Bicyclic aza compounds as muscarinic m1 receptor agonists, pharmaceutical composition comprising sai

专利摘要:
BICYCLIC AZA COMPOUNDS AS MUSCARIN M1 RECEPTOR AGONISTS. The present invention relates to compounds (Formula (1)) which are muscarinic M1 receptor agonists and which are useful in the treatment of diseases mediated by the muscarinic M1 receptor. These are also pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula where R1-R5, X1, X2 and p are as defined herein.
公开号:BR112015006029B1
申请号:R112015006029-3
申请日:2013-09-18
公开日:2022-01-25
发明作者:Giles Albert Brown；Julie Elaine Cansfield；Miles Stuart Congreve；Mark Pickworth；Benjamin Gerald Tehan
申请人:Heptares Therapeutics Limited；
IPC主号:

专利说明:

[001] The present invention relates to a class of novel amide compounds, their salts, pharmaceutical compositions containing them and their use in the therapy of the human body. In particular, the invention relates to a class of amide compounds, which are muscarinic M1 receptor agonists, and therefore useful in the treatment of Alzheimer's Disease, schizophrenia, cognitive disorders and other diseases mediated by the muscarinic M1 receptor, as well as in the treatment or relief of pain. FUNDAMENTALS OF THE INVENTION
[002]Muscarinic acetylcholine receptors (mAChRs) are members of the G protein-coupled receptor superfamily that mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous systems. Five mAChR subtypes were cloned, M1 to M5. mAChR M1 is predominantly expressed postsynaptically in the cortex, hippocampus, striatum and thalamus; M2 mAChRs are predominantly located in the brainstem and thalamus, although also in the cortex, hippocampus and striatum where they reside in cholinergic synaptic terminals (Langmead et al., 2008 Br J Pharmacol). However, M2 mAChRs are also expressed peripherally in cardiac tissue (where they mediate the vagal innervation of the heart) and in smooth muscle and exocrine glands. mAChRs M3 are expressed at a relatively low level in the CNS, but are widely expressed in smooth muscle and glandular tissues such as sweat and salivary glands (Langmead et al., 2008 Br J Pharmacol).
[003]Muscarinic receptors in the central nervous system, especially mAChR M1, play a key role in mediating higher cognitive processing. Diseases associated with cognitive impairments, such as Alzheimer's disease, are accompanied by the loss of cholinergic neurons in the basal forebrain (Whitehouse et al., 1982 Science). In schizophrenia, which is also characterized by cognitive impairments, mAChR density is reduced in the prefrontal cortex, hippocampus, and caudate putamen of schizophrenic individuals (Dean et al., 2002 Mol Psychiatry). Furthermore, in animal models, obstructions or lesions of central cholinergic pathways result in profound cognitive deficits and non-selective mAChR antagonists have been shown to induce psychotomimetic effects in psychiatric patients. Cholinergic replacement therapy was largely based on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds showed efficacy versus symptomatic cognitive decline in the clinical setting, but produced dose-limiting side effects resulting from stimulation of peripheral M2 and M3 mAChRs including gastrointestinal motility, bradycardia, nausea and vomiting. (http://www.drugs.com/pro/donepezil.html; http://www.drugs.com/pro/rivastigmine.html).
[004] Additional finding efforts have been directed at identifying direct mAChR M1 agonists to target increases in cognitive function. These efforts resulted in the identification of a range of agonists, exemplified by compounds such as xanomeline, AF267B, sabcomelin, milamelin, and cevimeline. Many of these compounds have been shown to be highly effective in preclinical models of cognition in rodents and/or non-human primates. Milamelin showed efficacy versus scopolamine-induced deficits in rodent working and spatial memory; sabcomelin exhibited efficacy on a visual object discrimination task in marmosets and xanomeline reversed mAChR antagonist-induced deficits in cognitive performance in a passive avoidance paradigm.
[005]Alzheimer's disease (AD) is the most common neurodegenerative disorder (26.6 million people worldwide in 2006) that affects the elderly, resulting in profound memory losses and cognitive dysfunction. The etiology of the disease is complex, but it is characterized by two characteristic brain sequelae: aggregates of amyloid plaques, abundantly composed of amyloid-β (Aβ) peptide, and neurofibrillary tangles, formed by hyperphosphorylated tau proteins. Aβ accumulation is thought to be the central feature in the progress of AD, and as such, many putative therapies for the treatment of AD are currently aimed at inhibiting Aβ production. Aβ is derived from the proteolytic cleavage of membrane-bound amyloid precursor protein (APP). APP is processed by two routes, non-amyloidogenic and amyloidogenic. Cleavage of APP by Y-secretase is common to both pathways, but in the former, APP is cleaved by an α-secretase to produce soluble APPα. The cleavage site is located in the Aβ sequence, thus preventing its formation. However, in the amyloidogenic pathway, APP is cleaved by β-secretase to produce soluble APPβ and also Aβ. In vitro studies have shown that mAChR agonists can promote APP processing in relation to the soluble non-amyloidogenic pathway. In vivo studies showed that the mAChR agonist, AF267B, altered disease-like pathology in the 3xTgAD transgenic mouse, a model of the different components of Alzheimer's disease (Caccamo et al., 2006 Neuron). Finally, the mAChR agonist cevimeline has been shown to provide a small but significant reduction in cerebrospinal fluid levels of Aβ in Alzheimer's patients, thus demonstrating potential disease-modifying efficacy (Nitsch et al., 2000 Neurol).
[006]Further, preclinical studies have suggested that mAChR agonists exhibit an atypical antipsychotic-like profile across a range of preclinical paradigms. The mAChR agonist, xanomeline, reverses a number of dopamine-driven behaviors, including amphetamine-induced locomotion in rats, apomorphine-induced ascent in mice, dopamine agonist-driven lateral movement in unilateral 6-OH-DA-lesioned rats, and motor restlessness. amphetamine-induced disease in monkeys (no tendency to EPS). It has also been shown to inhibit cell exchange and conditioned avoidance of dopamine A10, but not A9, and induce c-fos expression in the prefrontal cortex and nucleus accumbens, but not in the striatum in rats. These data are suggestive of an atypical antipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev).
[007]Xanomeline, sabcomelin, milamelin, and cevimeline have progressed through various stages of clinical development for the treatment of Alzheimer's disease and/or schizophrenia. Phase II clinical studies with xanomeline have demonstrated its efficacy versus several 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 schizophrenics and provided a significant reduction in positive and negative symptoms when compared to placebo control (Shekhar et al., 2008 Am J Psych). However, in all clinical studies, xanomeline and other related mAChR agonists exhibited an unacceptable safety margin with respect to cholinergic side effects, including nausea, gastrointestinal pain, diarrhea, diaphoresis (excess sweating), hypersalivation (excess salivation) , syncope and bradycardia.
[008]Muscarine receptors are involved in central and peripheral pain. Pain can be divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function in keeping the body safe from stimuli that can produce tissue damage, however, post-surgical pain management is required. Inflammatory pain can occur for many reasons, including tissue damage, autoimmune response, and pathogenic invasion and is triggered by the action of inflammatory mediators such as neuropeptides and prostaglandins that result in neuronal inflammation and resulting pain. Neuropathic pain is associated with abnormal painful sensations to non-painful stimuli. Neuropathic pain is associated with a number of different diseases/traumas such as spinal cord injury, multiple sclerosis, diabetes (diabetic neuropathy), viral infection (such as HIV or Herpes). They are also common in cancer either as a result of the disease or as a side effect of chemotherapy. Activation of muscarinic receptors has been shown to be analgesic across a range of pain states through activation of receptors in the spinal cord and higher pain centers in the brain. Increasing endogenous acetylcholine levels through acetylcholinesterase inhibitors, direct activation of muscarinic receptors with agonists or allosteric modulators has been shown to have analgesic activity. In contrast, obstruction of muscarinic receptors with antagonists or the use of knockout mice increases pain sensitivity. Evidence for the role of the M1 receptor in pain is examined by D. F. Fiorino and M. Garcia-Guzman, 2012.
[009] Recently, a small number of compounds have been identified that exhibit improved selectivity for the M1 mAChR subtype over 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 levels of selectivity versus the M3 mAChR subtype, some of these compounds retain significant agonist activity at both this subtype and the M2 mAChR subtype. In the present document, a series of compounds are described which exhibit unexpectedly high levels of selectivity for the mAChR M1 towards the M2 and M3 receptor subtypes. FIGURES
[010] The compounds of the invention reduce scopolamine-induced amnesia in a dose-dependent manner. Figure 1 shows that Isomer 2 of Example 9 reverses the paradigm's scopolamine-induced amnesia in a dose-dependent manner, with an ED50 approaching ca. 10 mg/kg (po). The effect of 30 mg/kg was similar to that produced by the cholinesterase inhibitor donepezil (0.1 mg/kg, ip) which served as a positive control. THE INVENTION
[011] The present invention provides compounds having an activity as muscarinic M1 receptor agonists. More particularly, the invention provides compounds which exhibit selectivity for the M1 receptor towards the M2 and M3 receptor subtypes.
[012] Correspondingly, in a first embodiment (Embodiment 1.1), the invention provides a compound of formula (1):
or a salt thereof, wherein: p is 0, 1 or 2; X1 and X2 are saturated hydrocarbon groups which together contain a total of five to nine carbon atoms and which are bonded so that the moiety:
form a bicyclic ring system;
[013] R1 is a C1-10 non-aromatic hydrocarbon group which is 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 substituted by one heteroatom selected from O, N and S and oxidized forms thereof;
[014] R2 is hydrogen or a C1-10 non-aromatic hydrocarbon group;
[015]or R1 and R2 together with the nitrogen atom to which they are attached form a four to nine ring membered non-aromatic heterocyclic ring, wherein the heterocyclic ring may optionally contain a second heteroatom selected from O, N and S and oxidized forms thereof; and wherein the heterocyclic ring may be optionally substituted with one to six substituents selected from C 1-2 alkyl; fluorine; and cyano;
[016] R3 is selected from hydrogen; halogen; cyan; hydroxy; C1-3 alkoxy; and a C1-5 non-aromatic hydrocarbon group which is 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 substituted by a heteroatom selected from of O, N and S;
[017] R4 is a C1-6 non-aromatic hydrocarbon group which is 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 substituted by one heteroatom selected from O, N and S and oxidized forms thereof; and
[018] R5 is fluorine.
[019] Particular and preferred compounds of formula (1) are as defined in Embodiments 1.2 to 1.64 below:
[020] 1.2 A compound according to Embodiment 1.1, wherein R1 is a C1-10 non-aromatic hydrocarbon group containing 0, 1 or 2 carbon-carbon multiple bonds, wherein the hydrocarbon group is optionally substituted by a to six fluorine atoms and wherein one or two, but not all, carbon atoms of the hydrocarbon group may be optionally replaced by a heteroatom selected from O, N and S and oxidized forms thereof.
[021] 1.3 A compound, according to either of Embodiments 1.1 and 1.2, wherein R1 is selected from C1-6 alkyl; C2-6 alkenyl; C2-6 alkynyl; and C1-10 non-aromatic hydrocarbon groups consisting of or containing a C3-10 cycloalkyl or C5-6 cycloalkenyl group; wherein each of said alkyl, alkenyl, alkylline and non-aromatic hydrocarbon groups is optionally substituted by one to six fluorine atoms and wherein one or two, but not all, carbon atoms of each of alkyl, alkenyl , alkynyl and non-aromatic hydrocarbon groups may be optionally substituted by a heteroatom selected from O, N and S and oxidized forms thereof.
[022] 1.4 A compound according to any one of Modalities 1.1 to 1.3, wherein R1 is selected from: • C1-6 alkyl optionally substituted by 1 to 6 fluorine atoms; • methoxy C1-4 alkyl optionally substituted by 1 to 6 fluorine atoms; • C1-6 alkoxy; • C2-6 alkynyl; • C2-6 alkynyl; • C3-6 cycloalkyl optionally substituted by one or two methyl groups; • C4-5 cycloalkyl -CH2- wherein the C4-5 cycloalkyl moiety is optionally substituted by a C1-2 alkyl group and wherein a carbon atom of the C4-5 cycloalkyl moiety may be optionally substituted by an oxygen atom; • cyclopropyl-C1-3 alkyl; • cyclopentenil; and • methyl-bicyclo[2.2.2]octanyl.
[023] 1.5 A compound according to Embodiment 1.4, wherein R1 is selected from: • C1-6 alkyl optionally substituted by 1 to 6 fluorine atoms; • C3-6 cycloalkyl optionally substituted by one or two methyl groups; • C4-5 cycloalkyl -CH2- wherein the C4-5 cycloalkyl moiety is optionally substituted by a C1-2 alkyl group and wherein a carbon atom of the C4-5 cycloalkyl moiety may be optionally substituted by an oxygen atom; • cyclopropyl-C1-3 alkyl; and •methyl-bicyclo[2.2.2]octanyl.
[024] 1.6 A compound according to Embodiment 1.5, wherein R1 is C16 alkyl optionally substituted by 1 to 6 fluorine atoms.
[025] 1.7 A compound according to Embodiment 1.5, wherein R1 is C3-6 cycloalkyl optionally substituted by one or two methyl groups.
[026] 1.8 A compound according to Embodiment 1.5, wherein R1 is C4-5 cycloalkyl -CH2- wherein the C4-5 cycloalkyl moiety is optionally substituted by a C1-2 alkyl group and wherein a carbon atom of the C4-5 cycloalkyl moiety may be optionally substituted by an oxygen atom.
[027] 1.9 A compound according to Embodiment 1.5, wherein R 1 is cyclopropyl-C 1-3 alkyl.
[028] 1.10 A compound according to Embodiment 1.5, wherein R1 is methylbicyclo[2.2.2]octanyl.
[029] 1.11 Composite, according to Modality 1.4, in which R1 is selected from groups A to AH below:


[030]where the asterisk denotes the point of attachment of the group to the amide nitrogen atom.
[031] 1.12 Compound, according to Modality 1.11, in which R1 is selected from groups A, B, D, E, F, G, L, M, N, O, Q, R, T, V, W, Y, AB, AE, AF, AG and AH.
[032] 1.13 A compound according to any one of Embodiments 1.1 to 1.4, wherein R1 is selected from 2-methyl propyl groups; 2,2-dimethyl propyl; tert-butyl; 2-methyl-but-2-yl; 2,3-dimethylbut-2-yl; cyclopropyl methyl; cyclobutyl methyl; cyclopentyl; cyclopentyl methyl; 1-methyl cyclobutyl; 1-methyl cyclopentyl; 1-methyl cyclohexyl; 1-methyl cyclopentyl methyl; cyclopropyl-prop-2-yl; 1-methyl cyclobutyl methyl, 1-ethyl-cyclobutyl methyl, 1-(fluoromethyl) cyclobutyl, 1-(1,1,1-trideuteromethyl) cyclobutyl and 1-(1,1,1-trideuteromethyl)-2,2,3 ,3,4,4-hexadeuterocyclobutyl.
[033] 1.14 A compound according to Embodiment 1.13, wherein R1 is selected from 2-methyl propyl and 1-methyl cyclobutyl.
[034] 1.15 A compound according to Embodiment 1.14, wherein R1 is 2-methyl propyl.
[035] 1.16 A compound according to Embodiment 1.14, wherein R1 is 1-methyl cyclobutyl.
[036] 1.17 A compound according to any one of Modalities 1.1 to 1.16, wherein R2 is selected from hydrogen and C1-6 alkyl.
[037] 1.18 A compound, according to Modality 1.17, wherein R2 is selected from hydrogen, methyl, ethyl and isopropyl.
[038] 1.19 A compound according to Embodiment 1.18, wherein R2 is hydrogen.
[039] 1.20 A compound according to any one of Embodiments 1.1 to 1.19, wherein R3 is selected from hydrogen, halogen, cyano, hydroxy, C1-3 alkoxy and C1-4 alkyl.
[040] 1.21 Compound, according to Modality 1.20, in which R3 is selected from hydrogen, fluorine, methyl and methoxy.
[041] 1.22 Compound, according to Modality 1.21, wherein R3 is selected from hydrogen, fluorine and methoxy.
[042] 1.23 A compound, according to Embodiment 1.22, wherein R3 is selected from hydrogen and fluorine.
[043] 1.24 A compound according to Embodiment 1.23, wherein R3 is hydrogen.
[044] 1.25 A compound, in accordance with Embodiment 1.23, wherein R3 is fluorine.
[045] 1.26 A compound according to any one of Embodiments 1.1 to 1.25, wherein R4 is a C1-6 acyclic hydrocarbon group.
[046] 1.27 A compound according to Embodiment 1.26, wherein R4 is a C1-3 acyclic hydrocarbon group.
[047] 1.28 A compound according to Embodiment 1.27, wherein R4 is a C1-3 alkyl group or a C2-3 alkynyl group.
[048] 1.29 A compound according to Embodiment 1.28, wherein R4 is selected from methyl, ethyl, ethynyl and 1-propynyl.
[049] 1.30 A compound according to Embodiment 1.29, wherein R4 is methyl.
[050] 1.31 Compound, according to any one of Modalities 1.1 to 1.30, where p is 0 or 1.
[051] 1.32 Compound, according to Modality 1.31, where p is 0.
[052] 1.33 Compound, according to Modality 1.31, where p is 1.
[053] 1.34 A compound according to any one of Embodiments 1.1 to 1.33, wherein X1 and X2 together contain six or seven carbon atoms.
[054] 1.35 A compound according to any one of Modalities 1.1 to 1.34, wherein the bicyclic ring system formed by the moiety:
is a bridged bicyclic ring system.
[055] 1.36 A compound according to Embodiment 1.35, wherein the bridged bicyclic ring system is an azabicyclooctane or azabicyclononane ring system.
[056] 1.37 A compound according to Embodiment 1.36 wherein the bridged bicyclic ring system is selected from an 8-aza-bicyclo[3.2.1]octane ring system, a 9-aza ring system -bicyclo[3.3.1]nonane and a 6-aza-bicyclo[3.2.1]octane ring system.
[057] 1.38 Compound, according to Modality 1.37, in which the bridged bicyclic ring system is selected from the BA, BB and BC ring systems:

[058] 1.39 A compound according to Embodiment 1.38, wherein the bridged bicyclic ring system is a BA ring system.
[059] 1.40 A compound in accordance with Embodiment 1.38, wherein the bridged bicyclic ring system is a BB ring system.
[060] 1.41 A compound according to Embodiment 1.38, wherein the bridged bicyclic ring system is a BC ring system.
[061] 1.42 A compound according to any one of Modalities 1.1 to 1.34, wherein the bicyclic ring system formed by the moiety:

[062]is a spirocyclic ring system.
[063] 1.43 A compound according to Embodiment 1.42, wherein the spirocyclic ring system is a 2-aza-spiro[3.4]octane ring system or a 6-aza-spiro[3.4]octane ring system.
[064] 1.44 Compound, according to Modality 1.43, in which the spirocyclic ring system is selected from the CA and CB ring systems below:

[065] 1.45 A compound according to Embodiment 1.44, wherein the spirocyclic ring system is a CA ring system.
[066] 1.46 A compound according to Embodiment 1.44, wherein the spirocyclic ring system is a CB ring system.
[067] 1.47 A compound according to any one of Embodiments 1.1 to 1.34, wherein the bicyclic ring system formed by the moiety:

[068]is a fused bicyclic ring system.
[069] 1.48 A compound according to Embodiment 1.47, wherein the fused bicyclic ring system is a cyclopentane pyrrolidine ring system.
[070] 1.49 A compound according to Embodiment 1.47 wherein the cyclopentane pyrrolidine ring system has the structure DA below

[071] 1.50 Compound, according to any one of Modalities 1.1 to 1.34, wherein the bicyclic ring system formed by the moiety:
is selected from:
[072] (a) an azabicyclooctane or azabicyclononane ring system; (b) a 2-aza-spiro[3.4]octane ring system or a 6-aza-spiro[3.4]octane ring system; and (c) a cyclopentane pyrrolidine ring system.
[073] 1.51 Compound, in accordance with Modality 1.50, wherein the bicyclic ring system formed by the moiety:

[074]is selected from the BA, BB, BC, CA, CB and DA ring systems below:

[075] 1.52 Compound, according to Modality 1.1, having the formula (2):

[076]wherein R1, R3, R4, R5 and p are as defined in any one of Embodiments 1.1 to 1.34; q is 1, 2, or 3 and r is 0 or 1, provided that the total of q and r is 2 or 3.
[077] 1.53 Compound, according to Embodiment 1.52, wherein (i) r is 0 and q is 2; (ii) r is 0 and q is 3; or (iii) r is 1 and q is 1.
[078] 1.54 Compound, according to Modality 1.1, having the formula (3):

[079]wherein R1, R3, R4, R5 and p are as defined in any one of Embodiments 1.1 to 1.34; s is 0 or 1 and t is 0 or 1.
[080] 1.55. Composite, according to Modality 1.54, where the total of s and t is 1.
[081] 1.56 Compound, according to Modality 1.55, where s is 0 and t is 1.
[082] 1.57 Composite, according to Modality 1.55, where s is 1 and t is 0.
[083] 1.58 Compound, according to Modality 1.1, having the formula (4):

[084] wherein R1, R3, R4, R5 and p are as defined in any one of Embodiments 1.1 to 1.34; and u, v, w and x are 0, 1 or 2 as long as the total u+v+w+x is at least 1 and does not exceed 5.
[085] 1.59 Compound, according to Modality 1.58, where each of u, v, w and x is equal to 1.
[086] 1.60 Compound, in accordance with Embodiment 1.1, which is as defined in any one of Examples 1 to 13.
[087] 1.61 Compound, according to any one of Modalities 1.1 to 1.60, having a molecular weight less than 550, for example, less than 500, or less than 450.
[088] 1.62 A compound according to any one of Modalities 1.1 to 1.61, which is in the form of a salt.
[089] 1.63 A compound according to Embodiment 1.62, wherein the salt is an acid addition salt.
[090] 1.64 A compound according to Embodiment 1.62 or 1.63, wherein the salt is a pharmaceutically acceptable salt. DEFINITIONS
[091]In this order, the following definitions apply, unless otherwise noted.
[092] The term “treatment”, in relation to the uses of compounds of formula (1), is used to describe any form of intervention where a compound is administered to an individual suffering from, or at risk of suffering from, or potentially at risk of. of suffering from the disease or disorder in question. Thus, the term "treatment" encompasses both preventive (prophylactic) treatment and treatment where measurable or detectable symptoms of the disease or disorder are being exhibited.
[093] The term "therapeutically effective amount" as used herein (e.g., in relation to methods of treating a disease or condition) refers to an amount of the compound that is effective in producing 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 may be, for example, complete elimination of pain or a reduction in pain severity.
[094] In formula (1), X1 and X2 are saturated hydrocarbon groups which together contain a total of five to nine carbon atoms and which bond together so that the moiety:

[095]form a bicyclic ring system. The term "bicyclic ring system" as used in the context of X1 and X2 includes fused bicyclic systems, bridged bicyclic systems, and spirocyclic systems containing two linked rings.
[096] The term "non-aromatic hydrocarbon group" (as per "C1-10 non-aromatic hydrocarbon group" or "C1-5 acyclic non-aromatic hydrocarbon group" refers to a group consisting of atoms of carbon and hydrogen and which does not contain aromatic rings. The hydrocarbon group may be fully saturated or may contain one or more carbon-carbon double bonds or carbon-carbon triple bonds, or mixtures of double and triple bonds. The hydrocarbon group may be a straight 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, cycloalkyl alkyl, cycloalkenyl alkyl, and so on.
[097]The terms "alkyl", "alkenyl", "alkynyl", "cycloalkyl" and "cycloalkenyl" are used in their conventional sense (eg, as defined in the IUPAC Gold Book) unless otherwise noted.
[098] The term "cycloalkyl" as used in question, where the specified number of carbon atoms permits, includes monocyclic cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and bicyclic and tricyclic groups. Bicyclic cycloalkyl groups include bridged ring systems such as bicycloheptane, bicyclooctane and adamantane.
[099] In the definitions of R1, R3 and R4 above, where stated, one or two, but well all, carbon atoms of the non-aromatic hydrocarbon group may be optionally replaced by a heteroatom selected from O, N and S and (in the case of R1 and R4) oxidized forms thereof. In defining the moiety Rb that forms part of R6, one or more, but not all, carbon atoms of the hydrocarbon group may be optionally replaced by a heteroatom selected from O, N and S or by a group selected from CO, X1C(X2), C(X2)X1, SO and SO2. It will be appreciated that when a carbon atom is replaced by a heteroatom, the lower valencies of the heteroatoms compared to carbon means that fewer atoms will be bonded to the heteroatoms than would be bonded to the carbon atom that has been replaced. So, for example, the replacement of a carbon atom (valence of four) in a CH2 group by oxygen (valence of two) will mean that the resulting molecule will contain two fewer hydrogen atoms and the replacement of one carbon atom (valence of four) in a CH2 group for nitrogen (valence of three) will mean that the resulting molecule will contain one less hydrogen atom.
[0100]Examples of substitutions of heteroatoms for carbon atoms include the replacement of a carbon atom in a -CH2-CH2-CH2- chain with oxygen or sulfur to provide a -CH2-O-CH2- ether or -CH2- thioether S-CH2-, the replacement of a carbon atom in a CH2-C=CH group with nitrogen to give a nitrile (cyano) group CH2-C=N, the replacement of a carbon atom in a -CH2-CH2 group -CH2- with C=O to give a ketone -CH2-C(O)-CH2-, the replacement of a carbon atom in a -CH2-CH2-CH2- group with S=O or SO2 to give a sulfoxide - CH2-S(O)-CH2- or sulfone -CH2-S(O)2-CH2-, the replacement of a carbon atom in a -CH2-CH2-CH2- chain with C(O)NH to provide an amide -CH2-CH2-C(O)-NH-, the replacement of a carbon atom in a -CH2-CH2-CH2- chain with nitrogen to give an amine -CH2-NH-CH2-, and the replacement of an atom of carbon in a -CH2-CH2-CH2- chain by C(O)O to give an ester (or carboxylic acid) -CH2-CH2-C(O)-O-. In each of these substitutions, at least one carbon atom of the hydrocarbon group must remain. salts
[0101] Many compounds of formula (1) may be present in the form of salts, for example acid addition salts or, in certain cases, salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of formula (1) include the salt forms of the compounds as defined in Embodiments 1.62 to 1.64. The salts are typically acid addition salts.
[0102] The salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods, such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. In general, these salts can be prepared by reacting the free acid or base forms of these compounds with the base or appropriate acids in water or an organic solvent, or a mixture of the two; in general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
[0103]Acid addition salts (as defined in Embodiment 1.63) can be formed from a wide variety of acids, both inorganic and organic. Examples of acid addition salts that fall within Embodiment 1.63 include monosalts or disalts formed by an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic acid (e.g., L-ascorbic) , L-aspartic, benzenesulfonic, benzoic, 4-acetamido benzoic, butanoic, (+) camphor, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic , sulfuric dodecyl, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxy ethanesulfonic, formic, fumaric, galactaric, gentisic, glucoeptonic, D-gluconic, glucuronic (eg, D-glucuronic), glutamic (eg, L- glutamic), a-oxoglutatic, glycolic, hippuric, hydrolic acids (e.g. hydrobromic, hydrochloric, hydroiodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-dissu Phosphoric, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L-tartaric, thiocyanic, sulfonic p-toluene, undecylenic and valeric, as well as acetylated amino acids and cation exchange resins.
[0104] When compounds of formula (1) contain an amine function, they can form quaternary ammonium salts, for example, by reaction with an alkylating agent according to methods well known to those skilled in the art. These quaternary ammonium compounds are within the scope of formula (1).
[0105] The compounds of the invention may be present as mono- or disalts depending on the pKa of the acid from which the salt is formed.
[0106] The salt forms of the compounds of the invention are typically 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 to 19. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms which can then be converted to pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful, for example, in purifying or separating compounds of the invention, also form part of the invention. stereoisomers
[0107] Stereoisomers are isomeric molecules having the same molecular formula and sequence of bonded atoms, but which differ only in the three-dimensional orientations of their atoms in space. Stereoisomers can be, for example, geometric isomers or optical isomers. geometric isomers
[0108]With geometric isomers, isomerism occurs due to different orientations of an atom or group around a double bond, as in cis and trans (Z and E) isomerism around a carbon-carbon double bond, or cis isomers and trans around an amide bond, or syn and anti isomerism around a carbon-nitrogen double bond (e.g. in an oxime), or gyratory isomerism around a bond where there is restricted rotation, or cis and trans isomerism around a ring, such as a cycloalkane ring.
[0109] Correspondingly, in another embodiment (Embodiment 1.65), the invention provides a geometric isomer of the Compound according to any one of Embodiments 1.1 to 1.64. optical isomers
[0110] When compounds of the formula contain one or more chiral centers, and may be present in the form of two or more optical isomers, references to the compounds include all optical isometric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either individual optical isomers, or mixtures (eg, racemic mixtures) or two or more optical isomers, unless the context indicates otherwise.
[0111] Correspondingly, in another embodiment (Embodiment 1.66), the invention provides the Compound according to any one of Embodiments 1.1 to 1.65 which contains a chiral center.
[0112]Optical isomers can be characterized and identified by their optical activity (i.e. as + and - isomers, or del isomers) or they can be characterized in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn , Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109 to 114, and see also Cahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385 to 415. Optical isomers can be separated by a number of techniques which include chiral chromatography (chromatography on a chiral support) and such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphor sulfonic acid, separating the diastereoisomers by preferential crystallization, and then dissociating the salts to provide the individual enantiomer of the free base.
[0113] When the compounds of the invention are present as two or more isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over another enantiomer, for example in terms of biological activity. Therefore, in certain circumstances, it may be desirable to use only a pair of enantiomers, or only a plurality of diastereoisomers, as a therapeutic agent.
[0114] Correspondingly, in another embodiment (Embodiment 1.67), the invention provides compositions containing the Compound, according to Embodiment 1.66, having one or more chiral centers, wherein at least 55% (e.g., at least 60 %, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Embodiment 1.65 are present as a single optical isomer (eg, enantiomer or diastereoisomer).
[0115] In a general embodiment (Embodiment 1.68), 99% or more (eg, substantially all) of the total amount of the compound (or compound for use) of Embodiment 1.66 is present as a single optical isomer.
[0116]For example, in one embodiment (Employment 1.69), the compound is present as a single enantiomer.
[0117]In another embodiment (Standard 1.70), the compound is present as a single diastereoisomer.
[0118] The invention also provides mixtures of optical isomers, which can be racemic or non-racemic. Therefore, the invention provides:
[0119]1.71 Compound, according to Modality 1.66, which is in the form of a racemic mixture of optical isomers.
[0120]1.72 A compound, in accordance with Modality 1.66, which is in the form of a non-racemic mixture of optical isomers. isotopes
[0121] Compounds of the invention, as defined in any one of Embodiments 1.1 to 1.72, may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes in its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope, respectively, 12C, 13C and 14C and 16O and 18O.
[0122]Similarly, a reference to a particular functional group also includes isotopic variations within its scope, except where the context indicates otherwise. For example, a reference to an alkyl group such as an ethyl group also encompasses variations in which one or more of the hydrogen atoms in the group are in the form of an isotope of deuterium or tritium, for example, as in an ethyl group in in which all five hydrogen atoms are in the isotropic form of deuterium (a lose-teroethyl group).
[0123]Isotopes can be radioactive or non-radioactive. In one embodiment of the invention (Embodiment 1.73), the compound according to any one of Embodiments 1.1 to 1.72 does not contain radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment (Embodiment 1.74), however, the compound according to any one of Embodiments 1.1 to 1.72 may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context. solvates
[0124] Compounds of formula (1), as defined in any one of Embodiments 1.1 to 1.74, may form solvates. Preferred solvates formed by incorporating into the solid state structure (e.g., crystal structure) of the compounds of the invention molecules of a non-toxic pharmaceutically acceptable solvent (hereinafter referred to as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention from a solvent or mixture of solvents containing the solvating solvent. One can determine whether or not a solvate has formed in any given instance by subjecting crystals of the compound to analysis using well-known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography. Solvates can be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.
[0125] Correspondingly, in additional embodiments 1.75 and 1.76, the invention provides:
[0126]1.75 A compound according to any one of Embodiments 1.1 to 1.74 in the form of a solvate.
[0127]1.76 A compound according to Embodiment 1.75, wherein the solvate is a hydrate.
[0128]For a more detailed discussion of solvates and the methods used to manufacture and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.
[0129] Alternatively, rather than being present as a hydrate, the compound of the invention may be anhydrous. Therefore, in another embodiment (Embodiment 1.77), the invention provides a compound, as defined in any one of Embodiments 1.1 to 1.74, in an anhydrous form (e.g., anhydrous crystalline form). Crystalline and amorphous forms
[0130] The compounds according to any one of Embodiments 1.1 to 1.77 may be present in a crystalline or non-crystalline (eg, amorphous) state. One can readily determine whether or not a compound is present in a crystalline state using standard techniques such as X-ray powder diffraction (XRPD). Crystals and their crystal structures can be characterized using a number of techniques including single crystal X-ray crystallography, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform (FTIR). The behavior of the crystals under conditions of variable humidity can be analyzed by gravimetric gas sorption studies and also by XRPD. Determination of the crystal structure of a compound can be accomplished by X-ray crystallography which can be performed according to conventional methods such as those described herein and as 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 (b/b), 0-19-85579-2 ( h/b)). This technique involves analyzing and interpreting the X-ray diffraction of a single crystal. In an amorphous solid, the three-dimensional structure that normally exists in a crystalline form does not exist and the positions of molecules relative to each other in the amorphous form are essentially random, see, for example, Hancock et al. J. Pharm. Sci. (1997), 86, 1).
[0131] Correspondingly, in additional embodiments, the invention provides:
[0132]1.78 A compound according to any one of Embodiments 1.1 to 1.77 in a crystalline form.
[0133]1.79 Compound, in accordance with any of Modalities 1.1 to 1.77, which is:
[0134](a) from 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.
[0135]1.80 Compound, according to any one of Modalities 1.1 to 1.77, which is in an amorphous form. prodrugs
[0136] Compounds of formula (1), as defined in any one of Embodiments 1.1 to 1.74, may be presented in the form of a prodrug. The term "prodrug" means, for example, any compound that is converted in vivo to a biologically active compound of formula (1) as defined in any one of Embodiments 1.1 to 1.74.
[0137] For example, some prodrugs are esters of the active compound (eg, a metabolically unstable and physiologically acceptable ester). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. Such esters may be formed by esterification, for example, of any hydroxyl groups present in the parent compound with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection, if necessary.
[0138] Likewise, some prodrugs are enzymatically activated to produce the active compound, or a compound that, upon an additional 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 it may be an amino acid ester derivative.
[0139] Correspondingly, in another embodiment (Embodiment 1.81), the invention provides a prodrug of a compound, as defined in any one of Embodiments 1.1 to 1.74, wherein the compound contains a functional group that is convertible under conditions physiological properties to form a hydroxyl group or amino group. Complexes and clathrates
[0140] Likewise, formula (1) covers complexes (eg inclusion complexes or clathrates with compounds, such as cyclodextrins, or complexes with metals) of the compounds of Embodiments 1.1 to 1.81 in Modalities 1.1 to 1.81.
[0141] Correspondingly, in another embodiment (Embodiment 1.82), the invention provides a compound according to any one of Embodiments 1.1 to 1.81 in the form of a complex or clathrate. Biological activity and therapeutic uses
[0142] The compounds of the present 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.
[0143] A significant advantage of the compounds of the invention is that they are highly selective for the M1 receptor over the M2 and M3 receptor subtypes. The compounds of the invention are agonists or antagonists of the M2 and M3 receptor subtypes. For example, while compounds of the invention typically have pEC50 values of at least 6 (preferably at least 6.5) and Emax values greater than 80 (preferably greater than 95) against the M1 receptor in the described functional assay in Example A, they may have pEC50 values less than 5 and Emax values less than 20% when tested against M2 and M3 subtypes in the functional assay of Example A.
[0144] Correspondingly, in Modalities 2.1 to 2.9, the invention provides:
[0145]2.1 A compound, according to any one of Modalities 1.1 to 1.82, for use in medicine.
[0146]2.2 A compound according to any one of Embodiments 1.1 to 1.82 for use as a muscarinic M1 receptor agonist.
[0147]2.3 A compound according to any one of Embodiments 1.1 to 1.82 which is a muscarinic M1 receptor agonist having a pEC50 in the range of 6.0 to 7.9 and an Emax of at least 90 against the M1 receptor in the assay of Example A herein or an assay substantially similar thereto.
[0148]2.4 A compound according to Embodiment 2.3 which is a muscarinic M1 receptor agonist having a pEC50 in the range of 6.5 to 7.5.
[0149]2.5 Composite, in accordance with Style 2.3 or Style 2.4, having an Emax of at least 95 against the M1 receiver.
[0150]2.6 A compound according to any one of Embodiments 2.3 to 2.5 that is selective for the M1 receptor compared to the muscarinic M2 and M3 receptors.
[0151]2.7 A compound, according to any one of Embodiments 2.3 to 2.6, that has a pEC50 of less than 5 and an Emax of less than 50 against the muscarinic M2 and M3 receptor subtypes.
[0152]2.8 A compound, in accordance with Modality 2.7, that has a pEC50 less than 4.5 and/or an Emax less than 30 against muscarinic M2 and M3 receptor subtypes.
[0153]2.9 A compound according to any one of Embodiments 1.1 to 1.82 and Embodiments 2.3 to 2.8, for use in the treatment of a disease or condition mediated by the muscarinic M1 receptor.
[0154] By virtue of their activity against the muscarinic M1 receptor, the compounds of the invention can be used in the treatment of Alzheimer's disease, schizophrenia and other psychotic disorders, cognitive disorders and other diseases mediated by the muscarinic M1 receptor, and can also be used in the treatment of various types of pain.
[0155] Correspondingly, in Modalities 2.10 to 2.26, the invention provides:
[0156]2.10 A compound according to any one of Embodiments 1.1 to 1.82 for use in the treatment of a cognitive disorder or psychotic disorder.
[0157]2.11 A compound for use in accordance with Modality 2.10 wherein the cognitive disorder or psychotic disorder comprises, arises from, or is associated with a condition selected from cognitive impairment, mild cognitive impairment, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, pre-senile dementia, senile dementia, Friederich's ataxia, Down syndrome, Huntington's chorea, hyperkinesia, mania, Tourette's syndrome, Alzheimer's disease, progressive supranuclear palsy, impaired cognitive functions including attention, orientation, learning disorders, memory disorders (eg, memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive dysfunction as a result of stroke, Huntington's disease, Pick's disease, AIDS-related dementia or other dementia states, such as multiple infarct dementia, alcoholic dementia, hypothyroid-related dementia, and dementia associated with other degenerative diseases , such as cerebellar atrophy and amyotrophic lateral sclerosis; other acute or subacute conditions that can cause cognitive decline, such as depression or delirium (pseudodementia states) trauma, head trauma, age-related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, cognitive impairment age-related, autism-related cognitive impairment, Down syndrome, psychosis-related cognitive impairment, and post-electroconvulsive treatment related to cognitive disorders; cognitive disorders due to drug abuse or drug withdrawal, including nicotine, cannabis, amphetamine, cocaine, Attention Deficit Hyperactivity Disorder (ADHD) and dyskinesia disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and dyskinesia schizophrenia, schizophreniform disorders, psychotic depression, mania, acute mania, paranoid disorders, hallucinogens and delusions, personality disorders, obsessive-compulsive disorder, schizotypal disorders, delusional disorders, malignancy psychosis, metabolic disorder, endocrine disorder or narcolepsy, psychosis due to drug abuse or drug withdrawal, bipolar disorders, and schizoaffective disorder
[0158]2.12 A compound according to any one of Embodiments 1.1 to 1.82 for use in the treatment of Alzheimer's disease.
[0159]2.13 A compound according to any one of Modalities 1.1 to 1.82 for use in the treatment of schizophrenia.
[0160]2.14 Method of treating a cognitive disorder in an individual (e.g., a mammalian patient, such as a human, e.g., a human being in need of such treatment), said method comprising administering a dose therapeutically compound, according to any one of Embodiments 1.1 to 1.82.
[0161]2.15Method, according to Modality 2.14, wherein the cognitive disorder comprises, arises from, or is associated with a condition, as defined in Modality 2.11.
[0162]2.16Method, according to Modality 2.15, wherein the cognitive disorder arises from or is associated with Alzheimer's disease.
[0163]2.17Method, according to Modality 2.16, in which the cognitive disorder and schizophrenia.
[0164]2.18 Use of the compound, according to any one of Embodiments 1.1 to 1.82, for the manufacture of a medicament for the treatment of a cognitive disorder.
[0165]2.19Use, in accordance with Mode 2.10, wherein the cognitive disorder comprises, arises from, or is associated with a condition as defined in Mode 2.11.
[0166]2.20Use, in accordance with Modality 2.19, where the cognitive disorder arises from or is associated with Alzheimer's disease.
[0167]2.21Use, according to Modality 2.19, where the cognitive disorder is schizophrenia.
[0168]2.22 A compound according to any one of Modalities 1.1 to 1.82 for the treatment or reduction in severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgias , visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or sore throat, or severe or intratable pain, nociceptive pain, episodic pain, postoperative pain, cancer pain.
[0169]2.23 Method of treating or reducing the severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgias, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or sore throat, or severe or intratable pain, nociceptive pain, episodic pain, postoperative pain, cancer pain, this method comprising the administration of a therapeutically effective dose of the compound according to any one of Embodiments 1.1 to 1.82.
[0170]2.24 A compound according to any one of Modalities 1.1 to 1.82 for the treatment of peripheral disorders, such as lowering intraocular pressure in glaucoma and treating dry eyes and xerostomia, including Sjogren's syndrome.
[0171]2.25 Method of treating peripheral disorders such as lowering intraocular pressure in glaucoma and treating dry eyes and xerostomia, including Sjogren's syndrome, this method comprising administering a therapeutically effective dose of the compound in accordance with any of Modalities 1.1 to 1.82.
[0172]2.26 Use of the compound, according to any one of Modalities 1.1 to 1.82, for the manufacture of a medicament intended for the treatment or reduction of the severity of acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgias, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache or sore throat, or severe or intratable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, or for the treatment of peripheral disorders, such as lowering intraocular pressure in glaucoma and treating dry eyes and xerostomia, including Sjogren's syndrome.
[0173]2.27 Use of the compound, according to any one of Embodiments 1.1 to 1.82, for use in the treatment of dermal lesions, eg, due to pemphigus, dermatitis herpetiformis, pemphigoid and blistering dermal conditions.
[0174]2.28 Use of the compound, according to any of Modalities 1.1 to 1.82, for use in the treatment, prevention, amelioration or reversal of conditions associated with altered gastrointestinal function and mobility, such as functional dyspepsia, irritable bowel syndrome, acid reflux (GER) and esophageal dysmotility, symptoms of gastroparesis and chronic diarrhea.
[0175]2.29 Use of the compound, according to any of Modalities 1.1 to 1.82, for use in the treatment of olfactory dysfunction such as Bosma-Henkin-Christiansen syndrome, chemical poisoning (eg, selenium and silver), hypopituitarism, Kallmann syndrome, skull fractures, tumor therapy and underactive thyroid gland. METHODS FOR PREPARING FORMULA COMPOUNDS (1)
[0176] The compounds of formula (1) can be prepared according to synthetic methods well known to the skilled person and as described herein.
[0177] Correspondingly, in another embodiment (Embodiment 3.1), the invention provides a process for the preparation of a compound as defined in any one of Embodiments 1.1 to 1.82, said process comprising: (A) the reaction of a compound of formula (10)

