Muscarinic agonists

Abstract

The present invention relates to compounds that are muscarinic M4 receptors and / or M4 receptor agonists and are suitable for treating diseases mediated by muscarinic M1 / M4 receptors. Also provided are pharmaceutical compositions containing the compounds and therapeutic uses of the compounds. The compounds include those according to formula 1a or salts thereof, wherein n, p, Q, R 1 , R 2 , R 3 , R 9 and R 4 is as defined herein.

Description

[0001] The present invention relates to compounds which are agonists of muscarinic M1 receptors and / or M4 receptors and are suitable for treating diseases mediated by muscarinic M1 / M4 receptors. Also provided are pharmaceutical compositions containing the compounds and therapeutic uses of the compounds. Background Art

[0002] Muscarinic acetylcholine receptor (mAChR) is a member of the G protein-coupled receptor superfamily, which mediates the effect of neurotransmitter acetylcholine in the central nervous system and peripheral nerve cells. Five mAChR subtypes have been cloned, M1 to M5. M1mAChR is mainly expressed postsynaptically in the cortex, hippocampus, striatum and thalamus; M2 mAChR is mainly located in the brainstem and thalamus, although also located in the cortex, hippocampus and striatum, where they reside in cholinergic synaptic terminals (Langmead et al., 2008Br JPharmacol). However, M2 mAChR is also expressed peripherally in cardiac tissue (wherein they mediate the vagal innervation of the heart) and in smooth muscle and exocrine glands. M3 mAChR is expressed at a fairly low level in the CNS, and is widely expressed in smooth muscle and glandular tissue (such as sweat glands and salivary glands) (Langmead et al., 2008Br J Pharmacol).

[0003] Muscarinic receptors (especially M1mAChR) in the central nervous system play an important role in mediating higher cognitive processing. Diseases associated with cognitive impairment (such as Alzheimer's disease) are accompanied by the loss of cholinergic neurons in the basal forebrain (Whitehouse et al., 1982Science). In schizophrenia, which also has cognitive impairment as a major component of clinical phenomena, mAChR density is reduced in the prefrontal cortex, hippocampus and caudate putamen of schizophrenia subjects (Dean et al., 2002Mol Psychiatry). In addition, in animal models, blocking or damaging central cholinergic pathways leads to significant cognitive deficits and non-selective mAChR antagonists have been shown to induce psychotomimetic effects in psychotic patients. Cholinergic replacement therapy is mostly based on the use of acetylcholinesterase inhibitors to prevent the decomposition of endogenous acetylcholine. These compounds have shown efficacy in the clinic for symptomatic cognitive impairment, but induce dose-limiting adverse events through stimulation of peripheral M2 and M3 mAChRs, including disturbed gastrointestinal motility, bradycardia, nausea, and vomiting ( http: / / www.drugs.com / pro / donepezil.html; http: / / www.drugs.com / pro / rivastigmine.html ).

[0004] Other discovery efforts have focused on the identification of direct M1 mAChR agonists with the goal of inducing selective improvements in cognitive function and a favorable adverse effect profile. Such work has enabled the identification of a range of agonists, exemplified by compounds such as xanomeline, AF267B, sabcomeline, miramemline, and cevimeline. Many of these compounds have been shown to be highly effective in preclinical cognitive models in both rodents and / or non-human primates. Miramemline has shown efficacy in rodents for scopolamine-induced working and spatial memory deficits; sabcomeline has demonstrated efficacy in marmosets in a visual object discrimination task, and xanomeline reverses mAChR antagonist-induced cognitive performance deficits in a passive avoidance paradigm.

[0005] Alzheimer's disease (AD) is the most common neurodegenerative disorder (266 million people worldwide in 2006), which affects the elderly, leading to significant memory loss and cognitive dysfunction. The etiology of the disease is very complex, but it is characterized by two characteristic brain pathological changes: aggregates of amyloid plaques composed mostly of amyloid-β peptides (Aβ) and neurofibrillary tangles in the form of hyperphosphorylated tau proteins. The accumulation of Aβ is considered to be an important characteristic of AD progression, and as such, many putative therapies for the treatment of AD currently target inhibition of Aβ production. Aβ is derived from the proteolytic cleavage of membrane-bound amyloid precursor protein (APP). APP is processed by two pathways, non-amyloid pathway and amyloid pathway. The cleavage of APP by γ-secretase is common to both pathways, but in the former, APP is cleaved by α-secretase to produce soluble APPα. However, in the amyloid pathway, APP is cleaved by β-secretase to produce soluble APPβ and also produce Aβ. In vitro studies have shown that mAChR agonists can promote APP processing toward soluble non-amyloid pathways. In vivo studies have shown that mAChR agonist AF267B alters disease-like pathology in 3xTgAD transgenic mice (a model of different composition of Alzheimer's disease) (Caccamo et al., 2006 Neuron). The mAChR agonist Cevimeline has been shown to cause a small but significant reduction in cerebrospinal fluid Aβ levels in Alzheimer's patients, thus confirming potential disease-modifying efficacy (Nitsch et al., 2000 Neurol).

[0006] Preclinical studies have shown that mAChR agonists display atypical antipsychotic sample curves in a series of preclinical models. mAChR agonist xanomeline reverses the restless movement (without EPS tendency) of amphetamine-induced in the dopamine agonist-driven transition and monkey in the rat of many dopamine-mediated behaviors (including the movement of amphetamine induction) in rats, the crawling of apomorphine induction in mice, unilateral 6-OH-DA damage. The agonist also shows inhibition of A10 rather than A9 (dopamine cell discharge and conditioned avoidance), and induces c-fos expression in rat prefrontal cortex and nucleus accumbens rather than in striatum. These data all show atypical antipsychotic sample curves (Mirza et al., 1999CNS Drug Rev).

[0007] Xanomeline, sabcomeline, miramemline, 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 of xanomeline have demonstrated its efficacy for various cognitive symptom domains, 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 schizophrenia and showed a significant reduction in positive and negative symptoms when compared to a placebo control (Shekhar et al., 2008 Am J Psych). However, in all clinical studies, xanomeline and other related mAChR agonists have demonstrated unacceptable safety margins for cholinergic adverse events, including nausea, gastrointestinal pain, diarrhea, diaphoresis (excessive sweating), hypersalivation (excessive saliva secretion), syncope, and bradycardia.

[0008] Muscarinic receptors are involved in central and peripheral pain. Pain can be divided into three different types: acute, inflammatory and neuropathic. Acute pain has an important protective function in protecting the safety of the organism from the influence of stimuli that can cause tissue damage, but it is necessary to manage postoperative pain. Inflammatory pain can occur for many reasons, including tissue damage, autoimmune response 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 pain sensations to non-painful stimuli. Neuropathic pain is associated with many different diseases / traumas such as spinal cord injury, multiple sclerosis, diabetes (diabetic neuropathy), viral infections (such as HIV or herpes). Neuropathic pain is also common in cancer due to the side effects of the disease or chemotherapy. Activation of muscarinic receptors has been shown to be analgesic for many pain stages by activating receptors in the spinal cord and higher pain centers in the brain. Increasing endogenous acetylcholine levels by acetylcholinesterase inhibitors, directly activating muscarinic receptors with agonists or allosteric modulators have been shown to have analgesic activity. Conversely, blocking muscarinic receptors using antagonists or using knockout mice increases pain sensitivity. Evidence for a role of the M1 receptor in pain is reviewed by DF Fiorino and M. Garcia-Guzman, 2012.

[0009] Recently, a small number of compounds have been identified that exhibit improved selectivity for the M1 mAChR subtype relative to peripherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg Med Chem Lett; Johnson et al., 2010 Bioorg Med Chem Lett; Budzik et al., 2010 ACS Med Chem Lett). Despite the increased level of selectivity for the M3 mAChR subtype, some of these compounds retain significant agonist activity at this subtype and the M2 mAChR subtype. Described herein is a series of compounds that unexpectedly exhibit high levels of selectivity for the M1 and / or M4 mAChR relative to the M2 and M3 receptor subtypes.

[0010] invention

[0011] The present invention provides compounds having activity as muscarinic M1 and / or M4 receptor agonists. More specifically, the present invention provides compounds that exhibit selectivity for the M1 receptor and / or M4 receptor over the M2 and M3 receptor subtypes.

[0012] Therefore, in a first embodiment (Embodiment 1.1), the present invention provides a compound of formula (1) or formula (1a):

[0013]

[0014] or a salt thereof, wherein

[0015] n is 1 or 2

[0016] p is 0, 1, or 2

[0017] Q is a five-, six- or seven-membered monocyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatom ring members selected from N, O and S;

[0018] R 1 Selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR 5 and SO2R 5 ; C optionally substituted by one to six fluorine atoms 1-6 non-aromatic hydrocarbon groups, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof; and optionally substituted 5- or 6-membered rings containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;

[0019] R 2 Selected from hydrogen; fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R6 SR 5 ;SOR 5 and SO2R 5 ; C 1-6 Non-aromatic hydrocarbon group; or R 1 and R 2 Can be linked together to form a 6-membered fused aromatic ring;

[0020] R 9 is selected from hydrogen, CH3, CH2OH, CH(CH3)OH, C(CH3)2OH and COOCH3;

[0021] R 3 is selected from hydrogen; fluorine; cyano; hydroxyl; amino; and C optionally substituted by one to six fluorine atoms 1-9 a non-aromatic hydrocarbon group, wherein one, two or three but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof;

[0022] R 4 is hydrogen or C optionally substituted by one to six fluorine atoms 1-6 a non-aromatic hydrocarbon group, wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof;

[0023] R 5 , R 6 and R 7 are the same or different and are each independently selected from hydrogen, non-aromatic C optionally substituted by one or more fluorine atoms 1-4 Hydrocarbon; or CH2N(R a )COOR b Group;

[0024] R a Selected from hydrogen and non-aromatic C 1-4 Hydrocarbon;

[0025] R b is a non-aromatic C optionally substituted by one or more groups selected from 1-4 Hydrocarbyl: fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; amino; or cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0026] and the dashed line indicates an optional second carbon-carbon bond, provided that when the second carbon-carbon bond is present, then R 3 Does not exist.

[0027]

[0028] or a salt thereof, wherein

[0029] n is 1 or 2

[0030] p is 0, 1, or 2

[0031] Q is a five-, six- or seven-membered monocyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatom ring members selected from N, O and S;

[0032] R 1 Selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR 5 and SO2R 5 ; C optionally substituted by one to six fluorine atoms 1-6 non-aromatic hydrocarbon groups, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof; and optionally substituted 5- or 6-membered rings containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;

[0033] R 2 Selected from hydrogen; fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR5 和 S02R 5; C 1-6 Non-aromatic hydrocarbon group; or R 1 and R 2 Can be linked together to form a 6-membered fused aromatic ring;

[0034] R 3 is selected from hydrogen; fluorine; cyano; hydroxyl; amino; and C optionally substituted by one to six fluorine atoms 1-9 a non-aromatic hydrocarbon group, wherein one, two or three but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof;

[0035] R 4 is hydrogen or C optionally substituted by one to six fluorine atoms 1-6 a non-aromatic hydrocarbon group, wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof;

[0036] R 5 , R 6 and R 7 are the same or different and are each independently selected from hydrogen, non-aromatic C optionally substituted by one or more fluorine atoms 1-4 Hydrocarbon; or CH2N(R a )COOR b Group;

[0037] R a Selected from hydrogen and non-aromatic C1-4 hydrocarbon groups;

[0038] R b is a non-aromatic C optionally substituted by one or more groups selected from 1-4 Hydrocarbyl: fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; amino; or cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0039] and the dashed line indicates an optional second carbon-carbon bond, provided that when the second carbon-carbon bond is present, then R 3 Does not exist.

[0040] Specific compounds of formula (1) or (1a) are defined as in Embodiments 1.2 to 1.180 listed below.

[0041] 1.2 A compound according to Embodiment 1.1 wherein Q is an aromatic or unsaturated heterocyclic ring.

[0042] 1.3 A compound according to Embodiment 1.2 wherein Q is an aromatic heterocycle.

[0043] 1.4 A compound according to Embodiment 1.3 wherein Q is an aromatic heterocycle containing a nitrogen ring member and optionally one or two further ring members selected from O, N and S.

[0044] 1.5 A compound according to Embodiment 1.4 wherein Q is an aromatic heterocycle containing a nitrogen ring member and optionally one other ring member selected from O, N and S.

[0045] 1.6 A compound according to Embodiment 1.5 wherein Q is an aromatic heterocycle containing one or two nitrogen ring members.

[0046] 1.7 A compound according to any one of Embodiments 1.1 to 1.6, wherein Q is a five-membered heterocyclic ring connected to an adjacent six-membered ring via a carbon atom of the five-membered heterocyclic ring.

[0047] 1.8 A compound according to any one of Embodiments 1.1 to 1.6, wherein Q is a five-membered heterocyclic ring connected to the adjacent six-membered ring via a nitrogen atom of the five-membered heterocyclic ring.

[0048] 1.9 A compound according to Embodiment 1.1 wherein Q is selected from 1-pyrrolyl, 2-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-thiazolyl, 2-oxazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl and tautomeric forms thereof.

[0049] 1.10 A compound according to Embodiment 1.6 wherein Q is a pyrrole ring.

[0050] 1.11 Compounds according to Embodiment 1.6, wherein Q is an imidazole ring

[0051] 1.12 A compound according to Embodiment 1.6 wherein Q is a pyrazole ring.

[0052] 1.13 A compound according to Embodiment 1.6 wherein Q is selected from 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl and tautomeric forms thereof.

[0053] 1.14 A compound according to Embodiment 1.1 wherein Q is a 6-membered ring containing one or more nitrogen atoms.

