HK1234408A - Muscarinic m1 receptor agonists - Google Patents

Description

Muscarinic M1 receptor agonists

The application is a divisional application of the application with the application number of 201280066372.3, the application date of 2012, 11, 16 and the title of 'pharmaceutical compound'.

The present invention relates to compounds that are agonists of the muscarinic M1 receptor and that are useful in the treatment of muscarinic M1 receptor mediated diseases. Also provided are pharmaceutical compositions containing these compounds and therapeutic uses of these compounds.

Background

Muscarinic activityAcetylcholine receptors (machrs) are members of the G protein-coupled receptor superfamily that mediate the role of the neurotransmitter acetylcholine in the central and peripheral nervous systems. 5 mAChR subtypes, M, have been cloned₁To M₅。M₁machrs are predominantly expressed postsynaptic in the cortex, hippocampus, striatum, and thalamus; m₂machrs are predominantly located in the brainstem and thalamus, but also in the cortex, hippocampus and striatum, where they are located on cholinergic synaptic terminals (Langmead et al, 2008 Br J Pharmacol (uk. journal of pharmacology)). However, M₂machrs are also expressed peripherally on cardiac tissue (where they mediate the vagal innervations of the heart) as well as in smooth muscle and exocrine glands. M₃machrs are expressed at relatively low levels in the CNS, but are widely expressed in smooth muscle and glandular tissues such as sweat and salivary glands (lamide et al, 2008, uk journal of pharmacology).

Muscarinic receptors, particularly M, in the central nervous system₁machrs, play a crucial role in mediating higher cognitive processes. Diseases associated with cognitive impairment, such as alzheimer's disease, are accompanied by loss of cholinergic neurons in the basal forebrain (Whitehouse et al, 1982 Science). In schizophrenia, which also has cognitive impairment as an important component of clinical manifestations, mAChR density is reduced in the prefrontal cortex, hippocampus and caudate putamen of schizophrenic subjects (Dean et al, 2002 Mol psychopath). In addition, in animal models, blockade or impairment of the central cholinergic pathway leads to severe cognitive deficits and non-selective mAChR antagonists have been shown to induce psychomimetic effects in psychiatric patients. Cholinergic replacement therapy is mainly based on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have been shown to show efficacy in clinical trials for symptomatic cognitive decline, but result from stimulation of peripheral M₂And M₃Dose-limiting adverse events caused by machrs, including gastrointestinal motility disorders, bradycardia, nausea and vomiting (http://www.drugs.com/pro/donepezil.html；http://www.drugs.com/ pro/rivastigmine.html)。

Other search efforts have been directed to authentication M₁mAChR direct agonists, aimed at causing selective improvement in cognitive function, with a favorable spectrum of adverse effects. Such work has led to the identification of a series of agonists exemplified by compounds such as xanomeline, AF267B, sabcomeline, melammeline (milameline) and cevimeline (cevimeline). Many of these compounds have been shown to be highly effective within preclinical cognitive models in rodents and/or non-human primates. Melammerine has shown efficacy in rodents against scopolamine-induced working and spatial memory deficits; sabcomeline demonstrated efficacy in the visual object discrimination task in marmosets and xanomeline reversed mAChR antagonist-induced cognitive performance deficits in a passive avoidance paradigm.

Alzheimer's Disease (AD) is the most common neurodegenerative disease affecting the elderly (twenty-six hundred and sixty thousand people worldwide in 2006), leading to severe memory loss and cognitive dysfunction. The etiology of the disease is complex, but is characterized by two hallmark brain pathologies: amyloid plaque aggregates consisting mainly of amyloid- β (a β) peptide and neurofibrillary tangles formed by hyperphosphorylated tau protein. A β accumulation is thought to be a central feature in AD progression, and thus, many putative therapies for treating AD currently target inhibition of a β production. A β results from proteolytic cleavage of membrane-bound Amyloid Precursor Protein (APP). APP is processed in two ways: non-amyloidogenic pathways and amyloidogenic pathways. Cleavage of APP by gamma-secretase is common to both pathways, but in the non-starch-like protein production pathway, APP is cleaved by alpha-secretase to produce soluble APP alpha. However, in the amyloidogenic pathway, APP is cleaved by β -secretase to produce soluble APP β and also a β. In vitro studies have shown that mAChR agonists can promote soluble processing of APP (non-amyloidogenic pathway). In vivo studies showed that mAChR agonists (AF267B) alter disease-like pathology in 3xTgAD ad transgenic mice (a different component model of alzheimer's disease) (Caccamo (camaro) et al, 2006 Neuron). It has been shown that the mAChR agonist cevimeline causes a small but significant reduction in Α β cerebrospinal fluid levels in alzheimer patients and thus shows potential disease-modifying efficacy (Nitsch et al, 2000 Neurol).

Preclinical studies have suggested that mAChR agonists display an atypical antipsychotic-like profile in a range of preclinical paradigms. mAChR agonists (xanomeline) reverse dopamine-mediated diverse behaviors including amphetamine-induced locomotion in rats, apomorphine-induced climbing in mice, dopamine agonist-driven turnover in unilateral 6-OH-DA injured rats, and amphetamine-induced motor instability in monkeys (in the absence of EPS liability). It has also been shown to inhibit a10 but not a9, dopamine cell discharge and conditioned avoidance, and to induce c-fos expression in the prefrontal cortex and nucleus accumbens but not in the striatum in rats. These data all suggest an atypical antipsychotic-like profile (Mirza et al, 1999 CNS Drug Rev (central nervous system Drug review)).

Xanomeline, sabcomeline, melammeline and cevimeline have all advanced to various stages of clinical development for the treatment of alzheimer's disease and/or schizophrenia. Phase II clinical studies on xanomeline demonstrate its efficacy against a range of cognitive symptoms, including behavioral disturbances and hallucinations associated with alzheimer's disease (Bodick et al, 1997 Arch Neurol). This compound was also evaluated in a small phase II study of schizophrenic patients and produced a significant reduction in positive and negative symptoms when compared to placebo controls (Shekhar et al, 2008 Am J Psych (journal of neurology usa)). However, xanomeline and other related mAChR agonists have shown unacceptable safety margins in all clinical studies with respect to cholinergic adverse events including nausea, gastrointestinal pain, diarrhea (diahorrrhea), profuse sweating (hyperhidrosis), salivation (hypersalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral neuropathic pain. Pain can be divided into three distinct types: acute, inflammatory and neuropathic. Acute pain plays an important protective role in maintaining biosafety from stimuli that may cause tissue damage; however, post-operative pain needs to be managed.

Inflammatory pain can occur for a number of reasons, including tissue damage, autoimmune reactions and pathogen invasion, and is triggered by the action of inflammatory mediators (such as neuropeptides and prostaglandins) that cause neuronal inflammation and pain. Neuropathic pain is associated with abnormal painful sensations to non-painful stimuli. Neuropathic pain is associated with many different diseases/wounds such as spinal cord injury, multiple sclerosis, diabetes (diabetic neuropathy), viral infections (e.g. HIV or herpes). It is also common in cancer, due to disease or chemotherapy side effects. Activation of muscarinic receptors has been shown to be analgesic in many pain states by activating receptors in the spinal cord and higher pain centers in the brain. Direct activation of muscarinic receptors with agonists or allosteric modulators by increasing endogenous acetylcholine levels via acetylcholinesterase inhibitors has been shown to have analgesic activity. In contrast, blocking muscarinic receptors with antagonists or using knockout mice increases pain sensitivity. Evidence for the role of the M1 receptor in pain is reviewed by d.f. fiorino (d.f. feolino) and m.garcia-Guzman (m.gaxia-gusman), 2012.

Recently, a few compounds have been identified which are directed against M₁The mAChR subtype shows improved selectivity over the peripherally expressed mAChR subtype (Bridges (brigs et al, 2008 Bioorg Med Chem Lett (bio-organic and medicinal chemical communication); Johnson (Johnson) et al, 2010 bio-organic and medicinal chemical communication; Budzik (bartz) et al, 2010 ACS Med ChemLett (ACS medicinal chemical communication)). Albeit for M₃The level of selectivity of the mAChR subtype is increased, but some of these compounds are directed to this subtype and M₂The mAChR subtypes retain significant agonist activity. Here we describe a series of compounds which are unexpectedly directed against M₁mAChR showed more than M₂And M₃High levels of selectivity for receptor subtypes.

Brief description of the invention

The present invention provides compounds that are active as muscarinic M1 receptor agonists. More specifically, the present invention provides compounds that exhibit M1 receptor selectivity relative to the M2, M3, and M4 receptor subtypes. Thus, in a first embodiment (example 1.1), the present invention provides a compound of formula (1):

or a salt thereof, wherein:

n is 1 or 2;

p is 0, 1 or 2;

q is 0, 1 or 2;

R¹is C_1-10A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by heteroatoms selected from O, N and S, and oxidised forms thereof;

R²is hydrogen or C_1-10A non-aromatic hydrocarbon group;

or R¹And R²Non-aromatic heterocyclyl forming a 4 to 9 membered ring together with the nitrogen atom to which they are attached, wherein the heterocyclyl may optionally contain a second heteroatom selected from O, N and S and oxidised forms thereof; and wherein the heterocyclic ring may optionally be selected from C_1-2An alkyl group; 1 to 6 more substituents of fluoro and cyano;

R³selected from hydrogen; halogen; a cyano group; a hydroxyl group; c_1-3An alkoxy group; and C_1-5Non-aromatic hydrocarbon radicals optionally substituted with 1 to 6 fluorine atoms and in which 1 or 2 but not all carbon atoms of the hydrocarbon radical may optionally be substituted by radicals selected fromO, N and a heteroatom substitution of S;

R⁴is C_1-6A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by heteroatoms selected from O, N and S, and oxidised forms thereof;

R⁵is absent or is fluorine; and is

R⁶Either absent or fluorine.

The present application provides the following:

item 1. a compound of formula (1):

or a salt thereof, wherein:

n is 1 or 2;

p is 0, 1 or 2;

q is 0, 1 or 2;

R¹is C_1-10A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by heteroatoms selected from O, N and S, and oxidised forms thereof;

R²is hydrogen or C_1-10A non-aromatic hydrocarbon group;

or R¹And R²Non-aromatic heterocyclyl forming a 4 to 9 membered ring together with the nitrogen atom to which they are attached, wherein the heterocyclyl may optionally contain a second heteroatom selected from O, N and S and oxidised forms thereof; and wherein the heterocyclic ring may optionally be selected from C_1-2An alkyl group; 1 to 6 more substituents of fluoro and cyano;

R³selected from hydrogen;halogen; a cyano group; a hydroxyl group; c_1-3An alkoxy group; and C_1-5A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by a heteroatom selected from O, N and S;

R⁴is C_1-6A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by heteroatoms selected from O, N and S, and oxidised forms thereof;

R⁵is absent or is fluorine; and is

R⁶Either absent or fluorine.

Item 2. the compound of item 1, wherein n is 2.

Item 3. the compound of item 1 or item 2, wherein R¹Selected from:

c optionally substituted with 1 to 6 fluorine atoms_1-6An alkyl group;

methoxy-C optionally substituted with 1 to 6 fluorine atoms_1-4An alkyl group;

C_1-6an alkoxy group;

C_2-6an alkenyl group;

C_2-6an alkynyl group;

c optionally substituted with 1 or 2 methyl groups_3-6A cycloalkyl group;

C_4-5cycloalkyl-CH₂-, in which C_4-5Cycloalkyl moieties optionally substituted with 1C_1-2Alkyl substituted and wherein C_4-5One carbon atom of the cycloalkyl moiety may optionally be replaced by an oxygen atom;

cyclopropyl-C_1-3An alkyl group;

a cyclopentenyl group;

an adamantyl group; and

methyl-bicyclo [2.2.2] octyl.

Item 4. the compound of any one of items 1 to 3, wherein R¹Selected from the group consisting of 2-methylpropyl, tert-butyl, 2-methylbutyl, 2-dimethylpropyl, 2-methylbut-2-yl, cyclobutylmethyl, cyclopropylmethyl, cyclopentylmethyl, isopropyl, 1-methylcyclohexyl, 1-methylcyclopentylmethyl, 2-cyclopropylpropyl, 1-methylcyclobutyl, cyclopentyl, 2, 3-dimethylbut-2-yl, 1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropyl-2-yl, cyclobutyl, 1-methylcyclocyclobutylmethyl, 1- (trifluoromethyl) cyclobutyl, 1-ethylcyclobutyl, ((s) trifluoromethyl) cyclobutyl²H₃) Methyl group (²H₆) Propyl and 2-methylpent-2-yl.

Item 5. the compound of any one of items 1 to 4, wherein R2 is selected from the group consisting of hydrogen, methyl, ethyl, and isopropyl.

Item 6. the compound of any one of items 1 to 5, wherein R3 is selected from hydrogen, fluoro, cyano, methoxy, and methyl.

Item 7. the compound of any one of items 1 to 6, wherein R4 is selected from methyl, ethyl, ethynyl, and 1-propynyl.

Item 8. the compound of any one of items 1 to 7, wherein p is 0.

Item 9. the compound of any one of items 1 to 8, wherein q is 0.

Item 10. the compound of item 1, having formula (2):

wherein R is¹、R³、R⁴R⁵、R⁶、pAnd q is as defined in any one of items 1 to 9.

Item 11. the compound of item 1, having formula (3):

wherein R1, R3, R4R5, R6, p and q are as defined in any one of items 1 to 9.

Item 12. the compound of items 10 or 11, wherein p is 0, q is 0 and R3 is H.

Item 13. the compound of any one of items 10 to 12, wherein R1 is selected from the group consisting of 2-methylpropyl, tert-butyl, 2-methylbutyl, 2-dimethylpropyl, 2-methylbut-2-yl, cyclobutylmethyl, cyclopropylmethyl, cyclopentylmethyl, isopropyl, 1-methylcyclohexyl, 1-methylcyclopentylmethyl, 2-cyclopropylpropyl, 1-methylcyclobutyl, cyclopentyl, 2, 3-dimethylbut-2-yl, 1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropan-2-yl, cyclobutyl, 1-methylcyclobutylmethyl, 1- (trifluoromethyl) cyclobutyl, 1-ethylcyclobutyl, (2H3) methyl (2H6) propyl and 2-methylpent-2-yl.

Item 14. the compound of item 1, wherein the compound is selected from the group consisting of compounds numbered 1-82 as shown in table 1.

Item 15. the compound of item 1, selected from:

4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

(4S) -ethyl 4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylate;

(4R) -ethyl 4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylate;

4- (4- ((1-methylcyclobutyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

(4S) -4- [4- [ (1-methylcyclobutyl) carbamoyl ] -1-piperidinyl ] azepine-1-carboxylic acid ethyl ester;

and salts thereof.