[0178] wherein R3 , R4 , R5 , X1 and X2 are as defined in any one of Embodiments 1.1 to 1.82 with a compound of formula R1R2NH under amide forming conditions; or (B) the reaction of a compound of formula (11):

[0179]with (i) a compound of formula Cl-C(=O)-CH2-R4, in the presence of a base; or (ii) a compound of formula R4-CH2-OH and triphosphogen; or (iii) with 4-nitrophenyl chloroformate followed by a compound of formula R4-CH2-OH, in the presence of the base;
[0180]and optionally: (C)converting a compound of formula (1) into another compound of formula (1).
[0181] In process variant (A), the reaction can be carried out in the presence of a reagent of the type commonly used in the formation of amide bonds. Examples of such reagents include 1,3-dicyclohexyl carbodiimide (DCC) (Sheehan et al, J. Amer. Chem Soc. 1955, 77, 1067), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (referred to in herein as EDC or EDAC) (Sheehan et al, J. Org. Chem., 1961, 26, 2525), uronium-based coupling agents such as O-(7-azabenzotriazol-1-yl)-N hexafluorophosphate, N,N',N'-tetramethyl uronium (HATU) and phosphonium-based coupling agents such as 1-benzo-triazolyloxy tris-(pyrrolidino) phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205). Carbodiimide-based coupling agents are advantageously used in combination with 1-hydroxy-7-azabenzotriazole (HOAt) (LA Carpino, J. Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxy benzotriazole (HOBt) ) (Konig et al, Chem. Ber., 103, 708, 2024-2034). A preferred amide coupling agent is HATU.
[0182] The coupling reaction is typically carried out in a non-aqueous non-protic solvent such as acetonitrile, dioxane, dimethyl sulfoxide, dichloromethane, dimethylformamide or N-methyl pyrrolidinone, or in an aqueous solvent optionally together with one or more co - miscible solvents. The reaction may be carried out at room temperature or, where the reactants are less reactive, at an appropriately elevated temperature, for example, a temperature of up to about 100°C, for example 50 to 80°C. The reaction may optionally be carried out in the presence of a non-interfering base, for example a tertiary amine such as triethylamine or N,N-diisopropylethylamine.
[0183] As an alternative, a reactive derivative of the carboxylic acid, for example an anhydride or acid chloride, can be used. Acid chloride is typically reacted with the compound of formula R1R2NH in the presence of a base, such as sodium bicarbonate. The acid chloride can be prepared using standard methods, for example, by treating the acid with oxalyl chloride in the presence of a catalytic amount of dimethylformamide.
[0184] Process variant (B) is typically performed in an aprotic solvent such as dichloromethane or dichloroethane in the presence of a non-interfering base such as triethylamine. The reaction can be carried out at room temperature.
[0185] The intermediate compounds of formula (10) can be prepared by the series of reactions shown in Scheme 1 below.
scheme 1
[0186] In Reaction Scheme 1, the piperidine ester (12, R'' = ethyl or methyl) is reacted with the substituted ketone (13) under reductive amination conditions. The reductive amination reaction is typically conducted with mild heating (e.g. at a temperature of about 40°C to about 70°C) in the presence of sodium cyanoborohydride in combination with zinc chloride or triacetoxy sodium borohydride in combination. with titanium isopropoxide in a solvent such as dichloromethane or dichloroethane containing acetic acid to provide an intermediate ester compound (14) which is then selectively hydrolyzed under mild conditions using lithium hydroxide sodium hydroxide to provide compound (10).
[0187]Compounds of formula (11) can be prepared by the sequence of reactions shown in Scheme 2 below.
scheme 2
[0188] In Scheme 2, the piperidine ester (12, R'' = ethyl or methyl) is reacted with the ketone (15) under amination conditions of the type described above to provide an intermediate ester (not shown) which is, then selectively hydrolyzed using lithium hydroxide to provide the carboxylic acid (16). The carboxylic acid (16) is then reacted with an amine HNR1R2 under amide forming conditions (see above) to provide an intermediate amide compound (not shown) which is then deprotected by removing the Boc group through treatment with acid (e.g. trifluoroacetic acid in dichloromethane) to provide compound (11).
[0189]Compounds of formula (10) can also be prepared by the sequence of reactions shown in Scheme 3 below.
Scheme 3
[0190] In Scheme 3, the substituted ketone (13) is reduced to alcohol (17) using sodium borohydride in methanol. The alcohol (17) is then activated as the sulfonic ester (18, R = methyl, trifluoromethyl or 4-methyl phenyl) using the corresponding sulfonyl chloride in dichloromethane in the presence of a tertiary amine such as triethylamine or N,N- diisopropyl ethylamine. The sulfonic ester (18) is reacted with the piperidine ester (12, R'' = ethyl or methyl) in a nucleophilic substitution reaction that is typically carried out with mild heating (e.g. at a temperature of about 40°C). at about 70°C) either neat, without solvent, or in a suitable solvent such as tetrahydrofuran, acetonitrile or dimethylacetamide to provide compound (14) which is then selectively hydrolyzed under mild conditions using lithium hydroxide or sodium hydroxide to provide compound (10).
[0191] Once formated, a compound of formula (1), or a protected derivative thereof, may be converted into another compound of formula (1) by methods well known to those of skill. Examples of synthetic procedures for converting one functional group to another functional group are given in standard texts such as Advanced Organic Chemistry and Organic Syntheses (see references above) or Fiesers' Reagents for Organic Synthesis, Volumes 1 to 17, John Wiley, edited by Mary Fieser (ISBN: 0-471-58283-2).
[0192] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from taking place at an undesired location in the molecule. Examples of protecting groups, and methods of 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).
[0193] Compounds made by the foregoing methods can be isolated and purified by any of a variety of methods well known to those skilled in the art and examples of such methods include recrystallization and chromatographic techniques such as column chromatography (e.g. flash chromatography) and HPLC. PHARMACEUTICAL FORMULATIONS
[0194]While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg formulation).
[0195] Correspondingly, in another embodiment (Embodiment 4.1) of the invention, there is provided a pharmaceutical composition comprising at least one compound of formula (1) as defined in any one of Embodiments 1.1 to 1.82 together with at least one excipient pharmaceutically acceptable.
[0196]In one embodiment (Employment 4.2), the composition is a tablet composition.
[0197]In another embodiment (Employment 4.3), the composition is a capsule composition.
[0198] The pharmaceutically acceptable excipient(s) may be selected, for example, from carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g. solid diluents such as fillers or agents bulkers; and liquid thinners such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release controlling agents (e.g. release retarders or retarding polymers or waxes), binding agents , disintegrants, buffering agents, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffering agents, tonicity adjusting agents, thickening agents, flavoring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions.
[0199]The term "pharmaceutically acceptable" as used herein means compounds, materials, compositions, and/or dosage forms that are, within the scope of medical judgment, suitable for use in contact with the tissues of an individual (e.g. , a human) without excessive toxicity, irritation, allergic response, or other problem or complication, proportionate to a reasonable benefit-to-risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with other ingredients in the formulation.
[0200] Pharmaceutical compositions containing compounds of formula (1) may be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
[0201] The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal, or transdermal administration.
[0202] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or gelatinous), caplets, pills, tablets, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets , wafers or plasters, such as mouth plasters.
[0203] Tablet compositions may contain a single dosage of active compound together with an inert diluent or carrier, such as sugar or sugar alcohol, for example; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar-derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof, such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinyl pyrrolidone, disintegrants (e.g. swellable cross-linked polymers such as cross-linked carboxy methyl cellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens) , antioxidants (e.g., BHT), buffering agents (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate/bicarbonate mixtures. Such excipients are well known and need not be discussed in detail here.
[0204]The tablets can be designed to release either by containing with stomach fluids (immediate-release tablets) or by controlled release (controlled-release tablets) over an extended period of time or with a specific region of the GI tract.
[0205] Pharmaceutical compositions typically comprise approximately 1% (w/w) to approximately 95%, preferably % (w/w) of active ingredient and from 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient (e.g. as defined above) or a combination of such excipients. Preferably, the compositions comprise from approximately 20% (w/w) to approximately 90% (w/w) of active ingredient and from 80% (w/w) to 10% of a pharmaceutically acceptable excipient or a combination of excipients. Pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may, for example, be in single dosage form, such as ampoules, vials, suppositories, pre-filled syringes, pills, powders, tablets or capsules.
[0206]Tablets and capsules may contain, for example, 0 to 20% disintegrants, 0 to 5% lubricants, 0 to 5% flow acids and/or 0 to 99% (w/w) fillers/ bulking agents (depending on drug dose). These can also contain 0 to 10% (w/w) of polymeric binders, 0 to 5% (w/w) of antioxidants, 0 to 5% (w/w) of pigments. In addition, slow-release tablets typically contain 0 to 99% (w/w) release-controlling polymers (eg, retarders) (depending on dose). Tablet or capsule film coatings typically contain 0 to 10% (w/w) polymers, 0 to 3% (w/w) pigments, and/or 0 to 2% (w/w) plasticizers.
[0207] Parenteral formulations typically contain 0 to 20% (w/w) of buffers, 0 to 50% (w/w) of co-solvents, and/or 0 to 99% (w/w) of water for injection (WFI) (depending on dose and whether it is freeze-dried). Formulations for intramuscular depots may also contain 0 to 99% (w/w) oils.
[0208]Pharmaceutical formulations may be presented to a patient in “patient packs” containing a complete course of treatment in a single package, usually a blister pack.
[0209] Generally, compounds of formula (1) will be presented in single dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, for example from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular subranges of compound are 0.1 milligram to 2 grams of active ingredient (more generally 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (e.g. 1 microgram to 10 milligrams, e.g. 0.1 milligram to 2 milligrams of active ingredient).
[0210]For oral compositions, a single dosage form may contain from 1 milligram to 2 grams, more typically, 10 milligrams to 1 gram, e.g. 50 milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of compound active.
[0211] The active compound will be administered to a patient in need thereof (e.g., a human or animal) in an amount sufficient to achieve a desired therapeutic effect (effective amount). The precise amounts of compound administered can be determined by a supervising physician in accordance with standard procedures. EXAMPLES
[0212] The invention will be illustrated, without limitation, by way of reference to the specific embodiments described in the following examples. EXAMPLES 1 to 32
[0213] The compounds of Examples 1 to 32 shown in Table 1 below were prepared. Their NMR and LCMS properties and the methods used to prepare them are shown in Table 3. The starting materials for each of the Examples are listed in Table 2. Table 1


GENERAL PROCEDURES
[0214]When no preparative route is included, the relevant intermediary is commercially available. Commercial reagents were used without further purification. Ambient temperature (rt) refers to approximately 20 to 27°C. 1H NMR spectra were recorded at 400 MHz on a Bruker or Jeol instrument. Chemical change values are expressed in parts per million (ppm), that is, (a)-values. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, BR = broad, d = doublet, t = triplet, q = quartet, quint = quintet, td = triplet of doublets, tt = triplet of triplets, qd = quartet of doublets, DDD = doublet of doublet of doublets, DDT = doublet of doublet of triplets, m = multiplet. Coupling constants are listed as J-values, measured in Hz. The NMR and mass spectrometry results were corrected for the background peaks. Chromatography refers to column chromatography performed using a 60 to 120 mesh silica gel and performed under nitrogen pressure conditions (flash chromatography). TLC for monitoring reactions refers to performing TLC using the specified mobile phase and Silica gel F254 as a stationary phase available from Merck. Microwave-mediated reactions were carried out in Biotage Initiator or CEM Discover microwave reactors.
[0215]Mass spectrometry was performed on Shimadzu LC-2010 EV, Waters ZQ-2000, UPLC-Mass SQD-3100 or Applied Biosystem API-2000 spectrometers using electrospray conditions as specified for each compound in the detailed experimental section.
[0216]Prep HPLC was typically performed under the following conditions, (Gilson Semi-Prep HPLC): Column: Phenomenex Gemini NX 5 µm C18 110A Axia (100 x 30 mm); Mobile phase: Solvent A: MeCN; Solvent B: Water containing a 0.1 or 0.2% solution of aqueous NH3 (28%) and 5% MeCN; Gradient: 20 to 60% Solvent A in Solvent B for 14.4 min, held 60% Solvent A in Solvent B for 1.6 min, 100% Solvent A for a flow rate of 1.6 min: 30 ml/min; detection wavelength.
[0217]LCMS experiments were typically performed using electrospray conditions as specified for each compound under the same conditions: METHOD A AND B
[0218] Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1 x 20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0 x 30 mm; Gradient [time (min)/solvent D in 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; Solvents: solvent C = 2.5 L of H2O + 2.5 mL of ammonia solution; solvent D = 2.5 L of MeCN + 135 mL of H2O + 2.5 mL of ammonia solution); Injection volume 3 uL; UV detection 230 to 400 nM; column temperature 45°C; Flow rate 1.5 mL/min. METHOD C
[0219]Instruments: HP1100, HP DAD G1315A detector, Micromass ZQ; Column: Phenomenex Gemini-NX C-18, 3 microns, 2.0 x 30 mm; Gradient [time (min)/solvent D in C (%)]: Method C: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10 .00/2; Solvents: solvent C = 2.5 L of H2O + 2.5 mL of ammonia solution; solvent D = 2.5 L of MeCN + 135 mL of H2O + 2.5 mL of ammonia solution); Injection volume 3 uL; UV detection 230 to 400 nM; column temperature 45°C; Flow rate 1.5 mL/min. METHOD D
[0220] Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ; Column: Waters X-Bridge C-18, 2.5 microns, 2.1 x 20 μm, flow rate 1.0 mL/min; injection volume 5 μL; 5-95% acetonitrile:water + 0.1% ammonium hydroxide. METHOD E
[0221]Instruments: Waters 2695 Alliance, Micromass ZQ, 2996 PDA and Varian 385-LC ELSD, Column: XBridge C18 3 x 100 mm x 3.5 μm, flow rate 1 mL/min; injection volume 20 μL, 5-95% acetonitrile:water + 2% formic acid
[0222]GC experiments were conducted under the following conditions: METHOD F
[0223]Instruments: Agilent 6890, CP 624 column selection; injection 200°C, 68.94 kPa (10 psi) H2; Det 250°C, 25 mL/min H2, 400 mL/min air; oven at 35°C (2 min) 8°C/min at 130°C (4.1 min) METHOD G
[0224]Instruments: Agilent 6890, CP 624 column selection; injection 200°C, 68.94 kPa (10 psi) H2; Det 250°C, 25 mL/min H2, 400 mL/min air; oven at 35°C (2 min) 4°C/min at 130°C (5.75 min)
[0225]GC data in the experimental section is given in the format: run time, retention time, percent peak area. ABBREVIATIONS d=day(s) DCM=dichloromethane DIPEA=diisopropyl ethylamine DMF=dimethylformamide DMSO=dimethyl sulfoxide ES=electrospray ionization EtOAc=ethyl acetate h=hour(s) HPLC=high performance liquid chromatography LC=MeCN liquid chromatography =acetonitrile MeOH=methanol min=minute(s) MS=mass spectrometry NMR=nuclear magnetic resonance rt=room temperature sat.=saturated(a) sol.=STAB solution=triacetoxy sodium borohydride THF=tetrahydrofuran TLC=layer chromatography thin Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary. GENERAL SYNTHETIC PROCEDURES: ROUTE A Typical procedure for the preparation of amides via STAB reductive amination and HATU coupling as exemplified by the preparation of the Isomer of Example 11, ethyl 3-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1 -yl}-8-azabicyclo[3.2.1]octane-8-carboxylate

