Bicyclic aza compounds as muscarinic m1 receptor agonists

Abstract

To provide compounds that are agonists of the muscarinic M1 receptor and / or M4 receptor and which are useful in the treatment of muscarinic M1 / M4 receptor mediated diseases.SOLUTION: Provided also are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. The compounds include those according to formula 1, or a salt thereof, where Q, R1, R2, R3 and R4 are as defined herein. The present invention provides compounds that show selectivity to the M1 receptor and / or M4 receptor compared to the M2 and M3 receptor subtypes.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an agonist of the muscarinic M1 receptor and / or M4 receptor, The present invention relates to compounds that are useful for treating M1 / M4 receptor-mediated diseases. Pharmaceutical compositions containing, and therapeutic uses for, the compounds are also provided. [Background technology]

[0002] Muscarinic acetylcholine receptors (mAChRs) are involved in both the central and peripheral nervous systems. On the other hand, the G protein-coupled receptor superfamily mediates the action of the neurotransmitter acetylcholine. She is a member of Millie. 1 ~M 5 Five mAChR subtypes have been cloned: M 1 mAChRs are expressed primarily in postsynaptic membranes of the cortex, hippocampus, striatum, and thalamus; M 2 mAChRs are located primarily in the brainstem and thalamus, but also in the cortex, hippocampus, and striatum. There they are present in cholinergic synaptic terminals (Langmead et al., 2008 Br J Pharmacol. However, 2 mAChR is expressed in cardiac tissue (where They mediate vagal innervation of the heart and are also peripherally expressed in smooth muscle and exocrine glands. M 3 mAChRs are expressed at relatively low levels in the CNS, but are also expressed in smooth muscle tissue and It is widely expressed in glandular tissues, including sweat glands and salivary glands (Langmead et al., 2008). J Pharmacol.

[0003] Muscarinic receptors in the central nervous system, especially M 1 mAChRs mediate higher cognitive processing Alzheimer's and other diseases associated with cognitive impairment play an important role in This is accompanied by loss of cholinergic neurons in the basal brain (Whitehouse et al., 1999). 82 Science). Schizophrenia with cognitive impairment as an important component of the clinical picture In schizophrenia, mAChR density is reduced in the prefrontal cortex, hippocampus, and caudate-putamen of subjects with schizophrenia (Dean et al., 2002 Mol Psychiatry). Furthermore, in animal models, Blockage or damage to the central cholinergic pathway results in severe cognitive impairment and nonselective mA ChR antagonists have been shown to induce psychotomimetic effects in patients with psychiatric disorders. Choline replacement therapy involves the administration of acetylcholine esters to prevent the breakdown of endogenous acetylcholine. These compounds have been used in clinical trials and are primarily based on the use of steroid inhibitors. It has been shown to be effective as a symptomatic treatment for the decline of gastrointestinal function, but it also causes abnormal gastrointestinal motility, bradycardia, nausea, and Peripheral M, including vomiting 2 and M 3 Dose-limiting adverse events due to stimulation of mAChRs Wake up (http: / / www.drugs.com / pro / donepezil. html;http: / / www.drugs.com / pro / rivastigmi ne.html).

[0004] Directly administer to induce selective improvements in cognitive function with a favorable adverse effect profile M 1 Further discovery efforts have been directed at identifying mAChR agonists. As a result of such efforts, xanomelin, AF267B, sabcomeline, miramelin and A series of agonists have been identified, exemplified by compounds such as cevimeline and cevimeline. Many of the compounds have been shown to be highly effective in preclinical models of cognition in both rodent and / or non-human primates. Miramelin has been shown to be effective in the working and spatial memory of rodents. It has been shown to be effective against scopolamine-induced disorders; Showing efficacy in visual discrimination tasks, xanomeline improved cognitive performance in a passive avoidance paradigm. The compound rescued mAChR antagonist-induced impairment in performance.

[0005] Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting older adults (2006 The disease affects 26.6 million people worldwide and causes severe memory loss and cognitive impairment. The pathogenesis of this disease is complex, but it is mainly the formation of amyloid plaques composed of amyloid-β peptides (Aβ). Tau protein is a protein that is responsible for the formation of neurofibrillary tangles and aggregations. AD is characterized by a distinctive brain pathology. Accumulation of Aβ is thought to be a central feature of the progression of AD. Thus, many putative therapeutics for the treatment of AD currently target the inhibition of Aβ production. Aβ is derived from the proteolytic cleavage of the membrane-bound amyloid precursor protein (APP). APP is involved in the synthesis of proteins through two pathways: the nonamyloidogenic pathway and the amyloidogenic pathway. APP is processed by the γ-secretase pathway. In the former case, APP is cleaved by α-secretase to generate soluble APPα However, in the amyloidogenic pathway, APP is involved in the synthesis of β-secretase. APPβ is cleaved by mAb to give soluble APPβ and also Aβ. ChR agonists promote APP processing to the soluble, nonamyloidogenic pathway In vivo studies have demonstrated that mAChR agonists, such as AF 267B is a 3xTgAD transgenic mouse model of Alzheimer's disease. It has been shown to alter disease-like pathology in fecund mice (Caccamo et al., 2013). 006 Neuron). The mAChR agonist cevimeline has been shown to be effective in treating Alzheimer's disease. It has been shown to slightly but significantly reduce cerebrospinal fluid levels of Aβ in have demonstrated potential disease-modifying efficacy (Nitsch et al., 2000 Neurol. ).

[0006] Preclinical studies have demonstrated that mAChR agonists exhibit atypical antipsychotic effects in a range of preclinical paradigms. These results suggest that the drug will exhibit a profile similar to that of a mAChR agonist. Sanomelin inhibits many dopamine-mediated behaviors, such as amphetamine-induced hyperactivity in rats. Locomotor activity, apomorphine-induced climbing in mice, and unilateral 6-OH-DA-lesioned rats Dopamine agonist-induced rotation in rats and amphetamine-induced hyperlocomotion in monkeys Xanomeline restores A but not A9 in rats. 10 dopamine cell firing and conditioned avoidance, and c- These data also show that it induces fos expression in the nucleus, but not in the striatum. All suggest an atypical antipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev. Muscarinic receptors are also implicated in the neurobiology of addiction. It is believed that the reinforcing effects of cocaine and other addictive substances are mediated by the mesolimbic dopamine system. The behavioral and neurochemical studies demonstrated that cholinergic muscarinic receptor subunits mediate the It has been shown that subtypes play an important role in regulating dopaminergic neurotransmission. For example, M(4)(- / -) mice showed significantly enhanced cognitive function as a result of exposure to cocaine. showed reward-driven behaviors that were consistent with those reported in the study (Schmidt et al., Psychopharmacolog y(2011)Aug;216(3):367-78). Furthermore, xanomeline It has been demonstrated that it blocks the effects of cocaine in these models.

[0007] Muscarinic receptors are also involved in the control of movement and are thought to play a role in Parkinson's disease, ADHD, and Huntington's disease. Dopaminergic pathways as underlying pathogenic factors inducing leukemia, Tourette syndrome and disorders It may represent a novel treatment for movement disorders as well as other syndromes associated with functional impairment.

[0008] Xanomeline, sabcomeline, miramelin and cevimeline are all used to treat Alzheimer's disease. and / or is in various stages of clinical development for the treatment of schizophrenia. Phase II clinical trials of the drug have demonstrated that it can reduce various symptoms, including behavioral disorders and hallucinations, associated with Alzheimer's disease. Its validity for cognitive symptom domains has been demonstrated (Bodick et al., 1997 Arc h Neurol) The compound was also evaluated in a small Phase II study in patients with schizophrenia. , significantly reduced positive and negative symptoms compared to placebo controls (Shekhar et al. , 2008 Am J Psych. However, all clinical trials Melin and other related mAChR agonists have been shown to reduce cholinergic adverse events, such as nausea and vomiting. , gastrointestinal pain, irregular bowel movements (diahorrhea), sweating (excessive sweating), excessive salivation (saliva The study showed unacceptable safety margins for hypersecretion, syncope, and bradycardia.

