbound brain exposure required for M1 agonist efficacy at a dose of approximately 22 mg, with a predicted human half-life of 15 hours (Figure 1). Parameters used to predict receptor occupancy (target engagement) MW=429.48 M1pEC 50 =7.17 Fu=0.682 Kpuu=1 Half-life (estimated) = 15 hours F=0.61 Cl=4.4mL / min / kg V = 5.9 mL / min / kg Ka=1 Definition: fu - percentage of unbound compound in plasma or brain tissue homogenate F-bioavailability; % of dose that reaches systemic circulation (plasma) Kp,uu - ratio of unbound brain concentration / unbound plasma concentration. Quantifying the net flux of drug across the blood-brain barrier (not confounded by non-specific binding in plasma and brain tissue, including the quantitative role of transporters) Gupta et al, DMD, 2006; Hammarlund-Udenaes et al, PharmRes, 2008

[0073] Example G: Attenuation of subchronic PCP-induced deficits in an operant reversal learning task in female Lister hooded rats (Example 1) Objectives and Results The ability of Example 1 (1, 3, 10 and 30 mg / kg, po, 1 hour pretreatment time, ptt) to attenuate disruptions in cognitive tasks induced by subchronic treatment with phencyclidine (scPCP) in female Lister hooded rats was examined. The percentage of correct responses in the reversal phase of the task was significantly (P<0.01) decreased in the scPCP group compared to vehicle (Figure 2). In the reversal phase, treatment with Example 1 at the lowest dose and the two intermediate doses (1, 3 and 10 mg / kg) significantly (P<0.05, P<0.05 and P<0.01, respectively) increased the percentage of correct responses compared to the scPCP group (Figure 2). Materials and Methods Female Lister hooded rats were used in this experiment. The average weight of the rats at the time of testing was 294 g ± 29 g. The rats were housed in groups of 3-5 under standard laboratory conditions with a 12-hour light-dark cycle (lights on at 07:00) and food restricted to 90% of their free-feeding body weight (12 g food per rat per day). Testing was performed during the light phase. Rats were randomly assigned to two treatment groups and received vehicle, n = 8 (0.9% saline solution, ip) or PCP, n = 48 (2 mg / kg, ip, twice daily for 7 days). On the day of testing, rats were randomly assigned to seven treatment groups (n = 6-8 per group) and received acute treatment with Example 1 (1, 3, 10 and 30 mg / kg, po, 1 h, ptt) or vehicle. Example 1 was dissolved in 1% methylcellulose and administered orally (po) at a volume of 5 mL / kg 1 hour before testing. The study was conducted in accordance with the Animals Scientific Procedures Act (UK, 1986) and was approved by AWERB (Animal Welfare and Ethical Review Body) of the University of Manchester.

[0074] Test procedure After acclimation to the operant chamber, rats were trained to respond for food on a fixed ratio 1 (FR1) schedule of reinforcement with both levers active. When responding was stable, rats were trained to press either the left or right lever for food reward, but the active lever was alternated between days. Each session lasted 20 min, and counts for each lever were recorded. Rats were then further trained to respond for food based on the location of a visual cue (illuminated LED). Half were trained to press the lever under the illuminated LED to receive a food reward, and the other half were trained on the reversed contingency (lever pressing under the unlit LED). The test session ended after a total of 128 lever presses and took approximately 30 min. Rats were then trained again until they reached criterion on the reversed contingency. The day before each reversal learning task session, a full 30 min operant training session (as described above) was conducted to ensure stable responding. For the reversal learning task, animals were first exposed to a 5 min period during which the contingency (location of the cue relative to the active lever) was the same as in the operant training session. During this period, responses on both the correct and incorrect levers were recorded. This part of the session is called the initial phase. During the next 5 min, the contingency was reversed. Responses made on the correct and incorrect levers were recorded again. This second period is called the reversal phase. At this stage, training was terminated and rats were treated with PCP (2 mg / kg, ip) or vehicle (0.9% saline, ip) for 7 days, followed by a washout period of at least 7 days. Rats were randomized so that all rats contained in a cage received different drug treatments.