[0226]Ethyl piperidine-4-carboxylate (0.797 g, 0.78 mL, 5.07 mmol) and N-ethoxy carbonylnortropinone (1.00 g, 5.07 mmol) were dissolved in DCM (30 mL) at room temperature and titanium isopropoxide (1.59 g, 1.7 mL, 5.58 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. STAB (2.15 g, 10.14 mmol) and acetic acid (0.2 mL) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was cooled by the addition of water (4 mL) and diluted with DCM, then filtered through a pad of celite. The filtrate was washed with saturated NaHCO3 solution, saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 □ m, 60 µm, 50 mL per minute, 2% gradient at 4, 5% MeOH in DCM]) to provide ethyl 3-[4-(ethoxycarbonyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate as a separate mixture of isomers. Isomer 1 (0.549 g, 32%) as a light yellow oil and isomer 2 (0.137 g, 8%) as a light yellow oil. LCMS (Method A): Isomer 1 m/z 339 (M+H)+ (ES+), in 1.78 min, UV inactive. LCMS (Method A): Isomer 2 m/z 339 (M+H)+ (ES+), in 1.68 min, UV inactive.
[0227]Ethyl 3-[4-(ethoxycarbonyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate Isomer 1 (0.549 g, 1.62 mmol) was dissolved in THF (10 mL) at room temperature and a 1M LiOH solution (1.62 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The pH was carefully adjusted to 6 by the addition of concentrated hydrochloric acid, the solvents were removed in vacuo to give 1-[8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine acid -4-carboxylic acid (0.50 g, 100%) as an off-white solid. LCMS (Method A): m/z 311 (M+H)+ (ES+), in 0.1 min, UV inactive
[0228] 1-[8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxylic acid (0.50 g considered as 1.62 mmol) was dissolved in DMF ( 8 mL) and (1-methyl cyclobutyl)amine hydrochloride (0.295 g, 2.44 mmol), HATU (0.926 g, 2.44 mmol) and DIPEA (1.05 g, 1.41 mL, 8.12 mmol ) were added. The reaction mixture was stirred at room temperature for 60 hours and the solvents were removed in vacuo. The residue was partitioned between DCM and a saturated solution of NaHCO3, the organic layer was washed with a saturated solution of NaCl. It is passed through a phase separator cartridge. The organic filtrate solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-6 3Dm, 60 °C, 25 mL per minute, gradient 0% to 10% MeOH in DCM]) to give isomer 1 of ethyl 3-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate ( 0.208 g, 34%) as a pale yellow gum. DATA IN TABLE 3 ROUTE B Typical procedure for preparing amides by reductive amination of NaCNBH3 and HATU coupling, as exemplified by the preparation of Isomer 1 of Example 5, ethyl 3-{4-methoxy-4-[(1-methyl cyclobutyl) carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate

[0229] 4-Methoxy piperidine-4-carboxylic acid methyl ester hydrochloride (0.500 g, 2.38 mmol) was dissolved in methanol (2 mL) and treated with K2CO3 (0.329 g, 2.38 mmol) in a minimum amount of water to desalinate. The mixture was concentrated in vacuo and azeotroped to dryness with toluene. The residue and N-ethoxy carbonylnortropinone (0.470 g, 2.39 mmol) were dissolved in methanol (20 mL) and zinc chloride (0.975 g, 7.15 mmol) was added. The reaction mixture was stirred at 50°C under an atmosphere of nitrogen for 2 hours, then cooled to room temperature. NaCNBH3 (0.299 g, 4.77 mmol) was added and the reaction mixture was stirred at 50°C overnight under nitrogen. The reaction mixture was cooled to room temperature and the solvents were removed in vacuo, the residue was diluted with DCM and treated with a saturated solution of NaHCO3, the resulting heterogeneous mixture was filtered through a pad of celite and the filtrate was washed with a saturated solution of NaHCO3, saturated solution of NaCl and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 Dm, 60 °C, 50 mL per minute, gradient 0% to 10% MeOH in DCM]) to provide ethyl 3-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate as a separate mixture of isomers. Isomer 1 (0.097 g, 12%) as a pale yellow oil and Isomer 2 (0.022 g, 2.5%) as a pale yellow oil.LCMS (Method A): Isomer 1 m/z 355 (M+H )+ (ES+), at 1.47 to 1.50 min, UV inactive. LCMS (Method A): Isomer 2 m/z 355 (M+H)+ (ES+), in 1.47 min, UV inactive.
[0230]Ethyl 3-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate isomer (0.097 g, 0.27 mmol) was dissolved in THF (5 mL) at room temperature and a 1M LiOH solution (0.3 mL) was added. The reaction mixture was stirred at room temperature for 7 days. The pH was carefully adjusted to 6 by the addition of concentrated hydrochloric acid, the solvents were removed in vacuo to give 1-[8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-acid. 4-Methoxy piperidine-4-carboxylic acid (0.093 g, 100%) as an off-white solid. LCMS (Method A): m/z 341 (M+H)+ (ES+), at 0.83 min, UV inactive.
[0231] 1-[8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methoxypiperidine-4-carboxylic acid (0.093 g, considered to be 0.27 mmol) was dissolved in DMF (5 mL) and (1-methyl cyclobutyl)amine hydrochloride (0.05 g, 0.411 mmol), HATU (0.156 g, 0.41 mmol) and DIPEA (0.177 g, 0.24 mL, 1.37 mmol) were added. The reaction mixture was stirred at room temperature for 60 hours and the solvents were removed in vacuo. The residue was partitioned between DCM and a saturated solution of NaHCO3, the organic layer was washed with a saturated solution of NaCl and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 Dm, 60 °C, 25 mL per minute, gradient 0% to 10% MeOH in DCM]) to give isomer 1 of ethyl 3-{4-methoxy-4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate 1 (0.028 g, 25%) as a pale yellow gum. DATE IN TABLE 3 ROUTE C
[0232]Typical procedure for the preparation of carbamates via chloroformate coupling, as exemplified by the preparation of Example 9, ethyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[ 3.4]octane-6-carboxylate

[0233]Ethyl piperidine-4-carboxylate (0.35 g, 0.32 mL, 2.22 mmol) and 6-azaspiro[3.4]octane-6-acid 2-oxo-, 1,1-dimethyl ethyl ester carboxylic acid (0.500 g, 2.22 mmol) were dissolved in DCM (20 mL) at room temperature and titanium isopropoxide (4.12 g, 4.40 mL, 14.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. STAB (0.694 g, 0.72 mL, 2.44 mmol) and acetic acid (0.05 mL) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was cooled by the addition of a saturated solution of NaHCO3 (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was separated and washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 4063 Dm, 60 °C, 50 mL per minute, gradient 0% to 5% MeOH in DCM ]) to give tert-butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 90.9%) as a pale yellow oil.
[0234]LCMS (Method A): m/z 367 (M+H)+ (ES+), at 1.94 / 1.99 min, UV inactive
[0235]tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 2.02 mmol) was dissolved in THF (10 mL) at room temperature and a 1M LiOH solution (2.02 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH 5 by the addition of 1M HCl solution and the solvents removed in vacuo to give 1-[6-(tert-butoxycarbonyl)-6-azaspiro[3.4] oct-2-yl]piperidine-4-carboxylic acid, which was used crude in the subsequent reaction.LCMS (Method A): m/z 339 (M+H)+ (ES+), in 0.12 min, UV inactive
[0236] 1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (5 mL) and (1-methyl cyclobutyl) hydrochloride amine (0.37 g, 3.03 mmol), HATU (0.844 g, 2.22 mmol) and DIPEA (1.305 g, 10.1 mmol) were added. The reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, organic layer washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 Dm, 60 °C, 50 mL per minute, gradient 0% to 10% MeOH in DCM]) to give tert-butyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 76.7% ) as a white foam.LCMS (Method A): m/z 406 (M+H)+ (ES+), in 1.81 min, UV inactive
[0237]tert-Butyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 1.55 mmol) was dissolved in DCM (8 ml) and TFA (2 ml) was added. The reaction mixture was stirred at room temperature overnight under nitrogen, then the solvents were removed in vacuo to give 1-(6-azaspiro[3.4]oct-2-yl)-N-trifluoroacetate. (1-methyl cyclobutyl)piperidine-4-carboxamide as a dark yellow oil that was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.49 g, 0.65 mL, 4.64 mmol) and ethyl chloroformate (0.25 mg, 0.18 mL, 0.57 mmol) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 Dm, 60 Å, 12 mL per minute, gradient 0% to 10% MeOH in DCM]) to provide ethyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.04 g, 13%) as a yellow gum as a mixture of diastereomers .DATA IN TABLE 3 ROUTE D
[0238]Typical procedure for the preparation of single diastereoisomers, followed by chloroformate coupling, as exemplified by the preparation of Isomer 2 of Example 9, ethyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl} -6- azaspiro[3.4]octane-6-carboxylate

[0239]6-Azaspiro[3.4]octane-6-carboxylic acid 2-oxo-, 1,1-dimethyl ethyl ester, (3.00 g, 13.33 mmol) was reduced to the alcohol, reacted under mesylation conditions and the resulting diastereoisomers were separated according to the information detailed in WO 2010/089510, to produce tert-butyl 2-[(methyl sulfonyl)oxy]-6-azaspiro[3.4]octane-6-carboxylate isomer 1 (1 .79 g, 44% over two steps) as a white crystalline solid and isomer 2 (0.965 g, 24% over two steps) as a white crystalline solid.LCMS (Method B): Isomer 1; m/z 306 (M+H)+ (ES+), at 3.36 min, UV inactive LCMS (Method B): Isomer 2; m/z 306 (M+H)+ (ES+), in 3.39 min, UV inactive
[0240] Isomer 1 of tert-butyl 2-[(methyl sulfonyl)oxy]-6-azaspiro[3.4]octane-6-carboxylate (1.79 g, 5.73 mmol) and ethyl isonipecotate (4.49 g , 28.62 mmol) were heated together at 65°C for 5 days. The reaction mixture was reduced in volume in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 100 g, 40-63 Dm, 60 Å, 50 mL per minute, gradient 1% to 4.5% MeOH in DCM]) to give tert-butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.264 g, 12.5 %) as a yellow oil.LCMS (Method A): m/z 367 (M+H)+ (ES+), in 1.97 min, UV inactive.
[0241]tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.080 g, 0.22 mmol) was stirred in DCM (10 mL) at room temperature and treated with 4M HCl/dioxane (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to give a yellow solid which was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.066 g, 0.1 mL, 0.66 mmol) and ethyl chloroformate (0.036 g, 0.03 mL, 0.32 mmol) were added and the mixture of The reaction was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 Dm, 60 Å, 12 mL per minute, gradient 0% to 8% MeOH in DCM]) to provide ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.069 g, 93%) as an amber oil. LCMS (Method A): m/z 339 ( M+H)+ (ES+), at 1.71 min, UV inactive.
[0242]Ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.069 g, 0.20 mmol) was dissolved in THF (4 mL) at room temperature. room and a 1M LiOH solution (0.31 mL) was added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was adjusted to pH 5 by the addition of 1M HCl solution and the solvents were removed in vacuo to give 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct- acid. 2-yl]piperidine-4-carboxylic acid which was used directly without further purification.LCMS (Method A): m/z 311 (M+H)+ (ES+), in 0.10 min, UV inactive.
[0243] 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid (0.368 g, 1.10 mmol) was dissolved in DMF (8 mL) and hydrochloride of (1-methyl cyclobutyl)amine (0.200 g, 1.64 mmol), HATU (0.458 g, 1.21 mmol) and DIPEA (0.708 g, 5.45 mmol) were added. The reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, and the organic layer washed with saturated NaCl solution and dried over MgSO4. Solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40 to 63 □ m, 60 °C, 12 mL per minute, gradient 1% to 8% of MeOH in DCM]) to give an isomer of ethyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate 2 (0.147 g, 35 .5%) as a white foam.DATA IN TABLE 3 ROUTE E
[0244]Typical procedure for preparing amides via reductive amination of NaCNBH3 and acid chloride coupling, as exemplified by the preparation of Example 11, ethyl 2-{4-fluoro-4-[(1-methyl cyclobutyl)carbamoyl]piperidin -1-yl}-6-azaspiro[3.4]octane-6-carboxylate