Item 16. the compound of any one of items 1 to 15, for use in medicine.

Item 17. a pharmaceutical composition comprising a compound as defined in any one of items 1 to 15 and a pharmaceutically acceptable excipient.

Item 18. the compound of any one of items 1 to 15, having muscarinic M1 receptor agonist activity.

Item 19. the invention as defined in any one of examples 1.1 to 1.70, 2.1 to 2.26, 3.1 and 4.1 to 4.3 herein.

Item 20. the compound according to items 1 to 15 for use in the treatment of a cognitive or psychiatric disorder or for the treatment or alleviation of the severity of acute, chronic, neuropathic or inflammatory pain.

Drawings

Figures 1-4 show the efficacy of the compounds of the present invention. FIGS. 1-3 relate to the passive avoidance assay described in section B. The study was performed as previously described by Foley et al, (2004) Neuropsychopharmacology. In the passive avoidance task, animals were obliterated to the paradigm by administering scopolamine (1mg/kg, i.p.) 6 hours after training. Dose ranges of 3, 10 and 30mg/kg (oral) free base were examined by oral gavage administration 90 minutes prior to the training phase. FIG. 1 shows that example 27 was found to reverse scopolamine-induced paradigm amnesia, ED, in a dose-dependent manner₅₀Approximately about 10mg/kg (oral). The effect of 30mg/kg was similar to that produced by the cholinesterase inhibitor donepezil (0.1mg/kg, i.p.) acting as a positive control.

Figure 2 shows that example 65 was found to reverse scopolamine-induced paradigm amnesia in a dose-dependent manner, with significant effects observed following acute administration of 10 and 30mg/kg (p < 0.05; Bonferroni's post hoc test). The effects at 10 and 30mg/kg were not significantly different relative to the effect produced by the cholinesterase inhibitor donepezil (0.1mg/kg, i.p.) acting as a positive control.

Figure 3 shows that example 65 was found to reverse scopolamine-induced amnesia in a dose-dependent manner, with a significant effect observed following acute administration of 10mg/kg (oral) (p < 0.05; bonafinil post-test). The effect at 10mg/kg was not significantly different compared to that produced by the cholinesterase inhibitor donepezil (0.1mg/kg, i.p.) acting as a positive control. Example 65 the combination of donepezil and donepezil did not result in loss of activity, but rather the combination had an additive effect at each dose combination as analyzed by the Mann Whitney (Mann-Whitney) u-test.

Figure 4 shows the role of example 65 in the rodent object recognition assay described in example D. Statistical analysis determined that the 10 and 30mg/kg treatments and the 3mg/kg positive control galantamine treatment of example 65 significantly improved the new object recognition memory (p <0.05) when compared to vehicle treated controls. Donepezil (0.1mg/kg) had no effect on new object identification. During the 10 minute training phase in the apparatus, the exploratory behavior of the animals was assessed. There was no difference in exploring either object or between vehicle treated controls and any drug treated groups.

Detailed Description

The present invention provides compounds that are active as muscarinic M1 receptor agonists. More specifically, the present invention provides compounds that exhibit M1 receptor selectivity relative to the M2, M3, and M4 receptor subtypes. Thus, in a first embodiment (example 1.1), the present invention provides a compound of formula (1):

or a salt thereof, wherein:

n is 1 or 2;

p is 0, 1 or 2;

q is 0, 1 or 2;

R¹is C_1-10A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by heteroatoms selected from O, N and S, and oxidised forms thereof;

R²is hydrogen or C_1-10A non-aromatic hydrocarbon group;

or R¹And R²Non-aromatic heterocyclyl forming a 4 to 9 membered ring together with the nitrogen atom to which they are attached, wherein the heterocyclyl may optionally contain a second heteroatom selected from O, N and S and oxidised forms thereof; and wherein the heterocyclic ring may optionally be selected from C_1-2An alkyl group; 1 to 6 more substituents of fluoro and cyano;

R³selected from hydrogen; halogen; a cyano group; a hydroxyl group; c_1-3An alkoxy group; and C_1-5A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by a heteroatom selected from O, N and S;

R⁴is C_1-6A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by heteroatoms selected from O, N and S, and oxidised forms thereof;

R⁵is absent or is fluorine; and is

R⁶Either absent or fluorine.

Particular and preferred compounds of formula (1) are as defined in examples 1.2 to 1.53 below:

1.2A compound according to example 1.1 wherein n is 1.

1.3A compound according to example 1.1 wherein n is 2.

A compound according to any one of embodiments 1.1 to 1.3 wherein R¹Is C_1-10A non-aromatic hydrocarbyl group optionally substituted with 1 to 6 fluorine atoms and wherein 1 or 2 but not all carbon atoms of the hydrocarbyl group may optionally be replaced by heteroatoms selected from O, N and S, and oxidised forms thereof; c_1-10The non-aromatic hydrocarbon group contains 0, 1 or 2 carbon-carbon multiple bonds.

1.5A compound according to any one of embodiments 1.1 to 1.4, wherein R¹Is selected from C_1-6An alkyl group; c_2-6An alkenyl group; c_2-6An alkynyl group; and from C_3-10Cycloalkyl or C_5-6Cycloalkenyl radicals or C containing the foregoing radicals_1-10A non-aromatic hydrocarbon group; each of said alkyl, alkenyl, alkynyl and non-aromatic hydrocarbyl groups being optionally substituted with 1 to 6 fluorine atoms; and wherein 1 or 2 but not all carbon atoms of each of the alkyl, alkenyl, alkynyl and non-aromatic hydrocarbyl groups may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof.

A compound according to any one of embodiments 1.1 to 1.5 wherein R¹Selected from:

c optionally substituted with 1 to 6 fluorine atoms_1-6An alkyl group;

methoxy-C optionally substituted with 1 to 6 fluorine atoms_1-4An alkyl group;

·C_1-6an alkoxy group;

·C_2-6an alkenyl group;

·C_2-6an alkynyl group;

c optionally substituted with 1 or 2 methyl groups_3-6A cycloalkyl group;

·C_4-5cycloalkanesradical-CH₂-, in which C_4-5Cycloalkyl moieties optionally substituted with 1C_1-2Alkyl substituted and wherein C_4-5One carbon atom of the cycloalkyl moiety may optionally be replaced by an oxygen atom;

cyclopropyl-C_1-3An alkyl group;

a cyclopentenyl group; and

methyl-bicyclo [2.2.2] octyl.

1.7 Compounds according to any of embodiments 1.1 to 1.5, wherein R¹Selected from:

c optionally substituted with 1 to 6 fluorine atoms_1-6An alkyl group;

c optionally substituted with 1 or 2 methyl groups_3-6A cycloalkyl group;

·C_4-5cycloalkyl-CH₂-, in which C_4-5Cycloalkyl moieties optionally substituted with 1C_1-2Alkyl substituted and wherein C_4-5One carbon atom of the cycloalkyl moiety may optionally be replaced by an oxygen atom;

cyclopropyl-C_1-3An alkyl group; and

methyl-bicyclo [2.2.2] octyl.

1.8A compound according to any one of embodiments 1.1 to 1.5, wherein R¹Is C optionally substituted with 1 to 6 fluorine atoms_1-6An alkyl group.

1.9 Compounds according to any of embodiments 1.1 to 1.5, wherein R¹Is C optionally substituted with 1 or 2 methyl groups_3-6A cycloalkyl group.

A compound according to any one of embodiments 1.1 to 1.5 wherein R¹Is C_4-5cycloalkyl-CH₂-, in which C_4-5Cycloalkyl moieties optionally substituted with 1C_1-2Alkyl substituted and wherein C_4-5One carbon atom of the cycloalkyl moiety may beOptionally replaced by an oxygen atom.

A compound according to any one of embodiments 1.1 to 1.5 wherein R¹Is cyclopropyl-C_1-3An alkyl group.

1.12 Compounds according to any of embodiments 1.1 to 1.5, wherein R¹Is methyl-bicyclo [2.2.2]And (4) octyl.

1.13 Compounds according to any of embodiments 1.1 to 1.5, wherein R¹Selected from the following groups a to AS:

wherein the asterisk indicates the point at which the group is attached to the amide nitrogen atom.

1.14 Compounds according to example 1.13, wherein R¹Selected from the group consisting of A, B, D, E, F, G, L, M, N, O, Q, R, T, V, W, Y, AA, AB, AC, AJ, AK, AO, AP and AR (wherein R is¹Selected from the group consisting of 2-methylpropyl, tert-butyl, 2-methylbutyl, 2-dimethylpropyl, 2-methylbut-2-yl, cyclobutylmethyl, cyclopropylmethyl, cyclopentylmethyl, isopropyl, 1-methylcyclohexyl, 1-methylcyclopentylmethyl, 2-cyclopropylpropyl, 1-methylcyclobutyl, cyclopentyl, 2, 3-dimethylbut-2-yl, 1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropyl-2-yl, cyclobutyl, 1-methylcyclocyclobutylmethyl, 1- (trifluoromethyl) cyclobutyl, 1-ethylcyclobutyl, ((s) trifluoromethyl) cyclobutyl²H₃) Methyl group (²H₆) Propyl and 2-methylpent-2-yl).

A compound according to any one of embodiments 1.1 to 1.6 wherein R¹Selected from 2-methylpropyl; 2, 2-dimethylpropyl; a tertiary butyl group; 2-methyl-but-2-yl; 2, 3-dimethylbut-2-yl; a cyclopropyl methyl group; a cyclobutylmethyl group; a cyclopentyl group; a cyclopentyl methyl group; 1-methylcyclobutyl; 1-methylcyclopentyl; 1-methylcyclohexyl group; 1-methylcyclopentyl-methyl; cyclopropyl-propan-2-yl; and 1-ethyl-cyclobutylmethyl.

1.15a Compound according to 1.14, wherein R¹Selected from the group consisting of A, F, G, O, R, T, V, W, Y, AA, AB, AJ, AO and AP (wherein R' is selected from the group consisting of 2-methylpropyl, 2-methylbut-2-yl, cyclobutylmethyl, 1-methylcyclohexyl, 2-cyclopropylpropyl, 1-methylcyclobutyl, cyclopentyl, 2, 3-dimethylbut-2-yl, 1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropyl-2-yl, 1-methylcyclobutylmethyl and 1-ethylcyclobutyl and (A), (F, G, O, R, T, V, W, Y, AA, AB, AJ, AO and AP)²H₃) Methyl group (²H₆) Propyl).

1.16 Compounds according to embodiment 1.15 or 1.15a, wherein R¹Selected from the group consisting of 2-methylpropyl and 1-methylcyclobutyl.

1.17 Compounds according to example 1.16, wherein R¹Is 2-methylpropyl.

1.18 Compounds according to example 1.16, wherein R¹Is 1-methylcyclobutyl.

A compound according to any one of embodiments 1.1 to 1.18 wherein R²Selected from hydrogen and C_1-6An alkyl group.

1.20 Compounds according to example 1.19, wherein R²Selected from hydrogen, methyl, ethyl and isopropyl.

1.21 Compounds according to example 1.20, wherein R²Is hydrogen.

A compound according to any one of embodiments 1.1 to 1.21 wherein R³Selected from hydrogen, halogen, cyano, hydroxy, C_1-3Alkoxy and C_1-4Alkyl radical。

1.23 Compounds according to example 1.22, wherein R³Selected from hydrogen, fluoro and methyl, cyano and methoxy.

1.23a Compounds according to example 1.22, wherein R³Selected from hydrogen, fluoro and methyl, cyano and methoxy, and R¹Is 1-methylcyclobutyl.

1.24 Compounds according to embodiment 1.23 or 1.23a, wherein R³Selected from hydrogen and fluorine.

1.25 Compounds according to example 1.24, wherein R³Is hydrogen.

1.26 Compounds according to example 1.24, wherein R³Is fluorine.

A compound according to any one of embodiments 1.1 to 1.26 wherein R⁴Is acyclic C_1-6A hydrocarbyl group.

1.28 Compounds according to example 1.27, wherein R⁴Is acyclic C_1-3A hydrocarbyl group.

1.29 Compounds according to example 1.20, wherein R⁴Is C_1-3Alkyl or C_2-3Alkynyl.

1.30 Compounds according to example 1.29, wherein R⁴Selected from the group consisting of methyl, ethyl, ethynyl and 1-propynyl.

1.31A compound according to example 1.30, wherein R⁴Is methyl.

A compound according to any one of embodiments 1.1 to 1.31 wherein R⁵Is fluorine.

A compound according to any one of embodiments 1.1 to 1.32 wherein p is 0 or 1.

A compound according to any one of embodiments 1.1 to 1.31 wherein p is 0.

A compound according to any one of embodiments 1.1 to 1.32 wherein p is 1.

1.36A compound according to any one of embodiments 1.1 to 1.35, wherein R⁶Is fluorine.

A compound according to any one of embodiments 1.1 to 1.36 wherein q is 0 or 1.

A compound according to any one of embodiments 1.1 to 1.35 wherein q is 0.

A compound according to any one of embodiments 1.1 to 1.36 wherein q is 1.

1.40 the compound according to example 1.1, having formula (2):

wherein R is¹、R³、R⁴、R⁵、R⁶P and q are as defined in any one of examples 1.1 and 1.3 to 1.39.

1.41A compound according to example 1.40, of formula (3):

wherein R is¹、R³、R⁴、R⁵、R⁶P and q are as defined in any one of examples 1.1 and 1.3 to 1.39.

1.42A compound according to example 1.40, of formula (4):

wherein R is¹、R³、R⁴、R⁵、R⁶P and q are as defined in any one of examples 1.1 and 1.3 to 1.39.

1.43A compound according to example 1.1, as defined in any one of examples 1 to 64.

1.43a compound according to example 1.1, as defined in any one of examples 65 to 82.

1.43b A compound according to example 1.1, as defined in any one of examples 1 to 82.

A compound according to example 1.43 selected from the compounds of examples 6, 7, 8, 9, 10, 11, 15, 16, 17, 18, 27, 30, 31, 37, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 63 and 64 and salts thereof or a compound according to example 1.43a selected from the compounds of examples 65, 66, 67, 73, 74, 75, 77, 78, 79, 80, 81 and 82 and salts thereof.

A compound according to example 1.44 which is ethyl 4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate or a salt thereof.

A compound according to example 1.45 which is ethyl (4S) -4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylate or a salt thereof.

A compound according to example 1.45 which is ethyl (4R) -4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylate or a salt thereof.

A compound according to example 1.44 which is ethyl 4- (4- ((1-methylcyclobutyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate or a salt thereof.