[0009] Muscarinic receptors are involved in central and peripheral pain. Pain can be mediated by three different Pain can be divided into three types: acute pain, inflammatory pain and neuropathic pain. Pain plays an important protective role in protecting the body from stimuli that may cause tissue damage. However, postoperative pain management is necessary. Inflammatory pain is caused by tissue damage, autoimmune responses, and Inflammation can occur for many reasons, including inflammation of neurons and pathogen invasion, leading to pain. It is caused by the action of inflammatory mediators such as neuropeptides and prostaglandins. Neuropathic pain involves abnormal pain sensations in response to non-painful stimuli. Many different diseases / injuries, e.g. spinal cord injury, multiple sclerosis, diabetes (diabetic neuropathies) Neuropathic pain is associated with disorders such as rheumatoid arthritis, bronchitis, and viral infections (e.g., HIV or herpes). Muscarinic receptors are also common in cancer, both due to the side effects of chemotherapy and due to the effects of muscarinic receptors. Activation of the α-aminobutyric acid (ABA) mediates many pain responses through activation of receptors in the spinal cord and higher pain centers in the brain. It has been shown to have an analgesic effect in these conditions. Increase endogenous levels of cetylcholine, agonists or allosteric modulators Direct activation of muscarinic receptors by nicotinamide adenine diamine phosphate has been shown to have analgesic activity. , Blocking muscarinic receptors by using antagonists or knockout mice For evidence on the role of M1 receptors in pain, see DF As reviewed by Fiorino and M. Garcia-Guzman, 2012 is.

[0010] Recently, the M mAChR subtype has been shown to be more potent than the peripherally expressed mAChR subtype. 1mAChR subtypes A few compounds have been identified that show improved selectivity against 08 Bioorg Med Chem Lett;Johnson et al., 2010 Bi oorg Med Chem Lett;Budzik et al., 2010 ACS Med Chem Lett. 3 Increasing levels of selectivity for mAChR subtypes Despite this, some of these compounds have been shown to be effective against this subtype and M 2 mACh Both of these agonists retain significant agonist activity at both R and R subtypes. Surprisingly, M 2 and M 3 Receptor subtype: M 1 and / or M. 4 For mAChR A series of compounds are described that exhibit high levels of selectivity.

[0011] Figure legends can be found in experimental sections B and C. [Brief description of the drawings]

[0012] [Figure 1] Figure 1 shows that Example 1-33 Isomer 2 reversed scopolamine-induced amnesia in a dose-dependent manner with an ED50 of approximately 10 mg / kg (po). The effect of 30 mg / kg was similar to that produced by the positive control cholinesterase inhibitor donepezil (0.1 mg / kg, i.p.). [Figure 2-1] Figure 2 shows the effect of novel test compounds on d-amphetamine-induced hyperlocomotion in rats. Antipsychotic-like behavior in rats was evaluated by inhibiting d-amphetamine-induced hyperlocomotion (or increased locomotor activity). Data for Examples 1-21 isomer 2, 1-32 isomer 2, 1-33 isomer 2, 2-7 isomer 2, and 2-17 isomer 2 are shown. [Figure 2-2]Figure 2 shows the effect of novel test compounds on d-amphetamine-induced hyperlocomotion in rats. Antipsychotic-like behavior in rats was evaluated by inhibiting d-amphetamine-induced hyperlocomotion (or increased locomotor activity). Data for Examples 1-21 isomer 2, 1-32 isomer 2, 1-33 isomer 2, 2-7 isomer 2, and 2-17 isomer 2 are shown. Summary of the Invention

[0013] The present invention relates to compounds having activity as muscarinic M1 and / or M4 receptor agonists. More specifically, the present invention provides a method for treating M1 and M2 receptor subtypes, as compared to M2 and M3 receptor subtypes. The present invention provides compounds that exhibit selectivity for the M1 and / or M4 receptors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Thus, in one embodiment (embodiment 1.1), the present invention provides a compound of formula (1) [ka] or a salt thereof, wherein Q is 1, 2, 3, or 4 heteroatom ring members selected from N, O, and S. is a 5- or 6-membered monocyclic heterocyclic ring containing; R 1 is hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CO NR 5 R 6 ;NR 7 COOR 5;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 ; C optionally substituted with 1 to 6 fluorine atoms 1-6 Non-aromatic hydrocarbon groups (1 or or two, but not all, of the carbon atoms of the hydrocarbon group are O, N and S, and may be optionally replaced by heteroatoms selected from their oxidized forms. and 0, 1, 2 or 3 selected from O, N and S and their oxidized forms. optionally substituted 5- or 6-membered rings containing heteroatoms; R 2 is hydrogen; fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 C ONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 ;C 1-6 or R 1 and R 2 are joined together capable of forming a fused six-membered aromatic ring; R 3 is hydrogen; fluorine; cyano; hydroxyl; amino; and 1 to 6 fluorine atoms. C optionally substituted 1-9 selected from non-aromatic hydrocarbon groups, Some, but not all, of the carbon atoms of the hydrocarbon group are O, N, and S, and and optionally oxidized forms of the heteroatoms selected from: R 4 is hydrogen or C optionally substituted with 1 to 6 fluorine atoms 1-6 Non An aromatic hydrocarbon group, one or two, but not all, of the carbon atoms of the hydrocarbon group The atoms are optionally substituted with heteroatoms selected from O, N and S and their oxidized forms. May be selectively replaced; R 5 , R 6 and R 7 are the same or different, and each is hydrogen, one or more Non-aromatic C optionally substituted with one or more fluorine atoms 1-4 or formula C H 2 N(R a )COOR b are independently selected from the group R a is hydrogen and non-aromatic C 1-4 selected from hydrocarbon groups; R b is fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or cyclo one selected from an alkyl, heterocycloalkyl, aryl or heteroaryl group; or a non-aromatic C optionally substituted with multiple groups 1-4 is a hydrocarbon group; The dotted line indicates an optional second carbon-carbon bond, but when a second carbon-carbon bond is present, is R 3 does not exist.

[0015] Thus, in one embodiment (embodiment 1.1a), the present invention provides a compound of formula (1a): [ka] or a salt thereof, wherein Q contains 1, 2, 3 or 4 heteroatom ring members selected from N, O and S. is a 5-, 6-, or 7-membered monocyclic heterocyclic ring having R 1 is hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CO NR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 ; C optionally substituted with 1 to 6 fluorine atoms 1-6 Non-aromatic hydrocarbon groups (herein In which one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, or S. and their oxidized forms, and 0, 1, 2 or 3 selected from O, N and S and their oxidized forms. an optionally substituted 5- or 6-membered ring containing 3 heteroatoms; ; R 2 is hydrogen; fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; OR 5 ;NR 5 R 6 ;COR5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 C ONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 ;C 1-6 or R 1 and R 2 are joined together capable of forming a fused six-membered aromatic ring; R 3 is hydrogen; fluorine; cyano; hydroxyl; amino; and 1 to 6 fluorine atoms. C optionally substituted 1-9 selected from non-aromatic hydrocarbon groups, Some, but not all, of the carbon atoms of the hydrocarbon group are O, N, and S, and and optionally oxidized forms of the heteroatoms selected from: R 4 is hydrogen or C optionally substituted with 1 to 6 fluorine atoms 1-6 Non An aromatic hydrocarbon group, one or two, but not all, of the carbon atoms of the hydrocarbon group The atoms are optionally substituted with heteroatoms selected from O, N and S and their oxidized forms. May be selectively replaced; R 5 , R 6 and R 7 are the same or different, and each is hydrogen, one or more Non-aromatic C optionally substituted with one or more fluorine atoms 1-4or formula C H 2 N(R a )COOR b are independently selected from the group R a is hydrogen and non-aromatic C 1-4 selected from hydrocarbon groups; R b is fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or cyclo one selected from an alkyl, heterocycloalkyl, aryl or heteroaryl group; or a non-aromatic C optionally substituted with multiple groups 1-4 is a hydrocarbon group; The dotted line indicates an optional second carbon-carbon bond, but when a second carbon-carbon bond is present, is R 3 does not exist.

[0016] Thus, in one embodiment (embodiment 1.1b), the present invention provides a compound of formula (1b): [ka] or a salt thereof, wherein Q is 1, 2, 3, or 4 heteroatom ring members selected from N, O, and S. an optionally substituted 5-, 6-, or 7-membered heterocycle containing R 3 is hydrogen; fluorine; cyano; hydroxyl; amino; and 1 to 6 fluorine atoms. C optionally substituted 1-9 selected from non-aromatic hydrocarbon groups, Some, but not all, of the carbon atoms of the hydrocarbon group are O, N, and S, and and optionally oxidized forms of the heteroatoms selected from: R 4 is hydrogen or C optionally substituted with 1 to 6 fluorine atoms 1-6 Non An aromatic hydrocarbon group, one or two, but not all, of the carbon atoms of the hydrocarbon group The atoms are optionally substituted with heteroatoms selected from O, N and S and their oxidized forms. May be selectively replaced; The dotted line indicates an optional second carbon-carbon bond, but when a second carbon-carbon bond is present, is R 3 does not exist.

[0017] Certain compounds of formula (1), (1a) or (1b) are described in embodiments 1.2 to 1.1 below. 80.

[0018] 1.2 The compound according to embodiment 1.1, wherein Q is an aromatic or unsaturated heterocycle.