[0054] 1.15 A compound according to Embodiment 1.14 wherein Q is pyridyl, pyrazolyl or 2-oxo-3N(3-piperidin-2-one) containing a 0-2C-C unsaturated bond.

[0055] 1.16 A compound according to Embodiment 1.1 wherein Q is a 5-, 6- or 7-membered unsaturated heterocyclic ring.

[0056] 1.17 A compound according to Embodiment 1.16 wherein Q is 5-pyrollidinyl.

[0057] 1.18 A compound according to any one of Embodiments 1.1 to 1.17 wherein R 1 Selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR 5 and SO2R 5 ; C optionally substituted by one to six fluorine atoms 1-6 non-aromatic hydrocarbon groups, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof; and optionally substituted 5- or 6-membered rings containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;

[0058] The optional substituents of the optionally substituted 5-membered or 6-membered ring are selected from the group R consisting of 8 :Hydrogen; Fluorine; Chlorine; Bromine; Cyano; Oxo; Hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR 5 and SO2R 5; C optionally substituted by one to six fluorine atoms 1-6 A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0059] 1.19 A compound according to Embodiment 1.18 wherein R 1 Selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR 5 and SO2R 5 ; C optionally substituted by one to six fluorine atoms 1-5 non-aromatic hydrocarbon groups, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof; and optionally substituted 5- or 6-membered rings containing 0, 1 or 2 heteroatoms selected from O, N and S and oxidized forms thereof;

[0060] The optional substituents of the optionally substituted 5-membered or 6-membered ring are selected from the group R consisting of 8 :Fluorine; Chlorine; Bromine; Cyano; Oxo; Hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR5; OCONR 5 R 6 SR 5 ;SOR 5and SO2R 5 ; C optionally substituted by one to six fluorine atoms 1-4 A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0061] 1.20 A compound according to Embodiment 1.19 wherein R 1 Selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR 5 and SO2R 5 ; C optionally substituted by one to six fluorine atoms 1-4 non-aromatic hydrocarbon groups, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof; and optionally substituted 5- or 6-membered aryl or heteroaryl groups containing 0, 1 or 2 heteroatoms selected from O, N and S and oxidized forms thereof;

[0062] The optional substituents of the optionally substituted 5-membered or 6-membered aryl or heteroaryl are selected from the group consisting of 8 :Fluorine; Chlorine; Bromine; Cyano; Oxo; Hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R6 SR 5 ;SOR 5 and SO2R 5 ; a C1-4 non-aromatic hydrocarbon group optionally substituted by one to six fluorine atoms, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0063] 1.21 A compound according to any one of Embodiments 1.1 to 1.17 wherein R 1 Selected from hydrogen; fluorine; chlorine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 ;SO2R 5 ; C optionally substituted by one to six fluorine atoms 1-4 A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof; and an optionally substituted 5-membered or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, wherein the optional substituents of the optionally substituted 5-membered or 6-membered ring are selected from the group consisting of 8 :Fluorine; Chlorine; Bromine; Cyano; Oxo; Hydroxyl; OR 5 NR5R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;OCONR 5 R 6 SR 5 ;SOR 5and SO2R 5 ; and C optionally substituted by one to six fluorine atoms 1-4 A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0064] 1.22 A compound according to Embodiment 1.21 wherein R 1 Selected from hydrogen; fluorine; chlorine; cyano; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR7CONR 5 R 6 NR7COOR 5 ;OCONR 5 R 6 ;SO2R 5 ; and C optionally substituted by one to six fluorine atoms 1-4 A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0065] 1.23 A compound according to Embodiment 1.22 wherein R 1 Selected from hydrogen; fluorine; chlorine; cyano; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 NR 7 CONR 5 R 6 NR 7 COOR 5 ;SO2R 5 ; and C optionally substituted by one to six fluorine atoms 1-4 Non-aromatic hydrocarbon groups.

[0066] 1.24 A compound according to Embodiment 1.23 wherein R 1 Selected from hydrogen; fluorine; chlorine; cyano; NR 5 R6 ;COR 5 ;COOR 5 and C optionally substituted by one to six fluorine atoms 1-6 Non-aromatic hydrocarbon groups.

[0067] 1.25 A compound according to Embodiment 1.24 wherein R 1 Selected from hydrogen; fluorine; chlorine; cyano; NH2, COR 5 ;COOR 5 and C optionally substituted by one to six fluorine atoms 1-4 Saturated non-aromatic hydrocarbon group.

[0068] 1.26 A compound according to Embodiment 1.25 wherein R 1 Selected from hydrogen; COR 5 ;COOR 5 ;CONR 5 R 6 and C 1-4 alkyl.

[0069] 1.27 A compound according to Embodiment 1.26 wherein R 1 Selected from hydrogen; COR 5 ;COOR 5 and C 1-3 alkyl.

[0070] 1.28 A compound according to Embodiment 1.27 wherein R 1 Selected from hydrogen; methyl; ethyl and COOR 5 .

[0071] 1.29 A compound according to Embodiment 1.28 wherein R1 是 hydrogen.

[0072] 1.30 A compound according to Embodiment 1.28 wherein R 1 It is methyl or ethyl.

[0073] 1.31 A compound according to any one of Embodiments 1.18 to 1.28 wherein R 1 COOMe; COOEt; COMe; COEt; CONH2; CF3; CONHMe; CON(Me)2; COCF3; CO-cyclopropyl; CO-cyclobutyl; CONHEt; COH; NH2; OMe;

[0074] 1.32 A compound according to any one of Embodiments 1.1 to 1.31 wherein R 2 is selected from hydrogen; fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; and C 1-6Non-aromatic hydrocarbon group; or 1 Connected together to form a 6-membered fused aromatic ring.

[0075] 1.33 A compound according to Embodiment 1.32 wherein R 2 is selected from hydrogen; fluorine; hydroxyl; methoxy; and C 1-6 Non-aromatic hydrocarbon groups.

[0076] 1.34 A compound according to Embodiment 1.33 wherein R 2 is selected from hydrogen; fluorine; methoxy; and C 1-4 Saturated hydrocarbon group.

[0077] 1.35 A compound according to Embodiment 1.34 wherein R 2 is selected from hydrogen; fluorine; methoxy; and C 1-4 alkyl.

[0078] 1.36 A compound according to Embodiment 1.35 wherein R 2 Selected from hydrogen and C 1-3 alkyl.

[0079] 1.37 A compound according to Embodiment 1.36 wherein R 2 is selected from hydrogen and methyl.

[0080] 1.38 A compound according to Embodiment 1.32 wherein R 2 With R 1 The 6-membered fused aromatic ring is linked together and the aromatic ring may be aryl or heteroaryl.

[0081] 1.39 Compounds according to Embodiments 1.1 to 1.38 wherein R 9 Selected from hydrogen, CH2OH, CH(CH3)OH, C(CH3)2OH and COOCH3.

[0082] 1.40 A compound according to any one of Embodiments 1.1 to 1.39, wherein the dashed line represents an optional second carbon-carbon bond and R 3 Does not exist.

[0083] 1.41 A compound according to any one of Embodiments 1.1 to 1.39 wherein R 3 is present and the optional second carbon-carbon bond is not present.

[0084] 1.42 A compound according to Embodiment 1.41 wherein R 3 is selected from hydrogen; fluorine; cyano; hydroxyl; amino; and C optionally substituted by one to six fluorine atoms 1-6A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0085] 1.43 A compound according to Embodiment 1.42 wherein R 3 is selected from hydrogen; fluorine; cyano; hydroxyl; amino; and C optionally substituted by one to six fluorine atoms 1-6 A non-aromatic hydrocarbyl group, and wherein one but not all carbon atoms of the hydrocarbyl group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0086] 1.44 A compound according to Embodiment 1.43 wherein R 3 Selected from hydrogen; fluorine; cyano; hydroxyl; amino; C 1-4 Alkyl and C 1-4 Alkoxy, wherein the C 1-4 Alkyl and C 1-4 The alkoxy groups are each optionally substituted with one to six fluorine atoms.

[0087] 1.45 A compound according to Embodiment 1.44 wherein R 3 is selected from hydrogen; fluorine; hydroxyl and methoxy.

[0088] 1.46 A compound according to Embodiment 1.45 wherein R 3 It's hydrogen.

[0089] 1.47 A compound according to any one of Embodiments 1.1 to 1.46 wherein R 4 is hydrogen or acyclic C 1-6 Hydrocarbon.

[0090] 1.48 A compound according to Embodiment 1.47 wherein R 4 is hydrogen or acyclic C 1-3 Hydrocarbon.

[0091] 1.49 A compound according to Embodiment 1.48 wherein R 4 is hydrogen or C 1-3 Alkyl or C 2-3 Alkynyl.

[0092] 1.50 A compound according to Embodiment 1.49 wherein R 4 is selected from hydrogen, methyl, ethyl, acetylene or 1-propyne.

[0093] 1.51 A compound according to Embodiment 1.50 wherein R 4 is selected from hydrogen and methyl.

[0094] 1.52 A compound according to Embodiment 1.51 wherein R 4 It's methyl.

[0095] 1.53 A compound according to any one of the preceding embodiments, wherein R 5 When present, it is a non-aromatic C optionally substituted with one or more fluorine atoms. 1-4 Hydrocarbon; or CH2N(R a )COOR b Group.

[0096] 1.54 A compound according to Embodiment 1.53 wherein the non-aromatic C 1-4 The hydrocarbon group is saturated C 1-4 Hydrocarbon.

[0097] 1.55 A compound according to any one of Embodiments 1.1 to 1.52 wherein R 5 When present it is hydrogen.

[0098] 1.56 A compound according to any one of Embodiments 1.1 to 1.52 wherein R 5 When present, it is selected from hydrogen and saturated C 1-4 Hydrocarbon.

[0099] 1.57 A compound according to Embodiment 1.54 or Embodiment 1.56 wherein the saturated C 1-4 The hydrocarbon group is C 1-4 alkyl.

[0100] 1.58 A compound according to Embodiment 1.57 wherein the saturated C 1-4 The hydrocarbon group is C 1-3 alkyl.

[0101] 1.59 A compound according to Embodiment 1.58 wherein said C 1-3 The alkyl group is selected from methyl, ethyl and isopropyl.

[0102] 1.60 A compound according to Embodiment 1.59 wherein said C 1-3 The alkyl group is ethyl.

[0103] 1.61 A compound according to any one of the preceding embodiments, wherein R 6 When present, it is non-aromatic C 1-4 Hydrocarbon.

[0104] 1.62 A compound according to Embodiment 1.61 wherein the non-aromatic C 1-4 The hydrocarbon group is saturated C 1-4 Hydrocarbon.

[0105] 1.63 A compound according to any one of Embodiments 1.1 to 1.60 wherein R 6 When present it is hydrogen.

[0106] 1.64 A compound according to any one of Embodiments 1.1 to 1.60 wherein R 6 When present, it is selected from hydrogen and saturated C 1-4 Hydrocarbon.

[0107] 1.65 A compound according to Embodiment 1.61 or Embodiment 1.64 wherein the saturated C 1-4 The hydrocarbon group is C 1-4 alkyl.

[0108] 1.66 A compound according to Embodiment 1.65 wherein the saturated C 1-4 The hydrocarbon group is C 1-3 alkyl.

[0109] 1.67 A compound according to Embodiment 1.66 wherein said C 1-3 The alkyl group is selected from methyl, ethyl and isopropyl.

[0110] 1.68 A compound according to any one of the preceding embodiments, wherein R 7 When present, it is non-aromatic C 1-4 Hydrocarbon.

[0111] 1.69 A compound according to Embodiment 1.68 wherein the non-aromatic C 1-4 The hydrocarbon group is saturated C 1-4 Hydrocarbon.

[0112] 1.70 A compound according to any one of Embodiments 1.1 to 1.67 wherein R 7 When present it is hydrogen.

[0113] 1.71 A compound according to any one of Embodiments 1.1 to 1.67 wherein R 7 When present, it is selected from hydrogen and saturated C 1-4 Hydrocarbon.

[0114] 1.72 A compound according to Embodiment 1.69 or Embodiment 1.71 wherein the saturated C 1-4 The hydrocarbon group is C 1-4 alkyl.

[0115] 1.73 A compound according to Embodiment 1.72 wherein the saturated C 1-4 The hydrocarbon group is C 1-3 alkyl.

[0116] 1.74 A compound according to Embodiment 1.73 wherein said C 1-3 The alkyl group is selected from methyl, ethyl and isopropyl.

[0117] 1.75 A compound according to any one of the preceding embodiments, wherein when R 1 When is an optionally substituted 5- or 6-membered ring, it is selected from an aromatic ring containing 0, 1 or 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

[0118] 1.76 A compound according to Embodiment 1.75 wherein the aromatic ring is a carbocyclic ring.

[0119] 1.77 A compound according to Embodiment 1.75 wherein the aromatic ring is a heterocyclic ring.

[0120] 1.78 A compound according to any one of Embodiments 1.1 to 1.74 wherein when R 1 When is an optionally substituted 5- or 6-membered ring, it is selected from non-aromatic rings containing 0, 1 or 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

[0121] 1.79 A compound according to Embodiment 1.78 wherein the non-aromatic ring is a carbocyclic ring.

[0122] 1.80 A compound according to Embodiment 1.78 wherein the non-aromatic ring is a heterocycle.

[0123] 1.81 A compound according to any one of Embodiments 1.75 to 1.80 wherein the ring is a 5-membered ring.

[0124] 1.82 A compound according to any one of Embodiments 1.75 to 1.80 wherein the ring is a 6-membered ring.