1.48a the compound according to example 1.48 which is ethyl (4S) -4- [4- [ (1-methylcyclobutyl) carbamoyl ] -1-piperidinyl ] azepine-1-carboxylate or a salt thereof.

1.49A compound according to any one of embodiments 1.1 to 1.48a having a molecular weight of less than 550 (e.g., less than 500 or less than 450).

A compound according to any one of embodiments 1.1 to 1.49, in salt form.

A compound according to example 1.50 wherein the salt is an acid addition salt.

A compound according to example 1.50 or example 1.51, wherein the salt is a pharmaceutically acceptable salt.

Definition of

In this application, the following definitions apply unless otherwise indicated.

The term "treatment" in relation to the use of a compound of formula (1) is used to describe any form of intervention in which the compound is administered to a subject suffering from, or at risk of possibly suffering from, the disease or condition in question. Thus, the term "treatment" covers both prophylactic (preventative) treatment and treatment in which a measurable or detectable symptom of a disease or condition is manifest.

The term "non-aromatic hydrocarbyl" (as in "C)_1-10Non-aromatic hydrocarbyl "or" acyclic C_1-5Non-aromatic hydrocarbon group) "means a group consisting of carbon atoms and hydrogen atoms and containing no aromatic ring. The hydrocarbyl group may be fully saturated or may contain one or more carbon-carbon double bonds or carbon-carbon triple bonds or a mixture of double and triple bonds. The hydrocarbon group may be a linear or branched group or may consist of or contain cyclic groups.

As used herein, the term "cycloalkyl" includes monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and bicyclic and tricyclic groups, as the case may be where the number of carbon atoms is allowed to be specified. Bicyclic cycloalkyl groups include bridged ring systems such as bicycloheptane, bicyclooctane and adamantane.

Salt (salt)

Various compounds of formula (1) may exist in the form of salts, such as acid addition salts or, in some cases, organic and inorganic bases, such as carboxylates, sulfonates and phosphates. All such salts are within the scope of the present invention and reference to a compound of formula (1) includes the salt forms of that compound as defined in examples 1.50 to 1.53.

Salts are generally acid addition salts.

Salts of the invention may be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods, such as Pharmaceutical Salts: Properties, Selection, and Use (Pharmaceutical Salts: Properties, Selection, and Use), p.heinrich Stahl (p. hainlisistahl) (eds.), camile g.wermuth (camier g. vermellaut) (eds.), ISBN:3-90639-026-8, hardcopy, page 388, 2002, 8 months. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with the appropriate base or acid in water or in an organic solvent or in a mixture of the two; typically, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is used.

Acid addition salts (as defined in example 1.51) may be formed with a wide variety of acids (inorganic and organic). Examples of acid addition salts falling within example 1.51 include mono-or di-salts formed with an acid and an acylated amino acid and a cation exchange resin, wherein the acid is selected from the group consisting of: acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+) - (1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, 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), alpha-ketoglutaric acid, glycolic acid, hippuric acid, hydrohalic acid (e.g., hydrobromic acid), Hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., (+) -L-lactic acid, (+ -) -DL-lactic acid), lactobionic acid, acetylleucine, 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, pamoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, (-) -D-tartaric acid, (-) -dibenzoyltartaric acid, Thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid.

In the case where the compounds of formula (1) contain amine functional groups, these compounds may form quaternary ammonium salts according to methods well known to the skilled person, for example by reaction with an alkylating agent. Such quaternary ammonium compounds are within the scope of formula (1).

The compounds of the invention may be present as mono-or di-salts depending on the pKa of the acid from which the salt is formed.

Salt forms of the compounds of the present invention are generally Pharmaceutically Acceptable Salts, and examples of Pharmaceutically Acceptable Salts are discussed in Berge et al, 1977, "pharmaceutical Acceptable Salts," j.pharm.sci (journal of pharmaceutical sciences), vol.66, pages 1-19. However, pharmaceutically unacceptable salts may also be prepared as intermediate forms which may subsequently be converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms which may be used, for example, for the purification or isolation of the compounds of the invention also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecular formula and order of atom bonding, but differ only in the spatial orientation of their atoms. Stereoisomers may be, for example, geometric or optical isomers.

Geometric isomers

For geometric isomers, the isomerization is due to different orientations of atoms or groups around the double bond, such as cis and trans (Z and E) isomers around a carbon-carbon double bond, or cis and trans isomers around an amide bond, or cis (syn) and trans (anti) isomers around a carbon-nitrogen double bond (e.g., in oximes), or rotational isomers around a bond where there is a restricted rotation, or cis and trans isomers around a ring such as a cycloalkane ring.

Thus, in another embodiment (example 1.53a), the invention provides a geometric isomer of a compound according to any one of examples 1.1 to 1.53.

Optical isomers

Where a compound of the formula contains one or more chiral centers and may exist in two or more optically isomeric forms, unless the context requires otherwise, reference to the compound includes all of its optically isomeric forms (e.g., enantiomers, epimers, and diastereomers), as individual optical isomers or as a mixture (e.g., a racemic mixture) of two or more optical isomers.

Thus, in another embodiment (example 1.54), the invention provides a compound containing a chiral center according to any one of examples 1.1 to 1.53.

Optical isomers can be characterized and identified by their optical activity (i.e., as the + and-isomers, or the d and l isomers) or they can be characterized in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold, and Prelog, see Advanced organic chemistry, 4 th edition, John Wiley & Sons, New York, 1992, page 109-. Optical isomers can be separated by a variety 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, optical isomers may be separated by: diastereomeric salts with chiral acids such as (+) -tartaric acid, (-) -tartaric acid, acetylleucine, (-) -pyroglutamic acid, (-) -xyloyl-L-tartaric acid, (+) -mandelic acid, (-) -malic acid and (-) -camphorsulfonic acid, separation of the enantiomers by preferential crystallization and subsequent dissociation of these salts to yield the individual enantiomers of the free base.

In the case where the compounds of the present invention exist as two or more optical isomeric forms, one enantiomer of a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in some cases, it may be desirable to use only one of a pair of enantiomers or only one of a plurality of enantiomers as a therapeutic agent.

Thus, in another embodiment (example 1.55), the invention provides a composition comprising a compound according to example 1.54 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 of example 1.54 exists as a single optical isomer (e.g., enantiomer or diastereomer).

In one general example (example 1.56), 99% or more (e.g., substantially all) of the total amount of the compound of example 1.54 (or the compound used therewith) is present as a single optical isomer.

For example, in one embodiment (example 1.57), the compound exists as a single enantiomer.

In another embodiment (example 1.58), the compound exists as a single diastereomer.

The present invention also provides mixtures of optical isomers, which may be racemic or non-racemic. Thus, the present invention provides:

1.59A compound according to example 1.54 in the form of a racemic mixture of optical isomers.

1.60A compound according to example 1.54, in the form of a non-racemic mixture of optical isomers.

Isotope of carbon monoxide

A compound of the invention as defined in any one of examples 1.1 to 1.60 may contain one or more isotopic substitutions, and reference to a particular element includes within its scope all isotopes of that element. For example, reference to hydrogen includes within its scope¹H、²H, (D) and³h (T). Similarly, references to carbon and oxygen, respectively, are included within their scope¹²C、¹³C and¹⁴c and¹⁶o and¹⁸O。

in a similar manner, reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, reference to an alkyl group such as ethyl also covers variants in which one or more hydrogen atoms in the group are in the deuterium or tritium isotope form, for example, as in ethyl (fully deuterated ethyl) in which all 5 hydrogen atoms are in the deuterium isotope form.

Isotopes may be radioactive or non-radioactive. In one embodiment of the invention (embodiment 1.61), the compound of any one of embodiments 1.1 to 1.60 is free of a radioisotope. Such compounds are preferably used for therapeutic purposes. However, in another example (example 1.62), the compound of any of examples 1.1 to 1.60 may contain one or more radioisotopes. Compounds containing such radioisotopes may be used in diagnostic settings.

Solvates

The compound of formula (1) as defined in any one of embodiments 1.1 to 1.62 may form a solvate. Preferred solvates are those formed by incorporating a non-toxic, pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid state structure (e.g., crystal structure) of the molecules of the compounds of the present invention. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates may be prepared by recrystallization of the compounds of the invention with a solvent or a solvent mixture containing a solvating solvent. Whether a solvate has formed in any given case can be determined by analyzing the crystals of the compound using well known and standard techniques such as thermogravimetric analysis (TGE), Differential Scanning Calorimetry (DSC), and X-ray crystallography. The solvate may be a stoichiometric or non-stoichiometric solvate. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrate, monohydrate, and dihydrate.

Thus, in other embodiments 1.63 and 1.64, the invention provides:

1.63A compound according to any one of embodiments 1.1 to 1.62 in the form of a solvate.

A compound according to example 1.63 wherein the solvate is a hydrate. For a more detailed discussion of solvates and methods used to generate and characterize them, see Bryn (Bling) et al, Solid-State Chemistry of drugs, 2 nd edition, SSCI, Inc of West Lafayette (West Lafaye corporation), IN, USA,1999, ISBN 0-967-.

Alternatively, the compounds of the present invention may be anhydrous, not present as hydrates. Thus, in another embodiment (example 1.65), the present invention provides a compound as defined in any one of examples 1.1 to 1.62 in anhydrous form (e.g. anhydrous crystalline form).

Crystalline and amorphous forms

The compound of any of examples 1.1 to 1.65 can exist in a crystalline or amorphous (e.g., amorphous) state. Whether a compound is present in a crystalline state can be readily determined by standard techniques such as X-ray powder diffraction (XRPD). Crystals and their crystal structures can be characterized using a variety of techniques including single crystal X-ray crystallography, X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), and infrared spectroscopy, such as fourier transform infrared spectroscopy (FTIR). The behavior of the crystals under different humidity conditions can be analyzed by gravimetric vapor absorption studies and also by XRPD. The crystal structure determination of the compound can be carried out by X-ray Crystallography, which can be carried out according to conventional methods, as described herein and as described in Fundamentals of Crystallography, c.giacrovazzo (c. gibco laozo), h.l.monaco (h.l. monanogram), d.viterbi (d. vitabo), f.scordar (f. scombria), g.gili (g. giri), g.zanoti (g. zanoti) and m.catti (m. cadi) (International Union of Crystallography/Oxford University Press), 1992ISBN 0-19-855578-4(p/b),0-19-85579-2 (p/b)). This technique involves analyzing and interpreting the X-ray diffraction of a single crystal. In amorphous solids, the three-dimensional structures normally present in the crystalline form are not present and the positions of the molecules relative to each other in the amorphous form are essentially random, see for example Hancock et al, J. Med. Sci. 1997, 86, 1).

Accordingly, in other embodiments, the invention provides:

1.66 the compound according to any one of embodiments 1.1 to 1.65 in crystalline form.

A compound according to any one of embodiments 1.1 to 1.65 which is:

(a) from 50% to 100% crystalline, and more particularly 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, for example 100% crystalline.

1.68A compound according to any one of embodiments 1.1 to 1.65, in amorphous form.

Prodrugs

A compound of formula (1) as defined in any one of embodiments 1.1 to 1.62 may be provided in prodrug form. By "prodrug" is meant, for example, any compound that is converted in vivo to a biologically active compound of formula (1) as defined in any one of examples 1.1 to 1.62.

For example, some prodrugs are esters (e.g., physiologically acceptable metabolically labile esters) of the active compound. During metabolism, the ester group (-C (═ O) OR) is cleaved to yield the active drug. Such esters may be formed, for example, by esterification of any hydroxy groups present in the parent compound, where appropriate prior protection of any other reactive groups present in the parent compound, followed by deprotection as required.

In addition, some prodrugs are activated enzymatically to yield the active compound or a compound that upon further chemical reaction yields the active compound (e.g., as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Thus, in another embodiment (embodiment 1.69), the present invention provides a prodrug of a compound as defined in any one of embodiments 1.1 to 1.62, wherein the compound contains a functional group that is convertible under physiological conditions to form a hydroxyl or amino group.

Complexes and cage compounds

Also encompassed by formula (1) in examples 1.1 to 1.69 are complexes of the compounds of examples 1.1 to 1.69 (e.g., inclusion or cage-type compounds containing the compounds such as cyclodextrins, or metal-containing complexes).

Thus, in another embodiment (example 1.70), the invention provides a compound according to any one of embodiments 1.1 to 1.69, in the form of a complex or cage compound.

Biological activity and therapeutic use

The compounds of the present invention have activity as muscarinic M1 receptor agonists. The muscarinic activity of a compound can be determined using the phospho-ERK 1/2 assay described below in example a.

A significant advantage of the compounds of the present invention is their selectivity for the M1 receptor over the M2 and M3 receptor subtypes. For example, the compounds of the invention generally have a pEC of at least 6 (preferably at least 6.5) against the M1 receptor in the functional assay described in example a₅₀Sum of values E greater than 80 (preferably greater than 100)_maxValues, however, when tested against the M2 and M3 subtypes in the functional assay of example a, they may have pEC of less than 6 (and usually less than 5)₅₀Value and E less than 50%_maxThe value is obtained. Thus, in examples 2.1 to 2.9, the invention provides:

2.1A compound for use as a medicament according to any one of embodiments 1.1 to 1.70.

2.2 a compound according to any one of embodiments 1.1 to 1.70 for use as a muscarinic M1 receptor agonist.

2.3A compound according to any one of embodiments 1.1 to 1.70, which is a muscarinic M1 receptor agonist having a pEC for the M1 receptor ranging from 6.0 to 7.9 in the assay of example A herein or a substantially similar assay₅₀And E of at least 90_max。

2.4A compound according to example 2.3 which is a muscarinic M1 receptor agonistThe agent has a pEC ranging from 6.5 to 7.5₅₀。

2.4a the compound according to example 2.3, which is a muscarinic M1 receptor agonist having a pEC ranging from 6.8 to 7.9₅₀。

2.4b the compound according to example 2.3 which is a muscarinic M1 receptor agonist having a pEC ranging from 7.1 to 7.9₅₀。

2.5 the compound according to example 2.3, example 2.4a or example 2.4b, which compound has an E of at least 100 for the M1 receptor_max。

2.6 the compound according to any one of embodiments 2.3 to 2.5, which is selective for the M1 receptor compared to the muscarinic M2 and M3 receptors.

2.7A compound according to any one of embodiments 2.3 to 2.6 having pEC less than 5 for the muscarinic M2 and M3 receptor subtypes₅₀And E less than 50_max。

2.8A compound according to example 2.7 having pEC less than 4.5 for the muscarinic M2 and M3 receptor subtypes₅₀And/or E less than 30_max。

2.9 a compound according to any one of embodiments 1.1 to 1.70 and embodiments 2.3 to 2.8 for use in the treatment of a disease or condition mediated by the muscarinic M1 receptor.