[0019] 1.3 The compound according to embodiment 1.2, wherein Q is an aromatic heterocycle.

[0020] 1.4 Q is a nitrogen ring member and, optionally, one or two selected from O, N and S. The compound according to embodiment 1.3, wherein the ring is an aromatic heterocycle containing two additional ring members.

[0021] 1.5 Q is a nitrogen ring member and, optionally, one further ring member selected from O, N and S. The compound according to embodiment 1.4, wherein the aromatic heterocycle contains the ring members:

[0022] 1.6 Embodiment 1, in which Q is an aromatic heterocycle containing 1 or 2 nitrogen ring members. 5. The compound according to claim 5.

[0023] 1.7 Q is a 5-membered heterocycle and the adjacent 6-membered heterocycle is connected to the 5-membered heterocycle by a carbon atom. The compound according to any one of embodiments 1.1 to 1.6, wherein the ring is linked to

[0024] 1.8 Q is a 5-membered heterocyclic ring, and the 5-membered heterocyclic ring any one of embodiments 1.1 to 1.6, wherein the nitrogen atom of The compound according to any one of claims 1 to 5.

[0025] 1.9 Q is 1-pyrrolyl, 2-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 5 -Pyrazolyl, 2-thiazolyl, 2-oxazolyl, triazolyl, tetrazolyl, thia 1. The aryl group is selected from diazolyl, oxadiazolyl, and tautomers thereof. 1. The compound according to claim 1.

[0026] 1.10 The compound according to embodiment 1.6, wherein Q is a pyrrole ring.

[0027] 1.11 The compound according to embodiment 1.6, wherein Q is an imidazole ring.

[0028] 1.12 The compound according to embodiment 1.6, wherein Q is a pyrazole ring.

[0029] 1.13 Q is 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl and tautomers thereof The compound according to embodiment 1.6, wherein the compound is selected from the group consisting of:

[0030] 1.14 Embodiment 1.1 in which Q is a six-membered ring containing one or more nitrogen atoms The compound according to claim 1,

[0031] 1.15 Q is pyridyl, pyrazyl or contains 0-2 C-C unsaturated bonds (c 2-oxo-3N(3-piperidin-2-one) ring, The compound according to claim 1.14.

[0032] 1.16 The compound according to embodiment 1.1, wherein Q is a 5-, 6- or 7-membered unsaturated heterocycle. Compound.

[0033] 1.17 Embodiment 1 in which Q is 5-pyrollidinyl .16. The compound described in

[0034] 1.18 The compound according to embodiment 1.1, in which Q is bicyclic; The compound described.

[0035] 1.19 Q has one or more substituents, e.g., 1, 2 or 3 substituents , it is one R 1 and / or R 2 R may be selected from 1 and R 2 Is it the same? or different. Further substituents on Q include (L)-R 10 , (L)-R 11 and (L)-R 12 where L is a bond or CH 2 It is a base; R 10 , R 11 and R 12 are hydrogen, fluorine, chlorine, bromine, cyano, oxo, and hydroxy. ;OR 15 ;NR 15 R 16 ;COR 15 ;CSR 15 ;COOR 15 ;COSR 15 ; OCOR 15 ;NR 17 COR 15 ;CONR 15 R 16 ;CSNR 15 R 16 ;NR 1 7 CONR 15 R 16 ;R 17 COOR 15 ;OCONR 15 R16 ;SR 15 ;SOR 15 and S.O. 2 R 15 C optionally substituted with 1 to 6 fluorine atoms 1-6 Non Aromatic hydrocarbon groups (wherein one or two, but not all, of the carbon atoms of the hydrocarbon group Optionally, a heteroatom selected from O, N and S and their oxidized forms. and selected from O, N and S and their oxidized forms. Optionally substituted 5- or 6-membered heteroatoms containing 0, 1, 2 or 3 heteroatoms are independently selected from the rings: Optional substituents on the optionally substituted 5- or 6-membered ring are hydrogen; fluorine; chlorine;bromine;cyano;oxo;hydroxy;OR 5 ;NR 5 R 6 ;COR 5 Chief Operating Officer R 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 C OOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 and 1 to 6 fluorines C optionally substituted with atoms 1-6 Non-aromatic hydrocarbon groups (1 or 2, but The carbon atoms of the hydrocarbon group, but not all of them, are O, N and S and their oxidized forms. and optionally replaced by a heteroatom selected from8 mosquito Selected from; R 15 , R 16 and R 17 are the same or different, or join together to form a ring each of which is optionally substituted with hydrogen, one or more fluorine atoms. non-aromatic C 1-6 Hydrocarbon group (one or two, but not all, of the said hydrocarbon group of the carbon atoms are substituted by heteroatoms selected from O, N and S and their oxidized forms. or a group of formula CH 2 N(R a )COOR b Based on; is the formula (L)-R 18 (where L is a bond or CH 2 is a group, R 18 If O, N, or S and their oxidized forms, an optionally substituted 5- or 6-membered ring; Optional substituents for the optionally substituted 5- or 6-membered ring are the groups R 8 Choose from The compound according to embodiment 1.1b,

[0036] 1.20 R 1 is hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ; NR 7 CONR 5 R 6 ;NR 7COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S O 2 R 5 C optionally substituted with 1 to 6 fluorine atoms 1-6 Non-aromatic hydrocarbons A hydrocarbon group in which one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, or Optionally replaced by a heteroatom selected from S and their oxidized forms. and 0, 1, 2 or 3 selected from O, N and S and their oxidized forms. or 3 heteroatoms, optionally substituted 5- or 6-membered rings And, Optional substituents on the optionally substituted 5- or 6-membered ring are hydrogen; fluorine; chlorine;bromine;cyano;oxo;hydroxy;OR 5 ;NR 5 R 6 ;COR 5 Chief Operating Officer R 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 C OOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 and 1 to 6 fluorines C optionally substituted with atoms 1-6 Non-aromatic hydrocarbon groups (1 or 2, but The carbon atoms of the hydrocarbon group, but not all of them, are O, N and S and their oxidized forms. and optionally replaced by a heteroatom selected from 8 mosquito The compound according to any one of embodiments 1.1 to 1.19, selected from:

[0037] 1.21 R 1 is hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ; NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S O 2 R 5 C optionally substituted with 1 to 6 fluorine atoms 1-5 Non-aromatic hydrocarbons A hydrocarbon group in which one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, or Optionally replaced by a heteroatom selected from S and their oxidized forms. and 0, 1, or 2 selected from O, N, and S and their oxidized forms. is selected from optionally substituted 5- or 6-membered rings containing two heteroatoms. Re; Optional substituents on the optionally substituted 5- or 6-membered ring are fluorine; Br;Cyano;Oxo;Hydroxy;OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5; OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 and 1 to 6 fluorine atoms Optionally substituted C 1-4 Non-aromatic hydrocarbon groups (1 or 2, but not all the carbon atoms of the hydrocarbon group are selected from O, N and S and their oxidized forms, The group R consists of a heteroatom selected from 8 Choose from The compound according to embodiment 1.20, wherein

[0038] 1.22 R 1 is hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ; NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S O 2 R 5C optionally substituted with 1 to 6 fluorine atoms 1-4 Non-aromatic hydrocarbons A hydrocarbon group in which one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, or Optionally replaced by a heteroatom selected from S and their oxidized forms. and 0, 1, or 2 selected from O, N, and S and their oxidized forms. is an optionally substituted 5- or 6-membered aryl or is selected from heteroaryl rings; to the optionally substituted 5- or 6-membered aryl or heteroaryl ring. The optional substituents are fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR. 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 C ONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 and C optionally substituted with 1 to 6 fluorine atoms. 1-4 Non-aromatic hydrocarbon groups (One or two, but not all, of the carbon atoms of the hydrocarbon group may be O, N, or S. and their oxidized forms, A group R consisting of 8 The compound according to embodiment 1.21, selected from:

[0039] 1.23 R 1 is hydrogen; fluorine; chlorine; cyano; oxo; hydroxy; OR 5 ;NR 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SO 2 R 5 1 to 6 fluorines C optionally substituted with atoms 1-4 Non-aromatic hydrocarbon groups, (1 or 2, However, not all of the carbon atoms of the hydrocarbon group are O, N and S and their oxidized forms. and optionally replaced by a heteroatom selected from O, N and S, and 0, 1, 2 or 3 heteroatoms selected from their oxidized forms. and optionally substituted 5- or 6-membered rings having the optionally substituted Optional substituents for a substituted 5- or 6-membered aryl or heteroaryl ring are Fluorine;Chlorine;Bromine;Cyano;Oxo;Hydroxy;OR 5 ;NR 5 R 6 ;COR 5 ;C OOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 ; and 1 to 6 C optionally substituted with fluorine atoms 1-4 Non-aromatic hydrocarbon groups (1 or 2, However, not all of the carbon atoms of the hydrocarbon group may be O, N, and S, and their oxidized forms. and optionally substituted with a heteroatom selected from the following: 8 The compound according to any one of embodiments 1.1 to 1.19, selected from:

[0040] 1.24 R 1 , hydrogen; fluorine; chlorine; cyano; hydroxyl; OR 5 ;NR 5 R 6 ; COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SO 2 R 5 and 1 to 6 fluorine atoms C optionally substituted with 1-4 Non-aromatic hydrocarbon groups (1 or 2, but not all) The carbon atoms of the hydrocarbon group that are not part of the and optionally replaced by a heteroatom selected from The compound described in Form 1.23.