[0125] 1.83 A compound according to any one of the preceding embodiments, wherein when R 1 When it is an optionally substituted 5-membered or 6-membered ring, it is substituted by 0, 1, 2 or 3 substituents R 8 replace.

[0126] 1.84 A compound according to Embodiment 1.83 wherein there are 0, 1 or 2 substituents R 8 .

[0127] 1.85 A compound according to Embodiment 1.84 wherein there are 0 substituents R 8 .

[0128] 1.86 A compound according to Embodiment 1.83 wherein there is 1 substituent R 8 .

[0129] 1.87 A compound according to Embodiment 1.83 wherein there are 2 substituents R 8 .

[0130] 1.88 A compound according to any one of Embodiments 1.82, 1.83, 1.84, 1.86 and 1.87 wherein R 8 When present is selected from fluoro; cyano; oxo; hydroxy; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 NR 7 COR 5 ;CONR 5 R 6 SR 5 ;SOR 5 and SO2R 5 ; and C optionally substituted by one to six fluorine atoms 1-6 A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0131] 1.89 A compound according to Embodiment 1.88 wherein R 8 Selected from fluorine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 and SO2R 5 ; and C optionally substituted by one to six fluorine atoms 1-4 A non-aromatic hydrocarbon group, and wherein one or two but not all carbon atoms of the hydrocarbon group may be optionally replaced by heteroatoms selected from O, N and S and oxidized forms thereof.

[0132] 1.90 A compound according to Embodiment 1.89 wherein R 8 Selected from fluorine; cyano; oxo; hydroxyl; OR 5 NR 5 R 6 ; and C optionally substituted by one to six fluorine atoms 1-4 Non-aromatic hydrocarbon groups.

[0133] 1.91 A compound according to Embodiment 1.90 wherein R 8 Selected from cyano; oxo; hydroxyl; OR 5 NR 5R 6 ; and C 1-4 alkyl.

[0134] 1.92 A compound according to any one of Embodiments 1.1 to 1.91 wherein p is 0.

[0135] 1.93 A compound according to any one of Embodiments 1.1 to 1.91 wherein p is 1.

[0136] 1.94 A compound according to any one of Embodiments 1.1 to 1.91 wherein p is 2.

[0137] 1.95 A compound according to any one of Embodiments 1.1 to 1.94 wherein n is 1.

[0138] 1.96 A compound according to any one of Embodiments 1.1 to 1.94 wherein n is 2.

[0139] 1.97 A compound according to any one of Embodiments 1.1 to 1.39 and 1.41 to 1.52 wherein the moiety:

[0140]

[0141] Selected from the following groups A to D:

[0142]

[0143] Where R 1 , R 2 and R 9 is as defined in any one of Embodiments 1.1 to 1.39 and 1.41 to 1.91.

[0144] 1.98 A compound according to formula (2):

[0145]

[0146] wherein n is 1 or 2, p is 0, 1 or 2, Q is an optionally substituted 5-, 6- or 7-membered heterocyclic or heteroaryl ring having one or more nitrogen atoms, and R 4 is as defined in any one of Embodiments 1.47 to 1.52.

[0147] 1.99 A compound according to Embodiments 1.1 to 1.91 having the following formula (3) or formula (3a):

[0148]

[0149] Where n is 1 or 2, p is 0, 1 or 2, R 1 , R2 , R 9 and R 4 is as defined in any one of Embodiments 1.1 to 1.39 and 1.41 to 1.91 and said Ring A is a five-membered heterocyclic or heteroaryl ring containing one or two nitrogen ring members.

[0150] 1.100 A compound according to Embodiment 1.99 wherein Ring A is a five-membered heteroaryl ring containing two nitrogen ring members.

[0151] 1.101 A compound according to Embodiment 1.100 wherein Ring A is an imidazole ring.

[0152] 1.102 A compound according to Embodiment 1.101 which has the following formula (4) or formula (4a):

[0153]

[0154] Where n is 1 or 2, p is 0, 1 or 2, R 1 , R 2 , R 9 and R 4 is as defined in any one of Embodiments 1.1 to 1.39 and 1.41 to 1.91.

[0155] 1.103 A compound according to Embodiment 1.100 wherein Ring A is a pyrazole ring.

[0156] 1.104 A compound according to Embodiment 1.103 which has the following formula (5) or formula (5a):

[0157]

[0158] Where n is 1 or 2, p is 0, 1 or 2, R 1 , R 2 , R 9 and R 4 is as defined in any one of Embodiments 1.1 to 1.39 and 1.41 to 1.91.

[0159] 1.105 A compound according to Embodiment 1.94 wherein Ring A is a 5-membered heteroaryl ring containing one nitrogen atom.

[0160] 1.106 A compound according to Embodiment 1.100 which has the following formula (6) or formula (6a):

[0161]

[0162] Where n is 1 or 2, p is 0, 1 or 2, R 1 , R2 , R 9 and R 4 is as defined in any one of Embodiments 1.1 to 1.39 and 1.41 to 1.91.

[0163] 1.107 A compound according to Embodiment 1.106 wherein the moiety:

[0164]

[0165] yes:

[0166]

[0167] 1.108 A compound according to Embodiment 1.1 wherein Q is a five-membered monocyclic heterocycle containing 1, 2, 3 or 4 heteroatom ring members selected from N, O and S.

[0168] 1.109 A compound according to Embodiment 1.1 which is as defined in any one of Embodiments 1-1 to 2.12.

[0169] 1.110 A compound according to any one of Embodiments 1.1 to 1.104 having a molecular weight of less than 550.

[0170] 1.111 A compound according to Embodiment 1.110 which has a molecular weight of less than 500.

[0171] 1.112 A compound according to Embodiment 1.111 which has a molecular weight of 450 or less.

[0172] 1.113 A compound according to any one of Embodiments 1.1 to 1.112 which is in the form of a salt.

[0173] 1.114 A compound according to Embodiment 1.113 wherein the salt is an acid addition salt.

[0174] 1.115 A compound according to Embodiment 1.113 or Embodiment 1.114 wherein the salt is a pharmaceutically acceptable salt.

[0175] definition

[0176] In this application, the following definitions apply unless indicated otherwise.

[0177] The term "treatment" in connection with the use of a compound of formula (1) or formula (1a) is used to describe any form of intervention in which the compound is administered to a subject suffering from, or at risk of, or potentially at risk of the disease or condition in question. Thus, the term "treatment" encompasses both preventive (prophylactic) treatment and treatment in which measurable or detectable symptoms of a disease or condition are exhibited.

[0178] As used herein, the term "therapeutically effective amount" (e.g., in connection with a method of treating a disease or condition) refers to an amount of a compound effective to produce a desired therapeutic effect. For example, if the condition is pain, then the therapeutically effective amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief can be, for example, complete removal of pain or a decrease in pain severity.

[0179] The term "non-aromatic hydrocarbon group" (as in "C 1-10 Non-aromatic hydrocarbon group" or "acyclic C 1-5 The term "non-aromatic hydrocarbon group" refers to a group consisting of carbon atoms and hydrogen atoms and not containing an aromatic ring. The hydrocarbon 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 bonds and triple bonds. The hydrocarbon group may be a straight chain or branched chain group or may consist of or contain a cyclic group. Therefore, the term non-aromatic hydrocarbon includes alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl and the like.

[0180] Unless otherwise indicated, the terms "alkyl," "alkenyl," "alkynyl," "cycloalkyl," aryl, heteroaryl, and "cycloalkenyl" are used in their conventional meanings (eg, as defined in the IUPAC Gold Book).

[0181] The term "saturated hydrocarbon group" as in "C 1-4 The term "saturated hydrocarbon group" refers to a hydrocarbon group that does not contain double or triple carbon-carbon bonds. The saturated hydrocarbon group may therefore be an alkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl or alkylcycloalkylalkyl group. 1-4 Examples of saturated hydrocarbon groups include C 1-4 alkyl, cyclopropyl, cyclobutyl and cyclopropylmethyl.

[0182] The term "cycloalkyl" as used herein includes monocyclic cycloalkyls (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl) and bicyclic and tricyclic groups, where the specified number of carbon atoms is permitted. Bicyclic cycloalkyls include bridged ring systems, such as bicycloheptane, bicyclooctane and adamantane.

[0183] In the above R 1 , R 2 , R 3 and R 4In the definition of, where specified, one or two, but not all, carbon atoms of the non-aromatic hydrocarbon group may optionally be selected from O, N and S and (in R 1 and R 4 In the case of a carbon atom, a carbon atom is replaced with a heteroatom (in the case of a carbon atom in an oxidized form thereof). It will be appreciated that when a carbon atom is replaced with a heteroatom, the lower valence of the heteroatom compared to carbon means that fewer atoms will be bound to the heteroatom than would have been bound to the replaced carbon atom. Thus, for example, replacing a carbon atom in a CH2 group (a compound is four) with oxygen (a valence of two) will mean that the resulting molecule will contain two fewer hydrogen atoms and replacing a carbon atom in a CH2 group (a valence of four) with nitrogen (a valence of three) will mean that the resulting molecule will contain one less hydrogen atom.

[0184] Examples of heteroatom replacement of carbon atoms include replacement of a carbon atom in a -CH2-CH2-CH2- chain with oxygen or sulfur to give an ether -CH2-O-CH2- or a thioether -CH2-S-CH2-, replacement of a carbon atom in a group CH2-C≡CH with nitrogen to give a nitrile (cyano) group CH2-C=N, replacement of a carbon atom in a group -CH2-CH2-CH2- with C=O to give a ketone CH2-C(O)-CH2-, replacement of a carbon atom in a group -CH2-CH2-CH2- with S=O or SO2 To obtain sulfoxide -CH2-S(O)-CH2- or sulfone -CH2-S(O)2-CH2-, to replace carbon atoms in the -CH2-CH2-CH2-chain with C(O)NH to obtain amides -CH2-CH2-C(O)-NH-, to replace carbon atoms in the -CH2-CH2-CH2-chain with nitrogen to obtain amines -CH2-NH-CH2-, and to replace carbon atoms in the -CH2-CH2-CH2-chain with C(O)O to obtain esters (or carboxylic acids) CH2-CH2-C(O)-O-. In each such substitution, at least one carbon atom of the hydrocarbon group must be retained.

[0185] Salt

[0186] Many compounds of formula (1) or (1a) may exist in salt form, for example acid addition salts or, in certain cases, salts of organic and inorganic bases, for example carboxylates, sulfonates and phosphates. All such salts are within the scope of the invention and reference to compounds of formula (1) or (1a) includes salt forms of said compounds as defined in Embodiments 1.113 to 1.115.

[0187] The salts are typically acid addition salts.

[0188] The salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods such as those described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used.

[0189] Acid addition salts (as defined in Embodiment 1.120) can be formed with a wide variety of acids (both inorganic and organic). Examples of acid addition salts falling within Embodiment 1.113 include monobasic or dibasic salts formed with an acid selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, butyric acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic 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, mucic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-ketoglutamic acid, ... Glutaric 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, 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, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid, as well as acylated amino acids and cation exchange resins.

[0190] In case the compounds of formula (1) or (1a) contain amine functional groups, these can form quaternary ammonium salts, for example by reaction with alkylating agents according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (1) or (1a), respectively.

[0191] The compounds of the present invention may exist as monobasic or dibasic salts depending on the pKa of the acid forming the salt.

[0192] The 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, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, pharmaceutically unacceptable salts may also be prepared as intermediate forms, which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in the purification or isolation of the compounds of the present invention, also form part of the present invention.

[0193] Stereoisomers

[0194] Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bound atoms but differ only in the three-dimensional orientation of their atoms in space. Stereoisomers may be, for example, geometric isomers or optical isomers.

[0195] Geometric isomers

[0196] In the case of geometric isomers, the isomerism is due to different orientations of atoms or groups about a double bond, such as cis and trans (Z and E) isomerism about a double bond, or cis and trans isomerism about an amide bond, or cis and trans isomerism about a carbon-nitrogen double bond (e.g., in oximes), or rotational isomerism about a bond about which there is hindered rotation, or cis and trans isomerism about a ring (such as a cycloalkane ring).

[0197] Thus, in another embodiment (Embodiment 1.121), the invention provides a geometric isomer of a compound according to any one of Embodiments 1.1 to 1.115.

[0198] Optical isomers

[0199] Unless the context requires otherwise, where a compound of a formula contains one or more chiral centers and can exist in the form of two or more optical isomers, reference to the compound includes all optical isomeric forms thereof (e.g., enantiomers, epimers, and diastereomers), either as individual optical isomers or as mixtures (e.g., racemic mixtures) or two or more optical isomers.

[0200] Thus, in another embodiment (Embodiment 1.132), the invention provides a compound according to any one of Embodiments 1.1 to 1.121 containing a chiral centre.

[0201] Optical isomers can be characterized and identified by their optical activity (i.e., as + and - isomers or d and l isomers) or they can be characterized according to their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry, Jerry March, 4th edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separated by a variety of techniques including chiral chromatography (chromatographic analysis on a chiral support), and such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid and (-)-camphorsulfonic acid, thereby separating the diastereomers by preferably crystallization and then dissociating the salts to obtain the individual enantiomers of the free base.

[0202] 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 enantiomers, for example, in terms of biological activity. Therefore, in some cases, it may be desirable to use only one of a pair of enantiomers or only one of a plurality of diastereomers as a therapeutic agent.

[0203] Thus, in another embodiment (Embodiment 1.133), the invention provides a composition comprising a compound having one or more chiral centers according to Embodiment 1.132, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Embodiment 1.132 exists in the form of a single optical isomer (e.g., enantiomer or diastereomer).