The compounds of the present invention may be used to treat alzheimer's disease, schizophrenia and other psychotic disorders, cognitive disorders, and other diseases mediated by the muscarinic M1 receptor by virtue of their muscarinic M1 receptor agonist activity.

Thus, in examples 2.10 to 2.13, the present invention provides:

a compound for use in the treatment of a cognitive or psychiatric disorder according to any one of embodiments 1.1 to 1.70.

2.11 a compound for use according to example 2.10, wherein the cognitive or mental disorder comprises, results from or is associated with a condition selected from: cognitive impairment, mild cognitive impairment, frontotemporal dementia, vascular dementia, dementia with lewy bodies, presenile dementia, senile dementia, Friederich's ataxia, down's syndrome, huntington's chorea, hyperkinesias, mania, Tourette's syndrome, alzheimer's disease, progressive supranuclear palsy, impaired cognitive function including attention, orientation, learning disorders, memory (i.e., memory disorders, amnesia, amnesic disorders, transient total amnesic syndrome and age-related memory impairment) and impaired speech function; cognitive impairment due to stroke, huntington's disease, Pick's disease, AIDS-related dementia or other dementing conditions such as multi-infarct dementia, alcoholism dementia, dementia associated with hypothyroidism and dementia associated with other degenerative diseases such as cerebellar atrophy and amyotrophic lateral sclerosis; other acute or subacute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states), trauma, head trauma, age-related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, age-related cognitive impairment, autism-related cognitive impairment, down syndrome, cognitive deficits and related psychosis, and related cognitive disorders following electroconvulsive therapy; cognitive disorders due to drug abuse or withdrawal including nicotine, cannabis, amphetamines, cocaine, Attention Deficit Hyperactivity Disorder (ADHD) and movement disorders such as parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesia, schizophrenia, schizophreniform disorder, psychotic depression, mania, acute mania, paranoid, hallucinogenic and delusional disorders, personality disorders, obsessive compulsive disorders, schizotypal disorders, delusional disorders, psychosis due to malignancy, metabolic disorders, endocrine disorders or narcolepsy, psychosis due to drug abuse or withdrawal, bipolar disorders and schizoaffective disorders.

A compound for use in the treatment of alzheimer's disease according to any of embodiments 1.1 to 1.70.

A compound for use in the treatment of schizophrenia according to any one of embodiments 1.1 to 1.70.

2.14A 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 such treatment) which comprises administering a therapeutically effective dose of a compound according to any one of embodiments 1.1 to 1.70.

2.15 the method according to example 2.14, wherein the cognitive disorder comprises, results from or is associated with a condition as defined in example 2.11.

2.16 the method according to example 2.15, wherein the cognitive disorder results from or is associated with alzheimer's disease.

2.17 the method according to example 2.16, wherein the cognitive disorder is schizophrenia.

2.18 use of a compound according to any one of embodiments 1.1 to 1.70 for the manufacture of a medicament for the treatment of cognitive disorders.

2.19 the use according to example 2.10, wherein the cognitive disorder comprises, results from or is associated with a condition as defined in example 2.11.

2.20 the use according to example 2.19, wherein the cognitive disorder results from or is associated with alzheimer's disease.

2.21 the use according to example 2.19, wherein the cognitive disorder is schizophrenia.

A compound according to any one of embodiments 1.1 to 1.70 for use in treating or ameliorating the severity of: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, systemic neuralgia, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain.

2.23A method of treating or lessening the severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain, comprising administering a therapeutically effective dose of a compound according to any one of examples 1.1 to 1.70.

2.24A compound according to any one of embodiments 1.1 to 1.70 for use in the treatment of peripheral diseases such as lowering intraocular pressure in glaucoma and the treatment of dry eye and dry mouth, including the sjogren's syndrome.

2.25A method of reducing intraocular pressure and treating dry eye and dry mouth (including sjogren's syndrome) in the treatment of peripheral disorders such as glaucoma, which comprises administering a therapeutically effective dose of a compound according to any one of examples 1.1 to 1.70.

2.26 the use of a compound according to any one of embodiments 1.1 to 1.70 for the manufacture of a medicament for the treatment or lessening the severity of: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, systemic neuralgia, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain, or for the treatment of peripheral diseases, such as lowering intraocular pressure in glaucoma and the treatment of dry eye and dry mouth, including sjogren's syndrome.

For preparing a compound of the formula1) Method of preparing a compound of (1)

The compounds of formula (1) may be prepared according to synthetic methods well known to the skilled person and as described herein.

Thus, in another embodiment (embodiment 3.1), the present invention provides a method of preparing a compound as defined in any one of embodiments 1.1 to 1.70, the method comprising:

(A) reacting a compound of formula (10)

Wherein R is³，R⁴，R⁵And R⁶As defined in any of examples 1.1 to 1.70, and having the formula R¹R²Reacting a compound of NH under amide forming conditions; or

(B) Reacting a compound of formula (11)

With a compound of formula Cl-C (═ O) O-CH₂-R⁴In the presence of a base;

and optionally:

(C) converting one compound of formula (1) into another compound of formula (1).

In process variant (a), the reaction can be carried out in the presence of reagents of the type which are frequently used for the formation of amide bonds. Examples of such reagents include 1, 3-Dicyclohexylcarbodiimide (DCC) (Sheehan et al, J.Amer.ChemSoc. (American society for chemical sciences)) 1955,771067), 1-ethyl-3- (3' -dimethylaminopropyl) -carbodiimide (referred to herein as EDC or EDAC) (Schen et alJ. org. chem. (J.org. chem., 1961,26,2525), uronium-based coupling agents such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and phosphonium-based coupling agents such as 1-benzo-triazolyloxytris- (pyrrolidine) phosphonium hexafluorophosphate (PyBOP) (Castro (Calc.) et al, Tetrahedron Letters, 1990,31,205). Carbodiimide-based coupling agents are advantageously used with 1-hydroxy-7-azabenzotriazole (HOAt) (l.a. carpino (l.a. carpinuo), j.amer.chem.soc (american society of chemistry), 1993,1154397) or 1-hydroxybenzotriazole (HOBt) (Konig et al, chem. Ber (German chemical), 103,708, 2024-. The preferred amide coupling agent is HATU.

The coupling reaction is typically carried out in a non-aqueous, aprotic solvent such as acetonitrile, dioxane, dimethylsulfoxide, dichloromethane, dimethylformamide or N-methylpyrrolidone, or in an aqueous solvent, optionally with one or more miscible co-solvents. The reaction may be carried out at room temperature or where the reactants are less reactive at a suitably elevated temperature, for example up to about 100 ℃, for example 50-80 ℃. The reaction may optionally be carried out in the presence of a non-interfering base, for example a tertiary amine such as triethylamine or N, N-diisopropylethylamine.

Alternatively, reactive derivatives of carboxylic acids, such as anhydrides or acid chlorides, may be used. Acid chlorides are generally reacted with a compound of formula R¹R²The compound of NH is reacted in the presence of a base such as sodium bicarbonate or sodium hydroxide. The acid chloride can be prepared using standard methods, for example by treating the acid with oxalyl chloride in the presence of catalytic amounts of dimethylformamide.

Process variant (B) is generally carried out in the presence of a non-interfering base such as triethylamine in an aprotic solvent such as dichloromethane or dichloroethane. The reaction can be carried out at room temperature.

The intermediate compound of formula (10) may be prepared by a series of reactions shown in scheme 1 below.

Scheme 1

In scheme 1, piperidine carboxylic acid (12) is reacted with substituted ketone (13) under reductive amination conditions. The reductive amination reaction is generally carried out using mild heating (e.g., to a temperature of about 40 ℃ to about 7 ℃) using a borohydride reducing agent such as triacetoxy-sodium borohydride in a solvent containing acetic acid such as dichloromethane or dichloroethane. In an alternative series of reactions, an ester (e.g., ethyl ester) of piperidinecarboxylic acid (12) is reacted with piperidone (13) in the presence of sodium cyanoborohydride in combination with zinc chloride or sodium triacetoxyborohydride in combination with titanium isopropoxide to produce an intermediate ester compound (not shown), which is then selectively hydrolyzed under mild conditions using lithium hydroxide or sodium hydroxide to produce compound (10). The compound of formula (11) can be prepared by a series of reactions shown in scheme 2 below.

Scheme 2

In scheme 2, piperidine ester (14, R ═ ethyl) is reacted with ketone (15) under reductive amination conditions of the type described above to produce an intermediate ester (not shown), which is then selectively hydrolyzed using lithium hydroxide to produce carboxylic acid (16). Carboxylic acid (16) followed by reaction with amine HNR¹R²Under amide forming conditions (see above) to yield an intermediate amide compound (not shown) which is subsequently deprotected by removal of the Boc group by treatment with an acid (e.g. trifluoroacetic acid in dichloromethane) to yield compound (11).

In formula (1) and the formulae shown in reaction schemes 1 and 2 above, when "n" is 2, the right-hand heterocycle is an azepine ring and the chiral center may be present at the carbon atom of the azepine ring attached to the piperidine ring. While individual optical isomers can be isolated and purified by standard methods at the end of the reaction series, it is also possible to prepare compounds of formula (1) wherein n is 2 having the desired stereochemistry at a chiral carbon atom by using chiral intermediates of formula (16).

A synthetic route is illustrated below in scheme 3, which provides that wherein n is 2 and R⁵Absent is a chiral intermediate compound of formula (16).

Scheme 3

The starting material for the reaction series shown in scheme 3 is a protected (4S) -4-aminoazepine derivative (17) in which the ring nitrogen of the azepine is protected with a Boc group and the 4-amino moiety is protected as (1R) -1-phenylethylamino group. The first step of the reaction series involves the removal of the phenethylamine protecting group using palladium hydroxide on carbon and ammonium formate in methanol with heating to produce 4-aminoacazepine (18). 4-aminoacazepine (18) is then reacted under reductive amination conditions as described above (e.g. using sodium triacetoxyborohydride) with a dialdehyde (20) which may be generated in situ by subjecting methyl cyclopent-3-ene-1-carboxylate to ozonolysis to give piperidinyl-azepine (21). Hydrolysis of the piperidinecarboxylic acid ester group with sodium hydroxide gives the (S) optical isomer of N-protected-azepinyl-piperidinecarboxylic acid (16).

To produce the corresponding (R) optical isomer of compound (16), the corresponding (4R) -4-aminoacazepine isomer of compound (17) can be used as a starting material.

Once formed, one compound of formula (1), or a protected derivative thereof, may be converted to another compound of formula (1) by methods well known to the skilled artisan. Examples of synthetic methods for converting one functional group to another are described in standard texts such as Advanced Organic Chemistry and Organic syntheses (see references above) or Fiesers' Reagents for Organic Synthesis (Fisher reagent for Organic Synthesis) edited by Mary Fieser (Mary Fisher), Vol.1-17, John Wiley (John Willi publishers Inc.), (ISBN: 0-471) -582.

In many of the reactions described above, it may be desirable to protect one or more groups to prevent the reaction from occurring at an unwanted location on the molecule. Examples of protecting Groups and methods for protecting and deprotecting functional Groups can be found in Protective Groups in Organic Synthesis (T.Greene (T. Green) and P.Wuts (P. Wooz); 3 rd edition; John Wiley and Sons (John Willi-father, Inc.), 1999).

The compounds produced by the foregoing methods may be isolated and purified by any of a variety of methods well known to those skilled in the art, and examples of such methods include recrystallization and chromatographic techniques such as column chromatography (e.g., flash chromatography) and HPLC.

Pharmaceutical formulations

Although the active compound may be administered alone, it is preferably presented as a pharmaceutical composition (e.g., formulation).

Thus, in another embodiment of the present invention (embodiment 4.1), there is provided a pharmaceutical composition comprising at least one compound of formula (1) as defined in any one of embodiments 1.1 to 1.70 together with at least one pharmaceutically acceptable excipient.

In one embodiment (example 4.2), the composition is a tablet composition.

In another embodiment (example 4.3), the composition is a capsule composition.

The pharmaceutically acceptable excipient or excipients may for example be selected from carriers (e.g. solid, liquid or semi-solid carriers), adjuvants, diluents (e.g. solid diluents such as fillers or extenders; and liquid diluents such as solvents and co-solvents), granulating agents, binders, glidants, coating agents, controlled release agents (e.g. delayed or delayed release polymers or waxes), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity adjusting agents, thickening agents, taste enhancers, sweeteners, pigments, plasticizers, taste masking agents, stabilizers or any other excipient conventionally used in pharmaceutical compositions.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissue of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, 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 compounds of formula (1) may be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences), Mack Publishing Company (mark Publishing Company), Easton (Easton), PA, USA.

The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets (caplets), pills, lozenges (lozenes), syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

Tablet compositions may contain a unit dose of the active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, for example; lactose, sucrose, sorbitol, or mannitol; and/or non-sugar derived diluents such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or derivatives thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose and starches such as corn starch. Tablets may also contain such standard ingredients as binders and granulating agents, for example, polyvinylpyrrolidone, disintegrating agents (e.g. swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (e.g. phosphate esters or citrate buffers) and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and need not be discussed in detail herein.

Tablets may be designed to release the drug on contact with gastric fluid (immediate release tablets) or in a controlled manner over an extended period of time or in a specific region of the gastrointestinal tract (controlled release tablets).

Pharmaceutical compositions generally comprise from about 1% (w/w) to about 95%, preferably (w/w), of the active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (e.g., as defined above) or a combination of such excipients. Preferably, the composition comprises from about 20% (w/w) to about 90% (w/w) of the active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient. The pharmaceutical compositions of the invention may, for example, be in unit dosage form, such as in the form of ampoules, vials, suppositories, pre-filled injections, dragees, powders, tablets or capsules.

Tablets and capsules may for example contain 0-20% disintegrant, 0-5% lubricant, 0-5% glidant and/or 0-99% (w/w) filler/or filler (depending on the drug dose). They may also contain 0-10% (w/w) of a polymeric binder, 0-5% (w/w) of an antioxidant, 0-5% (w/w) of a pigment. Sustained release tablets will typically additionally contain 0-99% (w/w) of a controlled release (e.g. delayed release) polymer (depending on the dose). The film coating of tablets or capsules generally contains 0-10% (w/w) polymer, 0-3% (w/w) pigment 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 the dose and if freeze-dried). Formulations for intramuscular depot may also contain 0-99% (w/w) oil.

The pharmaceutical formulations may be presented to the patient in a single package (usually a blister pack) containing a "patient pack" that completes the complete course of treatment.