[0075] Data are expressed as percentage of correct responses (± SEM), and values ​​for the initial and reversal phases are presented for different drug treatment groups (Figure 2). The percentage of correct responses data was used to determine whether drugs significantly affected response accuracy (e.g., may reflect cognitive impairment). Statistical significance was estimated when P<0.05 and was determined using one-way ANOVA to detect the main effect of drug treatment in the initial and reversal phases. The total number of lever presses recorded during both the initial and reversal phases was not significantly different after treatment with either vehicle or Example 1 (Table 2), confirming the absence of non-specific effects on general responding in this study. Table 2. Effects of acute treatment with Example 1 (1.0, 3.0, 10.0 & 30.0 mg / kg, po) in scPCP-treated rats (2 mg / kg, ip, twice daily for 7 days followed by a washout period of at least 7 days) on general performance in the reversal learning task. Data are expressed as the mean total number of lever presses during the initial and reversal phases of the reversal learning task (± SEM (n=6-9)). [Table 8] [Brief description of the drawings]

[0076] [Figure 1] Figure 1 shows predicted target engagement for the effective dose of Example 1 from allometric scaling across mouse, rat, dog and monkey species after oral dosing. Data is shown as a function of calculated % target engagement of the M1 receptor, where 50% corresponds to an unbound exposure equivalent to recombinant human EC50 (86 nM or 28 ng / mL). Based on the measured equivalent unbound plasma:brain distribution profile (Kpuu=1), the exposure shown represents either the plasma or brain compartment. [Diagram 2] FIG. 2 shows the effect of acute treatment with Example 1 (1.0, 3.0, 10.0 & 30.0 mg / kg, po) on performance in a reversal learning task in scPCP-treated rats (2 mg / kg, ip, twice daily for 7 days, followed by at least 7 days of washout). Data are presented as mean correct responding % ± SEM (n=6-9). The dashed line separates the initial (left) and reversal (right) phases of the task. Data were analyzed by one-way ANOVA followed by LSD test. ***P<0.001; correct responding % in the reversal phase of the task was significantly decreased compared to the sc saline + vehicle group. #P<0.05;##P=0.01;###P<0.001; correct responding % in the reversal phase of the task was significantly increased compared to the scPCP + vehicle group.

[0077] Equivalent The foregoing examples are given for the purpose of illustrating the present invention and should not be construed as imposing any limitations on the scope of the present invention. It will be readily apparent that many modifications and variations can be made to the specific embodiments of the present invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and variations are intended to be embraced by this application.

Claims

1. Formula (1): 【Chemistry 1】 （１） or a salt thereof.

2. Formula (2): 【Chemistry 2】 （２） The compound according to claim 1 or a salt thereof,

3. A salt of the compound according to claim 1 or 2.

4. A pharma- ceutically acceptable salt of the compound of claim 1 or 2.

5. 3. An acid addition salt of the compound according to claim 1 or 2.

6. 3. The hydrochloride salt of a compound according to claim 1 or 2.

7. 3. A monohydrochloride salt of the compound according to claim 1 or 2.

8. Formula (2b): 【Chemistry 3】 (2b) The compound of claim 1 ,

9. Formula (2c): 【Chemistry 4】 (2c) The compound of claim 1 ,

10. 10. A pharmaceutical composition comprising a compound according to claim 1, 2, 8 or 9, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

11. 10. A muscarinic M1 and M4 receptor agonist comprising a compound according to claim 1, 2, 8 or 9, or a pharma- ceutically acceptable salt thereof.

12. 11. A pharmaceutical composition according to claim 10 for use in treating a cognitive or psychiatric disorder, or for treating or reducing the severity of acute, chronic, neuropathic or inflammatory pain.

13. The pharmaceutical composition of claim 12, wherein the disorder is Alzheimer's disease.

14. 13. The pharmaceutical composition of claim 12, wherein the disorder is dementia with Lewy bodies.

15. The pharmaceutical composition of claim 12, wherein the disorder is schizophrenia.

Images