[0204] In one general embodiment (Embodiment 1.134), 99% or more (eg, substantially all) of the total amount of the compound of Embodiment 1.132 (or the compound for use) is present as a single optical isomer.

[0205] For example, in one embodiment (Embodiment 1.135), the compound exists as a single enantiomer.

[0206] In another embodiment (Embodiment 1.136), the compound exists as a single diastereoisomer.

[0207] The present invention also provides a mixture of optical isomers, which may be racemic or non-racemic. Therefore, the present invention provides:

[0208] 1.136 A compound according to Embodiment 1.132 which is in the form of a racemic mixture of optical isomers.

[0209] 1.137 A compound according to Embodiment 1.132 which is in the form of a non-racemic mixture of optical isomers.

[0210] isotope

[0211] The compounds of the invention as defined in any one of Embodiments 1.1 to 1.137 may contain one or more isotopic substitutions, and a reference to a specific element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope 1H, 2 H(D) and 3 H(T). Similarly, references to carbon and oxygen include within their scope 12 C. 13 C and 14 C and 16 O and 18 O.

[0212] In a similar manner, reference to a specific functional group also includes isotopic variations within its scope unless the context indicates otherwise. For example, reference to an alkyl group such as an ethyl group also includes variations in which one or more hydrogen atoms in the group are in the form of deuterium or tritium isotopes, for example, as in an ethyl group in which all five hydrogen atoms are in the form of deuterium isotopes (perdeuterated ethyl group).

[0213] Isotopes may be radioactive or non-radioactive. In one embodiment of the invention (Embodiment 1.140), none of the compounds of any one of Embodiments 1.1 to 1.137 contain a radioactive isotope. The compounds are preferably used for therapeutic purposes. However, in another embodiment (Embodiment 1.141), the compounds of any one of Embodiments 1.1 to 1.137 may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes may be useful in a diagnostic context.

[0214] Solvate

[0215] Compounds of formula (1) or (1a) as defined in any one of Embodiments 1.1 to 1.141 may form solvates. Preferred solvates are solvates formed by incorporating molecules of a non-toxic pharmaceutically acceptable solvent (hereinafter referred to as a solvating solvent) into a solid state structure (e.g., a crystal structure) of a compound of the invention. Examples of the solvent include water, alcohols (such as ethanol, isopropanol and butanol) and dimethyl sulfoxide. Solvates may be prepared by recrystallizing the compound of the invention with a solvent or a solvent mixture containing a solvating solvent. Whether a solvate has been formed in any given case may be determined by subjecting the crystals of the compound to analysis using known and standard techniques, such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography. Solvates may be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates.

[0216] Accordingly, in further embodiments 1.150 and 1.151, the invention provides:

[0217] 1.151 A compound according to any one of Embodiments 1.1 to 1.141 which is in the form of a solvate.

[0218] 1.152 A compound according to Embodiment 1.151 wherein the solvate is a hydrate.

[0219] For a more detailed discussion of solvates and methods for making and characterizing the same, see Bryn et al., Solid-State Chemistry of Drugs, 2nd edition, published by SSCI, Inc., West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0220] Alternatively, the compounds of the invention may be anhydrous rather than existing as a hydrate. Thus, in another embodiment (Embodiment 1.153), the invention provides a compound as defined in any one of Embodiments 1.1 to 1.141 in anhydrous form (eg anhydrous crystalline form).

[0221] Crystalline and amorphous forms

[0222] The compound described in any one of Embodiments 1.1 to 1.153 can exist in a crystalline or non-crystalline (e.g., amorphous) state. Whether a compound exists in a crystalline state can be easily determined by standard techniques such as X-ray powder diffraction (XRPD). A variety of techniques can be used to characterize crystals and their crystal structures, 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 crystals under different humidity conditions can be studied by gravity vapor sorption and can also be analyzed by XRPD. Determination of the crystal structure of a compound can be performed by X-ray crystallography which can be performed according to conventional methods such as those described herein and those described in Fundamentals of Crystallography, C. Giacovazzo, HL Monaco, D. Viterbo, F. Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union of Crystallography / Oxford University Press, 1992 ISBN 0-19-855578-4 (p / b), 0-19-85579-2 (h / b)). This technique involves the analysis and interpretation of X-ray diffraction of single crystals. In an amorphous solid, there is no three-dimensional structure that normally exists in a crystalline form, and the positions of the molecules relative to each other in an amorphous form are essentially random, see, for example, Hancock et al., J. Pharm. Sci. (1997), 86, 1).

[0223] Therefore, in further embodiments, the present invention provides:

[0224] 1.160 A compound according to any one of Embodiments 1.1 to 1.153 which is in crystalline form.

[0225] 1.161 A compound according to any one of Embodiments 1.1 to 1.153 which:

[0226] (a) is 50% to 100% crystalline, and more particularly is at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline, e.g. 100% crystalline.

[0227] 1.162 A compound according to any one of Embodiments 1.1 to 1.153 which is in amorphous form.

[0228] Prodrug

[0229] A compound of formula (1) or (1a) as defined in any one of Embodiments 1.1 to 1.162 may be presented in the form of a prodrug. "Prodrug" means any compound which is converted in vivo to a biologically active compound of formula (1) or (1a) as defined in any one of Embodiments 1.1 to 1.162.

[0230] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable metabolically labile esters). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. The esters can be formed, for example, by esterification of any hydroxyl groups present in the parent compound, if appropriate, with any other reactive groups present in the parent compound before protection, followed by deprotection as needed.

[0231] Likewise, some prodrugs are enzymatically activated to produce the active compound, or a compound that, after further chemical reaction, produces 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.

[0232] Thus, in another embodiment (Embodiment 1.170), the invention provides a prodrug of a compound as defined in any one of Embodiments 1.1 to 1.170 wherein the compound contains a functional group which is convertible under physiological conditions to form a hydroxyl or amino group.

[0233] Complexes and inclusion compounds

[0234] Also encompassed by formula (1) or formula (1a) of Embodiments 1.1 to 1.170 are complexes of the compounds of Embodiments 1.1 to 1.170 (eg, inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals).

[0235] Thus, in another embodiment (Embodiment 1.180), the invention provides a compound according to any one of Embodiments 1.1 to 1.170 in the form of a complex or inclusion compound.

[0236] born Bioactivity and therapeutic uses

[0237] The compounds of the invention have activity as muscarinic M1 receptor agonists. The muscarinic activity of the compounds can be determined using the phospho-ERK1 / 2 assay described in Example A below.

[0238] A significant advantage of the compounds of the present invention is that they have a high selectivity for the M1 receptor over the M2 and M3 receptor subtypes. The compounds of the present invention are not agonists of the M2 and M3 receptor subtypes. For example, the compounds of the present invention generally have a pEC of at least 6 (preferably at least 6.5) in the functional assay described in Example A. 50 and an E of greater than 80 (preferably greater than 95) for the M1 receptor. max values, which may have a pEC value of less than 5 when tested against M2 and M3 subtypes in the functional assay of Example A. 50 value and less than 20% of E max value.

[0239] The compounds of the present invention also have high selectivity for the M4 receptor over the M1 receptor. Examples of such compounds include the compounds of Examples 2-11 (Isomer 2).

[0240] Other compounds of the invention have activity at the M1 and M4 receptors. Examples of such compounds include the compounds of Examples 1 to 4 and 8 to 10.

[0241] Therefore, in embodiments 2.1 to 2.9, the present invention provides:

[0242] 2.1 A compound according to any one of Embodiments 1.1 to 1.180 for use in medicine.

[0243] 2.2 A compound according to any one of Embodiments 1.1 to 1.180 for use as a muscarinic M1 and / or M4 receptor agonist.

[0244] 2.3 A compound according to any one of Embodiments 1.1 to 1.180 having a pEC in the range of 6.0 to 8.5 in an assay of Example A herein or an assay substantially analogous thereto. 50 and at least 90% E for the M1 receptor max A muscarinic M1 receptor agonist.

[0245] 2.4 A compound according to Embodiment 2.3, which has a pEC in the range of 6.5 to 7.5 50 A muscarinic M1 receptor agonist.

[0246] 2.5 A compound according to Embodiment 2.3 or Embodiment 2.4 having an E of at least 95 for the M1 receptor max .

[0247] 2.6 A compound according to any one of Embodiments 1.1 to 1.180 having a pEC in the range of 6.0 to 9.1 in an assay of Example A herein or an assay substantially analogous thereto50 and at least 90% E for the M4 receptor max A muscarinic M4 receptor agonist.

[0248] 2.7 A compound according to Embodiment 2.6 having a pEC in the range of 6.5 to 8.0 50 A muscarinic M4 receptor agonist.

[0249] 2.8 A compound according to Embodiment 2.6 or Embodiment 2.7 having an E of at least 95 for the M4 receptor max .

[0250] 2.9 A compound according to any one of Embodiments 2.3 to 2.8 which has selectivity for M1 and / or M4 receptors over muscarinic M2 and M3 receptors.

[0251] 2.10 A compound according to Embodiment 2.9 which is selective for the M1 receptor over the muscarinic M2 and M3 receptors.

[0252] 2.11 A compound according to Embodiment 2.9 which is selective for the M4 receptor over the muscarinic M2 and M3 receptors.

[0253] 2.12 A compound according to any one of Embodiments 2.3 to 2.5 which is selective for the M1 receptor over the muscarinic M2, M3 and M4 receptors.

[0254] 2.13 A compound according to any one of Embodiments 2.6 to 2.8 which has selectivity for the M4 receptor over the muscarinic M1 , M2 and M3 receptors.

[0255] 2.14 A compound according to any one of Embodiments 2.3 to 2.8 which is selective for M1 and M4 receptors over muscarinic M2 and M3 receptors.

[0256] 2.15 A compound according to any one of Embodiments 2.3 to 2.14 having a pEC of less than 5 50 and an E of less than 50 for muscarinic M2 and M3 receptor subtypes mx。

[0257] 2.16 A compound according to Embodiment 2.15 having a pEC of less than 4.5 50 and / or an E of less than 30 for muscarinic M2 and M3 receptor subtypes mx .

[0258] 2.17 A compound according to any one of Embodiments 1.1 to 1.180 and Embodiments 2.3 to 2.16 for use in treating a disease or condition mediated by the muscarinic M1 receptor.

[0259] By virtue of their muscarinic M1 and / or M4 receptor agonist activity, the compounds of the present invention can be used to treat Alzheimer's disease, schizophrenia and other psychiatric disorders, cognitive disorders and other diseases mediated by muscarinic M1 and / or M4 receptors, and can also be used to treat various types of pain.

[0260] Thus, in embodiments 2.18 to 2.35, the present invention provides:

[0261] 2.18 A compound according to any one of Embodiments 1.1 to 1.180 for use in treating a cognitive disorder or a psychiatric disorder.

[0262] 2.19 A compound for use according to Embodiment 2.18, wherein the cognitive disorder or psychiatric disorder comprises, is caused by, or is associated with a condition selected from the group consisting of: cognitive impairment, mild cognitive impairment, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, presenile dementia, senile dementia, Friederich's ataxia, Down syndrome, Huntington's chorea, hyperkinesia, mania, Tourette syndrome, Alzheimer's disease, progressive supranuclear palsy, impairment of cognitive function including attention, orientation, learning disabilities, memory (i.e., memory impairment, amnesia, amnestic disorders, transient global amnesia syndrome, and age-related memory impairment), and language function; cognitive impairment due to stroke, Huntington's disease, Pick's disease, AIDS-related dementia or other dementia states such as multi-infarct dementia, alcoholic dementia, hypothyroidism-related dementia, and dementia associated with other degenerative conditions such as cerebellar atrophy and amyotrophic lateral sclerosis; Other acute or subacute conditions causing cognitive decline such as delirium or depression (pseudo-dementia status), trauma, head trauma, age-related cognitive decline, stroke, neurodegenerative diseases, drug-induced states, neurotoxic agents, age-related cognitive impairment, autism-related cognitive impairment, Down's syndrome, cognitive deficits associated with psychosis, and cognitive disorders associated with post-electroconvulsive therapy; cognitive disorders due to drug abuse or drug withdrawal (including nicotine, marijuana, amphetamines, cocaine), attention deficit hyperactivity disorder (ADHD), and movement disorders such as Parkinson's disease, neuroleptic-induced Parkinson's disease and tardive dyskinesia, schizophrenia, schizophreniform disorders, psychotic depression, mania, acute mania, paranoid, hallucinogenic and delusional disorders, personality disorders, obsessive-compulsive disorder, schizotypal disorder, delusional disorder, psychosis due to malignancy, metabolic disorders, endocrine diseases or narcolepsy, psychosis due to drug abuse or drug withdrawal, bipolar disorder, epilepsy, and schizoaffective disorder.

[0263] 2.20 A compound according to any one of Embodiments 1.1 to 1.180 for use in treating Alzheimer's disease.

[0264] 2.21 A compound according to any one of Embodiments 1.1 to 1.180 for use in treating schizophrenia.

[0265] 2.22 A compound according to any one of Embodiments 1.1 to 1.180 for use in treating Alzheimer's disease and / or Lewy body dementia.

[0266] 2.23 A method of treating a cognitive disorder in a subject (eg, a mammalian patient such as a human, eg, a human in need of such treatment), the method comprising administering a therapeutically effective dose of a compound according to any one of Embodiments 1.1 to 1.180.

[0267] 2.24 A method according to Embodiment 2.20 wherein the cognitive disorder comprises, is caused by or is associated with a condition as defined in Embodiment 2.19.

[0268] 2.25 A method according to Embodiment 2.24 wherein the cognitive disorder comprises, is caused by or is associated with Alzheimer's disease.

[0269] 2.26 A method according to Embodiment 2.24 wherein the cognitive disorder is schizophrenia.