[0245]Ethyl-4-fluoropiperidine-4-carboxylate hydrochloride (0.376 g, 1.77 mmol) was dissolved in methanol (5 mL) and treated with K2CO3 (0.244 g, 1.77 mmol) in a minimal amount of water to desalinate. The mixture was concentrated in vacuo and azeotroped to dryness with toluene. The residue was dissolved in methanol (10 mL) and zinc chloride (0.969 g, 7.11 mmol) was added. The reaction mixture was stirred at 50°C under an atmosphere of nitrogen for 2 hours, then cooled to room temperature. NaCNBH3 (0.222 g, 3.54 mmol) was added and the reaction mixture was stirred at 50°C overnight under nitrogen. The reaction mixture was cooled to room temperature and the solvents were removed in vacuo, the residue was diluted with DCM and treated with a saturated solution of NaHCO3, the resulting heterogeneous mixture was filtered through a pad of celite and the filtrate was washed with a saturated solution of NaHCO3, a saturated solution of NaCl and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 Dm, 60 °C, 50 mL per minute, gradient 1% to 9% MeOH in DCM]) to provide tert-butyl 2-[4-fluoro-4-(methoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.300 g, 46%) as a colorless oil.LCMS (Method A): m/z 371 (M+H)+ (ES+), at 1.79 and 1.82 min, UV inactive. Transesterification takes place under these reaction conditions.
[0246]tert-Butyl 2-[4-fluoro-4-(methoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.300 g, 0.81 mmol) was dissolved in DCM (4 ml) and TFA (1 ml) was added. The reaction mixture was stirred at room temperature overnight under nitrogen, then the solvents were removed in vacuo to give ethyl 1-(6-azaspiro[3.4]oct-2-yl)-4 trifluoroacetate -fluoropiperidine-4-carboxylate, as a dark yellow oil that was used directly without further purification. The residue was dissolved in DCM (8 mL) at room temperature. NEt3 (0.246 g, 0.34 mL, 2.43 mmol) and ethyl chloroformate (0.176 g, 0.16 mL, 1.62 mmol) were added and the reaction mixture was stirred at room temperature overnight for the another under nitrogen. The reaction mixture was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 □ m, 60 Å, 12 mL per minute, gradient 0% to 10% MeOH in DCM]) to provide ethyl 2-[4-fluoro-4-(methoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.440 g, 158% impure) as a pale yellow oil.LCMS (Method A): m/z 343 (M+H)+ (ES+), at 1.56 and 1.59 min, UV inactive.
[0247]Ethyl 2-[4-fluoro-4-(methoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (taken as 0.81 mmol) was dissolved in THF (5 mL ) at room temperature and a 1M LiOH solution (0.81 mL) was added. The reaction mixture was stirred at room temperature for 2 days. The pH was carefully adjusted to 6 by the addition of concentrated hydrochloric acid, the solvents were removed in vacuo to give 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-4- acid 4-carboxylic fluoropiperidine as an off-white solid, which was used directly without further purification.LCMS (Method A): m/z 329 (M+H)+ (ES+), at 0.79 and 0.86 min, inactive UV.
[0248] Crude 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-4-fluoropiperidine-4-carboxylic acid was suspended in thionyl chloride (3 mL) and the reaction was stirred. at 90°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and (1-methyl cyclobutyl) amine hydrochloride (0.196 g, 1.62 mmol) and DIPEA (0.523 g, 0.71 mL, 4.05 mmol) were added, the mixture reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 Dm, 60 Å, 12 mL per minute, gradient 0% to 6% MeOH in DCM]) to provide ethyl 2-{4-Fluoro-4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.09 g, 28%) as a yellow-yellow gum pale as a mixture of diastereomers. DATA IN TABLE 3 ROUTE F
[0249]Typical procedure for preparing amides, followed by chloroformate coupling, as exemplified by the preparation of Example 14, ethyl 2-[4-(tert-butyl carbamoyl)piperidin-1-yl]-6-azaspiro[3.4] octane-6-carboxylate

[0250]Ethyl piperidine-4-carboxylate (0.35 g, 0.32 mL, 2.22 mmol) and 6-azaspiro[3.4]octane-6-acid 2-oxo-, 1,1-dimethyl ethyl ester carboxylic acid (0.500 g, 2.22 mmol) were dissolved in DCM (20 mL) at room temperature and titanium isopropoxide (4.12 g, 4.40 mL, 14.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. STAB (0.694 g, 0.72 mL, 2.44 mmol) and acetic acid (0.05 mL) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was cooled by the addition of a saturated solution of NaHCO3 (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was separated and washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 4063 Dm, 60 °C, 50 mL per minute, gradient 0% to 5% MeOH in DCM]) to give tert-butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 90.9%) as a yellow oil -pale.
[0251]LCMS (Method A): m/z 367 (M+H)+ (ES+), at 1.94 / 1.99 min, UV inactive
[0252]tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 2.02 mmol) was dissolved in THF (10 mL) at room temperature and a 1M LiOH solution (2.02 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH 5 by the addition of 1M HCl solution and the solvents were removed in vacuo to give 1-[6-(tert-butoxycarbonyl)-6-azaspiro[3, 4]oct-2-yl]piperidine-4-carboxylic acid, which was used crude in the subsequent reaction.LCMS (Method A): m/z 339 (M+H)+ (ES+), in 0.12 min, UV inactive
[0253] 1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (2 mL) and t-butylamine (0.087 g , 1.20 mmol), HATU (0.227 g, 0.60 mmol) and DIPEA (0.193 g, 1.50 mmol) were added. The reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 Dm, 60 °C, 12 mL per minute, gradient 0% to 10% MeOH in DCM]) to give tert-butyl-2-[4-(tert-butyl carbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.071 g, 60.5% ) as a yellow oil.LCMS (Method A): m/z 394 (M+H)+ (ES+), at 1.79 min, UV inactive
[0254] tert-Butyl-2-[4-(tert-butyl carbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 1.55 mmol) was dissolved in DCM (4 ml) and TFA (1 ml) was added. The reaction mixture was stirred at room temperature overnight under nitrogen then the solvents were removed in vacuo to give 1-(6-azaspiro[3,4]oct-2-yl)-trifluoroacetate N-tert-butyl piperidine-4-carboxamide (1:2) as an oil that was used directly without further purification. The residue was dissolved in DCM (8 mL) and NEt3 (0.056 g, 0.08 mL, 0.54 mmol) and ethyl chloroformate (0.024 mg, 0.02 mL, 0.22 mmol) were added and the mixture of The reaction was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 □ m, 60 Å, 12 mL per minute, gradient 0% to 10% MeOH in DCM]) to provide ethyl 2-[4-(tert-butyl carbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.027 g, 41%) as an off-white solid as a mixture of diastereomers .DATA IN TABLE 3 ROUTE G
[0255]Alternative procedure for preparing carbamates via amide coupling, as exemplified by the preparation of Example 13, ethyl 2-{4-[(2-methyl propyl)carbamoyl]piperidin-1-yl}-6-azaspiro[ 3,4]octane-6-carboxylate

[0256]Ethyl piperidine-4-carboxylate (0.35 g, 0.32 mL, 2.22 mmol) and 6-azaspiro[3.4]octane-acid 2-oxo-, 1,1-dimethyl ethyl ester 6-carboxylic acid (0.500 g, 2.22 mmol) was dissolved in DCM (20 mL) at room temperature and titanium isopropoxide (4.12 g, 4.40 mL, 14.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. STAB (0.694 g, 0.72 mL, 2.44 mmol) and acetic acid (0.05 mL) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was cooled by the addition of a saturated solution of NaHCO3 (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was separated and washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 4063 Dm, 60 °C, 50 mL per minute, gradient 0% to 5% MeOH in DCM]) to give tert-butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 90.9%) as a yellow oil -pale.LCMS (Method A): m/z 367 (M+H)+ (ES+), at 1.94 / 1.99 min, UV inactive
[0257]tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (3.00 g, 8.20 mmol) was dissolved in DCM (40 mL) and stirred with 4M HCl in Dioxane (10 mL) at room temperature overnight. The reaction mixture was concentrated in vacuo to give ethyl 1-(6-azaspiro[3.4]oct-2-yl)piperidine-4-carboxylate trifluoroacetate (1:2) as a pale pink solid which was used in the next step without further purification. A residue of ethyl 1-(6-azaspiro[3,4]oct-2-yl)piperidine-4-carboxylate trifluoroacetate (1:2) was dissolved in DCM (40 mL) and NEt3 (2.49 g, 3 .42 mL, 24.6 mmol) and ethyl chloroformate (1.07 g, 0.93 mL, 9.84 mmol) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 Dm, 60 Å, 50 mL per minute, gradient 0% to 10% MeOH in DCM]) to provide ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3,4]octane-6-carboxylate (2.474 g, 89%) as an orange oil.LCMS (Method A): m/z 339 (M+H)+ (ES+), at 1.67/1.71 min, UV inactive.
[0258]Ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (2.474 g, 7.32 mmol) was dissolved in THF (25 mL) at room temperature and a 1M LiOH solution (7.32 mL) was added. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was adjusted to pH 5 by the addition of a 1M HCl solution and the solvents were removed in vacuo to give 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4] oct-2-yl]piperidine-4-carboxylic acid which was used directly without further purification.LCMS (Method A): m/z 311 (M+H)+ (ES+), at 0.85/ 0.91 min, UV inactive.
[0259] 1-[6-(ethoxycarbonyl)-6-azaspiro[3,4]oct-2-yl]piperidine-4-carboxylic acid (0.200 g, 0.65 mmol) was dissolved in DMF (5 mL) , isobutylamine (0.071 g, 0.97 mmol), HATU (0.270 g, 0.71 mmol) and DIPEA (0.417 g, 3.23 mmol) were added. The reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 Dm, 60 °C, 12 mL per minute, gradient 0% to 10% MeOH in DCM]) to give ethyl 2-{4-[(2-methyl propyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.089 g, 37.7% ) as a pale yellow gum as a mixture of diastereomers. DATA IN TABLE 3 ROUTE H
[0260]Alternative procedure for preparing carbamates via a para-nitro phenylcarbamate activation, as exemplified by the preparation of Example 25, (2,2,2-trideutero)ethyl 2-{4-[(1-methyl cyclobutyl) carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate

[0261]Ethyl piperidine-4-carboxylate (0.35 g, 0.32 mL, 2.22 mmol) and 6-azaspiro[3.4]octane-acid 2-oxo-, 1,1-dimethyl ethyl ester 6-carboxylic acid (0.500 g, 2.22 mmol) was dissolved in DCM (20 mL) at room temperature and titanium isopropoxide (4.12 g, 4.40 mL, 14.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. STAB (0.694 g, 0.72 mL, 2.44 mmol) and acetic acid (0.05 mL) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. The reaction mixture was cooled by the addition of a saturated solution of NaHCO3 (5 mL) and stirred for 5 minutes. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was separated and washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 4063 Dm, 60 °C, 50 mL per minute, gradient 0% to 5% MeOH in DCM]) to give tert-butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 90.9%) as a yellow oil -pale.LCMS (Method A): m/z 367 (M+H)+ (ES+), at 1.94 / 1.99 min, UV inactive
[0262]tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.739 g, 2.02 mmol) was dissolved in THF (10 mL) at room temperature and a 1M LiOH solution (2.02 mL) was used. The reaction mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH 5 by the addition of 1M HCl solution and the solvents removed in vacuo to give 1-[6-(tert-butoxycarbonyl)-6-azaspiro[3.4] ]oct-2-yl]piperidine-4-carboxylic acid, which was used crude in the subsequent reaction.LCMS (Method A): m/z 339 (M+H)+ (ES+), in 0.12 min, UV inactive
[0263] 1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3,4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (5 mL) and (1-methyl cyclobutyl hydrochloride) ) amine (0.37 g, 3.03 mmol), HATU (0.844 g, 2.22 mmol) and DIPEA (1.305 g, 10.1 mmol) were added. The reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM and saturated NaHCO3 solution, the organic layer washed with saturated NaCl solution and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 Dm, 60 °C, 50 mL per minute, gradient 0% to 10% MeOH in DCM]) to give tert-butyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 76, 7%) as a white foam.LCMS (Method A): m/z 406 (M+H)+ (ES+), at 1.81 min, UV inactive
[0264] tert-Butyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.747 g, 1.84 mmol) was dissolved in DCM (8 ml) and TFA (2 ml) was added. The reaction mixture was stirred at room temperature overnight under nitrogen then the solvents were removed in vacuo to give 1-(6-azaspiro[3,4]oct-2-yl)-trifluoroacetate N-(1-methyl cyclobutyl)piperidine-4-carboxamide as a dark yellow oil that was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.56 g, 0.77 mL, 5.52 mmol) and 4-nitrophenyl chloroformate (0.555 g, 2.76 mmol) were added and the reaction mixture was stirred at room temperature overnight under nitrogen. Solvents were removed in vacuo, and the residue was partitioned between DCM (15 mL) and 1N NaOH solution (15 mL). The aqueous layer was extracted with DCM (4 x 20 ml), dried over MgSO4 and the solvent evaporated. The residue was semi-purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 Dm, 60 Å, 25 mL per minute, gradient 0% to 10% MeOH in DCM]) to provide 4-nitrophenyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.60 g, 69%) as a gum yellow as a mixture of diastereomers.LCMS (Method C): m/z 471 (M+H)+ (ES+), at 4.60 min, UV active.
[0265]Ethanol-2,2,2-d3 (0.186 g, 0.22 mL, 3.78 mmol) was dissolved in THF (12.6 mL) and cooled to 0°C. Sodium hydride (0.202 g, 5.044 mmol) was added and stirred for 1 hour. 4-Nitrophenyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.600 g, 1.26 mmol) dissolved in THF ( 12.6 mL) was added and the mixture stirred overnight under nitrogen. The mixture was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (4 x 30 mL), dried over MgSO4 and the solvent evaporated. The residue was semi-purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 Dm, 60 Å, 25 mL per minute, gradient 0% to 10% MeOH in DCM]) to provide ethyl-2,2,2-d3 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate (0.240 g, 50% ) as a yellow gum as a mixture of diastereomers. Separation of diastereomers was achieved via preparative HPLC to provide an isomer 1 of (2,2,2-trideutero)ethyl 2-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro [3,4]octane-6-carboxylate (0.094 g, 39%) as an off-white gum and an isomer 2 (0.085 g, 35%) as an off-white gum. DATA IN TABLE 3 SYNTHESIS OF INTERMEDIATES: ROUTE I
[0266]Typical procedure for the preparation of amines, as exemplified by the preparation of intermediate 19, 1-(1,1,1-trideuteromethyl)cyclobutan-1-amine hydrochloride

[0267]Magnesium (2.67 g, 110 mmol) was stirred in dry ether in a three-necked flask equipped with a thermometer and an addition funnel. 1,1,1-Trideuteromethyl iodide (6.24 mL, 100 mmol) in diethyl ether (40 mL) was charged to the addition funnel and a small crystal of iodine added to the magnesium suspension. The magnesium suspension was heated briefly until the acid coloration dissipated, then the 1,1,1-trideuteromethyl iodide solution was added dropwise (causing a small exotherm). Once the addition was complete, the mixture was heated at 32°C for 30 minutes, then cooled to 0°C. Cyclobutanone (5 mL, 67 mmol) was dissolved in diethyl ether (20 mL), dried over magnesium sulfate and filtered. The solution was added dropwise to the reaction mixture, keeping the temperature <15°C, then allowed to reach room temperature overnight. The mixture was partitioned between aqueous ammonium chloride (100 ml) and diethyl ether (100 ml) and extracted an additional 4 times with ether. The organic layer was dried over sodium sulfate and concentrated (250 mbar, 40°C) to provide a yellow oil (5.9 g, 75%). 1H NMR (300 MHz, CDCl3 ) □ : 1.41 to 1.52 (1H, m), 1.60 to 1.81 (2H, m), 1.952.06 (4H, m).
[0268]Chloroacetonitrile (21.6 mL, 340 mmol) was added to a solution of 1-(1,1,1-trideuteromethyl)cyclobutan-1-ol (10.14 g, 113.7 mmol) and acetic acid ( 3.1 ml). The mixture was cooled to 0°C and concentrated sulfuric acid (18.3 mL) was added dropwise. Once the addition was complete, the solution was allowed to reach room temperature and stirred for 2 hours. The reaction was poured into ice/water (200 mL) and extracted with dichloromethane (3 x 150 mL). The organic layers were combined, washed with aqueous sodium carbonate solution (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated to provide a yellow oil. This oil was azeotroped with toluene to provide a beige solid (19.7 g, 105%) which was directly used in purification.1H NMR (300 MHz, CDCl3) □: 1.79 to 1.90 (2H, m), 1.99 to 2.06 (2H, m), 2.23 to 2.32 (2H, m), 3.94 (2H, s), 6.59 (1H, bs).
[0269] A solution of 2-chloro-N-(1-(1,1,1-trideuteromethyl)cyclobutyl)acetamide (10g, 60.7mmol) and thiourea (5.69g, 74.8mmol) in ethanol (45 ml) and acetic acid (6.1 ml) was refluxed overnight. The reaction mixture was allowed to cool to room temperature and concentrated to approximately 22 mL. The mixture was added to water (45 mL) and filtered to remove the precipitate. The filtrate was washed in diethyl ether (100 mL, discarded), then basified with NaOH (aqueous) at pH 13. The basic layer was extracted with dichloromethane (4 x 100 mL), combined and dried over sodium sulfate and concentrated. (200 mbar, 40°C) to give a yellow oil (2.08 g). The oil was dissolved in diethyl ether (80 mL) and stirred while HCl in diethyl ether (17 mL, 2M) was stirred dropwise. The resulting precipitate was filtered, washed with diethyl ether, then dried under vacuum at 40°C to provide 1-(1,1,1-trideuteromethyl)cyclobutan-1-amine hydrochloride (2.35 g, 31%) . 1H NMR (300 MHz, D2O) □ : 1.79 to 1.89 (2H, m), 1.98 to 2.03 (2H, m), 2.15 to 2.25 (2H, m). NMR (300 MHz, D2O) □: 13.0, 22.5 (m), 32.0, 54.0. ROUTE J
[0270]Typical procedure for the preparation of amines, as exemplified by the preparation of intermediate 20, 1-(fluoromethyl)cyclobutan-1-amine hydrochloride