[0041] 1.25 R 1 , hydrogen; fluorine; chlorine; cyano; hydroxyl; OR 5 ;NR 5 R 6 ; COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;SO 2 R 5 and optionally substituted with 1 to 6 fluorine atoms C 1-4 The compound according to embodiment 1.24, wherein the aromatic hydrocarbon group is selected from the group consisting of aromatic hydrocarbon groups. thing.

[0042] 1.26 R 1 , hydrogen; fluorine; chlorine; cyano; NR 5 R 6 ;COR 5 ;COOR 5 and C optionally substituted with 1 to 6 fluorine atoms 1-6 Non-aromatic hydrocarbon groups The compound according to embodiment 1.25, selected from:

[0043] 1.27 R 1 But hydrogen; fluorine; chlorine; cyano; NH 2 , C.O.R. 5 ;COOR 5 and C optionally substituted with 1 to 6 fluorine atoms 1-4 Saturated non-aromatic hydrocarbon group The compound according to embodiment 1.26, selected from:

[0044] 1.28 R 1But hydrogen; COR 5 ;COOR 5 ;CONR 5 R 6 and C 1-4 Alki The compound according to embodiment 1.27, wherein the compound is selected from the group consisting of aryl, ... and aryl.

[0045] 1.29 R 1 But hydrogen; COR 5 ;COOR 5 and C 1-3 alkyl groups The compound according to embodiment 1.28,

[0046] 1.30 R 1 Hydrogen; methyl; ethyl and COOR 5 In one embodiment, .29.

[0047] 1.31 R 1 The compound according to embodiment 1.30, wherein is hydrogen.

[0048] 1.32 R 1 The compound according to embodiment 1.30, wherein is methyl or ethyl.

[0049] 1.33 R 1 But COOMe;COOEt;COMe;COEt;CONH 2 ;CF 3 ;CONHMe;CON(Me) 2 ;COCF 3 ;CO-Cyclopropyl;CO-Cyc lobutyl;CONHEt;COH;NH 2 ; OMe, embodiments 1.20 to 1.30 The compound according to claim 1,

[0050] 1.34 R 2 but hydrogen; fluorine; chlorine; bromine; cyano; hydroxyl; methoxy; and C 1-6 or R1 and bonded to form a six-membered fused aromatic The compound according to any one of embodiments 1.1 to 1.33, which forms a ring.

[0051] 1.35 R 2 Hydrogen; fluorine; hydroxyl; methoxy; and C 1-6 Non-aromatic carbonization The compound according to embodiment 1.34, wherein R is selected from a hydrogen group.

[0052] 1.36 R 2 is hydrogen; fluorine; methoxy; and C 1-4 A saturated hydrocarbon group is selected from the group consisting of The compound according to embodiment 1.35,

[0053] 1.37 R 2 is hydrogen; fluorine; methoxy; and C 1-4 Selected from alkyl groups , the compound described in embodiment 1.36.

[0054] 1.38 R 2 But hydrogen and C 1-3 In embodiment 1.37, the alkyl group is selected from the group consisting of aryl, ... and aryl. The compound described.

[0055] 1.39 R 2 Compounds according to embodiment 1.38, wherein is selected from hydrogen and methyl. .

[0056] 1.40 R 2 But R 1 to form a six-membered fused aromatic ring, which may be aryl or The compound according to embodiment 1.34, wherein can be heteroaryl.

[0057] 1.41 The dotted line represents the second carbon-carbon bond, and R 3 In the embodiment 1.1 to 1. A compound according to any one of claims 1.40.

[0058] 1.42 R 3 is present and the optional second carbon-carbon bond is absent, -1.40.

[0059] 1.43 R 3 Hydrogen; fluorine; cyano; hydroxyl; amino; and 1 to 6 fluorines C optionally substituted with a hydrogen atom 1-6 Non-aromatic hydrocarbon groups (1 or 2, However, not all of the carbon atoms of the hydrocarbon group are O, N and S and their oxidized forms. and optionally replaced by a heteroatom selected from , the compound described in embodiment 1.42.

[0060] 1.44 R 3 Hydrogen; fluorine; cyano; hydroxyl; amino; and 1 to 6 fluorines C optionally substituted with a hydrogen atom 1-6 Non-aromatic hydrocarbon radicals (one, but not all) the carbon atoms of the hydrocarbon group are selected from O, N and S and their oxidized forms, and optionally replaced by a heteroatom selected from the group consisting of The compound according to embodiment 1.43.

[0061] 1.45 R 3 , hydrogen; fluorine; cyano; hydroxyl; amino; C 1-4 Alkyl and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4 Alkoxy is The compound according to embodiment 1.44, wherein each of the fluorine atoms is optionally substituted with 1 to 6 fluorine atoms. thing.

[0062] 1.46 R 3 is selected from hydrogen; fluorine; hydroxy and methoxy; The compound described in 1.45.

[0063] 1.47 R 3 The compound according to embodiment 1.46, wherein is hydrogen.

[0064] 1.48 R 4 is hydrogen or acyclic C 1-6 Hydrocarbon group, embodiment 1.1 to 1 .47. A compound according to any one of claims 1 to 47.

[0065] 1.49 R 4 is hydrogen or acyclic C 1-3 In embodiment 1.48, the hydrocarbon group The compound described.

[0066] 1.50 R 4 is hydrogen or C 1-3 Alkyl group or C 2-3 Alkynyl group , the compound described in embodiment 1.49.

[0067] 1.51 R 4 is selected from hydrogen, methyl, ethyl, ethynyl and 1-propynyl; The compound according to embodiment 1.50,

[0068] 1.52 R 4 Compounds according to embodiment 1.51, wherein is selected from hydrogen and methyl. .

[0069] 1.53 R 4 The compound according to embodiment 1.52, wherein is methyl.

[0070] 1.54 R 5 is optionally substituted with one or more fluorine atoms, when present Non-aromatic C 1-4 is a hydrocarbon group; or of the formula CH 2 N(R a )COOR b Based on The compound of any one of the preceding embodiments,

[0071] 1.55 Nonaromatic C 1-4 The hydrocarbon group is saturated C 1-4 Hydrocarbon group, embodiment The compound described in 1.54.

[0072] 1.56 R 5 Any of embodiments 1.1 to 1.53, wherein, when present, is hydrogen. The compound described in 1.

[0073] 1.57 R 5 When present, hydrogen and saturated C 1-4 selected from hydrocarbon groups, The compound according to any one of embodiments 1.1 to 1.53.

[0074] 1.58 Saturation C 1-4 The hydrocarbon group is C 1-4 Alkyl Group, embodiment 1.55 Or a compound as described in embodiment 1.56.

[0075] 1.59 Saturation C 1-4 The hydrocarbon group is C 1-3 Alkyl Group, embodiment 1.58 The compound according to claim 1,

[0076] 1.60 C 1-3 the alkyl group is selected from methyl, ethyl and isopropyl; The compound according to embodiment 1.59.

[0077] 1.61 C 1-3 The compound according to embodiment 1.60, wherein the alkyl group is ethyl.

[0078] 1.62 R 6 When present, non-aromatic C 1-4 The preceding embodiments are hydrocarbon groups. 2. The compound according to claim 1 ,

[0079] 1.63 Nonaromatic C 1-4 The hydrocarbon group is saturated C 1-4 Hydrocarbon group, embodiment The compound according to claim 1.62.

[0080] 1.64 R 6 Any of embodiments 1.1 to 1.61, wherein, when present, is hydrogen. The compound described in 1.

[0081] 1.65 Saturation C 1-4 The hydrocarbon group is C 1-3 Alkyl group, embodiment 1.63 The compound according to claim 1,

[0082] 1.66 C 1-3 the alkyl group is selected from methyl, ethyl and isopropyl; The compound according to embodiment 1.65.

[0083] 1.67 R 7 When present, non-aromatic C 1-4 The preceding embodiments are hydrocarbon groups. 2. The compound according to claim 1 ,

[0084] 1.68 Nonaromatic C 1-4 The hydrocarbon group is saturated C 1-4 Hydrocarbon group, embodiment The compound described in 1.67.