[0270] 2.27 Use of a compound according to any one of Embodiments 1.1 to 1.180 for the manufacture of a medicament for treating a cognitive disorder.

[0271] 2.28 The use according to Embodiment 2.27 wherein the cognitive disorder comprises, is caused by or is associated with a condition as defined in Embodiment 2.11.

[0272] 2.29 The use according to Embodiment 2.28 wherein the cognitive disorder comprises, is caused by or is associated with Alzheimer's disease.

[0273] 2.30 The use according to Embodiment 2.28 wherein the cognitive disorder is schizophrenia.

[0274] 2.31 A compound according to any one of Embodiments 1.1 to 1.180 for use in treating or lessening the severity of acute, chronic neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, breakthrough pain, postoperative pain or cancer pain.

[0275] 2.32 A method of treating or lessening the severity of acute, chronic neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or refractory pain, nociceptive pain, breakthrough pain, postoperative pain or cancer pain, comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1.1 to 1.180.

[0276] 2.33 A compound according to any one of Embodiments 1.1 to 1.180 for use in treating a peripheral disorder such as reducing intraocular pressure in glaucoma and treating dry eyes and dry mouth (including Sjogren's syndrome).

[0277] 2.34 A method of treating a peripheral disorder, such as reducing intraocular pressure in glaucoma and treating dry eyes and dry mouth (including Sjogren's syndrome), comprising administering a therapeutically effective amount of a compound according to any one of Embodiments 1.1 to 1.180.

[0278] 2.35 Use of a compound according to any one of Embodiments 1.1 to 1.180 for the manufacture of a medicament for treating or lessening the severity of acute, chronic neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, visceral pain, osteoarthritis pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postoperative pain or cancer pain, or for the treatment of peripheral conditions such as reducing intraocular pressure in glaucoma and treating dry eyes and dry mouth (including Sjogren's syndrome).

[0279] Method for preparing compounds of formula (1) and formula (1a)

[0280] Compounds of formula (1) and formula (1a) can be prepared according to synthetic methods well known to the skilled artisan and as described herein.

[0281] Thus, in another embodiment (Embodiment 3.1), the invention provides a process for preparing a compound as defined in any one of Embodiments 1.1 to 1.180, the process comprising:

[0282] (A) making the compound of the following formula (10) or formula (10a)

[0283]

[0284] With the following compound of formula (11):

[0285]

[0286] Reaction under reductive amination conditions; wherein R 1 , R 2 , R 3 , R 9 , R 4 and Q is as defined in any one of Embodiments 1.1 to 1.180; or

[0287] (B) making the following compound of formula (12) or formula (12a):

[0288]

[0289] With the formula Cl-C(=O)-CH2-R 4 The compounds are reacted in the presence of a base; or

[0290] (C) making the following compound of formula (10) or formula (10a)

[0291]

[0292] With the following compound of formula (13):

[0293]

[0294] Reacts under nucleophilic substitution conditions; where R 1 , R 2 , R 3 , R 9 , R 4 and Q is as defined in any one of Embodiments 1.1 to 1.180; and optionally:

[0295] (D) converting one compound of formula (1) or formula (1a) into another compound of formula (1) or formula (1a), respectively.

[0296] In process variant (A), piperidine heterocycle (10) or (10a) is reacted with substituted ketone (11) under reductive amination conditions. The reductive amination reaction is typically carried out in a solvent such as dichloromethane or dichloroethane containing acetic acid at ambient temperature using a borohydride reducing agent such as sodium triacetoxy-borohydride.

[0297] In process variant (C), the piperidine heterocycle (10) or (10a) is reacted with a sulfonate (13, R = methyl, trifluoromethyl or 4-methylphenyl) in a nucleophilic substitution reaction, which is typically carried out neat without solvent or in a suitable solvent such as tetrahydrofuran, acetonitrile and dimethylacetamide with mild heating (e.g., to a temperature of about 40° C. to about 70° C.).

[0298] Intermediate compounds of formula (12) and formula (12a) can be prepared by the series of reactions shown below in Scheme 1 and Scheme 1a, respectively.

[0299]

[0300] Option 1a

[0301]

[0302] Solution 1

[0303] In Reaction Scheme 1 or Scheme 1a, the piperidine heterocycle (10) or (10a), respectively, is reacted with a Boc-protected spiroketone (14) under reductive amination conditions. The reductive amination reaction is typically carried out in a solvent containing acetic acid such as dichloromethane or dichloroethane in the presence of a combination of sodium cyanoborohydride and zinc chloride or a combination of sodium triacetoxyborohydride and isopropoxytitanium under mild heating (e.g., to a temperature of about 40° C. to about 70° C.) to give the intermediate piperidine compound (15) or (15a), respectively, which is then deprotected by removing the Boc group via treatment with an acid (e.g., trifluoroacetic acid in dichloroethane) to give compound (12) or (12a), respectively.

[0304] Compounds of formula (12) or formula (12a) can also be prepared by the reaction sequence shown below in Scheme 2 or Scheme 2a, respectively.

[0305]

[0306] Option 2a

[0307]

[0308] Solution 2

[0309] In Scheme 2 or Scheme 2a, the Boc-protected spiroketone (14) is reduced to the alcohol (16) using sodium borohydride in methanol. The alcohol (16) is then activated to the sulfonate (17, R = methyl, trifluoromethyl or 4-methylphenyl) using the corresponding sulfonyl chloride in dichloromethane in the presence of a tertiary amine such as triethylamine or N,N-diisopropylethylamine. The sulfonate (17) is reacted with the piperidine heterocycle (10) or (10a) in a nucleophilic substitution reaction, which is carried out neat without solvent or in a suitable solvent such as tetrahydrofuran, acetonitrile or dimethylacetamide under mild heating (e.g., to a temperature of about 40°C to about 70°C) to give compounds (15) or (15a), respectively, which are then deprotected by removing the Boc group by treatment with an acid (e.g., trifluoroacetic acid in dichloromethane) to give compounds (12) or (12a), respectively.

[0310] Once formed, one compound of formula (1) or formula (1a) or its protected derivatives can be converted to another compound of formula (1) or formula (1a) respectively by methods well known to the skilled person. Examples of synthetic procedures for converting one functional group to another functional group are listed in standard texts such as Advanced Organic Chemistry and Organic Syntheses (see above references) or Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2). Examples of these conversions include amide bond formation, urea formation, carbamate formation, alkylation reactions, N-arylation reactions, and C-C bond coupling reactions.

[0311] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at undesirable positions of 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 and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

[0312] The compounds produced by the aforementioned methods can be isolated and purified according to any of a variety of standard techniques well known to those skilled in the art and examples of such methods include recrystallization and chromatographic techniques, such as column chromatography (eg, flash chromatography) and HPLC.

[0313] Pharmaceutical preparations

[0314] While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation).

[0315] Thus, in another embodiment of the invention (Embodiment 4.1), there is provided a pharmaceutical composition comprising at least one compound of formula (1) or formula (1a) as defined in any one of Embodiments 1.1 to 1.180 together with at least one pharmaceutically acceptable excipient.

[0316] In one embodiment (Embodiment 4.2), the composition is a tablet composition.

[0317] In another embodiment (Embodiment 4.3), the composition is a capsule composition.

[0318] Pharmaceutically acceptable excipients can be selected from, for example, carriers (e.g., solid, liquid or semisolid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or extenders; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release controlling agents (e.g., release retarding or delaying polymers or waxes), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity modifiers, thickeners, flavoring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions.

[0319] The term "pharmaceutically acceptable" as used herein means compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects (e.g., human subjects) without excessive toxicity, irritation, allergic response, or other problems or complications, 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.

[0320] Pharmaceutical compositions containing compounds of formula (1) or (1a) can be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0321] The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration.

[0322] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0323] Tablet compositions may contain a unit dose of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g., lactose, sucrose, sorbitol, or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and starch such as corn starch. Tablets may also contain such standard ingredients as binders and granulators such as polyvinylpyrrolidone, disintegrants (e.g., swollen cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0324] Tablets may be designed to release the drug upon contact with gastric fluid (immediate release tablets) or to release the drug in a controlled manner over an extended period of time or in a specific area of ​​the gastrointestinal tract (controlled release tablets).

[0325] The pharmaceutical composition generally comprises about 1% (w / w) to about 95%, preferably % (w / w) of active ingredient and 99% (w / w) to 5% (w / w) of pharmaceutically acceptable excipients (e.g., as defined above) or a combination of such excipients. Preferably, the composition comprises about 20% (w / w) to about 90% (w / w) of active ingredient and 80% (w / w) to 10% of a pharmaceutical excipient or a combination of excipients. The pharmaceutical composition comprises about 1% to about 95%, preferably about 20% to about 90% of active ingredient. The pharmaceutical composition according to the present invention can, for example, be in the form of a unit dose, such as in the form of an ampoule, a vial, a suppository, a prefilled syringe, a dragee, a powder, a tablet or a capsule.

[0326] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers and / or expanders (depending on the drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Sustained-release tablets may typically additionally contain 0-99% (w / w) polymers that control (e.g., delay) release (depending on the dose). The film coating of the tablet or capsule typically contains 0-10% (w / w) polymers, 0-3% (w / w) pigments and / or 0-2% (w / w) plasticizers.

[0327] Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) cosolvent and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether lyophilized). Formulations for intramuscular sustained release may also contain 0-99% (w / w) oil.

[0328] The pharmaceutical formulation may be provided to the patient in the form of a "patient pack" containing the entire course of treatment in a single package, usually a blister pack.

[0329] The compound of formula (1) or formula (1a) will generally be presented in a unit dosage form and as such will generally contain enough compound to provide the desired level of biological activity. For example, the formulation may contain 1 nanogram to 2 grams of active ingredient, for example 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of the compound are 0.1 milligram to 2 grams of active ingredient (more typically 10 milligrams to 1 gram, for example 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, for example 0.1 milligram to 2 milligrams of active ingredient).

[0330] For oral compositions, unit dosage forms may contain 1 mg to 2 g, more usually 10 mg to 1 g, for example 50 mg to 1 g, for example 100 mg to 1 g, of active compound.

[0331] The active compound will be administered to a patient in need thereof (eg, a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amount of compound administered can be determined by the supervising physician according to standard procedures. Example

[0332] The invention will now be illustrated by reference to specific embodiments described in the following examples, but is not limited to these embodiments.

[0333] Examples 1-1 to 2-12

[0334] The compounds of Examples 1-1 to 2-12 shown in the following Table 1 have been prepared. Their NMR and LCMS properties and the methods used to prepare them are listed in Table 3.

[0335] Table 1

[0336]

[0337]

[0338] General Procedure

[0339] Where preparative routes are not included, the relevant intermediates are commercially available. Commercially available reagents were utilized without further purification. Room temperature (rt) refers to approximately 20°C-27°C. 1 H NMR spectra were recorded at 400 MHz on Bruker or Jeol instruments. Chemical shift values ​​are expressed in parts per million (ppm), i.e. (δ)-values. The following abbreviations are used for the multiplets of NMR signals: s = singlet, br = broad peak, d = doublet, t = triplet, q = quartet, quint = quintet, td = triplet of doublet, tt = triplet of triplet, qd = quartet of doublet, ddd = doublet of doublet of doublet, ddt = doublet of doublet of triplet, m = multiplet. Coupling constants are listed as J values, measured in Hz. NMR and mass spectrometry results are corrected to account for background peaks. Chromatography refers to column chromatography performed using 60-120 mesh silica gel and under nitrogen pressure (flash chromatography). TLC used to monitor the reaction refers to TLC run using a specified flowability and silica gel F254 (Merck) as the stationary phase. Microwave-mediated reactions were performed in either a Biotage Initiator or a CEM Discover microwave reactor.

[0340] LCMS experiments were typically performed under the following conditions using the electrospray conditions specified for each compound:

[0341] LCMS methods A and B

[0342] Instrument: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1x20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0x30 mm; Gradient [time (min) / D (%) in solvent C]: Method A: 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 C = 2.5 L H2O + 2.5 mL ammonia solution; Solvent D = 2.5 L MeCN + 135 mL H2O+2.5mL ammonia solution); injection volume 3μL; UV detection 230 to 400nM; column temperature 45°C; flow rate 1.5mL / min.

[0343] LCMS Method C

[0344] Instrument: Agilent 1260 Infinity LC with diode array detector, Agilent 6120B Single Quadrupole MS with API-ES source; Column: Phenomenex Gemini-NX C-18, 3 micron, 2.0x30 mm; Gradient [time (min) / B (%) in solvent A]: method: 0.00 / 5, 2.00 / 95, 2.50 / 95, 2.60 / 5, 3.00 / 5; Solvent: Solvent A = 2.5 L H2O + 2.5 mL (28% NH3 solution in H2O); Solvent B = 2.5 L MeCN + 130 mL H2O + 2.5 mL (28% NH3 solution in H2O); Injection volume 0.5 μL; UV detection 190 to 400 nM; Column temperature 40°C; Flow rate 1.5 mL / min.

[0345] LCMS methods D and E

[0346] Instrument: HP1100 with G1315A DAD, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1x20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0x30 mm; Gradient [time (min) / D (%) in solvent C]: Method D: 0.00 / 2, 0.10 / 2, 2.50 / 95, 3.50 / 95, 3.55 / 2, 4.00 / 2 or Method E: 0.00 / 2, 0.10 / 2, 8.40 / 95, 9.40 / 95, 9.50 / 2, 10.00 / 2; Solvent: Solvent C = 2.5 L H2O + 2.5 mL 28% ammonia in H2O; Solvent D = 2.5 L MeCN + 135 mL H2O + 2.5 mL 28% ammonia in H2O); injection volume 1 μL; UV detection 230 to 400 nM; mass detection 130 to 800 AMU (+ve and -ve electrospray); column temperature 45°C; flow rate 1.5 mL / min.