The compound of formula (1) will generally be presented in unit dosage form and, therefore, will generally contain sufficient compound to provide the desired level of biological activity. For example, the formulation may contain from 1 nanogram to 2 grams of active ingredient, for example from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular subranges of the compounds are from 0.1 to 2 grams of the active ingredient (more typically from 10 to 1 gram, e.g., 50 to 500 milligrams), or from 1 microgram to 20 milligrams (e.g., 1 microgram to 10 milligrams, e.g., 0.1 to 2 milligrams of the active ingredient).

For oral compositions, the unit dosage form may contain from 1mg to 2g, more typically 10mg to 1g, for example 50mg to 1g, for example 100mg to 1g, of the active compound.

The active compound will be administered to a patient (e.g., a human or animal patient) in need thereof in an amount (effective amount) sufficient to achieve the desired therapeutic effect. The precise amount of the compound to be administered can be determined by a supervising physician according to standard methods.

Examples of the invention

The invention will be illustrated, but not limited, by reference to the specific embodiments described in the following examples.

Examples 1 to 82

The compounds of examples 1 to 82 shown in table 1 below have been prepared. Their NMR and LCMS properties and the methods used to prepare them are set forth in table 2.

TABLE 1

General procedure

The intermediates involved are commercially available without inclusion of preparative routes. Commercial reagents were used without further purification. Room temperature (rt) means about 20-27 ℃. Recording at 400MHz on the instrument Bruker (Bruker) or Jeol (Joer)¹H NMR spectrum. Chemical shift values are expressed in parts per million (ppm), i.e. -values. The following abbreviations are used for multiplicity of NMR signals: s is singlet, br is broad, d is doublet, t is triplet, q is quartet, quint is quintet, td is triplet of doublet, tt is triplet of triplet, qd is quartet of doublet, ddd is doublet of doublet, ddt is doublet of triplet, m is multiplet. The coupling constants are listed as J values, measured in Hz. The NMR results and mass spectrometry results were corrected to account for background peaks. Chromatography refers to column chromatography using 60-120 mesh silica gel and performed under nitrogen pressure (flash chromatography). TLC for monitoring the reaction refers to a TLC run using a specified mobile phase from Merck (Merck) and silica gel F254 as the stable phase. Microwave-mediated reactions were performed in Biotage Initiator (betazier Initiator) or CEM Discover (CEM explorer) microwave reactors.

Mass spectrometry was performed on Shimadzu (Shimadzu) LC-2010EV, Waters (Watts) ZQ-2000, UPLC-Mass SQD-3100 (UPLC-Mass Spectrometry SQD-3100), or Applied biosystems (Applied biosystems) API-2000 Mass spectrometers using electrospray conditions as specified for each compound in the detailed experimental section.

Preparative HPLC (waters HPLC) is generally carried out under the following conditions: column: XSelect CSH Prep C-18, 19X 50mm, 5 μm; mobile phase: a gradient of water and MeCN (each containing 0.1% formic acid); the gradient is as follows: as 28 mL/min, 5% MeCN in 0.1HCOOH in water (30 seconds), 5% to 40% (over 7 minutes), followed by 95% MeCN in 0.1HCOOH in water (1 minute), followed by 5% MeCN in 0.1HCOOH in water (1.5 minutes).

LCMS experiments were generally performed using electrospray conditions as specified for each compound under the following conditions:

methods A and B

Instrument Waters Alliance 2795 Watts union 2796 Watts 2996PDA detector Micromass ZQ column Waters X-Bridge C-18, 2.5 micron, 2.1 × 20mm or PhenomenexGemini (Philomenbi) -NX C-18, 3 micron, 2.0 × 30mm column radiation [ time (min)/C solvent D (%)]The method A comprises the following steps: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 or method B: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2; solvent: solvent C2.5L H₂O +2.5mL of ammonia solution; solvent D2.5L MeCN +135mL H₂O +2.5mL ammonia solution); injection volume 3 uL; UV detection 230 to 400 nM; the column temperature was 45 ℃; the flow rate was 1.5 mL/min.

Method C

The instrument comprises the following steps: agilent (Agilent) 1200 LCMS. Column: agilent Zorbax extended (Agilent liquid phase silica gel extension) RRHT, 1.8 μm, 4.6x 30 mm. Detection wavelength: 254 nm. Gradient [ time (min)/solvent B (%) in a, flow rate ]: 0.00/5(2.5 mL/min), 3.00/95(2.5 mL/min), 3.01/95(4.5 mL/min), 3.50/95(4.5 mL/min), 3.60/5(3.5 mL/min), 3.90/95(3.5 mL/min), 4.00/5(2.5 mL/min) (solvent A: water with 0.1% formic acid; solvent B: MeCN with 0.1% formic acid).

Method D

The instrument comprises the following steps: LCMS (Agilent 1200-6110) with UV and ELSD detectors using Watts X-bridge C18(4.6mm 50mm, 3.5um) and water (0.05% TFA) and acetonitrile (0.05% TFA) as mobile phases at 40 ℃. The eluent gradient program was from 5% to 100% MECN (0.05% TFA) for 1.6 min and 100% MECN (0.05% TFA) for 1.4 min. The flow rate was 2.0 mL/min.

Method E

The instrument comprises the following steps: LCMS (Agilent 1200-6110) with UV and ELSD detectors using Watts X-bridge C18(4.6mm 50mm, 3.5um) and water (0.05% TFA) and acetonitrile (0.05% TFA) as mobile phases at 40 ℃. The eluent gradient program was 5% to 100% MECN (0.05% TFA) for 5 min and 100% MECN (0.05% TFA) for 1.0 min. The flow rate was 2.0 mL/min.

LCMS data in the experimental section are given in the following format: mass ions, retention time, approximate purity.

Abbreviations

d is day

DCE ═ dichloroethane

DCM ═ dichloromethane

DMF ═ dimethylformamide

DMSO ═ dimethyl sulfoxide

ESI-electrospray ionization

EtOAc ═ ethyl acetate

h is hour

HATU ═ 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate

HPLC ═ high performance liquid chromatography

LC-liquid chromatography

MeCN ═ acetonitrile

min is minutes

MS mass spectrometry

NMR (nuclear magnetic resonance)

rt-room temperature

sat. (saturation)

sol. ═ solution

Sodium Triacetoxyborohydride (STAB)

THF ═ tetrahydrofuran

TLC ═ thin layer chromatography

The prefixes n-, s-, i-, t-and tert-have their usual meaning: normal, secondary, iso and tertiary.

And (3) synthesis of an intermediate:

intermediate 1

Preparation of 1'- (ethoxycarbonyl) -1,4' -bipiperidine-4-carboxylic acid

A solution of isoperidol (8.0g, 61.0mmol) in DCE (80mL) was treated with acetic acid (10.7mL, 185mmol) and 1-carbethoxy-4-piperidone (12.7g, 74.3 mmol). The reaction mixture was stirred at 40 ℃ for 1 hour. STAB (29.2g, 92.8mmol) was then added, the reaction mixture was stirred at 70 ℃ for 6 hours, cooled to room temperature and the solvent removed in vacuo. The residue was purified by column chromatography (CHCl)₃Medium 0% to 50% MeOH gradient) to give 1'- (ethoxycarbonyl) -1,4' -bipiperidine-4-carboxylic acid (16.0g, 92.2%) as a beige solid, intermediate 1.

Mass spectrometry: (ESI + ve)285.1[ M + H ]]⁺，

¹H NMR：(400MHz,CD₃OD)：1.26(t,J＝7.1,3H),1.61(qd, J ═ 12.3,8.0,2H),1.83-2.17(m,5H),2.32-2.44(m,1H),2.75-3.14(m,4H),3.23-3.28(m,2H),3.35-3.50(m,2H),4.12(q, J ═ 7.1,2H),4.26-4.30(m,2H), no OH protons were observed.

Intermediate 2

Preparation of 1- (1- (ethoxycarbonyl) azepin-4-yl) piperidine-4-carboxylic acid

Ethyl isoperidate (2.54g, 2.50mL, 16.2mmol) and ethyl 4-oxoazepine-1-carboxylate (3.00g, 16.2mmol) were dissolved in DCM (100mL) at room temperature and titanium isopropoxide (5.07g, 5.40mL, 17.8mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. STAB (13.7g, 32.4mmol) and acetic acid (0.5mL) were added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was quenched by addition of water (5mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was taken up with saturated NaHCO₃The solution, saturated NaCl solution was washed and MgSO₄And (5) drying. The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ Biotage (beitaqi) SNAP tubular column KP-sil50g, 40-63 μm,50mL per minute, 2% to 4% MeOH gradient in DCM]) To give 4- [4- (ethoxycarbonyl) piperidin-1-yl as a pale yellow oil]Azepine-1-carboxylic acid ethyl ester (2.56g, 48%).

LCMS (method a): m/z 327(M + H)⁺(ES⁺) UV inactivity at 1.68 min

¹H NMR：(400MHz,DMSO-d₆)：1.17(t,J＝7.0,6H),1.49-1.55(m,6H),1.75-1.78(m,5H),2.14-2.23(m,1H),2.37(t,J＝9.1,1H),2.64-2.72(m,2H),3.18-3.24(m,2H),3.41-3.44(m,2H),3.61-3.70(m,1H),3.99-4.08(m,4H)

Ethyl 4- [4- (ethoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate (1.10g, 3.4mmol) was dissolved in THF (60mL) at room temperature and a 1M LiOH solution (10mL) was added. The reaction mixture was stirred at room temperature for 5 days. The pH was carefully adjusted to pH 6 by the addition of concentrated hydrochloric acid and the solvent was removed under vacuum to give 1- (1- (ethoxycarbonyl) azepin-4-yl) piperidine-4-carboxylic acid (1.5g), intermediate 2, as a viscous pale yellow oil for crude use in subsequent reactions.

LCMS (method a): m/z 299(M + H)⁺(ES⁺) At 0.12 min, UV is inactive

¹H NMR：(400MHz,CD₃OD)1.22-1.32(m,3H),1.60-2.38(m,11H),2.08-2.22(m,1H),3.13-3.26(m,2H),3.33-3.51(m,2H),3.52-3.76(m,2H),4.08-4.18(m,2H), OH protons were not observed.

Intermediate 3

Preparation of 1- [1- (ethoxycarbonyl) azepin-4-yl ] -4-fluoropiperidine-4-carboxylic acid

4-Fluoropiperidine-4-carboxylic acid ethyl ester hydrochloride (3.00g, 14.2mmol) was dissolved in methanol (20mL) and washed with K₂CO₃(1.95g, 14.2mmol) was treated in minimal water for desalting. The reaction mixture was concentrated under vacuum and azeotroped with toluene to dryness. The residue and ethyl 4-oxoazepine-1-carboxylate (2.62g, 14.2mmol) were dissolved in methanol (50mL) and zinc chloride (7.23g, 56.7mmol) was added. The reaction mixture was stirred at 50 ℃ under nitrogen for 2 hours, then cooled to room temperature. Addition of NaCNBH₄(1.78g, 28.4mmol (and the reaction mixture stirred at 50 ℃ under nitrogen overnight. the reaction mixture was cooled to room temperature and the solvent removed in vacuo, the residue diluted with DCM and saturated NaHCO₃The solution was treated, the resulting heterogeneous mixture was filtered through a pad of celite and the filtrate was filtered with saturated NaHCO₃Washing with NaCl solutionWashed and over MgSO₄And (5) drying. The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil50g, 40-63 μm,50mL per minute, 0% to 4% MeOH gradient in DCM]) To give 4- [ 4-fluoro-4- (ethoxycarbonyl) piperidin-1-yl as a colorless oil]Azepine-1-carboxylic acid ethyl ester (2.26g, 46%).

LCMS (method a): m/z 331(M + H)⁺(ES⁺) UV inactivity at 1.84 min

¹H NMR：(400MHz,CDCl₃)：1.24-1.31(m,6H),1.43-1.59(m,2H),1.61-1.69(m,2H),1.86-2.15(m,7H),2.54-2.67(m,4H),3.32-3.32(m,2H),3.48-3.61(m,2H),4.12(q,J＝6.8,2H),4.22(q,J＝7.2,2H)

Ethyl 4- [ 4-fluoro-4- (ethoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate (2.26g, 6.85mmol) was dissolved in THF (60mL) at room temperature and 1M LiOH solution (6.5mL) was added. The reaction mixture was stirred at room temperature overnight. The pH was carefully adjusted to pH 6 by the addition of concentrated hydrochloric acid and the solvent was removed under vacuum to give 1- [1- (ethoxycarbonyl) azepin-4-yl ] -4-fluoropiperidine-4-carboxylic acid (3.21g), intermediate 3, which was used crude in subsequent reactions as a white waxy solid.

LCMS (method a): m/z 317(M + H)⁺(ES⁺) At 0.24 min, UV is inactive

Intermediate 4

Preparation of 1- [1- (ethoxycarbonyl) azepin-4-yl ] -4-methylpiperidine-4-carboxylic acid

4-methylpiperidine-4-carboxylic acid ethyl ester hydrochloride (0.50g, 2.42mmol) was dissolved in methanol (10mL) and washed with K₂CO₃(0.33g，2.42mmol)Treated in minimal water for desalination. The reaction mixture was concentrated under vacuum and azeotroped with toluene to dryness. The residue and ethyl 4-oxoazepine-1-carboxylate (0.45g, 2.42mmol) were dissolved in DCM (20mL) at room temperature and titanium isopropoxide (0.76g, 0.8mL, 2.66mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. STAB (2.05g, 9.66mmol) and acetic acid (0.3mL) were added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was quenched by addition of water (5mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was taken up with saturated NaHCO₃The solution, saturated NaCl solution was washed and MgSO₄And (5) drying. The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil25g, 40-63 μm,25mL per minute, 0% to 4% MeOH gradient in DCM]) To give 4- [ 4-methyl-4- (ethoxycarbonyl) piperidin-1-yl as a pale yellow oil]Azepine-1-carboxylic acid ethyl ester (0.37g, 45.0%).

LCMS (method a): m/z 341(M + H)⁺(ES⁺) UV inactivity at 1.73 min

¹H NMR：(400MHz,CDCl₃)：1.16(s,3H),1.23-1.27(t,J＝7.2,6H),1.40-1.89(m,5H),1.92-1.93(m,4H),2.11-2.62(m,6H),3.25-3.51(m,4H),4.09-4.17(m,4H)。

Ethyl 4- [ 4-methyl-4- (ethoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate (0.37g, 1.09mmol) was dissolved in THF (10mL) at room temperature and 1M LiOH solution (3.3mL) was added. The reaction mixture was stirred at room temperature overnight. The pH was carefully adjusted to pH 6 by the addition of concentrated hydrochloric acid and the solvent was removed under vacuum to give 1- [1- (ethoxycarbonyl) azepin-4-yl ] -4-methylpiperidine-4-carboxylic acid (0.66g), intermediate 4, as a viscous colorless oil for crude use in subsequent reactions.