[0085] 1.69 R 7 Any of embodiments 1.1 to 1.66, wherein, when present, is hydrogen. The compound described in 1.

[0086] 1.70 R 7 When present, hydrogen and saturated C 1-4 selected from hydrocarbon groups, A compound according to any one of embodiments 1.1 to 1.66.

[0087] 1.71 Saturation C 1-4 The hydrocarbon group is C 1-4 Alkyl group, embodiment 1.68 Or a compound as described in embodiment 1.70.

[0088] 1.72 Saturation C 1-4 The hydrocarbon group is C 1-3 Alkyl group, embodiment 1.71 The compound according to claim 1,

[0089] 1.73 C 1-3 the alkyl group is selected from methyl, ethyl and isopropyl; The compound according to embodiment 1.72.

[0090] 1.74 R 1 When is an optionally substituted 5- or 6-membered ring, it is O 0, 1 or 2 or 3 heteroaryl groups selected from N and S and their oxidized forms. The compound of any one of the preceding embodiments, wherein the ring is selected from an aromatic ring containing atoms.

[0091] 1.75 The compound according to embodiment 1.74, wherein the aromatic ring is carbocyclic.

[0092] 1.76 The compound according to embodiment 1.74, wherein the aromatic ring is heterocyclic.

[0093] 1.77 R 1 When is an optionally substituted 5- or 6-membered ring, it is O 0, 1 or 2 or 3 heteroaryl groups selected from N and S and their oxidized forms. In any one of embodiments 1.1 to 1.73, a non-aromatic ring containing atoms is selected from The compound described.

[0094] 1.78 The compound according to embodiment 1.77, wherein the non-aromatic ring is carbocyclic.

[0095] 1.79 The compound according to embodiment 1.77, wherein the non-aromatic ring is heterocyclic.

[0096] 1.80 According to any one of embodiments 1.74 to 1.79, wherein the ring is a 5-membered ring. compound.

[0097] 1.81 According to any one of embodiments 1.74 to 1.79, wherein the ring is a 6-membered ring. compound.

[0098] 1.82 R 1 When is an optionally substituted 5- or 6-membered ring, it is , 1, 2 or 3 substituents R 8 As described in any one of the preceding embodiments, Compound.

[0099] 1.83 0, 1 or 2 substituents R 8 The compound according to embodiment 1.82, wherein thing.

[0100] 1.84 0 substituents R 8 The compound of embodiment 1.83, wherein

[0101] 1.85 1 substituent R 8 The compound of embodiment 1.82, wherein

[0102] 1.86 Two substituents R 8 The compound of embodiment 1.82, wherein

[0103] 1.87 R 8 When present, fluorine; cyano; oxo; hydroxy; OR 5 ;N R 5 R 6 ;COR 5 ;COOR 5 ;OCOR 5 ;NR 7 COR 5;CONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 and optionally substituted with 1 to 6 fluorine atoms C 1-6 Non-aromatic hydrocarbon groups (one or two, but not all, of the hydrocarbon group) Carbon atoms are bounded by heteroatoms selected from O, N and S and their oxidized forms. Optionally, the embodiment 1.81, 1.82, 1. 83, 1.85 and 1.86.

[0104] 1.88 R 8 Fluorine; Cyano; Oxo; Hydroxy; OR 5 ;NR 5 R 6 ;CO R 5 ;COOR 5 ;OCOR 5 and S.O. 2 R 5 and optionally 1 to 6 fluorine atoms C has been replaced by 1-4 Non-aromatic hydrocarbon groups (one or two, but not all, The carbon atoms of the hydrocarbon group are selected from O, N and S and their oxidized forms. In embodiment 1.87, The compound according to claim 1,

[0105] 1.89 R 8 Fluorine; Cyano; Oxo; Hydroxy; OR 5 ;NR 5 R 6 and C optionally substituted with 1 to 6 fluorine atoms 1-4 Selected from non-aromatic hydrocarbon groups The compound according to embodiment 1.88, wherein

[0106] 1.90 R 8 , cyano; oxo; hydroxy; OR 5 ;NR 5 R 6 ; and C 1-4 The compound according to embodiment 1.89, wherein the alkyl is selected from alkyl.

[0107] 1.91 part: [ka] However, the following groups AAA~ACB: [ka] [ka] According to any one of the embodiments 1.1 to 1.40 and 1.42 to 1.53, The compounds listed above.

[0108] 1.92 Equation (2): [ka] wherein Q is an optionally substituted 5 or 6-membered alkyl group having one or more nitrogen atoms; A 6-membered heterocyclic or heteroaryl ring, R 4 is an embodiment As defined in any one of 1.48 to 1.53; or formula (2a) [ka] wherein Q is an optionally substituted 5, 6 or 7-aminopropyl group having one or more nitrogen atoms. or a 7-membered heterocyclic or heteroaryl ring; R 4 is implemented As defined in any one of forms 1.48 to 1.53; Compounds relating to

[0109] 1.93 Compounds according to formula (2) or formula (2a), in which Q is one or It has multiple substituents, e.g., 1, 2 or 3 substituents, which are (L)-R 10 , (L )-R 11 and (L)-R 12 where L is a bond or CH 2 base ;R 10 , R 11 and R 12 are hydrogen, fluorine, chlorine, bromine, cyano, oxo, and hydroxyl. doxy;OR 15 ;NR 15 R 16 ;COR 15 ;CSR 15 ;COOR 15 ;COS R 15 ;OCOR 15 ;NR 17 COR 15 ;CONR 15 R 16 ;CSNR 15 R 16 ;NR 17 CONR 15 R 16 ;R 17 COOR 15 ;OCONR 15 R 16 ;SR 15 ;SOR 15 and S.O. 2 R 15 C optionally substituted with 1 to 6 fluorine atoms 1-6 Non-aromatic hydrocarbon groups (one or two, but not all, of the carbon atoms of the hydrocarbon group) The nitrogen atoms are selected from O, N and S and their oxidized forms by heteroatoms. and O, N and S and their oxidized forms. Optionally substituted 5 or 6 alkyl groups containing 0, 1, 2 or 3 heteroatoms are independently selected from 6-membered rings; Optional substituents on the optionally substituted 5- or 6-membered ring are hydrogen; fluorine; chlorine;bromine;cyano;oxo;hydroxy;OR 5 ;NR 5 R 6 ;COR 5 Chief Operating Officer R 5 ;OCOR 5 ;NR 7 COR 5 ;CONR 5 R 6 ;NR 7 CONR 5 R 6 ;NR 7 C OOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S.O. 2 R 5 and 1 to 6 fluorine atoms C optionally replaced by its children 1-6 Non-aromatic hydrocarbon radicals (1 or 2, but Not all of the carbon atoms of the hydrocarbon group are selected from O, N and S and their oxidized forms. and optionally replaced by a heteroatom selected from 8 from Selected; R 15 , R 16 and R 17 are the same or different, or joined together to form a ring each of which is optionally substituted with hydrogen, one or more fluorine atoms. Non-aromatic C 1-6 Hydrocarbon group (one or two, but not all, of the hydrocarbon The carbon atoms of the group are surrounded by heteroatoms selected from O, N and S and their oxidized forms. or a group of formula CH 2 N(R a )COOR b Based on or formula (L)-R 18 where L is a bond or CH 2 Based on R 18 is 0, 1, 2 or 3 selected from O, N and S and their oxidized forms an optionally substituted 5- or 6-membered ring containing 3 heteroatoms; Optional substituents for the optionally substituted 5- or 6-membered ring are the groups R 8 mosquito The compound is selected from the group consisting of

[0110] 1.94 Equation (3): [ka] wherein R 1 , R 2 and R 4 are embodiments 1.1 to 1.40 and 1.42 to 1.90 and ring A is a 5-membered ring containing 1 or 2 nitrogen ring members. The compound according to embodiments 1.1-1.93, wherein the heterocyclic or heteroaryl ring is

[0111] 1.95 An embodiment in which Ring A is a 5-membered heteroaryl ring containing two nitrogen ring members. The compound described in embodiment 1.94.

[0112] 1.96 The compound according to embodiment 1.95, wherein ring A is an imidazole ring.

[0113] 1.97 Equation (4): [ka] wherein R 1 , R 2 and R4 In embodiments 1.1 to 1.40 and 1.42 to 1.9 The compound according to embodiment 1.96, wherein:

[0114] 1.98 The compound according to embodiment 1.95, wherein ring A is a pyrazole ring.