[0347] LCMS Method F

[0348] Instrument: Waters 2695, photodiode array, ZQ-2000 detector; Column: X-Bridge C18, 3.5 micron, 150x4.6 mm; Gradient [time (min) / solvent is B (%) in A]: 0.00 / 5, 5.00 / 90, 5.80 / 95, 10 / 95; Solvent: Solvent A = 0.1% ammonia in H2O; Solvent B = 0.1% ammonia in MeCN; Injection volume 10 μL; UV detection 200 to 400 nM; Mass detection 60 to 1000 AMU (+ve electrospray); Column at ambient temperature; Flow rate 1.0 mL / min.

[0349] LCMS Method G

[0350] Instrument: Agilent 1260 Infinity LC with diode array detector, Agilent 6120B Single Quadrupole MS with API-ES source; Column: Phenomenex Gemini-NX C-18, 3 microns, 2.0x30 mm; Gradient [time (min) / B (%) in solvent A]: method: 0.00 / 2, 0.10 / 2, 8.40 / 95, 10.00 / 95; Solvent: Solvent A = 2.5 L H2O + 2.5 mL (28% NH3 solution in H2O); Solvent B = 2.5 L MeCN + 130 mL H2O + 2.5 mL (28% NH3 solution in H2O); Injection volume 0.5 μL; UV detection 190 to 400 nM; Column temperature 40°C; Flow rate 1.5 mL / min.

[0351] LCMS data in the experimental section are given in the following format: mass ion, retention time, UV activity.

[0352] abbreviation

[0353] d = number of days

[0354] DCE = dichloroethane

[0355] DCM = dichloromethane

[0356] DIPEA = diisopropylethylamine

[0357] DMF = dimethylformamide

[0358] DMSO = dimethyl sulfoxide

[0359] ES = electrospray ionization

[0360] EtOAc = Ethyl acetate

[0361] h = hours

[0362] HPLC = High Performance Liquid Chromatography

[0363] LC = Liquid Chromatography

[0364] MeCN = acetonitrile

[0365] MeOH = methanol

[0366] min = minutes

[0367] MS = Mass Spectrometry

[0368] Et3N=Triethylamine

[0369] NMR = Nuclear Magnetic Resonance

[0370] rt = room temperature

[0371] sat.=saturated

[0372] sol.=solution

[0373] STAB = Sodium triacetoxyborohydride

[0374] THF = Tetrahydrofuran

[0375] TLC = Thin Layer Chromatography

[0376] The prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso and tertiary. Final compounds were named using the software package ACD / ChemSketch version 12. Intermediates and reagents were named using the software package ACD / ChemSketch version 12 or were referred to using common names commonly found in their suppliers' catalogs.

[0377] Synthesis of intermediates:

[0378] Path 1

[0379] Typical procedure for the preparation of ketones, for example the intermediate 26-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester

[0380]

[0381] 2-Boc-6-oxo-2-azaspiro [3.3] heptane (0.65 g, 3.08 mmol) was added to hydrogen chloride (4 M dioxane solution, 3.10 mL, 12.40 mmol) in batches. After 24 h, the reactant was concentrated in vacuo and the residual solid was dissolved in a mixture of Et3N (0.86 mL, 6.15 mmol) and DCM (13.5 mL). After completion of the dissolution, the solution was immediately cooled to 0 ° C, and then ethyl chloroformate (0.32 mL, 3.38 mmol) was added dropwise. After 18 h, the mixture was poured into DCM (50 mL) and NaHCO3 solution (50 mL) and extracted with DCM (2 × 50 mL). The organic layers were combined, washed with brine (10 mL), and then dried with MgSO4. The solvent was removed in vacuo and the product was purified by column chromatography (normal phase, [Biotage SNAP column KP-sil 25 g, 40-63 μm, The residue was purified by HPLC-MS / MS (50 mL / min, gradient 1% to 10% MeOH in DCM]) to give intermediate 26-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester as a colorless oil which solidified to needles upon standing (0.17 g, 30%).

[0382] The data for Intermediate 2 are in Table 2

[0383] Path 2

[0384] Typical procedure for the preparation of pyrrolidin-2-ones, such as intermediate 18 (S)-5-methylpyrrolidin-2-one

[0385]

[0386] To (5R)-5-(hydroxymethyl)pyrrolidin-2-one (5.0 g, 43.4 mmol) in DCM (50 mL) was added triethylamine (7.7 mL, 55.5 mmol) and the mixture was stirred at 0-5 °C for 10 min. To the mixture was added p-toluenesulfonyl chloride (9.9 g, 51.9 mol) in batches at 0-5 °C within 10 min and ZnCl (0.1 g, 0.7 mmol) and the reaction mixture were stirred at rt for 7 h. The solvent was removed in vacuo and the residue was distributed between H O (250 mL) and DCM (200 mL). The aqueous layer was extracted with DCM (2×200 mL), the combined organics were dried (Na SO ) and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase basic activated alumina, 0 to 2.5% MeOH in DCM) to give (R)-(5-oxopyrrolidin-2-yl)methyl 4-toluenesulfonate (5.3 g, 45%) as a white solid.

[0387] LCMS (Method F): m / z 270 (M+H) + (ES + ), UV activity at 3.44 min.

[0388] To (R)-(5-oxopyrrolidin-2-yl)methyl 4-toluenesulfonate (5.0 g, 18.5 mmol) in acetone (10 mL), lithium bromide (4.8 g, 55.6 mmol) was added and the reaction mixture was stirred overnight at 80 ° C. The solvent was then removed in vacuo and the reaction mixture was distributed between H2O (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2x100 mL), the combined organics were dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by column chromatography (normal phase alkaline activated alumina, 0.2% to 1.0% MeOH in DCM) to obtain (R)-5-(bromomethyl)pyrrolidin-2-one (3.0 g, 90%) as a pale yellow liquid.

[0389] LCMS (Method F): m / z 178 / 180 (M+H) + (ES + ), UV activity at 2.24 min.

[0390] To a solution of (R)-5-(bromomethyl)pyrrolidin-2-one (3.0 g, 30 mmol) in MeOH (50 mL) was added Pd / C (0.3 g) and triethylamine (7.0 mL, 50 mmol) and 1166 psi H2(g) pressure was applied overnight in an autoclave at 60°C. The reaction was filtered and the solvent was removed from the filtrate in vacuo. The residue was purified by column chromatography (normal phase basic activated alumina, 1.0% to 5.0% MeOH in DCM) to give intermediate 18 (S)-5-methylpyrrolidin-2-one (1.0 g, 60%) as a pale yellow liquid.

[0391] The data for intermediate 18 are given in Table 2

[0392] Path 3

[0393] Typical procedure for the preparation of piperidines, for example, the preparation of intermediate 11 (5S)-5-methyl-1-(piperidin-4-yl)pyrrolidin-2-one

[0394]

[0395] (S)-5-Methylpyrrolidin-2-one (100 mg, 1.0 mmol), 4-iodopyridine (255 mg, 1.0 mmol), KCO (410 mg, 3.0 mmol), copper iodide (38 mg, 0.2 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (43 mg, 0.2 mmol) were dissolved in dioxane (10 mL) and the reaction mixture was stirred at 150°C for 18 h. The solvent was removed in vacuo and the residue was partitioned between H2O (100 mL) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (2 x 80 mL), the combined organics were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase basic activated alumina, 1.0% to 5.0% MeOH in DCM) to give (S)-5-methyl-1-(pyridin-4-yl)pyrrolidin-2-one (100 mg, 60%) as a light yellow solid.

[0396] LCMS (Method F): m / z 177 (M+H) + (ES + ), UV activity at 2.70 min.

[0397] To a solution of (S)-5-methyl-1-(pyridin-4-yl)pyrrolidin-2-one (200 mg, 1.1 mmol) in acetone (20 mL) was added benzyl bromide (210 mg, 1.2 mmol) and the reaction mixture was stirred for 18 h at 80° C. The solvent was then removed in vacuo to give (S)-1-benzyl-4-(2-methyl-5-oxopyrrolidin-1-yl)pyridin-1-ium (200 mg, 69%) as a light yellow solid, which was used directly crude in the next step.

[0398] To a solution of (S)-1-benzyl-4-(2-methyl-5-oxopyrrolidin-1-yl)pyridin-1-ium (400 mg, 1.5 mmol) in ethanol / water (10 mL, 1:1) was added NaBH4 (330 mg, 9.0 mmol) and the reaction mixture was stirred at rt for 18 h. The solvent was then removed in vacuo and the residue was partitioned between H2O (100 mL) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (2×80 mL), the combined organics were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase basic activated alumina, 1.0% to 5.0% MeOH in DCM) to give (S)-1-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpyrrolidin-2-one (130 mg, 30%) as a light yellow solid.

[0399] LCMS (Method F): m / z 271 (M+H) + (ES + ), UV activity at 4.04 min.

[0400] To (S)-1-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpyrrolidin-2-one (100 mg, 0.4 mmol) in EtOAc (10 mL) was added Pd / C (50 mg) and 569 psi H2(g) was applied overnight in an autoclave at 60° C. The reaction mixture was filtered and the solvent was removed from the filtrate in vacuo to give intermediate 11 (S)-5-methyl-1-(piperidin-4-yl)pyrrolidin-2-one (42 mg, 62%) as a light yellow liquid.

[0401] The data for intermediate 11 are given in Table 2

[0402] Path 4

[0403] Typical procedure for the preparation of pyrrolidin-2-ones, such as intermediate 22 (5R)-5-ethylpyrrolidin-2-one

[0404]

[0405] To (5S) -5- (hydroxymethyl) pyrrolidin-2-one (2.0g, 17mmol) and 4- methylbenzenesulfonyl chloride (5.3g, 28mmol) in DCM (24mL) solution, triethylamine (12mL, 86mmol) was added. The resulting mixture was stirred overnight at RT and then concentrated. The residue was dissolved in DCM and washed with 1M HCl aqueous solution (x3) and brine (x1), then passed through a phase separator and concentrated to obtain a brown solid. The solid was recrystallized from DCM / isohexane to obtain a tan solid, which was removed by filtration, washed with a DCM / isohexane mixture and dried in air to obtain [(2S) -5- oxopyrrolidin-2-yl] methyl 4- methylbenzenesulfonate (3.13g, 67%).

[0406] LCMS (Method C): m / z 270 (M+H) + (ES + ), at 0.97min, UV activity

[0407] Under stirring, methyl lithium (1.5M in ether, 7.4mL, 11mmol) was quickly added to a suspension of copper iodide (1.06g, 5.6mmol) in THF (6mL), pre-cooled in ice water under N2. The light brown solution was stirred in ice water for 45min and then cooled to -20°C. A solution of 4-methylbenzenesulfonic acid [(2S)-5-oxopyrrolidin-2-yl] methyl ester (0.50g, 1.9mmol) in THF (6mL) was added in batches within 2min and the resulting solution was stirred at -20°C for 45min, then overnight in ice water, making the cold bath slowly ineffective. The mixture was quenched with saturated NH4Cl aqueous solution (15mL) and stirred for several hours. The biphasic mixture was extracted with diethyl ether (x3), the organic phase was washed with brine, passed through a phase separator and concentrated to give crude (5R)-5-ethylpyrrolidin-2-one (0.124 g, 59%) of Intermediate 22 as an oil.

[0408] The data for intermediate 22 are given in Table 2

[0409] Path 5

[0410] Procedure for the preparation of piperidines, for example, intermediate 30 (R)-3-methyl-5-(1-(piperidin-4-yl)pyrrolidin-2-yl)oxazol-2(3H)-one trifluoroacetate

[0411]

[0412] To a solution of (tert-butoxycarbonyl)-D-proline (10.0 g, 46.4 mmol) in DCM (100 mL) was added HATU (35.2 g, 92.8 mmol) at 0°C and the reaction mixture was stirred at 0°C for 1 h. N,O-dimethylhydroxylamine (4.98 g, 46.4 mmol) and DIPEA (24.0 mL, 139 mmol) were added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was partitioned between saturated NaHCO3 solution (150 mL) and DCM (60 mL), the aqueous layer was further extracted with DCM (2x60 mL), the organic layers were combined, dried (Na2SO4) and the solvent removed in vacuo. The crude residue was purified by column chromatography (silica, 0% to 30% methanol in EtOAc) to give (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (12.00 g, 100%) as a colorless gum.

[0413] LCMS (Method F): m / z 259 (M+H) + (ES + ), at 1.91min, UV is inactive

[0414] At -15 ° C under nitrogen to (R) -2- (methoxy (methyl) amino formyl) pyrrolidine -1- carboxylic acid tert-butyl ester (12.0g, 46.4mmol) in THF (120mL) solution of methylmagnesium bromide (3.0M solution) (23.2mL, 69.7mmol) was added dropwise, the reaction mixture was stirred at rt for 3h. The reaction mixture was distributed between saturated NH4Cl solution (60mL) and EtOAc (30mL), the aqueous layer was further extracted with EtOAc (2x30mL), the organic layer was merged, dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silicon dioxide, 0% to 40% EtOAc in hexane), to obtain (R) -2- acetyl pyrrolidine -1- carboxylic acid tert-butyl ester (9.75g, 98.48%) in a yellow liquid.