LCMS (method a): m/z 317(M + H)⁺(ES⁺) At 0.24 min, UV is inactive

Intermediate 5

Preparation of 1- (azepin-4-yl) -N- (2-methylpropyl) piperidine-4-carboxamide TFA salt

Ethyl isoperidate (2.28g, 2.25mL, 14.5mmol) and tert-butyl 4-oxoazepine-1-carboxylate (3.00g, 14.5mmol) were dissolved in DCM (60mL) at room temperature and titanium isopropoxide (4.12g, 4.40mL, 14.5mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. STAB (13.74g, 32.4mmol) and acetic acid (0.5mL) were added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was quenched by addition of water (5mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was taken up with saturated NaHCO₃The solution, saturated NaCl solution was washed and MgSO₄And (5) drying. The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil50g, 40-63 μm,50mL per minute, 0% to 4% MeOH in DCM gradient) to give 4- [4- (tert-butoxycarbonyl) piperidin-1-yl as a pale yellow oil]Azepine-1-carboxylic acid ethyl ester (2.61g, 50.8%).

LCMS (method a): m/z 355(M + H)⁺(ES⁺) UV inactivity at 1.93 min

Ethyl 4- [4- (tert-butoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate (2.61g, 7.4mmol) was dissolved in THF (60mL) at room temperature and a 1M LiOH solution (10mL) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum to yield 1- (1- (tert-butoxycarbonyl) azepin-4-yl) piperidine-4-carboxylic acid, which was used crude in the subsequent reaction.

LCMS (method a): m/z 327(M + H)⁺(ES⁺) And is at 0.UV inactivity at 15 min

The residue was dissolved in DMF (30mL) and isobutylamine (0.81g, 1.1mL, 11.0mmol), HATU (4.20g, 11.0mmol) and DIPEA (4.76g, 6.41mL, 36.8mmol) were added. The reaction mixture was stirred at room temperature under nitrogen for 48 hours. The solvent was removed in vacuo and the residue was taken up in DCM and saturated NaHCO₃The solution was partitioned, and the organic layer was washed with saturated NaCl solution and MgSO₄And (5) drying. The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil50g, 40-63 μm,50mL per minute, 0% to 10% MeOH gradient in DCM]) To give tert-butyl 4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepin-1-carboxylate (1.95g, 69.4%) as a pale yellow oil.

LCMS (method a): m/z 382(M + H)⁺(ES⁺) UV inactivity at 1.76 min

Tert-butyl 4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate (1.95g, 5.1mmol) was dissolved in DCM (16mL) and TFA (4mL) was added. The reaction mixture was stirred at room temperature under nitrogen for 2 hours, then the solvent was removed in vacuo to yield 1- (azepin-4-yl) -N- (2-methylpropyl) piperidine-4-carboxamide TFA salt (2.02g), intermediate 5, as a dark yellow oil, which was used directly without further purification.

LCMS (method a): m/z 282(M + H)⁺(ES⁺) UV inactivity at 1.34 min

Intermediates 6- (R) and 6- (S)

Tert-butyl 4-oxoazepine-1-carboxylate (90g, 422mmol) and (R) -1-phenylethylamine in THF (1000mL)(56.4g, 465mmol) of the mixture was stirred at room temperature for 15 min and STAB (107.4g, 510mmol) was added. The mixture was cooled to 0 ℃ in an ice bath, followed by the addition of acetic acid (26.7g, 450 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo, the residue was dissolved in DCM (800mL) and saturated NaHCO₃The solution (2 × 300mL) was washed and dried (Na)₂SO₄). The solvent was removed in vacuo and the residue was purified by column chromatography (gradient 0% to 3% MeOH in DCM) to give 4- { [ (1R) -1-phenylethyl as a mixture of two diastereomers]Amino } azepine-1-carboxylic acid tert-butyl ester (90g, 67.0%).

LCMS (method D): m/z 319(M + H) + (ES +), 95% at 1.25 min

Using CHIRALPAK AY-H (2.0cm i.d. × 25cm L.5 μm) and (acetonitrile/isopropanol) (0.2% DEA)/CO2 ═ 1.2/4.8/94(V/VV) as mobile phase, HPLC was prepared by chiral prep at 35 ℃ [ instrument: waters THar (Watts-Talc) -SFC200 with UV detector GILSON UV-1(-151/152/155/156) 70g of the mixture were separated. The flow rate was 120 mL/min (all solvents were HPLC grade). The system back pressure was 100 bar. The SFC system was monitored at 214nm ] to provide tert-butyl (4S) -4- { [ (1R) -1-phenylethyl ] amino } azepine-1-carboxylate (26g, 24.9% yield) as a yellow oil and tert-butyl (4R) -4- { [ (1R) -1-phenylethyl ] amino } azepine-1-carboxylate (30g, 28.6% yield) as a yellow oil.

(4S) -4- { [ (1R) -1-phenylethyl ] amino } azepine-1-carboxylic acid tert-butyl ester

¹H NMR：(400MHz,CDCl₃): 1.26(d, J ═ 7.1,3H),1.33(s,9H),1.34-1.43(m,3H),1.72-1.97(m,3H),2.34-2.39(m,1H),3.01-3.45(m,4H),3.80(q, J ═ 7.2,1H),7.15-7.25(m,5H), no NH protons observed

[α]_D ²⁰= 57.0(MeOH with c ═ 0.5)

The absolute configuration was determined by X-ray analysis of o-bromobenzoate of tert-butyl (4S) -4- { [ (1R) -1-phenylethyl ] amino } azepine-1-carboxylate. (A. Alker (A. Acker) et al, bioorg.Med.chem.Lett. (Bioorganic and medicinal chemical communications) 20(2010)4521-4525)

(4R) -4- { [ (1R) -1-phenylethyl ] amino } azepine-1-carboxylic acid tert-butyl ester

¹H NMR：(400MHz,CDCl₃): 1.27(d, J ═ 7.0,3H),1.34(s,9H),1.34-1.42(m,3H),1.74-1.96(m,3H),2.35-2.41(m,1H),3.02-3.45(m,4H),3.81(q, J ═ 7.1,1H),7.16-7.26(m,5H), no NH protons observed

[α]_D ²⁰= 31.8(MeOH with c ═ 0.5)

Intermediate 6- (S)

Preparation of tert-butyl (4S) -4- [4- (methoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate

Pd (OH)₂/C (10%, 550mg), (4S) -4- { [ (1R) -1-phenylethyl]Amino } azepine-1-carboxylic acid tert-butyl ester (5.5g, 17.3mmol) and HCOONH₄A suspension of (3.3g, 51.9mmol) in MeOH (80mL) was heated at reflux for 1.5 h. The reaction mixture was cooled to room temperature and filtered, and the solvent of the filtrate was removed in vacuo. The residue was purified by column chromatography (gradient 0% to 10% MeOH in DCM) to give (4S) -4-aminoaczepine ring-1-carboxylic acid tert-butyl ester (3.2g, 87.3%).

LCMS (method E): m/z 215(M + H)⁺(ES⁺) UV inactivity at 1.53 min

¹H NMR：(400MHz,CDCl₃)：1.34-1.42(m,3H),1.39(s,9H),1.45-1.53(m,2H),1.60-1.86(m,3H),2.80-2.90(m,1H),3.08-3.53(m,4H)

[α]_D ²⁰= 21.3(MeOH with c ═ 1.0)

Methyl cyclopent-3-ene-1-carboxylate (4.42g, 35mmol) was dissolved in DCM/MeOH (160mL, 3:1) and cooled to-78DEG C. Ozone was passed through the solution until the blue color persisted. By drying N₂Excess ozone is purged from the reaction mixture. Dimethyl sulfide (10mL) was added and the reaction mixture was warmed to room temperature and the solvent was removed under vacuum. The residue was added to (4S) -4-aminoaczepine-1-carboxylic acid tert-butyl ester (7.5g, 35mmol), STAB (18.57g, 87.6mmol), NEt₃(4.26g, 42.1mmol) and acetic acid (1.8mL) in DCE (200 mL). The mixture was stirred at room temperature for 3 hours and then poured over Na₂CO₃The mixture was extracted with EtOAc (3 × 200mL), and the organic phase was washed with water (100mL) and brine (100mL) and washed with Na₂SO₄And (5) drying. The solvent was removed in vacuo and the residue was purified by column chromatography (0% to 25% EtOAc gradient in petroleum ether) to give (4S) -4- [4- (methoxycarbonyl) piperidin-1-yl as a yellow oil]Tert-butyl azepin-1-carboxylate (7.7g, yield 64.6%).

LCMS (method D): m/z 341(M + H)⁺(ES⁺) UV inactivity at 1.49 min

Reacting (4S) -4- [4- (methoxycarbonyl) piperidin-1-yl]Tert-butyl azepane-1-carboxylate (7.7g, 22.7mmol) was dissolved in THF and water (60mL, 1:1) and cooled to 0 ℃. NaOH (1.0g, 24.5mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The organic solvent was removed in vacuo and the aqueous phase was acidified with acetic acid to pH 3-4 and then concentrated to dryness. The residue was suspended in CHCl₃(40mL) and filtered to remove inorganic salts. The filtrate was evaporated to dryness to give 1- { (4S) -1- [ (tert-butoxycarbonyl) carbonyl as a yellow oil]Azepin-4-yl } piperidine-4-carboxylic acid (6.2g, 84% yield).

LCMS (method D): m/z 327(M + H)⁺(ES⁺) UV inactivity at 1.35 min

¹H NMR：(400MHz,DMSO-d₆)：1.38(s,9H),1.45-1.53(m,6H),1.70-1.78(m,4H),2.08-2.20(m,3H),2.35-2.42(m,1H),2.65-2.69(m,2H),3.12-3.19(m,2H),3.30-3.41(m,2H),8.32(br.s,1H)

[α]_D ²⁰＝+11.0(MeOH c ═ 1.8)

Intermediate 6- (R)

Preparation of tert-butyl (4R) -4- [4- (methoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate

The title compound (6.1g, 18.7mmol) was prepared from tert-butyl (4R) -4- { [ (1R) -1-phenylethyl ] amino } azepin-1-carboxylate (5.5g, 17.3mmol) using the method outlined above for intermediate 6- (S).

LCMS (method D): m/z 327(M + H)⁺(ES⁺) UV inactivity at 1.35 min

¹H NMR：(400MHz,DMSO-d₆)：1.39(s,9H),1.45-1.53(m,6H),1.70-1.78(m,4H),2.08-2.20(m,3H),2.35-2.41(m,1H),2.64-2.69(m,2H),3.12-3.19(m,2H),3.30-3.41(m,2H),8.32(br.s,1H)

[α]_D ²⁰10.7(MeOH c 2.0.)

Intermediate 7

Preparation of 1- (azepin-4-yl) -4-methoxy-N- (1-methylcyclobutyl) piperidine-4-carboxamide TFA salt

4-Methoxypiperidine-4-carboxylic acid methyl ester hydrochloride (0.50g, 2.38mmol) was dissolved in methanol (10mL) and washed with K₂CO₃(0.328g, 2.38mmol) was treated in minimal water for desalting. The reaction mixture was concentrated under vacuum and azeotroped with toluene to dryness. The residue and tert-butyl 4-oxoazepine-1-carboxylate (0.745g, 2.38mmol) were dissolved in methanol (20mL) at room temperature and treated with zinc chloride (0.975g, 7.15 mmol). The reaction mixture was stirred at 50 ℃ for 3hThen (c) is performed. The solution was cooled to room temperature, sodium cyanoborohydride (0.299g, 4.77mmol) was added and the reaction mixture was stirred under nitrogen overnight at 50 ℃. The solvent was removed in vacuo and the residue was taken up in DCM and saturated NaHCO₃The phases were split between solutions, the aqueous phase was extracted with DCM (2 × 20mL), the organics were combined, washed with saturated NaCl solution and dried through a betetazic phase separator tubular column, the solvent was removed under vacuum, and the residue was purified by column chromatography (normal phase, [ betetazic SNAP tubular column KP-sil25g, 40-63 μm,50mL per minute, 1% to 10% MeOH gradient in DCM]) To give 4- [ 4-methoxy-4- (methoxycarbonyl) piperidin-1-yl as a colorless oil]Tert-butyl azepine-1-carboxylate (0.163g, 15.5%).

LCMS (method a): m/z 371(M + H)⁺(ES⁺) UV inactivity at 1.72 min

Tert-butyl 4- [ 4-methoxy-4- (methoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate (0.06g, 0.17mmol) was dissolved in medium THF (5mL) at room temperature and 1M LiOH solution (0.35mL) was added. The reaction mixture was stirred at room temperature for 8 days. The pH was carefully adjusted to pH 6 by the addition of concentrated hydrochloric acid and the solvent was removed under vacuum to yield 1- [1- (tert-butoxycarbonyl) azepin-4-yl ] -4-methoxypiperidine-4-carboxylic acid which was used crude in the subsequent reaction.

LCMS (method a): m/z 357(M + H)⁺(ES⁺) At 0.24 min, UV is inactive

1- [1- (tert-Butoxycarbonyl) azepin-4-yl]-4-methoxypiperidine-4-carboxylic acid (0.163g, 0.44mmol) was dissolved in DMF (5mL) and (1-methyl) cyclobutylamine hydrochloride (0.08g, 0.66mmol), HATU (0.25g, 0.66mmol) and DIPEA (0.284g, 0.38mL, 2.20mmol) were added. The reaction mixture was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo and the residue was taken up in DCM and saturated NaHCO₃The organic layer was washed with saturated NaCl solution and MgSO₄And (5) drying. Removing the solvent under vacuum, andand the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil25g, 40-63 μm,50mL per minute, 1% to 6% MeOH gradient in DCM]) To give 4- { 4-methoxy-4- [ (1-methylcyclobutyl) carbamoyl group as a pale yellow oil]Piperidin-1-yl } azepine-1-carboxylic acid tert-butyl ester (0.025g, 13.4%).

LCMS (method a): m/z 424(M + H)⁺(ES⁺) UV inactivity at 1.88 min

Tert-butyl 4- { 4-methoxy-4- [ (1-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylate (0.25g, 0.06mmol) was dissolved in DCM (4mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature under nitrogen overnight, then the solvent was removed in vacuo to yield 1- (azepin-4-yl) -4-methoxy-N- (1-methylcyclobutyl) piperidine-4-carboxamide TFA salt (0.26g), intermediate 7, as a dark yellow oil, which was used directly without further purification.