[0271]To a stirred solution of (methyl sulfinyl)benzene (23.0 g, 164 mmol) in chloroform (80 mL) under argon at room temperature was added diethylamino sulfur trifluoride (43.0 mL, 328 mmol) by droplet. and the reaction mixture was stirred for 2 days at this temperature, then at 60°C overnight. The mixture was added dropwise to a stirred solution of saturated aqueous sodium hydrogen carbonate at 0°C, then extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to provide (fluoromethyl)(phenyl)sulfane (20.0 g, 86%) as a yellow oil. 1H NMR (300 MHz, CDCI3) □ : 5.64 (sec) , 1H), 5.81 (s, 1H), 7.38 to 7.24 (m, 3H), 7.53 to 7.46 (m, 2H).
[0272]To a stirred solution of (fluoromethyl)(phenyl)sulfan (20.0 g, 140 mmol) in dichloromethane (300 mL) was added meta-chloroperoxybenzoic acid (84.0 g, 475 mmol) in portions at 0°C. °C The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The mixture was poured into a stirred solution of saturated aqueous sodium hydrogen carbonate at 0°C, then extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The residue was purified by flash column chromatography on silica (eluent: heptane:ethyl acetate, 9:1 to 4:1) to give ((fluoromethyl)sulfonyl)benzene (22.9 g, 93%) as a yellow oil . 1H NMR (300 MHz, CDCl 3 ) □: 5.05 (s, 1H), 7.63 (t, 2H), 7.73 (t, 1H), 7.97 (d, 2H).
[0273] A mixture of titanium (IV) ethoxide (22.4 mL, 107 mmol) and cyclobutanone (5.37 mL, 71.0 mmol) in tetrahydrofuran (120 mL) was stirred for 10 minutes. Tert-butane sulfinamide (7.17 g, 59.0 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. The mixture was concentrated and the residue dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated to give N-cyclobutylidene-2-methylpropane-2-sulfinamide (9.51 g, 77%) as a pale yellow oil which was used directly without purification.
[0274]1H NMR (300 MHz, CDCl3 ) □ : 1.18 (s, 9H), 2.12 to 1.97 (m, 2H), 3.10 to 3.00 (m, 2H), 3, 29 to 3.11 (m, 1H), 3.52 to 3.37 (m, 1H).LCMS (Method D): m/z 174 (M+H)+ (ES+), in 1.10 min.
[0275]To a stirred solution of ((fluoromethyl)sulfonyl)benzene (5.0 g, 28.7 mmol) in tetrahydrofuran (100 mL) at -78°C under argon was added n-butyl lithium (18.0 mL, 28.7 mmol) and the reaction mixture was stirred for 40 minutes at this temperature. N-cyclobutylidene-2-methylpropane-2-sulfinamide (3.23 g, 18.7 mmol) was added to the mixture at -78°C and the reaction mixture was allowed to slowly warm to room temperature and stirred overnight. the other. The reaction mixture was cooled by the addition of water and extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a brown oil. The residue was purified by flash column chromatography on silica (eluent: heptane:ethyl acetate, 3:2 to 2:3) to give N-(1-(fluoro(phenylsulfonyl)methyl)cyclobutyl)-2-methylpropane-2 - sulfinamide (3.00 g, 33%) as a yellow oil.1H NMR (300 MHz, CDCl3) □: 1.27 (s, 9H), 1.96 to 1.82 (m, 1H), 2, 14 to 2.00 (m, 2H), 2.38 to 2.26 (m, 1H), 2.59 to 2.43 (m, 1H), 2.91 to 2.76 (m, 1H), 5.04 (s, 1H), 5.53 to 5.55 (m, 1H), 7.52 to 7.55 (m, 2H), 7.62 to 7.65 (m, 1H), 7, 93 to 7.95 (m, 2H).LCMS (Method D): m/z 348 (M+H)+ (ES+), in 1.54 min.
[0276]To a stirred solution of N-(1-(fluoro(phenylsulfonyl)methyl)cyclobutyl)-2-methylpropane-2-sulfinamide (1.50 g, 4.32 mmol) in N,N-dimethyl formamide (270 mL) a buffer solution of sodium acetate (22.6 g, 276 mmol) in acetic acid (34.6 mL) was added and the reaction mixture was stirred for 15 minutes at room temperature. Magnesium chips (6.92 g, 289 mmol) were added and the mixture stirred at 65°C for 24 hours. The mixture was treated with water and saturated aqueous sodium hydrogen carbonate and extracted 3 times with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated to give a yellow oil. The residue was purified by flash column chromatography on silica (eluent: heptane:ethyl acetate 1:1 to 0:1) to give N-(1-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfinamide (560 mg , 53%) as a yellow oil. 1H NMR (300 MHz, CDCl 3 ) □ : 1.20 (s, 9H), 1.99 to 1.68 (m, 2H), 3.62 (br s, 1H) , 4.36 to 4.38 (m, 1H), 4.52 to 4.54 (m, 1H).
[0277]To a stirred solution of N-(1-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfinamide (1.50 g, 7.23 mmol) in methanol (20 mL) was added hydrochloric acid (20 mL, 7.23 mmol, 4M in dioxane) at 0°C under argon and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was concentrated and the crude product triturated in diethyl ether and tert-butyl methyl ether to provide the desired product 1-(fluoromethyl)cyclobutan-1-amine hydrochloride (0.90 g, 90%).1H NMR (300 MHz , CDCl3) □: 1.92 to 1.76 (m, 2H), 2.09 to 1.93 (m, 2H), 2.36 to 2.16 (m, 2H), 4.54 (s, 1H), 4.70 (s, 1H), 8.68 (br s, 2H).LCMS (Method D): m/z 104 (M+H)+ (ES+), in 1.31 min. ROUTE K
[0278]Typical procedure for the preparation of amines, as exemplified by the preparation of Intermediate 21, 1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutan-1-amine hydrochloride

[0279]Malonic acid-d4 (165 g, 1.53 mol), sulfuric acid-d2 (5.0 mL) and methane(ol-d) (330 mL) in dichloromethane (825 mL) were stirred at room temperature for 4 days. Deuterium oxide (100 mL) was added and the phases separated. The aqueous phase was extracted again with dichloromethane (100 ml). The combined organic phases were dried over sodium sulfate and concentrated to give a colorless oil. The residue was purified by distillation (bp: 105°C at 25 mmHg) to give the desired product 2,2-dideuteriomalonic acid dimethyl ester (161 g, 79%) as a colorless oil. 1H NMR (300 MHz, CDCI3 ) □ : 3.76 (s, 6H). 13 C NMR (300 MHz, CDCI3 ) □: 40.7, 52.6, 167.0. GC (Method F): 20 min, at 11.91 min, 99.65%.
[0280] The reaction was carried out in 2 batches of 80.5 g. Lithium aluminum deuteride (40.0 g, 0.90 mol) was added in portions to anhydrous tetrahydrofuran (1.0 L) under argon and cooled to 0°C. 2,2-Dideuterio-malonic acid dimethyl ester (80.5 g, 0.60 mol) in anhydrous tetrahydrofuran (300 mL) was slowly added keeping the temperature below 35°C and the reaction mixture was stirred at room temperature. overnight. Water (40 mL) was carefully added followed by sodium hydroxide (40 mL, 15% aqueous solution), then more water (120 mL) and the mixture was stirred at room temperature overnight. The mixture was filtered through a pad of celite washing with tetrahydrofuran:methanol (1:3, 1.0 L) and the filtrate concentrated to give a crude residue (76.0 g). The aluminum salts were suspended in ethyl acetate:methanol (2:1, 3.0 L), stirred for 1 hour, filtered and the filtrate concentrated to provide an additional culture of crude residue (126 g). The two residues were combined and purified by distillation to provide the desired product 1,1,2,2,3,3-hexadeuterio-propane-1,3-diol (56.0 g, 57%).13C NMR (300 MHz , CDCl 3 ) □: 35.1, 57.6, 171.0 GC (Method F): 20 min, at 10.96 min, 99.22%.
[0281] The reaction was carried out in 2 batches. N-bromo succinimide (196 g, 1.10 mol) was added in portions to a solution of 1,1,2,2,3,3-hexadeuterio-propane-1,3-diol (28.0 g, 0.368 mol ) and triphenyl phosphine (289 g, 1.10 mol) in acetonitrile (500 mL) and dichloromethane (500 mL) keeping the temperature below 35°C. The reaction mixture was stirred at room temperature overnight. Hexane (1 L) was added and the layers separated and re-extracted with hexane (400 mL). The combined hexane layers were washed with sodium hydroxide (250 mL, 2M), then saturated aqueous sodium sulfite (200 mL), brine (200 mL), dried over magnesium sulfate, and concentrated. The residue was triturated with heptane and the solid filtered off. The filtrate was concentrated and the residue triturated a second time with heptane. The solid was filtered off and the filtrates from each batch concentrated to give a crude product (44.0 g and 34.0 g respectively). The combined residues were purified by distillation to give 1,1,2,2,3,3-hexadeuterium-1,3-dibromopropane (44.0 g, 62%).GC (Method F): 20 min, at 12, 10 min, 73.71%.
[0282]To a cooled suspension of sodium hydride (20.3 g, 508 mmol, 60% oil dispersion) in dimethyl sulfoxide (450 mL) and diethyl ether (110 mL) was added to a solution of 1. 1,2,2,3,3-hexadeuterium-1,3-dibromopropane (44.0 g, 213 mmol) and p-toluene sulfonylmethyl isocyanide (33.4 g, 171 mmol) in dimethyl sulfoxide (100 mL) and diethyl ether (25 mL) drip. The reaction mixture was stirred at 0°C for 15 minutes, then warmed to room temperature over 1 hour. During this period, a solid precipitated and the reaction mixture solidified. Dimethyl sulfoxide (200 mL) was added, the solid broken up and the mixture stirred for 3 hours. Water (500 mL) was carefully added, the solid collected by filtration and dried to give 1-((1-isocyano-2,2,3,3,4,4-hexadeuterocyclobutane)sulfonyl)-4-methylbenzene (41 .6 g, 80%) as a brown solid, which was used without further purification. 1H NMR (400 MHz, CDCI3) □ : 2.46 (s, 3H), 7.38 - 7.42 (m, 2H) , 7.83 -7.86 (m, 2H). 13 C NMR (300 MHz, CDCl 3 ) □ : 14.2, 21.9, 30.8, 73.9, 129.9, 130.6, 146, 5, 164.88.
[0283]To a solution of 1-((1-isocyano-2,2,3,3,4,4-hexadeuterocyclobutane)sulfonyl)-4-methylbenzene (41.6 g, 172 mmol) in distilled sulfolane (120 mL) a cooled mixture of sulfuric acid-d2 (9.4 mL) and deuterium oxide (9.4 mL) was added in one portion. The reaction mixture was subjected to high vacuum (using potassium carbonate and potassium hydroxide traps) and heated to 120°C. The product was collected on a cold finger before pumping. The crude product was dissolved in diethyl ether and the phases separated. The organic layer was dried over sodium sulfate and concentrated keeping the water bath at 40°C and pressure at 250 mbar to provide 2,2,3,3,4,4-hexadeuterocyclobutanone (5.45 g, 42% ) as a yellow oil.GC (Method F): 20 min, at 4.93 min, 99.03%.
[0284]To a stirred suspension of magnesium (8.70 g, 0.358 mol) and iodine (1 crystal) in diethyl ether (25 mL) under argon were added a few drops of a solution of 1,1,1-iodide. trideuteromethyl in diethyl ether and the mixture was gently heated for 1 minute until the color dissipated. The remaining 1,1,1-trideuteromethyl iodide (8.91 mL, 0.143 mol) in diethyl ether (25 mL) was added at a rate to control the exotherm and keep the reaction at a gentle reflux. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes, then cooled to 0°C. A solution of 2,2,3,3,4,4-hexadeuterocyclobutanone (5.45 g, 0.0720 mmol) in diethyl ether (25 mL) was slowly added during the period in which a reflux exotherm occurred. The reaction mixture was stirred at 0°C for 30 minutes, then at room temperature for 30 minutes. The mixture was cooled by the careful addition of saturated aqueous ammonium chloride, diluted with water (400 mL), then diethyl ether (400 mL). The phases were separated and the aqueous phase extracted with diethyl ether (400 ml). The combined organic layers were washed with brine, dried over sodium sulfate and carefully concentrated to give 1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutanol (2.42 g , 36%).GC (Method F): 20 min, at 5.84 min, 96.38%.
[0285]To a cooled stirred solution of 1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutanol (2.42 g, 25.4 mmol) in 2-chloroacetonitrile (8.0 mL, 127 mmol) was added acetic acid-d4 (7.3 mL, 127 mmol) and sulfuric acid-d2 (4.2 mL, 76.3 mmol) and the reaction mixture was slowly heated to room temperature and stirred for 3 hours. The mixture was added to ice and extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with aqueous sodium carbonate solution (30 mL), then brine, dried over sodium sulfate, and concentrated to provide 2-chloro-N-(1-(1,1,1-trideuteromethyl) )-2,2,3,3,4,4-hexadeuterocyclobutyl)acetamide (3.95 g, 91%).LCMS (Method D): m/z 169 (M+H)+ (ES+), at 1, 04 min.
[0286]To a stirred solution of 2-chloro-N-(1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl)acetamide (8.52 g, 48, 2 mol) in industrial methylated liquids (50 mL) and acetic acid (10 mL) was added thiourea (7.60 g, 99.8 mmol) and the reaction mixture was heated to reflux overnight. The solid was filtered off and washed with industrial methylated liquids. Hydrochloric acid (10 mL, 2M) was added to the filtrate, then industrial methylated liquids were removed under reduced pressure. The residue was partitioned between diethyl ether and water. The aqueous layer was basified to pH 10 by the addition of sodium hydroxide (2M) and extracted with diethyl ether (3 x 50 mL). The combined organic layers were dried over sodium sulfate. Hydrochloric acid (4M in dioxane) was added and the mixture stirred for 1 hour at room temperature. The mixture was concentrated and azeotroped 3 times with toluene and isopropyl alcohol to give a pale yellow solid. The solid was triturated in diethyl ether and dried in a vacuum oven to provide 1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutan-1-amine hydrochloride (1, 29 g, 43%). LCMS (Method E): m/z 95 (M+H)+ (ES+), at 0.92 min. GC (Method G): 30 min, at 20.56 min, 90.57%.