[0115] 1.99 Equation (5): [ka] wherein R 1 , R 2 and R 4 In embodiments 1.1 to 1.40 and 1.42 to 1.9 The compound according to embodiment 1.98, wherein:

[0116] 1.100 Equation (6): [ka] wherein R 1 , R 2 and R 4 In embodiments 1.1 to 1.40 and 1.42 to 1.9 The compound according to embodiment 1.98, wherein:

[0117] 1.101 Embodiment 1.9 in which Ring A is a 5-membered heterocycle containing one nitrogen atom 4. The compound according to claim 4.

[0118] 1.102 Equation (7): [ka] wherein R 1 , R 2 and R 4 In embodiments 1.1 to 1.40 and 1.42 to 1.9 The compound according to embodiment 1.101, wherein:

[0119] 1.103 Part: [ka] However, the following groups BAA to BCZ: [ka] [ka] [ka] The compound according to embodiment 1.101, selected from:

[0120] 1.104 Equation (8): [ka] wherein R 1 , R 2 and R 4 In embodiments 1.1 to 1.40 and 1.42 to 1.9 The compound according to embodiment 1.101, wherein:

[0121] 1.105 part: [ka] However, the following groups CAA~CBX: [ka] [ka] The compound according to embodiment 1.101, selected from:

[0122] 1.106 Q is a ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S. The compound according to embodiment 1.1, wherein the ring is a 6-membered monocyclic heterocyclic ring containing one or more members.

[0123] 1.107 part: [ka] However, the following groups DAA~DBG: [ka] The compound according to embodiment 1.106, selected from:

[0124] 1.108 Q is a ring containing 1, 2, 3 or 4 heteroatoms selected from N, O and S. The compound according to embodiment 1.1, wherein the ring is a 7-membered monocyclic heterocyclic ring containing 15 members.

[0125] 1.109 part: [ka] However, the following groups EAA to EAB: [ka] The compound according to embodiment 1.108, selected from:

[0126] 1.110 Examples 1-1 to 1-73, 2-1 to 2-138, 3-1 to 3-16, 4- 1 to 4-20 or 5-1 to 5-2, .The compound described in .1.

[0127] 1.111 Any one of embodiments 1.1 to 1.110 having a molecular weight of less than 550 The compound according to any one of claims 1 to 5.

[0128] 1.112 The compound of embodiment 1.111, having a molecular weight of less than 500.

[0129] 1.113 The compound of embodiment 1.112, having a molecular weight of 450 or less.

[0130] 1.114 The compound according to any one of embodiments 1.1 to 1.113, which is in the form of a salt. Compound.

[0131] 1.115 The compound according to embodiment 1.114, wherein the salt is an acid addition salt.

[0132] 1.116 The embodiment 1.115 or the embodiment in which the salt is a pharma- ceutically acceptable salt. The compound described in 1.115.

[0133] definition In this application, the following definitions apply unless otherwise indicated.

[0134] The term "treatment" in relation to the use of a compound of formula (1), (1a) or (1b) means Suffering from, or at risk of, or being at risk of suffering from, the disease or disorder in question Used to describe any form of intervention in which a compound is administered to a subject who may have Therefore, the term "treatment" should be used interchangeably with "preventative" (prophylactic). rophylactic) treatment, and measurable or detectable symptoms of a disease or disorder The present invention includes both of the treatments indicated.

[0135] As used herein (e.g., in connection with methods of treating a disease or condition), "therapeutic The term "effective amount" refers to an amount of a compound that is effective to produce a desired therapeutic effect. For example, if the condition is pain, a therapeutically effective amount would be sufficient to provide a desired level of pain relief. The desired level of pain relief can be, for example, a complete elimination of pain or a reduction in the severity of pain. There may be a reduction in severity of the condition.

[0136] ("C 1-10 "Non-aromatic hydrocarbon group" or "Acyclic C 1-5 "Non-aromatic hydrocarbon groups" The term "non-aromatic hydrocarbon group" (as in the formula (I)) consists of carbon and hydrogen atoms, A hydrocarbon group may be fully saturated or may contain one or more aromatic rings. or multiple carbon-carbon double bonds or carbon-carbon triple bonds, or double and triple bonds The hydrocarbon group may be a straight chain group or a branched chain group, or They may consist of or contain cyclic groups. Hence, they are called non-aromatic hydrocarbons. Such terms include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Cycloalkylalkyl, cycloalkenylalkyl and the like are included.

[0137] "Alkyl", "alkenyl", "alkynyl", "cycloalkyl", aryl, The terms "aryl" and "cycloalkenyl" are used in their respective embodiments unless otherwise indicated. These terms are used in their traditional sense (e.g., as defined in the IUPAC Gold Book).

[0138] "C 1-4 The term "saturated hydrocarbon group" as in "saturated hydrocarbon group" refers to a carbon- A saturated hydrocarbon group is one that does not contain carbon double or triple bonds. Alkyl group, cycloalkyl group, cycloalkylalkyl group, alkylcycloalkyl group C can be an alkyl group or an alkylcycloalkylalkyl group. 1-4 Saturated Hydrocarbons Examples of radicals include C 1-4 The alkyl groups cyclopropyl, cyclobutyl and cyclopropyl Contains methyl.

[0139] As used herein, the term "cycloalkyl" refers to any alkyl group having a specified number of carbon atoms. Where permitted, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl are It includes both monocyclic cycloalkyl groups, such as chloroheptyl, and bicyclic and tricyclic groups. Bicyclic cycloalkyl groups include bicycloheptane, bicyclooctane, and adamantane. Which bridged ring systems are included.

[0140] R above 1 , R 2 , R 3 and R 4 In the definition of The carbon atoms of the non-aromatic hydrocarbon group are preferably selected from the group consisting of O, N, and S, and (R 1 and R 4 In the latter case, the heteroatom is optionally replaced by a heteroatom selected from its oxidized form. When a carbon atom is replaced by a heteroatom, the number of atoms of the heteroatom relative to the carbon may be A lower valency means that the atom is bonded to a lower valency than the atom that would have been bonded to the carbon atom that is being replaced. It will be understood that this means that fewer atoms may be bonded to the heteroatom. For example, CH 2 Replacing a carbon atom (valence 4) of a group with oxygen (valence 2) results in This means that the resulting molecule may contain two fewer hydrogen atoms, CH 2 Carbon atom of the group Replacing a nitrogen atom (valence 3) with a carbon atom (valence 4) results in a molecule with one This would mean that it may contain fewer hydrogen atoms.

[0141] Examples of heteroatom substitutions for carbon atoms include the ether -CH 2 -O-CH 2 -Also is thioether -CH 2 -S-CH 2 -CH with oxygen or sulfur to give - 2 -C H 2 -CH 2 - Substitution of carbon atoms in the chain, nitrile (cyano) group CH 2 To obtain -C≡N Nitrogen from the group CH 2 Substitution of carbon atoms in -C≡CH, ketone -CH 2 -C(O)-C H 2 -CH group via C=O to give 2 -CH 2 -CH 2 -Substitution of carbon atoms in Sulfoxide-CH 2 -S(O)-CH 2 - or sulfone-CH 2 -S(O) 2 -CH 2 - S=O ​​or SO to obtain 2 The group -CH 2 -CH 2 -CH 2 - of the carbon atom in Substituted, Amide -CH 2 -CH 2 -C by C(O)NH to give -C(O)-NH- H 2 -CH 2 -CH 2 - Substitution of carbon atoms in the chain, amine -CH 2 -NH-CH 2 -Get Nitrogen for -CH 2 -CH 2 -CH 2 - Substitution of carbon atoms in the chain and esters ( or carboxylic acid)-CH 2 -CH 2 -by C(O)O to obtain -C(O)-O- CH 2 -CH 2 -CH 2 - substitution of carbon atoms in the chain. For each such substitution , at least one carbon atom of the hydrocarbon group must remain.

[0142] salt Many of the compounds of formula (1), (1a) or (1b) may be in the form of a salt, for example an acid addition salt or or, in certain cases, organic and inorganic salts such as carboxylates, sulfonates and phosphates. All such salts are within the scope of the present invention and are within the scope of the formula (1 For compounds of formula (1a), (1b) or (1c), the formula is as defined in embodiments 1.114 to 1.116. This includes salt forms of the compounds as defined above.

[0143] The salts are typically acid addition salts.

[0144] The salts of the present invention are described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (ed.), C Amille G. Wermuth (editor), ISBN:3-90639-026-8, Hardcover, 388 pages, August 2002. Can be synthesized by chemical methods from a parent compound that contains a basic or acidic moiety Generally, such salts are prepared by reacting the free acid or base form of these compounds with an appropriate base or It is prepared by reacting with an acid in water or an organic solvent, or in a mixture of the two. can be prepared from ether, ethyl acetate, ethanol, isopropanol or A non-aqueous medium such as acetonitrile or acetonitrile is used.