LCMS (method a): m/z 324(M + H)⁺(ES⁺) UV inactivity at 0.18 min

Intermediate 8

Preparation of 1- [1- (ethoxycarbonyl) azepin-4-yl ] -4-methoxypiperidine-4-carboxylic acid

4-Methoxypiperidine-4-carboxylic acid methyl ester hydrochloride (0.50g, 2.38mmol) was dissolved in methanol (10mL) and washed with K₂CO₃(0.328g, 2.38mmol) was treated in minimal water for desalting. The reaction mixture was concentrated under vacuum and azeotroped with toluene to dryness. The residue and ethyl 4-oxoazepine-1-carboxylate (0.441g, 2.38mmol) were dissolved in methanol (20mL) at room temperature and treated with zinc chloride (0.975g, 7.15 mmol). The reaction mixture is added at 5Stirred at 0 ℃ for 2 hours. The solution was cooled to room temperature, sodium cyanoborohydride (0.299g, 4.77mmol) was added and the reaction mixture was stirred under nitrogen overnight at 50 ℃. The solvent was removed in vacuo and the residue was suspended in DCM and saturated NaHCO₃Between the solutions. The cloudy mixture was passed through a pad of celite, which was washed with DCM. The organic layers were combined, washed with saturated NaCl solution and dried by means of a beitachizil phase separator tubular column. The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil25g, 40-63 μm,50mL per minute, 1% to 6% MeOH gradient in DCM]) To give 4- [ 4-methoxy-4- (methoxycarbonyl) piperidin-1-yl as a colorless oil]Azepine-1-carboxylic acid ethyl ester (0.136g, 16.4%).

LCMS (method a): m/z 343(M + H)⁺(ES⁺) UV inactivity at 1.46 min

Ethyl 4- [ 4-methoxy-4- (methoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate (0.136g, 0.39mmol) was dissolved in THF (5mL) at room temperature and a 1M LiOH solution (0.4mL) was added. The reaction mixture was stirred at room temperature for 2 days. The pH was carefully adjusted to pH 6 by the addition of concentrated hydrochloric acid and the solvent was removed under vacuum to give 1- [1- (ethoxycarbonyl) azepin-4-yl ] -4-methoxypiperidine-4-carboxylic acid (0.131g), intermediate 8, as a yellow oil which was used directly without further purification.

LCMS (method a): m/z 329(M + H)⁺(ES⁺) At 0.13 min, UV is inactive

Intermediate 9

Preparation of 4-cyano-1- [1- (ethoxycarbonyl) azepin-4-yl ] piperidine-4-carboxylic acid

4-Cyanopiperidine (0.40g, 3.62mmol) was dissolved in MeOH (15mL), and ethyl 4-oxoazepine-1-carboxylate (0.672g, 3.62mmol) and zinc chloride (1.98g, 14.48mmol) were added. The reaction mixture was heated at 50 ℃ for 2 hours. The solution was then cooled on ice and treated with sodium cyanoborohydride (0.456g, 7.24mmol) portionwise and heated to 50 ℃ overnight. The reaction mixture was concentrated under vacuum to a white solid. This white solid dissolved in saturated NH₄Cl solution and extracted with EtOAc (3 × 50 mL.) the combined organics were washed with saturated NaCl solution over MgSO₄Dried, filtered and concentrated under vacuum. The residue was purified by column chromatography (normal phase, [ Betazier SNAP tubular column KP-sil25g, 40-63 μm,50mL per minute, 0% to 4% MeOH gradient in DCM]) To give ethyl 4- (4-cyanopiperidin-1-yl) azepine-1-carboxylate (0.090g, 8.9%) as an oil.

LCMS (method a): m/z 280(M + H)⁺(ES⁺) UV inactivity at 1.67 min

1.0M lithium bis (trimethylsilyl) amide (4.48mL, 7.17mmol) was added to anhydrous THF (20mL) under nitrogen and cooled to-78 ℃. The solution was treated dropwise with ethyl 4- (4-cyanopiperidin-1-yl) azepine-1-carboxylate (0.400g, 1.43mmol) as a solution in anhydrous THF (2 mL). The solution was stirred at-78 ℃ under nitrogen for 1 hour, and ethyl chloroformate (0.17g, 1.57mmol) was added dropwise. The solution was stirred at-78 ℃ for an additional 2 hours and then allowed to warm to room temperature overnight. The reaction mixture was quenched by addition of water and the solvent was removed under vacuum. The residue was taken up in DCM and saturated NaHCO₃The solution is segmented. The organic layer was washed with saturated NaCl solution and dried by passage through a betezetil phase separator tubular column. The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil10g, 40-63 μm,50mL per minute, 2% to 4% MeOH gradient in DCM]) To give 4- [ 4-cyano-4- (ethoxycarbonyl) piperidin-1-yl as an amber oil]Azepine-1-carboxylic acid ethyl ester (0.067g, 12.7%).

LCMS (method a): m/z 352(M + H)⁺(ES⁺) UV inactivity at 1.70 min

Ethyl 4- [ 4-cyano-4- (ethoxycarbonyl) piperidin-1-yl ] azepine-1-carboxylate (0.067g, 0.182mmol) was dissolved in methanol (4mL) at room temperature and 1M LiOH solution (0.2mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The pH was carefully adjusted to pH 6 by the addition of concentrated hydrochloric acid and the solvent was removed under vacuum to give 4-cyano-1- [1- (ethoxycarbonyl) azepin-4-yl ] piperidine-4-carboxylic acid, (0.62g), intermediate 9, as a yellow oil which was used directly without further purification.

LCMS (method a): m/z 324(M + H)⁺(ES⁺) At 0.10 min, UV is inactive

Pathway a

General procedure for the preparation of amides by the Schotten-Baumann (schottky-bowman) reaction, as described in preparation example 1: 4- (2-methylpropyl) -carbamoyl) -1,4 '-bipiperidine-1' -carboxylic acid ethyl ester

1'- (ethoxycarbonyl) -1,4' -bispiperidine-4-carboxylic acid (0.60g, 2.11mmol) is dissolved in DCM (30mL), the reaction mixture is cooled to 0 ℃ and oxalyl chloride (0.27mL, 3.17mmol) and DMF (0.1mL) are added. The solution was stirred at room temperature for 2 hours and then concentrated under vacuum. A portion of the residue (0.53mmol) was dissolved in DCM (5mL) and isobutylamine (0.06g, 0.08mL, 0.79mmol) and saturated NaHCO were added₃Solution (5 ml). The reaction mixture was stirred at rt overnight and then in DCM and saturated NaHCO₃The solution is segmented. The organic layer was washed with saturated NaCl solution and dried (MgSO₄) Is on trueThe solvent was removed under air. The residue was purified by trituration from diethyl ether to give 4- (2-methylpropyl) carbamoyl) -1,4 '-bipiperidine-1' -carboxylic acid ethyl ester (0.01g, 9%) as a white solid.

Data in Table 2

Pathway b

Common procedure for the preparation of amides by HATU coupling, as in preparation example 6: illustrative of ethyl 4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate

1- (1- (ethoxycarbonyl) azepin-4-yl) piperidine-4-carboxylic acid (0.26g, assumed 0.89mmol) was dissolved in DMF (4mL) and isobutylamine (0.81g, 1.1mL, 11.0mmol), HATU (0.51g, 1.34mmol) and DIPEA (0.46g, 0.62mL, 3.56mmol) were added. The reaction mixture was stirred at room temperature overnight and the solvent was removed under vacuum. The residue was taken up in DCM and saturated NaHCO₃The solution was partitioned, and the organic layer was washed with saturated NaCl solution and dried (MgSO)₄). The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil25g, 40-63 μm,25mL per minute, 0% to 3% MeOH gradient in DCM]) To give ethyl 4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepin-1-carboxylate (17mg, 2%) as a pale yellow gum.

Data in Table 2

Examples 7-16, 19 and 20 were purified by preparative HPLC.

Route c

The usual procedure for the preparation of amides by acid chloride coupling, as described in preparation example 27: illustrative of ethyl 4- (4- ((1-methylcyclobutyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate

Thionyl chloride (5mL) was added to 1- (1- (ethoxycarbonyl) azepin-4-yl) piperidine-4-carboxylic acid (0.2g, assuming 0.34mmol) and the reaction was stirred at 90 ℃ for 3 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in DCM (5mL) and (1-methylcyclobutyl) amine HCl (60.1mg, 0.50mmol) and DIPEA (0.23mL, 1.34mmol) were added and the reaction mixture was stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC and the resulting product was loaded onto an SCX column (1g) in 5% AcOH in MeOH. The column was washed with MeOH and then the product was eluted with 0.7M ammonia in MeOH to give the nominal compound as a white solid (26mg, 21%).

An alternative working procedure would be: the reaction mixture was taken up in DCM and saturated NaHCO₃The solution was partitioned, and the organic layer was washed with saturated NaCl solution and MgSO₄And (5) drying. The residue was purified by column chromatography (normal phase, [ Betazier SNAP tubular column KP-sil25g, 40-63 μm,12mL per minute, 0% to 6% MeOH gradient in DCM]) To produce a nominal compound.

Data in Table 2

Route d

The usual procedure for the preparation of amides by acid chloride coupling, as described in preparation example 43: illustrative of ethyl 4- (4-fluoro-4- ((tert-butyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate

Thionyl chloride (4mL) was added to 1-, [ 2]1- (ethoxycarbonyl) azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid (1.24g, assuming 3.92mmol) and the reaction stirred at 90 ℃ for 3 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. To a portion of the residue (0.65mmol) was added DCM (4mL), followed by tert-butylamine (0.14mL, 1.31mmol) and DIPEA (0.57mL, 3.27mmol), and the reaction mixture was stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue was taken up in DCM (50mL) and saturated NaHCO₃The solutions (25mL) were partitioned, and the organic layer was washed with saturated NaCl solution (25mL) and over MgSO₄And (5) drying. The residue was purified by column chromatography (normal phase, [ bepotazid SNAP tubular column KP-sil25g, 40-63 μm,25mL per minute, 0% to 7% MeOH gradient in DCM]) To give ethyl 4- (4-fluoro-4- ((tert-butyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate (0.11g, 46.8%) as a yellow oil.

Data in Table 2

Pathway e

A common method for preparing carbamates by means of chloroformate coupling, as in preparation example 57: prop-2-yn-1-yl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate as exemplified

1- (azepin-4-yl) -N- (2-methylpropyl) piperidine-4-carboxamide TFA salt (0.15g, 0.38mmol) was dissolved in DCM (8mL) at room temperature. Addition of NEt₃(0.16mL, 1.14mmol) and propargyl chloroformate (0.06mL, 0.57mmol) and the reaction mixture was stirred at room temperature under nitrogen for 2 hours. The solvent was removed in vacuo and the residue was taken up in DCM and saturated NaHCO₃The solution was partitioned, and the organic layer was washed with saturated NaCl solution and MgSO₄And (5) drying. The residue was purified by column chromatography (normal phase, [ Betaziq SNAP tubular column KP-sil 10g，40-63μm，12mL per minute, 0% to 10% MeOH gradient in DCM]) To give prop-2-yn-1-yl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate (0.04g, 31%) as a yellow gum.

Data in Table 2

Pathway f

The usual procedure for chiral derivatives, as in preparation example 63: exemplified by ethyl (4S) -4- [4- ((2-methylpropyl) methylcarbamoyl) -piperidin-1-yl ] azepine-1-carboxylate

Reacting (4S) -4- [4- (methoxycarbonyl) piperidin-1-yl]Tert-butyl azepane-1-carboxylate (0.3g, 0.92mmol) was dissolved in DMF (4mL) and isobutylamine (0.14g, 0.18mL, 1.84mmol), HATU (0.53g, 1.38mmol) and DIPEA (0.36g, 0.48mL, 2.76mmol) were added. The reaction mixture was stirred at room temperature for 48 hours and the solvent was removed under vacuum. The residue was taken up in DCM and saturated NaHCO₃The solution was partitioned, and the organic layer was washed with saturated NaCl solution and dried (MgSO)₄). The solvent was removed under vacuum and the residue was purified by column chromatography (normal phase, [ bepotazil SNAP tubular column KP-sil10g, 40-63 μm,12mL per minute, 0% to 10% MeOH gradient in DCM]) To give (4S) -4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl as a pale yellow gum]Tert-butyl azepane-1-carboxylate (0.12g, 35%).

LCMS (method a): m/z 382(M + H)⁺(ES⁺) At 1.72 minutesUV inactive

1- [ (4S) -azepan-4-yl]N- - (2-methylpropyl) piperidine-4-carboxamide the residue was dissolved in DCM (4mL) and TFA (1mL) was added. The reaction mixture was stirred at room temperature under nitrogen for 2 hours, followed by removal of the solvent under vacuum. The residue was dissolved in DCM (8mL) at room temperature. Addition of NEt₃(0.13mL, 0.96mmol) and ethyl chloroformate (0.05mL, 0.48mmol) and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo and the residue was taken up in DCM and saturated NaHCO₃The solution was partitioned, and the organic layer was washed with saturated NaCl solution and MgSO₄And (5) drying. The residue was purified by column chromatography (normal phase, [ bepotazid SNAP tubular column KP-sil10g, 40-63 μm,12mL per minute, 0% to 10% MeOH gradient in DCM]) To give (4S) -4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl as a yellow gum]Azepine-1-carboxylic acid ethyl ester (0.24g, 21%).

Data in Table 2

Biological activity

Example A

Phosphoryl-ERK 1/2 assay

Functional assays were performed using the Alphascreen Surefire phosphoryl-ERK 1/2 assay (Crouch and Osmond, omb. chem. high through hput Screen, 2008). ERK1/2 phosphorylation is a downstream consequence of both Gq/11 and Gi/o protein-coupled receptor activation, making it highly suitable for the evaluation of (Gq/11-coupled) M1, M3 and (Gi/o-coupled) M2, M4 receptors, rather 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) into MEM- α + 10% dialyzed FBS on 96-well tissue culture plates. Once attached, cells were serum starved overnight. Agonist stimulation was performed by adding 5 μ L of agonist to the cells for 5 minutes (37 ℃). The medium was removed and 50 μ L lysis buffer was added. After 15 minutes, 4 μ Ι _ of sample was transferred to 384 well plates and 7 μ Ι _ of detection mixture was added. The plates were incubated in the dark for 2 hours with gentle stirring and then read on a PHERAstar plate reader.

Calculation of pEC from the data obtained for each receptor subtype₅₀FIGS. E and E_maxFigure (a).

The results are set forth in table 3 below.