BIOLOGICAL ACTIVITY EXAMPLE A Phospho-Erk1/2 Assays
[0287]Functional assays were performed using the Phospho-ERK1/2 Alphascreen Surefire 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 the evaluation of M1, M3 (Gq/11-coupled) and M2, M4 ( coupled to Gi/o), rather than using different assay formats for different subtypes. CHO cells stably expressing human M1, M2, M3 or M4 muscarinic receptor were plated (25K/well) in 96-well tissue culture plates in MEM-alpha + 10% dialyzed FBS. Once adhered, the cells were serum deprived overnight. Agonist stimulation was performed by adding 5 μL of agonist to cells for 5 minutes (37°C). The medium was removed and 50 µl of lysis buffer added. After 15 minutes, a 4 μL sample was transferred to the 384-well plate and 7 μL detection mix added. Plates were incubated for 2 hours with gentle shaking in the dark and then read on a PHERAstar plate reader.
[0288] Figures pEC50 and Emax were calculated from the resulting data for each receptor subtype. The results are shown in Table 4 below. Table 4


NT - Not tested EXAMPLE B passive avoidance
[0289]Studies were conducted as previously described by Foley et al., (2004) Neuropsychopharmacology. In the passive avoidance task, the administration of scopolamine (1 mg/kg, i.p.) at 6 hours after training made the animals paragon amnesiacs. A dose range of 3, 10, and 30 mg/kg (po) of free base, administered 90 minutes before the training period via oral gavage, was examined.
[0290] Isomer 2 of Example 9 was found to reverse the paradigm scopolamine-induced amnesia in a dose-dependent manner, with an approximate ED50 of 10 mg/kg (po). The effect of 30 mg/kg was similar to that produced by the cholinesterase inhibitor donepezil (0.1 mg/kg, ip) which served as a positive control (Figure 1). EXAMPLE C cell exchange ca1
[0291] Rat hippocampal slices 400 μm thick were cut in artificial cerebrospinal fluid (aCSF, composition in mM: NaCl 127, KCl 1.6, KH2PO4 1.24, MgSO4 1.3, CaCl2 2.4, NaHCO3 26 and D-glucose 10) cooled (<4°C) using vibratome. The slices were kept in oxygenated aCSF (95% O2 / 5% CO2) at room temperature for at least 1 hour before the electrophysiological recording, after which they were transferred to an interface chamber and constantly sprayed with aCSF. heated oxygenate (30°C) at a flow rate of 1.5 to 3 ml.min-1. Schaffer collaterals were then stimulated (1-20 V, 0.1 ms pulse width, 0.033 Hz) with a concentric bipolar electrode to evoke field excitatory postsynaptic potentials (fEPSPs) recorded from the stratum radiatum of the CA1 region. Experiments were performed to examine the effect of the compound compared to 1 μM carbachol (CCh), on the amplitude of fEPSPs in the CA1 region of rat hippocampal slices. 1 μM CCh was initially applied until a steady state was achieved, followed by washing, before performing a five-point cumulative concentration response to the compound. Each compound was tested on 6 slices and the results were averaged. Drug preparation; the compound was dissolved in 100% DMSO at a stock concentration of 30 mM, and diluted according to requirements, carbamoylcholine chloride (CCh) was purchased from Sigma (Cat#C4382) and dissolved at a stock concentration of 1 mM in ddH2O.Table 5
EXAMPLE D pharmaceutical formulations (i) Tablet formulation
[0292] A tablet composition containing a compound of formula (1) 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 to form a tablet in known manner. (ii) Capsule formulation
[0293] A capsule formulation is prepared by mixing 100 mg of a compound of formula (1) with 100 mg of lactose and, optionally, 1% by weight of magnesium stearate and filling the resulting mixture into capsules standard opaque hard gelatines. EQUIVALENTS
[0294] The above examples have been presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will be readily apparent that various modifications and changes can be made to the specific embodiments of the invention described and illustrated in the examples without departing from the principles underlying the invention. This application is intended to cover such modifications and amendments.

权利要求:
Claims (18)
[0001]
1. Compound CHARACTERIZED by the fact that it has the formula (1):
[0002]
2. Compound according to claim 1, CHARACTERIZED in that R1 is selected from: C1-6 alkyl optionally substituted with 1 to 6 fluorine atoms; methoxy-C 1-4 alkyl optionally substituted with 1 to 6 fluorine atoms; C1-6 alkoxy; C2-6 alkenyl; C2-6 alkynyl; C3-6 cycloalkyl optionally substituted with one or two methyl groups; C4-5-cycloalkyl-CH2-, wherein the C4-5 cycloalkyl moiety is optionally substituted with a C1-2 alkyl group and wherein a carbon atom of the C4-5 cycloalkyl moiety may be optionally substituted with an oxygen atom; cyclopropyl-C 1-3 alkyl; cyclopentenyl; and methyl-bicyclo[2,2,2]octanyl.
[0003]
3. Compound according to claim 1 or 2, CHARACTERIZED in that R1 is selected from 2-methyl propyl groups; 2,2-dimethyl propyl; TERC-butyl; 2-methyl-but-2-yl; 2,3-dimethylbut-2-yl; cyclopropyl methyl; cyclobutyl methyl; cyclopentyl; cyclopentyl methyl; 1-methyl cyclobutyl; 1-methyl cyclopentyl; 1-methyl cyclohexyl; 1-methyl cyclopentyl methyl; cyclopropyl-prop-2-yl; 1-methyl cyclobutyl methyl and 1-ethyl cyclobutyl methyl.
[0004]
4. Compound according to any one of claims 1 to 3, CHARACTERIZED in that R2 is selected from hydrogen, methyl, ethyl and isopropyl.
[0005]
5. Compound according to any one of claims 1 to 4, CHARACTERIZED by the fact that R3 is selected from hydrogen, fluorine and methoxy.
[0006]
6. Compound according to any one of claims 1 to 5, CHARACTERIZED in that R4 is selected from methyl, ethyl, ethynyl and 1-propynyl.
[0007]
7. Compound according to any one of claims 1 to 6, CHARACTERIZED by the fact that p is 0.
[0008]
8. Compound, according to any one of claims 1 to 7, CHARACTERIZED by the fact that the bicyclic ring system formed by the moiety:
[0009]
9. Compound, according to claim 8, CHARACTERIZED by the fact that the bicyclic ring system formed by the portion:
[0010]
10. Compound, according to claim 1, CHARACTERIZED by the fact that it has the formula (3):
[0011]
11. Compound, according to claim 10, CHARACTERIZED by the fact that s = 0 and t = 1.
[0012]
12. Compound according to claim 1, CHARACTERIZED in that it is selected from: 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3,2, 1]octane-8-carboxylate, ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-9-azabicyclo[3.3.1]nonane-9-carboxylate, 3- Ethyl {4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azabicyclo[3.2.1]octane-6-carboxylate, 5-{4-[(1-methylcyclobutyl)carbamoyl]piperidin Ethyl -1-yl}hexahydrocyclopenta[c]pyrrola-2(1H)-carboxylate, 2-{4-fluoro-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3, Ethyl 4]octane-6-carboxylate, ethyl 6-{4-[(1-methyl cyclobutyl)carbamoyl]piperidin-1-yl}-2-azaspiro[3,4]octane-2-carboxylate, 6-{ Prop-2-yn-1-yl 4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-2-azaspiro[3,4]octane-2-carboxylate, 2-{4-[(1- ethyl methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1- il}-6-azaspi ethyl ro[3,4]octane-6-carboxylate, (2s,4r)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane- Ethyl 6-carboxylate, ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate , (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate ethyl, (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate of ethyl, 2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3 ethyl ,4]octane-6-carboxylate, (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl] ethyl carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate, (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)- Ethyl 2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate, 2-(4-{[1-(fluoromethyl) )cyclobutyl]carbamoyl}piperidin- Ethyl 1-yl)-6-azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)- Ethyl 6-azaspiro[3,4]octane-6-carboxylate, (2s,4r)-2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro [3 ethyl ,4]octane-6-carboxylate, 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate(2,2, 2-trideutero)ethyl, (2r,4s)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate (2,2 ,2-trideutero)ethyl, (2s,4r)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate (2, 2,2-trideutero)ethyl, 2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate (2,2,2-trideutero)ethyl, (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro (2,2,2-Trideutero)ethyl, (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}[3,4]octane-6-carboxylate piperidin-1-yl) (2,2,2-Trideutero)ethyl -6-azaspiro[3,4]octane-6-carboxylate, 2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3 (2,2,2-Trideutero)ethyl ,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate, (2r,4s)- 2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4] (2,2,2-trideuteromethyl)-ethyl, (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3, octane-6-carboxylate (2,2,2-Trideutero)ethyl 4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate, 2-(4-{[1-( 1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate (2, 2,2-trideutero)ethyl, 2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate (2,2, 2-trideutero)ethyl, (2r,4s)-2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate ( 2,2,2-trideutero)ethyl, (2s,4r)-2-(4-{[1-fluoromethyl )cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate (2,2,2-trideutero)ethyl, 2-{4-[(1-methylcyclobutyl)carbamoyl] (1,1,2,2,2-pentadeutero)ethyl piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-{4-[(1 (1,1,2,2,2-pentadeutero)ethyl, (2s,4r)-2-{ -methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate (1,1,2,2,2-pentadeutero)ethyl 4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate, 2-(4 -{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate (1,1,2,2,2- pentadeutero)ethyl, (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6 (1,1,2,2,2-pentadeutero)ethyl, (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-carboxylate (1,1,2,2,2-pentadeutero)ethyl, 2-(4-{[1-(1,1,1-trideuteromethyl)yl)-6-azaspiro[3,4]octane-6-carboxylate -2,2,3,3,4,4-hexadeuterocyclobutyl]carbam (1,1,2,2,2-pentadeutero)ethyl, (2r,4s)-2-(4-{ oil}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate [1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate (1,1,2,2,2-pentadeuteromethyl)ethyl, (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4, (1,1,2,2,2-pentadeutero)ethyl 4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate.
[0013]
13. Compound according to claim 12, CHARACTERIZED in that it is selected from: (2r,4s)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6- ethyl azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6 - ethyl azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4, Ethyl 4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl Ethyl }piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}- (2,2,2-Trideuteromethyl)ethyl, (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl 6-azaspiro[3,4]octane-6-carboxylate (2,2,2-trideutero)ethyl ]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate, (2r,4s)-2-(4-{[1- (1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxyl (2,2,2-trideutero)ethyl, (2r,4s)-2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4] (2,2,2-trideutero)ethyl, (2r,4s)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4] octane-6-carboxylate (1,1,2,2,2-pentadeutero)ethyl, (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl]octane-6-carboxylate (1,1,2,2,2-pentadeutero)ethyl, (2r,4s)-2-(4-{[1]piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate (1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3,4]octane-6-carboxylate ,1,2,2,2-pentadeutero)ethyl.
[0014]
14. Compound according to claim 1, CHARACTERIZED in that it is 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3,4]octane-6-carboxylate of ethyl.
[0015]
15. Compound according to claim 1, CHARACTERIZED in that it is 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azabicyclo[3.2.1]octane-6 -ethyl carboxylate.
[0016]
16. Compound according to claim 1, CHARACTERIZED in that it is 6-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-2-azaspiro[3,4]octane-2-carboxylate of ethyl.
[0017]
17. Pharmaceutical composition CHARACTERIZED in that it comprises a compound, as defined in any one of claims 1 to 16, and a pharmaceutically acceptable excipient.
[0018]
18. Use of a compound, as defined in any one of claims 1 to 16, CHARACTERIZED in that it is for the manufacture of a medicament to treat a cognitive disorder or psychotic disorder or to treat or reduce the severity of acute, chronic pain , neuropathic or inflammatory.

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同族专利:

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CN104640851B|2017-05-31|

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US20170247369A1|2017-08-31|

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AU2017204256A1|2017-07-13|

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WO2014045031A1|2014-03-27|

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ES2602039T3|2017-02-17|

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AU2013319989A1|2015-03-12|

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HK1212328A1|2016-06-10|

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EP2897948A1|2015-07-29|

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CN104640851A|2015-05-20|

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US20160128996A1|2016-05-12|

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AU2013319989B2|2017-03-30|

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EP2897948B1|2016-08-31|

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JP6204476B2|2017-09-27|

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US9669013B2|2017-06-06|

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SG11201501620QA|2015-04-29|

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US20180258085A1|2018-09-13|

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CN107098899A|2017-08-29|

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US20150232443A1|2015-08-20|

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JP2015528489A|2015-09-28|

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US9975890B2|2018-05-22|

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AU2013319989C1|2017-08-17|

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BR112015006029A2|2017-07-04|

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CA2883210A1|2014-03-27|

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JP6438091B2|2018-12-12|

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JP2018021057A|2018-02-08|

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CA2883210C|2021-06-15|

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AU2017204256B2|2018-10-18|

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DK2897948T3|2016-12-05|

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CN107098899B|2019-09-06|

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US10259802B2|2019-04-16|

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-03-20| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |

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2019-08-13| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-11-09| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2022-01-25| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/09/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261702330P| true| 2012-09-18|2012-09-18|

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US61/702,330|2012-09-18|

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US201361823606P| true| 2013-05-15|2013-05-15|

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PCT/GB2013/052442|WO2014045031A1|2012-09-18|2013-09-18|Bicyclic aza compounds as muscarinic m1 receptor agonists|

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