[0415] LCMS (Method F): m / z 214 (M+H) + (ES + ), at 1.97min, UV is inactive

[0416] To a solution of (R)-2-acetylpyrrolidine-1-carboxylic acid tert-butyl ester (9.75 g, 45.0 mmol) in THF (20.0 mL) was added dropwise Et3N (19.1 mL, 45.0 mmol) followed by trimethylsilyl trifluoromethanesulfonate (15.26 g, 68.6 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 h. A solution of N-bromosuccinimide (9.56 g, 54.0 mmol) in THF (50 mL) was added dropwise at 0°C and the reaction mixture was stirred at 0°C for 30 min. The reaction mixture was partitioned between saturated NH4Cl solution (150 mL) and EtOAc (70 mL), the aqueous layer was further extracted with EtOAc (2x70 mL), the organic layers were combined, dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 0% to 45% EtOAc in hexanes) to give (R)-tert-butyl 2-(2-bromoacetyl)pyrrolidine-1-carboxylate (4.00 g, 29.9%) as a yellow gum.

[0417] LCMS (Method F): m / z 292 (M+H) + (ES + ), at 2.12min, UV is inactive

[0418] To a solution of (R)-tert-butyl 2-(2-bromoacetyl)pyrrolidine-1-carboxylate (4.00 g, 13.7 mmol) in DMF (15.0 mL) was added KCO (2.84 g, 20.5 mmol) and thiazolidinedione (2.08 g, 17.8 mmol) and the reaction mixture was stirred at rt for 3 h. The solvent was removed in vacuo and the residue was partitioned between saturated NHCl solution (100 mL) and EtOAc (50 mL), the aqueous layer was further extracted with EtOAc (2 x 50 mL), the organic layers were combined, dried (NaSO) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 0% to 2% methanol in DCM) to give (R)-tert-butyl 2-(2-(2,4-dioxothiazolidin-3-yl)acetyl)pyrrolidine-1-carboxylate (2.40 g, 53.45%) as a white solid.

[0419] LCMS (Method F): m / z 329 (M+H) + (ES + ), at 2.15min, UV is inactive

[0420] To a solution of (R)-tert-butyl 2-(2-(2,4-dioxothiazolidin-3-yl)acetyl)pyrrolidine-1-carboxylate (2.40 g, 7.30 mmol) in dry THF (25.0 mL) was added LiOH (2M in water) (875 mg) at 0° C. and the reaction mixture was stirred at rt for 1 h. The reaction mixture was poured onto 5 mL of acetic acid (5 mL) and then partitioned between H2O (50 mL) and EtOAc (30 mL), the aqueous layer was further extracted with EtOAc (2×30 mL), the organic layers were combined, dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography (silica, 0% to 3% methanol in DCM) to give (R)-tert-butyl 2-(2-oxo-2,3-dihydrooxazol-5-yl)pyrrolidine-1-carboxylate (1.25 g, 67.20%) as a light yellow solid.

[0421] LCMS (Method F): m / z 255 (M+H) + (ES + ), at 1.91min, UV is inactive

[0422] To a solution of (R)-2-(2-oxo-2,3-dihydrooxazol-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 5.89 mmol) in DMF (30.0 mL) was added NaH (60%) (0.71 g, 17.7 mmol) at 0°C under nitrogen and the reaction mixture was stirred for 30 min at 0°C. Iodomethane (1.25 g, 8.85 mmol) was added dropwise at 0-10°C and the reaction mixture was stirred for 30 min at rt. The reaction mixture was partitioned between saturated NH4Cl solution (50 mL) and EtOAc (40 mL), the aqueous layer was further extracted with EtOAc (2x40 mL), the organic layers were combined, dried (Na28O4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 0% to 2% methanol in DCM) to give (R)-tert-butyl 2-(3-methyl-2-oxo-2,3-dihydrooxazol-5-yl)pyrrolidine-1-carboxylate (1.50 g, 94.94%) as a colorless gum.

[0423] LCMS (Method F): m / z 213 (M+H) + (ES + ), at 2.01min, UV is inactive

[0424] To a solution of (R)-tert-butyl 2-(3-methyl-2-oxo-2,3-dihydrooxazol-5-yl)pyrrolidine-1-carboxylate (1.50 g, 5.59 mmol) in DCM (10.0 mL) under nitrogen was added TFA (5.00 mL) and the reaction mixture was stirred at rt for 3 h. Toluene (10.0 mL) was added and the solvent was removed in vacuo and the residue was azeotroped with toluene (2 x 10 mL) to give (R)-5-(pyrrolidin-2-yl)oxazol-2(3H)-one (897 mg, 95.43%) as a colorless gum.

[0425] LCMS (Method H): m / z 169 (M+H) + (ES + ), at 2.21min, UV is inactive

[0426] To a solution of (R)-5-(pyrrolidin-2-yl)oxazol-2(3H)-one (897 mg, 5.33 mmol) in methanol (20.0 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (1.06 g, 5.33 mmol), EtN (2.23 mL, 16.0 mmol) and zinc chloride (0.26 mL, 0.26 mmol) under nitrogen and the reaction mixture was stirred at 50-60 ° C for 16 h. NaCNBH (1.00 g, 16.0 mmol) was added in portions at 0-10 ° C and the reaction mixture was stirred at rt for 6 h. The reaction mixture was partitioned between H O (50 mL) and EtOAc (35 mL), the aqueous layer was further extracted with EtOAc (2x30 mL), the organic layers were combined, dried (Na SO ) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 0% to 5% methanol in DCM) to give (R)-tert-butyl 4-(2-(3-methyl-2-oxo-2,3-dihydrooxazol-5-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (1.50 g, 80.04%) as a yellow gum.

[0427] LCMS (Method F): m / z 352 (M+H) + (ES + ), at 1.67min, UV activity

[0428] To a solution of (R)-tert-butyl 4-(2-(3-methyl-2-oxo-2,3-dihydrooxazol-5-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (1.50 g, 4.27 mmol) in DCM (20.0 mL) under nitrogen was added TFA (5.00 mL) and the reaction mixture was stirred at rt for 3 h. Toluene (10.0 mL) was added and the solvent was removed in vacuo and the residue was azeotroped with toluene (2 x 10 mL) to give intermediate 30 (R)-3-methyl-5-(1-(piperidin-4-yl)pyrrolidin-2-yl)oxazol-2(3H)-one.TFA (900 mg, 83.95%) as a brown gum.

[0429] The data for intermediate 30 are given in Table 2

[0430] Path 6

[0431] Procedure for the preparation of piperidines, for example, the preparation of intermediate 32 4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidine trifluoroacetate

[0432]

[0433] At -78 ° C, 4-oxopyrrolidine-1,2-dicarboxylic acid (R) -1- tert-butyl 2-methyl esters (5.00g, 20.5mmol) were dissolved in DCM (15mL) and DAST (8.1mL, 30.8mmol) was added dropwise. The reaction mixture was warmed to rt and stirred for 16h. The reaction mixture was diluted with DCM (100mL) and washed with saturated NaHCO (aqueous solution) (2x100mL), the combined water layer was washed with DCM (100mL), the organic layers were merged, dried (Na2SO4) and the solvent was removed in vacuo to obtain 4,4-difluoropyrrolidine-1,2-dicarboxylic acid (R) -1- tert-butyl 2-methyl esters (5.34g, 98%) as a yellow oil.

[0434] LCMS (Method F): m / z 210 (M+H-56) + (ES + ), at 2.17min, UV is inactive

[0435] At 0 ° C, 4,4-difluoropyrrolidine-1,2-dicarboxylic acid (R) -1- tert-butyl 2-methyl esters (5.34g, 20.1mmol) in THF (13.4mL, 3.0M solution of lithium borohydride in THF (40.3mmol) are added and reactant is warmed to RT and stirred for 3h. The solvent is removed in vacuo, and the reaction mixture is diluted with DCM (50mL) and washed with saturated NaHCO3 aqueous solution (2x50mL), the combined water layer is dried with DCM (50mL), the organic layer is merged, and dried (Na2SO4) and the solvent is removed in vacuo. The residue is purified by column chromatography (silicon dioxide, 0% to 14% EtOAc in hexane), to obtain (2R) -4,4-difluoro-2- (hydroxymethyl) pyrrolidine -1- carboxylic acid tert-butyl ester (4.3g, 90%) in yellow jelly.

[0436] LCMS (Method F): m / z 186 (M+H-56) + (ES + ), at 1.97min, UV is inactive

[0437] To a solution of (2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.8 g, 16.0 mmol) in DCM (20 mL) was added TFA (10 mL) and the reaction mixture was stirred at rt for 3 h. The solvent was removed in vacuo and the residue was azeotroped with DCM (10 mL) and ether (10 mL) to give (2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine trifluoroacetate (2.2 g, 100%) as a brown gum.

[0438] LCMS (method I): m / z 138 (M+H) + (ES + ), at 3.78 min, UV was inactive.

[0439] (2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine trifluoroacetate (1.2 g, 8.7 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.74 g, 8.7 mmol), triethylamine (6.1 mL, 43.7 mmol) and ZnCl2 (1.0 M in ether) (0.4 mL, 0.43 mmol) were dissolved in MeOH (20 mL) and the reaction mixture was stirred at 60 ° C for 5 h. The mixture was cooled to 0 ° C and NaCNBH3 (1.65 g, 26.2 mmol) was added in batches. The resulting reaction mixture was stirred at rt for 8 h. The solvent was removed in vacuo and the residue was distributed between H2O (100 mL) and DCM (80 mL). The aqueous layer was extracted with DCM (2 × 80 mL), and the combined organics were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 0% to 10% MeOH in DCM) to give tert-butyl 4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidine-1-carboxylate (2.5 g, 89%) as a yellow gum.

[0440] LCMS (Method I): m / z 265 (M+H-56) + (ES + ), at 4.08min, UV is inactive

[0441] To a solution of tert-butyl 4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidine-1-carboxylate (2.5 g, 7.8 mmol) in DCM (20 mL) was added TFA (10 mL) and the reaction mixture was stirred at rt for 3 h. The solvent was removed in vacuo and the residue was azeotroped with DCM (10 mL) and ether (10 mL) to give crude intermediate 32 4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidine trifluoroacetate (1.71 g, 100%) as a brown gum.

[0442] The data for intermediate 32 are given in Table 2

[0443] Path 7

[0444] Procedure for the preparation of piperidines, for example, the preparation of Intermediate 33 4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidine-1-carboxylic acid tert-butyl ester

[0445]

[0446] To a solution of oxalyl chloride (6.39 mL, 75 mmol) in DCM (200 mL) was added DMSO (10.66 mL, 150 mmol) dropwise at -78°C under nitrogen and the reaction mixture was stirred at -78°C for 15 min. (tert-Butyloxycarbonyl)-D-proline (10.0 g, 46.4 mmol) in DCM (50 mL) was added dropwise to the reaction mixture at -78°C over 1 h and then the reaction mixture was stirred at -78°C for 15 min. Et3N (28 mL, 200 mmol) was added dropwise to the reaction mixture at -78°C and the reaction mixture was allowed to warm to 0°C and left under nitrogen for 1 h. The reaction mixture was quenched with saturated NaHCO3(aq) (200 mL), the combined aqueous layers were washed with DCM (100 mL), the organic layers were combined, dried (Na2SO4) and the solvent removed in vacuo to give (2R)-tert-butyl 2-formylpyrrolidine-1-carboxylate (11.1 g, 100%) as a colorless oil. It was used directly without further purification.

[0447] In 10min, at 0°C under nitrogen, to a solution of thick (2R)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (17.8g, 89mmol) in MeOH (300mL), KCO (36.85g, 267mmol) was added in batches, followed by addition of (p-toluenesulfonyl)methyl isocyanide TosMIC (17.46g, 89mmol). The reaction mixture was heated at 80°C for 21h under nitrogen, then cooled to rt in 16h. The solvent was removed in vacuo and the residue was distributed between DCM (100mL) and ice water (300mL), and the aqueous layer was further extracted with DCM (2x100mL). The organic layers were merged and washed with brine (100mL), dried by passing it through a Biotage phase separator and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 100% DCM) to give tert-butyl (2R)-2-(1,3-oxazol-5-yl)pyrrolidine-1-carboxylate (8.1 g, 38.0%) as a yellow gum.

[0448] LCMS (Method A): m / z 183 (M+H-56) + (ES + ), at 1.07min, UV is inactive

[0449] Tert-butyl (2R)-2-(1,3-oxazol-5-yl)pyrrolidine-1-carboxylate (8.1 g, 34 mmol) was dissolved in 4M HCl in dioxane (100 mL) and the reaction mixture was stirred overnight at rt under N2. The solvent was removed in vacuo to give 5-[(2R)-pyrrolidin-2-yl]-1,3-oxazole hydrochloride (5.9 g, 100%) as a yellow foam. It was used directly without further purification.

[0450] To a solution of 5-[(2R)-pyrrolidin-2-yl]-1,3-oxazole hydrochloride (5.9 g, 34 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (6.71 g, 34 mmol) in DMF (150 mL), DIPEA (8.9 mL, 51 mmol) was added and the mixture was stirred for 2 h at 40 ° C under N2. The solution was cooled to rt, STAB (18.0 g, 85 mmol) and AcOH (1.95 mL, 34 mmol) were added and the reaction mixture was heated for 72 h at 40 ° C under N2. The reaction mixture was cooled to rt and the solvent was removed in vacuo, the residue was carefully distributed between saturated NaHCO3 aqueous solution (200 mL) and DCM (100 mL), and the aqueous layer was further extracted with DCM (3x100 mL). The organic layers were combined and washed with brine (100 mL), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, 0 to 10% MeOH in DCM) to give Intermediate 33 tert-butyl 4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (3.42 g, 31.5%) as a yellow gum.