NT-not tested

Example B

Passive avoidance

The study was performed as previously described by Fulai et al, (2004) neuropsychopharmacology. In the passive avoidance task, animals were obliterated to the paradigm by administering scopolamine (1mg/kg, i.p.) 6 hours after training. Dose ranges of 3, 10 and 30mg/kg (oral) free base were examined by oral gavage administration 90 minutes prior to the training phase.

Example 27 was found to reverse scopolamine-induced paradigm amnesia, ED, in a dose-dependent manner₅₀Approximately about 10mg/kg (oral). The effect of 30mg/kg was similar to that produced by the cholinesterase inhibitor donepezil (0.1mg/kg, i.p.) acting as a positive control (figure 1).

Example 65 was found to reverse scopolamine-induced paradigm amnesia in a dose-dependent manner, with significant effects observed after acute administration of 10 and 30mg/kg (p < 0.05; bangfeioni post hoc test). The effects at 10 and 30mg/kg were not significantly different relative to the effect produced by the cholinesterase inhibitor donepezil (0.1mg/kg, i.p.) acting as a positive control (figure 2).

Example 65 was found to reverse scopolamine-induced amnesia in a dose-dependent manner, with a significant effect observed following acute administration of 10mg/kg (oral) (p < 0.05; bonafiloni post-hoc test). The effect at 10mg/kg was not significantly different compared to that produced by the cholinesterase inhibitor donepezil (0.1mg/kg, i.p.) acting as a positive control. Example 65 the combination of donepezil and donepezil did not result in loss of activity, but rather the combination had an additive effect at each dose combination as analyzed by the mann-whitney u-test (figure 3).

Example C

Irwin (Irwin) Spectrum

The method for detecting the main effects of test substances on behavioral and physiological functions follows the method described by Irwin (Europe) (1968) Psychopharmacologia (psychopharmacology). Cholinergic side effects may be evident in the behavioral readout of the owen assay, and the absence of these side effects may be considered to indicate that agonism of the M2 and M3 receptors is not evident in vivo.

Rats were administered the test substance or its vehicle and observed in a simultaneous comparison with the control group. Behavioral modification, physiological and neurotoxic symptoms, anal temperature and pupil diameter were recorded according to a standardized observation table derived from the euro observation table. The table contains the following items: death, convulsions, tremors, castration, tail lifting by stuub (Straub tail), altered mobility, jumping, abnormal gait (rolling, \36433;, foot), motor incoordination, altered abdominal muscle tone, loss of grip, inability to move, rigidity, loss of traction, loss of balance, pronating-paw peduncle breaking (for-paw training), writhing, piloerection, stereotyped (sniffing, chewing, head movement), head twitching, scratching, altered respiration, aggression, fear/fright changes, altered touch responsiveness, ptosis, exophthalmos, loss of righting reflex, loss of corneal reflex, analgesia, defecation/diarrhea, salivation, lacrimation, anal temperature (hypothermia/hyperthermia) and pupil diameter (miosis/mydriasis). Observations were made 15, 30, 60, 120, 180 minutes and 24 hours after administration of example 27. No effect on any parameter was observed at any time point at doses 3, 10, 30 and 75mg/kg (oral) when compared to vehicle control.

Observations were made 15, 30, 60, 120 and 180 minutes after administration of example 65. No significant effect on any of the parameters was observed at these time points at doses 5, 10, 20 and 40mg/kg when compared to vehicle control.

Example D

New object recognition

The new object recognition paradigm is based on the more spontaneous exploration of new objects than familiar objects shown by rodents (ennace and delaour, 1988). This paradigm is considered a model of working memory and does not involve a level of reinforcement such as food return or noxious stimuli, thus making it similar to memory tests used in human clinical trials. Cognitive performance of male Wistar (vista) rats was evaluated in a test device containing an open field, placed in an anechoic chamber under dim lighting. Images of the open field are captured by a digital camera and the images are viewed on a monitor in the adjacent room. Each rat was subjected to the procedure separately and any olfactory/gustatory cues were carefully removed by cleaning the field and test subjects with ethanol between the test and the rat. Without knowledge of the treatment, the video evaluated all the trials. After the 10 minute habituation phase, each rat was placed in the test field in the presence of two identical objects (plastic shapes). Each rat was placed at the same location in the field, facing the same direction, and the time it took to actively explore the object during the 5 minute training phase (T1) was recorded. Rats were returned to their home cages between trials. After 24 hours, each rat was again placed in the test field for 5 minutes in the presence of one familiar object and a new object (T2), and the time taken to explore both objects was again recorded. The presentation order and position (left/right) of the objects was randomized between rats to prevent order or position preference bias. Test compounds were administered at doses of 3, 10 or 30mg/kg (n-8) by oral gavage 90 minutes prior to training. Donepezil (0.1mg/kg) and galantamine (3mg/kg) were administered by intraperitoneal injection 60 minutes prior to training. Vehicle treated controls were used for comparison.

Statistical analysis determined that the 10 and 30mg/kg treatments and the 3mg/kg positive control galantamine treatment of example 65 significantly improved the new object recognition memory (p <0.05) when compared to vehicle treated controls (figure 4). Donepezil (0.1mg/kg) had no effect on new object identification. During the 10 minute training phase in the apparatus, the exploratory behavior of the animals was assessed. There was no difference in exploring either object or between vehicle treated controls and any drug treated groups.

Example E

CA1 cell discharge

Using a vibrating microtome in ice cold condition (<4 ℃) artificial cerebrospinal fluid (aCSF, composition in mM: NaCl 127, KCl 1.6, KH₂PO₄1.24，MgSO₄1.3，CaCl₂2.4，NaHCO₃26 and D-glucose 10) 400 μm thick slices of the rat hippocampus were cut out. Sections were oxygenated at room temperature (95% O) prior to electrophysiological recording₂/5％CO₂) Maintained in aCSF for at least 1 hour, after which they are transferred to the interfaceChambers were perfused constantly with warmed (30 ℃) oxygenated aCSF at a flow rate of 1.5-3 ml.min-1. Subsequently, non-collateral branches of the sand (Schaffer collatoral) (1-20V, 0.1ms pulse width, 0.033Hz) were stimulated with concentric bipolar electrodes to excite the field excitatory postsynaptic potential (fEPSP) recorded from the radiation layer of the CA1 area. Experiments were performed to examine the effect of compounds on fEPSP amplitude in the CA1 region of rat hippocampal slices, compared to 1 μ M carbachol (CCh). Initially 1 μ M CCh was applied until steady state followed by washing before 5-point cumulative concentration-response of the compounds. Each compound was tested on 6 slices and the results were averaged. Preparing a medicament; compounds were dissolved in 100% DMSO at 30mM stock concentration and diluted as required, carbamoylcholine chloride (CCh) purchased from Sigma (Sigma) (Cat. No. C4382) and dissolved in ddH at 1mM stock concentration₂And (4) in O.

Example F

Pharmaceutical formulations

(i) Tablet formulation

Preparing a tablet composition containing a compound of formula (1) by: 50mg of the compound is mixed with 197mg of lactose (BP) as a diluent and 3mg of magnesium stearate as a lubricant and compressed to form tablets in a known manner.

(ii) Capsule formulations

Capsule formulations were prepared by: 100mg of a compound of formula (1) is mixed with 100mg of lactose and optionally 1% by weight of magnesium stearate and the resulting mixture is filled into standard opaque hard gelatin capsules.

Equivalents of

The foregoing examples are set forth for the purpose of illustrating the invention and are not to be construed as limiting in any way the scope of the invention. It will be readily apparent that many modifications and variations of the specific embodiments of the invention as described and illustrated in the foregoing description and examples may be made without departing from the principles underlying the invention. All such modifications and variations are intended to be included herein by the present application.

Claims (12)

1. A compound of formula (1):

or a salt thereof, wherein:

n is 1 or 2;

p is 0, 1 or 2;

q is 0, 1 or 2;

R¹selected from 2-methylpropyl, tert-butyl, 2-methylbutyl, 2-dimethylpropylA group, 2-methylbut-2-yl group, cyclobutylmethyl group, cyclopropylmethyl group, cyclopentylmethyl group, isopropyl group, 1-methylcyclohexyl group, 1-methylcyclopentylmethyl group, 2-cyclopropylpropyl group, 1-methylcyclobutyl group, cyclopentyl group, 2, 3-dimethylbut-2-yl group, 1-ethylcyclobutylmethyl group, 1-methylcyclopentyl group, 2-cyclopropylpropyl-2-yl group, cyclobutyl group, 1-methylcyclobutylmethyl group, 1- (trifluoromethyl) cyclobutyl group, 1-ethylcyclobutyl group, ((S-methyl-2-yl group), (S-methyl-1-ethylcyclobutyl group), (S-methyl-1-ethylcyclobutyl group), (²H₃) Methyl group (²H₆) Propyl and 2-methylpent-2-yl;

R²selected from hydrogen, methyl, ethyl and isopropyl;

or R¹And R²Non-aromatic heterocyclyl forming a 4 to 9 membered ring together with the nitrogen atom to which they are attached, wherein the heterocyclyl may optionally contain a second heteroatom selected from O, N and S and oxidised forms thereof; and wherein said heterocycle may optionally be substituted with a substituent selected from C_1-2An alkyl group; 1 to 6 more substituents of fluoro and cyano;

R³selected from hydrogen, fluoro, cyano, methoxy and methyl;

R⁴selected from methyl, ethyl, ethynyl and 1-propynyl;

R⁵is absent or is fluorine; and is

R⁶Either absent or fluorine.

2. The compound of claim 1, wherein n is 2.

3. The compound of claim 1, wherein p is 0.

4. The compound of claim 1, wherein q is 0.

5. The compound of claim 1, having formula (2):

wherein R is¹、R³、R⁴、R⁵、R⁶P and q are as defined in claim 1.

6. The compound of claim 1, having formula (3):

wherein R is¹、R³、R⁴、R⁵、R⁶P and q are as defined in claim 1.

7. The compound according to any one of claims 1 to 6, wherein p is 0, q is 0 and R is³Is H.

8. The compound of claim 1, wherein the compound is selected from the group consisting of:

4- (2-methylpropyl) carbamoyl) -1,4 '-bipiperidine-1' -carboxylic acid ethyl ester;

4- ((3, 3-difluoropyrrolidin-1-yl) carbamoyl) -1,4 '-bispiperidine-1' -carboxylic acid ethyl ester;

4- (2, 3-dimethylbut-2-yl) carbamoyl) -1,4 '-bipiperidine-1' -carboxylic acid ethyl ester;

4- (1, 1-dimethylpropyl) carbamoyl) -1,4 '-bipiperidine-1' -carboxylic acid ethyl ester;

4- (1-methylcyclobutyl) carbamoyl) -1,4 '-bipiperidine-1' -carboxylic acid ethyl ester;

4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((1, 1-dimethylethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((2-methylbutyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((2, 2-dimethylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((1, 1-dimethylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((cyclobutylmethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((diethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((ethyl (prop-2-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((3-methoxy-2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((cyclopropylmethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((cyclopentylmethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((1-methylcyclohexyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (([ 1-methylcyclopentyl ] methyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((2,2, 2-trifluoroethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((3,3, 3-trifluoro-2-methoxypropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((tetrahydrofuran-3-ylmethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((methoxy (methyl)) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((prop-2-yloxy)) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((2-methylallyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (butylcarbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((cyclopropylmethyl) (ethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((1-methylcyclobutyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((1-cyclopropylpropan-2-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (cyclopent-3-en-1-ylcarbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (cyclopentylcarbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((2, 3-dimethylbut-2-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (allylcarbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (2-methylpiperidine-1-carbonyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (diisopropylcarbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((2-methylbut-3-yn-2-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (methyl (prop-2-yn-1-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- (((1-ethylcyclobutyl) methyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((1,1, 1-trifluoro-2-methylprop-2-yl)) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4- ((2-cyclopropylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((1, 1-dimethylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((cyclobutylmethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((tert-butyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((2, 3-dimethylbut-2-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((1-cyclopropylpropan-2-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((2, 2-dimethylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((1-methylcyclopropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((1-methylcyclopentyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- (((1-ethylcyclobutyl) methyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((1-methylcyclobutyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((cyclopentyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((cyclopropylmethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((cyclopentylmethyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((2-cyclopropylpropan-2-yl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-fluoro-4- ((cyclobutyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- (4-methyl-4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

prop-2-yn-1-yl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate;

but-2-yn-1-yl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepin-1-carboxylate;

2-fluoroethyl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate;

2-methoxyethyl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate;

2-propyl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate;

2,2, 2-trifluoroethyl-4- (4- ((2-methylpropyl) carbamoyl) piperidin-1-yl) azepine-1-carboxylate;

(4S) -ethyl 4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylate;

(4R) -ethyl 4- [4- ((2-methylpropyl) methylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylate;

(4S) -4- {4- [ (1-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

(4R) -ethyl 4- {4- [ (1-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylate;

(4S) -4- [4- (tert-butylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylic acid ethyl ester;

(4R) -4- [4- (tert-butylcarbamoyl) piperidin-1-yl ] azepine-1-carboxylic acid ethyl ester;

ethyl 4- (4- { [ (1-methylcyclobutyl) methyl ] carbamoyl } piperidin-1-yl) azepine-1-carboxylate;

4- (4- { [1- (trifluoromethyl) cyclobutyl ] carbamoyl } piperidin-1-yl) azepine-1-carboxylic acid ethyl ester,

4- {4- [ (2-methylcyclopentyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4- {4- [ (3-methylenecyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4- {4- [ (3-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4- {4- [ (1-ethylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4-(4-{[2-(²H₃) Methyl group (²H₆) Propyl radical]Carbamoyl } piperidin-1-yl) azepine-1-carboxylic acid ethyl ester;

4- {4- [ (1-fluoro-2-methylprop-2-yl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4- {4- [ (2-methylpent-2-yl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4- { 4-methyl-4- [ (1-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4- { 4-methoxy-4- [ (1-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester;

4- { 4-methoxy-4- [ (1-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid but-2-yn-1-yl ester;

ethyl 4- (4-methoxy-4- { [ (1-methylcyclobutyl) methyl ] carbamoyl } piperidin-1-yl) azepine-1-carboxylate;

4- { 4-cyano-4- [ (1-methylcyclobutyl) carbamoyl ] piperidin-1-yl } azepine-1-carboxylic acid ethyl ester; and salts thereof.

9. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for use in the treatment of a cognitive or psychiatric disorder or for the treatment or alleviation of the severity of acute, chronic, neuropathic, or inflammatory pain.

11. The use according to claim 10, wherein the cognitive disorder is alzheimer's disease.

12. The use according to claim 10, wherein the cognitive disorder is dementia with lewy bodies.