[0145] Acid addition salts (as defined in embodiment 1.120) can be prepared from a wide variety of acids, both inorganic and organic. Examples of acid addition salts encompassed by embodiment 1.120 include acetic acid, 2, 2-Dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid) acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid Acid, butanoic acid, (+) camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor Far-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, Cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2- Hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucohesis acid protonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, halogenated Hydrochloric acid (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), isethionic acid, lactic acid (e.g., , (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-Malic acid, malonic acid, (±)-DL-Mandelic acid, methanesulfonic acid, naphtha Naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthalene Phthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid , Phosphate, Propionic Acid, Pyruvic Acid, L-Pyroglutamic Acid, Salicylic Acid, 4-Amino -Salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L- The group consisting of tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid and a mono-acylamino acid formed with an acylated amino acid and a cation exchange resin. or a di-salt.

[0146] When the compounds of formula (1), (1a) or (1b) contain an amine functional group, they The quaternary ammonium salt can be reacted with an alkylating agent, for example, according to methods well known to those skilled in the art. Such quaternary ammonium compounds can be formed by the reaction of formula (1), (1a) or or (1b).

[0147] The compounds of the present invention may exist as mono- or di-salts depending on the pKa of the acid with which the salt is formed. You may.

[0148] The salt forms of the compounds of the present invention are typically pharma- ceutically acceptable salts, Examples of salts which may be used are described in Berge et al., 1977, "Pharmaceutically cceptable Salts,” J.Pharm.Sci.,Vol.66,pp. However, pharma- ceutically unacceptable salts are prepared as intermediate forms. The phenylalanine derivatives may be prepared by the procedure described above, which may then be converted into a pharma- ceutically acceptable salt. Unacceptable salt forms may be useful, for example, in the purification or separation of the compounds of the invention. which also form part of the present invention.

[0149] stereoisomer Stereoisomers have the same molecular formula and arrangement of bonded atoms, but differ in the arrangement of their atoms in space. Stereoisomers are isomers that differ only in their dimensional arrangement. or optical isomers.

[0150] geometric isomer In the case of geometric isomers, isomerism can be cis and trans (Z and E) isomerism, or cis and trans isomers around the amide bond, or (e.g., oxy Syn and anti isomerism, or restricted rotation around the carbon-nitrogen double bond (in the cyclohexane group) Rotational isomerism around existing bonds, or cis and cis rings, such as cycloalkane rings It is due to different arrangement of atoms or groups around a double bond, such as trans isomerism.

[0151] Therefore, in another embodiment (embodiment 1.121), the present invention relates to the 1. A geometric isomer of a compound according to any one of claims 1 to 116 is provided.

[0152] optical isomer The compound of formula (I) contains one or more chiral centers and exists in the form of two or more optical isomers. Where present, reference to the compound is to be construed as including therein, unless otherwise required by context. All optical isomeric forms (e.g., enantiomers, epimers and diastereoisomers) are individually an optical isomer of, or a mixture (e.g., a racemic mixture) of, two or more optical isomers Includes either:

[0153] Thus, in another embodiment (embodiment 1.132), the present invention provides a compound comprising a chiral center. The present invention provides a compound according to any one of embodiments 1.1 to 1.121.

[0154] Optical isomers may be characterized and identified by their optical activity (i.e., + and and -isomers, or d and l isomers), or they are The absolute stereochemistry of the points is determined using the "R and S" nomenclature developed by D and Prelog. It may be characterized from Advanced Organic Chemistry. by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114; see also Cahn, Ingold & Prelog,Angew.Chem.Int.Ed.Engl.,1966,5, 385-415. Optical isomers can be separated by chiral chromatography (chiral support) These can be separated by several techniques, including on-chip chromatography. Such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, (+) -Tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)- Chiral acids such as mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid Formation of stereoisomeric salts, separation of diastereoisomers by preferential crystallization, and subsequent desalting The optical isomers can be separated by obtaining the individual enantiomers of the free base. Cut.

[0155] When a compound of the present invention exists in two or more optical isomeric forms, it may be a pair of enantiomers. - one enantiomer has an advantage over the other, for example in terms of biological activity Therefore, in certain circumstances, only one of the pair of enantiomers may be present. Alternatively, it may be desirable to use only one of the diastereoisomers as a therapeutic agent. obtain.

[0156] Thus, in another embodiment (embodiment 1.133), the present invention provides one or more A composition comprising a compound according to embodiment 1.132 having a chiral center, At least 55% (e.g., at least 60%, 65%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 28 0%, 75%, 80%, 85%, 90% or 95% of the mixture is a single optical isomer (e.g., The compositions are provided in the form of a mixture of isomers (antiomers or diastereoisomers).

[0157] In one general embodiment (embodiment 1.134), the compound of embodiment 1.132 ( or for use in a method comprising the steps of: It exists as an isomer.

[0158] For example, in one embodiment (embodiment 1.135), the compound is It exists as such.

[0159] In another embodiment (embodiment 1.136), the compound is present as a single diastereoisomer. It exists.

[0160] The present invention also provides mixtures of optical isomers, which may be racemic or non-racemic. Thus, the present invention provides the following:

[0161] 1.137 The compound according to embodiment 1.132, which is in the form of a racemic mixture of optical isomers. Compound.

[0162] 1.138 The compound according to embodiment 1.132, which is in the form of a non-racemic mixture of optical isomers. compound.

[0163] Isotopes The compound of the invention as defined in any one of embodiments 1.1 to 1.138 may comprise one or more may contain multiple isotopic substitutions, and a reference to a particular element includes within its scope the full isotopic representation of that element. For example, a reference to hydrogen includes within its scope 1 H, 2 H(D), and 3 Similarly, references to carbon and oxygen include within their scope, respectively. 1 2 C. 13 C and 14 C and 16 O and 18 Contains O.

[0164] Likewise, reference to a particular functional group is intended to encompass that category unless the context dictates otherwise. For example, a reference to an alkyl group such as an ethyl group includes isotopic variations within that group. one or more hydrogen atoms are in the form of a deuterium or tritium isotope; For example, the ethyl group (perdeuteroethyl) has five hydrogen atoms that are deuterium isotopes. Also included are variations such as aryl groups.

[0165] The isotope may be radioactive or non-radioactive. In 0), the compound of any one of embodiments 1.1 to 1.138 contains a radioisotope. Such compounds are preferred for therapeutic use. However, in another embodiment (Embodiment 1), In .141), the compound of any one of embodiments 1.1 to 1.138 may be one or more Compounds containing such radioisotopes may be useful in diagnostic applications. This may be useful in some aspects.

[0166] solvate Formula (1), (1a) or (1b) as defined in any one of embodiments 1.1 to 1.141. The compounds of formula 1b) may form solvates. Preferred solvates are solid forms of the compounds of the invention. The state structure (e.g., crystal structure) is dissolved in a non-toxic pharma- ceutically acceptable solvent (hereinafter, solvating agent). A solvate is formed by the incorporation of molecules of a solvent (called a solvent). Examples of solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol). ) and dimethylsulfoxide. Solvates are compounds of the invention dissolved in a solvent or solvent mixture. It can be prepared by recrystallization from a mixture of solvents containing a miscible solvent. In a given example, whether a solvate is formed can be determined by thermogravimetric analysis (TGE), differential The compounds were analyzed using well-known standard techniques such as differential scanning calorimetry (DSC) and X-ray crystallography. The solvates can be determined by subjecting the crystals to analysis. Particularly preferred solvates are hydrates, and hydrates may be non-stoichiometric or non-stoichiometric solvates. Examples include the hemihydrate, monohydrate and dihydrate.

[0167] Thus, in further embodiments 1.150 and 1.151, the present invention provides do.

[0168] 1.151 The compound according to any one of embodiments 1.1 to 1.141, in the form of a solvate. The compounds listed above.

[0169] 1.152 The compound according to embodiment 1.151, wherein the solvate is a hydrate.

[0170] For a more detailed description of solvates and the methods used to prepare and characterize them, see For more information, see Bryn et al., Solid-State Chemistry of Drugs, 2nd edition, published by SSCI, Inc., West Lafayette, USA, 1999, ISBN Please refer to N 0-967-06710-3.

[0171] Alternatively, the compounds of the invention may be anhydrous, rather than existing as hydrates. Thus, in another embodiment (embodiment 1.153), the present invention provides a method for the preparation of a medicament for use in a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising: The compound as defined in any one of embodiments 1.1 to 1.141 is provided in anhydrous crystalline form. Provide.