[0451] The data for intermediate 33 are given in Table 2

[0452] Path 8

[0453] Procedure for the preparation of piperidines, for example, the preparation of intermediate 13 4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidine dihydrochloride

[0454]

[0455] To tert-butyl 4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (390 mg, 1.2 mmol) was added 4M HCl in dioxane (4 mL) and the reaction mixture was stirred overnight at rt under N. The mixture was then concentrated in vacuo to give intermediate 13 4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidine dihydrochloride (330 mg, 92%) as a gum which solidified after further azeotroping with DCM.

[0456] The data for intermediate 13 are given in Table 2

[0457] General synthesis procedure:

[0458] Path a

[0459] For the preparation of piperidines via sodium triacetoxyborohydride reductive amination, Boc-deprotection and alkylcarbamate formation, for example, Preparation Example 1-26-[4-(1-methyl-1H-imidazol-2-yl)

[0460] Typical procedure for ethyl]piperidin-1-yl-2-azaspiro[3.3]heptane-2-carboxylate

[0461]

[0462] 4-(1-Methyl-1H-imidazol-2-yl-piperidine hydrochloride (0.303 g, 1.50 mmol) and 2-Boc-6-oxo-2-azaspiro[3.3]heptane (0.317 g, 1.50 mmol) were suspended in DCM (10 mL) at rt and triethylamine (0.42 mL, 3.0 mmol) was added. The reaction mixture was stirred at rt for 1 h, acetic acid (0.26 mL, 4.50 mmol) was added and stirred for 3 h. STAB (0.80 g, 3.75 mmol) was added and the reaction mixture was stirred overnight under nitrogen. The reaction mixture was purified by adding saturated NaHC03. O3 aqueous solution (15mL) is used to quench the reaction mixture, and its DCM (4x30mL) is extracted and the solvent is removed in vacuo. The residue is dissolved in DCM (15mL), 4M hydrogen chloride in dioxane (1.88ml, 7.50mmol) is added and the reaction mixture is stirred for 18h at rt. Then volatiles are removed in vacuo and the residue is dissolved in DCM (15mL) and triethylamine (2.10mL, 15.0mmol). Ethyl chloroformate (214 μL, 2.25mmol) is added dropwise and the solution is stirred for 18h at rt. Then the mixture is poured into NaHCO 3( The product was added to 1% ethanol (40 ml) and DCM (40 ml), extracted with DCM (3 x 50 ml), and the combined DCM extracts were washed and concentrated in vacuo. The product was purified by column chromatography (normal phase, [Biotage SNAP column KP-sil 25 g, 40-63 μm, The residue was purified by preparative reverse phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100 x 30 mm, eluted with 20% to 55% MeCN / solvent B at 30 mL / min in 14.4 min [wherein solvent B is 0.2% (28% NH3 / H2O) in H2O] and fractions were collected by monitoring at 205 nm) to afford Example 1-26-[4-(1-methyl-1H-imidazole-2-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester (60 mg, 12%) as a colorless solid.

[0463] The data for Examples 1-2 are in Table 3.

[0464] Path b

[0465] Typical procedure for preparing piperidines via sodium triacetoxyborohydride reductive amination, e.g., Preparation Example 1-3 6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester

[0466]

[0467] 4-(1H-pyrazol-1-yl)piperidine (0.14 g, 0.93 mmol) and ethyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (0.17 g, 0.93 mmol) were dissolved in DCM (7.5 mL) at rt and titanium isopropoxide (0.55 mL, 1.02 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was cooled to -5 °C, then STAB (0.392 g, 1.852 mmol) and acetic acid (22 μL, 0.37 mmol) were added and the reaction mixture was stirred overnight under nitrogen while allowing it to warm to rt. The reaction mixture was purified by adding NaHCO 3(饱和水溶液) The reaction mixture was quenched with 4% paraformaldehyde (50 mL) and diluted with DCM (50 mL) and then filtered through a celite pad. The layers were separated and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (10 mL) and then dried over MgSO4. The solvent was removed in vacuo and the product was purified by column chromatography (normal phase, [BiotageSNAP column KP-sil 25 g, 40-63 μm, The residue was purified by preparative reverse phase HPLC (Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100x30 mm, eluted with 35% to 45% MeCN / solvent B at 30 mL / min in 12.5 min [wherein solvent B is 0.2% (28% NH3 / H2O) in H2O] and fractions were collected by monitoring at 218 nm) to obtain Example 1-36-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester (55.2 mg, 19%) as a colorless oil.

[0468] The data of Examples 1-3 are shown in Table 3.

[0469] Path c

[0470] Typical procedure for the preparation of piperidines via sodium triacetoxyborohydride reductive amination, Boc-deprotection and amide / carbamate / urea formation, e.g., Preparation of Example 2-4 6-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester

[0471]

[0472] 6-oxo-2-azaspiro [3.4] octane-2-carboxylic acid ethyl ester (0.15g, 0.6mmol) is dissolved in DMF (2mL) and 2-(piperidin-4-yl) pyrrolidine-1-carboxylic acid (S)-tert-butyl ester (0.12g, 0.60mmol) and acetic acid (0.05mL, 0.9mmol) are added. The reaction mixture is stirred for 5h at rt, then STAB (0.25g, 1.2mmol) is added and the reaction mixture is stirred overnight at rt under nitrogen. The solvent is removed in vacuum and the crude mixture is redissolved in dichloromethane (25mL) and washed with 1.0M NaOH. (水溶液) The organic layer was collected, washed with brine (25 mL), passed through a Biotage phase separator, and the residue was then concentrated in vacuo to give an inseparable isomeric mixture of ethyl 6-{4-[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate (0.26 mg, 99%) as a brown oil.

[0473] LCMS (Method D): m / z 436 (M+H) + (ES +), at 2.30 min, UV was inactive.

[0474] 6-{4-[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester (0.26g, 0.6mmol) is dissolved in DCM (1.0mL) and TFA (1.0mL).Reaction mixture is stirred to 2h at rt.Volatile matter is removed in vacuum and residue is dissolved in DCM (1.0mL) and diisopropylethylamine (0.23mL, 1.37mmol).Methylcarbamyl chloride (0.23g, 0.60mmol) is added and solution is stirred to 2h at rt.Mixture is poured in dichloromethane (25mL) and extracted with 1.0M NaOH (aqueous solution) (3x25mL). The organic layer was collected, washed with brine (25 mL), passed through a Biotage phase separator, and the residue was then concentrated in vacuo and purified by column chromatography (normal phase, [Biotage SNAP column KP-sil 25 g, 40-63 μm, The residue was purified by HPLC-MS / MS (50 mL / min, gradient MeOH: 1% to 20% 3.5N NH3 in DCM) to afford Example 2-4 6-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester (0.11 g, 45%) as a yellow oil.

[0475] The data of Examples 2-4 are in Table 3

[0476] Path d

[0477] Typical procedure for preparing piperidines via sodium cyanoborohydride reductive amination, e.g., Preparation Example 2-5 6-(4-((S)-2-methyl-5-oxopyrrolidin-1-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylate

[0478]

[0479] (S)-5-methyl-1-(piperidin-4-yl)pyrrolidin-2-one (42.0 mg, 0.22 mmol), ethyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate (45.0 mg, 0.22 mmol), triethylamine (0.06 mL, 0.44 mmol) and ZnCl2 (1.5 mg, 0.01 mmol) were dissolved in MeOH (10 mL) and the reaction mixture was stirred at 60 ° C for 8 h. The mixture was cooled to 0 ° C and NaCNBH3 (19.0 mg, 0.29 mmol) was added in batches. The resulting reaction mixture was stirred at 25 ° C for 17 h, after which the solvent was removed in vacuo and the residue was distributed between H2O (100 mL) and EtOAc (80 mL). The aqueous layer was extracted with EtOAc (2×80 mL), and the combined organics were dried (Na2SO4) and the solvent was removed in vacuo. The crude residue was purified by preparative HPLC [reverse phase (X-BRIDGEC-18, 150×19 mm, 5 μm, 15 mL / min, gradient 25% to 100% (in 20.0 min), 100% (in 3.0 min), then 30% (in 2.0 min), 0.1% NH3 in MeCN / water] to give Example 2-56-(4-((S)-2-methyl-5-oxopyrrolidin-1-yl)piperidin-1-yl)-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester (10.0 mg, 11%) as a light yellow semisolid.

[0480] The data of Examples 2-5 are in Table 3

[0481] Path

[0482] Typical procedure for preparing piperidines via sodium triacetoxyborohydride reductive amination, e.g., Preparation of Example 1-5 6-{4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester

[0483]

[0484] To a solution of 4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidine dihydrochloride (229 mg, 0.89 mmol) and 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester (163 mg, 0.89 mmol) in DMF (4 mL) was added DIPEA (0.23 mL, 1.34 mmol) and the mixture was stirred at 50 ° C under N2 for 2 h. The solution was cooled to rt, after which STAB (472 mg, 2.23 mmol) and AcOH (0.05 mL, 0.89 mmol) were added and heated for another 16 h at 40 ° C under N2. The reaction mixture was cooled to rt, quenched with saturated NaHCO3 aqueous solution (10 mL) and concentrated in vacuo. The aqueous layer was extracted with DCM (3×10 mL), the combined organics were dried (Biotage phase separator column) and the solvent was removed in vacuo. The crude residue was purified by column chromatography (normal phase, [Biotage SNAP column KP-sil25g, gradient 0 to 10% MeOH in DCM) to afford Example 1-5 racemate 6-{4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester (55 mg, 16%) as a yellow gum.

[0485] The data of Examples 1-5 are in Table 3

[0486] Table 2

[0487] Characterization data and commercial sources of intermediates

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497] Biological Activity

[0498] Example A

[0499] Phospho-ERK1 / 2 assay

[0500] Functional assays were performed using the Alphascreen Surefire phospho-ERK1 / 2 assay (Crouch & Osmond, Comb. Chem. High Throughput Screen, 2008). ERK1 / 2 phosphorylation is a downstream consequence of Gq / 11 and Gi / o protein-coupled receptor activation, making it highly suitable for assessing M1, M3 (Gq / 11 coupled) and M2, M4 receptors (Gi / o coupled) rather than using different assay formats for different receptor subtypes. CHO cells stably expressing muscarinic M1, M2, M3 or M4 receptors were plated onto (25K / well) 96-well tissue culture plates in MEM-α + 10% dialyzed FBS. Once attached, the cells were serum starved overnight. Agonist stimulation was performed by adding 5 μL of agonist to the cells for 5 min (37° C.). The culture medium was removed and 50 μL of lysis buffer was added. After 15 min, 4 μL of sample was transferred to a 384-well plate and 7 μL of detection mixture was added. The plates were incubated for 2 h in the dark with gentle agitation and then read on a PHERAstar plate reader. pEC was calculated from the resulting data for each receptor subtype. 50 and E max number.

[0501] The results are listed in Table 4 below.

[0502]

[0503]

[0504] NT - Not tested

[0505] Example B

[0506] Pharmaceutical preparations

[0507] (i) Tablet preparation

[0508] A tablet composition containing a compound of formula (1) or (1a) is prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant and compressing in a known manner to form tablets.

[0509] (ii) Capsule preparation

[0510] Capsule formulations are prepared by mixing 100 mg of a compound of formula (1) or (1a) with 100 mg of lactose and optionally 1 wt% of magnesium stearate and filling the resulting mixture into standard opaque hard gelatin capsules.

[0511] Equivalent solutions

[0512] The above examples are presented for the purpose of illustrating the present invention, and should not be construed as imposing any limitation on the scope of the present invention. It will be readily apparent that many modifications and changes may be made to the specific embodiments of the present invention described above and illustrated in the examples without departing from the principles of the present invention. All such modifications and changes are intended to be encompassed by the application.

Claims

1. A compound selected from formula (4), formula (5) or formula (6): or a salt thereof, wherein: n is 1 or 2; p is 1; In formula (4), R4 is hydrogen or C 1-6 Non-aromatic hydrocarbon groups; In formula (5), R1 is hydrogen; R2 is hydrogen; R4 is hydrogen or C 1-6 Non-aromatic hydrocarbon groups; In formula (6), R1 is CONR 5 R 6 ; R2 is hydrogen; R4 is hydrogen or C 1-6 non-aromatic hydrocarbon group; and R 5 and R 6 are the same or different and are each independently selected from hydrogen and C 1-4 a non-aromatic hydrocarbon group; and The "non-aromatic hydrocarbon group" refers to a completely saturated straight-chain or branched-chain group consisting of carbon atoms and hydrogen atoms.

2. The compound or salt thereof according to claim 1, wherein n is 1.

3. The compound or salt thereof according to claim 1, wherein n is 2.

4. The compound or a salt thereof according to claim 1, wherein the compound is selected from Formula (4) or Formula (5).

5. The compound or a salt thereof according to claim 1, wherein the compound is of formula (6).

6. The compound or a salt thereof according to claim 1, wherein the compound is of formula (6), and R1 is CONHMe.

7. The compound or a salt thereof according to claim 1, wherein the compound is of formula (4).

8. The compound or salt thereof according to any one of claims 1 to 7, wherein R4 is selected from hydrogen and methyl.

9. A compound selected from: 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid methyl ester; 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-2-(3-methyl-2-oxo-2,3-dihydro-1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2S)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylic acid ethyl ester; 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylic acid methyl ester; 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; 6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; 6-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; 6-{4-[(2S)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; Ethyl 6-{4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; 6-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid methyl ester; 6-{4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; 6-{4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid methyl ester; 6-{4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylic acid ethyl ester; or a salt thereof.

10. A compound which is methyl 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate or a salt thereof.

11. A compound which is ethyl 6-{4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate or a salt thereof.

12. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 11 or a salt thereof and a pharmaceutically acceptable excipient.

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