[0172] Crystalline and amorphous forms The compound of any one of embodiments 1.1 to 1.153 may be crystalline or amorphous (e.g., Whether a compound exists in a crystalline state can be determined by X-ray powder diffraction (XRD). This can be readily determined by standard techniques such as reverse transcription spectroscopy (RPD). has been studied by single crystal X-ray crystallography, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Infrared spectroscopy, using several techniques including Fourier transform infrared spectroscopy (FTIR) Water vapor sorption gravimetric tests and further XRPD have revealed that various The behavior of crystals under humidity conditions can be analyzed. The determination of the crystal structure of a compound is described in the present specification. The methods and Fundamentals of Crystallography described in the literature ,C.Giacovazzo,HLMonaco,D.Viterbo,F.Sco rdari, G. Gilli, G. Zanotti and M. Catti, (Int ernational Union of Crystallography / Oxfo rd University Press,1992 ISBN 0-19-85557 8-4(p / b), 0-19-85579-2(h / b)) This can be done by X-ray crystallography, which can be carried out according to conventional methods such as: It involves the analysis and interpretation of X-ray diffraction patterns of single crystals. In amorphous solids, the There is no three-dimensional structure to be determined, and the relative positions of molecules to one another in amorphous form are essentially random. For example, see Hancock et al., J. Pharm. Sci. (1997), 86, 1). Please refer to.

[0173] Thus, in a further embodiment, the present invention provides:

[0174] 1.160 The compound according to any one of embodiments 1.1 to 1.153, which is in crystalline form. Compound.

[0175] 1.161 (a) 50% to 100% crystalline, more specifically at least 50% crystalline crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline % 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 The crystals of embodiments 1.1 to 1.153, which are at least 99.9% crystalline, for example 100% crystalline. The compound according to any one of the preceding claims.

[0176] 1.162 The compound according to any one of embodiments 1.1 to 1.153, which is in amorphous form. compound.

[0177] Prodrug Formula (1), (1a) or (1b) as defined in any one of embodiments 1.1 to 1.162. The compound of 1b) may exist in the form of a prodrug. A "prodrug" is, for example, , Formula (1), (1a) or (1b) as defined in any one of embodiments 1.1 to 1.162. 1b) means any compound which is converted in vivo into a biologically active compound of formula (I).

[0178] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable During metabolism, the ester group (-C(=O)OR) is cleaved. Such esters can be prepared, for example, by removing any hydroxy groups present in the parent compound. They may be formed by esterification of hydroxyl groups, where appropriate by esterification of other groups present in the parent compound. Any reactive groups are pre-protected and then deprotected if necessary.

[0179] Also, some prodrugs can be enzymatically activated to the active compound or further These are compounds that become active compounds upon a chemical reaction (e.g., ADEPT, GDEPT, For example, prodrugs may be sugar derivatives or other glycoside conjugates. It may be a jugate or it may be an amino acid ester derivative.

[0180] Thus, in another embodiment (embodiment 1.170), the present invention relates to embodiments 1.1 to 1. A prodrug of a compound as defined in any one of 1.170, wherein the compound is a hydroxylase. Contains a functional group that is convertible under physiological conditions to form a hydroxyl or amino group The present invention provides such a prodrug.

[0181] Complexes and clathrates Formula (1), (1a) or (1b) of embodiments 1.1 to 1.170 may include any of the formulae (1), (1a) and (1b) of embodiment 1. Complexes of compounds of 1-1.170 (e.g., inclusion complexes with compounds such as cyclodextrin) or clathrates, or complexes with metals).

[0182] Thus, in another embodiment (embodiment 1.180), the present invention provides a complex or class The compound according to any one of the embodiments 1.1 to 1.170 is provided in the form of a carboxylate. .

[0183] Biological Activity and Therapeutic Uses The compounds of the present invention have activity as muscarinic M1 receptor agonists. Muscarinic activity was determined using the phospho-ERK1 / 2 assay described in Example A below. It is possible.

[0184] A major advantage of the compounds of the present invention is that they are specific to the M receptor subtypes compared to the M2 and M3 receptor subtypes. The compounds of the present invention are highly selective for the M2 and M3 receptors. For example, the compounds of the present invention are not agonists of the functional agonist described in Example A. A pE of at least 6 (preferably at least 6.5) for M1 receptors in C 50 value and E above 80 (preferably above 95) max Typically has value In contrast, when tested against M2 and M3 subtypes in the functional assay of Example A, These are pEC<5. 50 value and E less than 20% max It may have a value.

[0185] Some of the compounds of the present invention are also highly selective for the M4 receptor compared to the M1 receptor. Examples of such compounds are shown in Examples 1-6, 1-9, 1-21 and 2-17. This includes compounds of the formula:

[0186] Other compounds of the invention have activity at both the M1 and M4 receptors. Examples include the compounds of Examples 1-1 to 1-4, 1-8 to 1-10, and 2-116.

[0187] Thus, in embodiments 2.1 to 2.9, the present invention provides:

[0188] 2.1 According to any one of the embodiments 1.1 to 1.180 for use in medicine The compound described.

[0189] 2.2 Implementation for Use as Muscarinic M1 and / or M4 Receptor Agonists A compound according to any one of forms 1.1 to 1.180.

[0190] 2.3 In the assay of Example A herein or an assay substantially similar thereto pEC50 ranged from 6.0 to 8.1 for M1 receptors. 50 and at least 90 E ma x Any of embodiments 1.1 to 1.180, wherein the muscarinic M1 receptor agonist has the formula The compound according to any one of claims 1 to 5.

[0191] 2.4 pEC in the range of 6.5-7.5 50 A muscarinic M1 receptor agonist having The compound according to embodiment 2.3, wherein

[0192] 2.5 E of at least 95 for M1 receptors max Also, in embodiment 2.3, is a compound according to embodiment 2.4.

[0193] 2.6 In the assay of Example A herein or an assay substantially similar thereto pEC50 ranged from 6.0 to 9.0 for the M4 receptor. 50 and at least 90 E ma x Any of embodiments 1.1 to 1.180, wherein the muscarinic M4 receptor agonist has the formula The compound according to any one of claims 1 to 5.

[0194] 2.7 pEC in the range of 6.5-9.0 50 A muscarinic M4 receptor agonist having The compound according to embodiment 2.6, wherein

[0195] 2.8 E of at least 95 for M4 receptor max In embodiment 2.6, is a compound according to embodiment 2.7.

[0196] 2.9 Muscarinic M1 and / or M4 receptors compared to M2 and M3 receptors The compound according to any one of embodiments 2.3 to 2.8, which is selective for

[0197] 2.10 Selective for muscarinic M1 receptors compared to M2 and M3 receptors , the compound according to embodiment 2.9.

[0198] 2.11 Selective for muscarinic M4 receptors compared to M2 and M3 receptors , the compound according to embodiment 2.9.

[0199] 2.12 Selective for muscarinic M1 receptors compared to M2, M3 and M4 receptors The compound according to any one of embodiments 2.3 to 2.5, wherein

[0200] 2.13 Selective for the M4 receptor compared to the muscarinic M1, M2 and M3 receptors The compound according to any one of embodiments 2.6 to 2.8, wherein

[0201] 2.14 Selectivity for Muscarinic M1 and M4 Receptors Over M2 and M3 Receptors The compound according to any one of embodiments 2.3 to 2.8,

[0202] 2.15 pEC50 of less than 5 for muscarinic M2 and M3 receptor subtypes 50 Reach and E below 50 max The compound according to any one of embodiments 2.3 to 2.14, thing.

[0203] 2.16 pEC50 of less than 4.5 for muscarinic M2 and M3 receptor subtypes 5 0 and / or E less than 30 max The compound according to embodiment 2.15, having the formula:

[0204] 2.17 Use in treating diseases or conditions mediated by muscarinic M1 receptors Any one of embodiments 1.1 to 1.180 and embodiments 2.3 to 2.16 for The compound according to claim 1,

[0205] Due to their muscarinic M1 and / or M4 receptor agonist activity, the compounds of the present invention is a treatment for Alzheimer's disease, schizophrenia and other psychotic disorders, cognitive impairment and muscarinic M1 and / or in the treatment of other diseases mediated by the M4 receptor, It can also be used in the treatment of various types of pain.

[0206] Thus, in embodiments 2.18 to 2.34, the present invention provides:

[0207] 2.18 Embodiment 1.1 for use in the treatment of cognitive or psychotic disorders - A compound according to any one of claims 1 to 180.

[0208] 2.19 Cognitive or psychotic disorder is classified as cognitive impairment, mild cognitive impairment, frontal lobectomy Cephalic dementia, vascular dementia, Lewy body dementia, presenile dementia, senile dementia, Friedrichshafen dementia, Lich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia, mania, Tourette's syndrome syndrome, Alzheimer's disease, progressive bulbar palsy, attention, orientation, learning disabilities, memory (i.e. memory impairment, amnesia, amnesic disorder, transient global amnesia syndrome and age-associated memory impairment) and language function. Cognitive impairment as a result of stroke, Huntington's disease, Pick's disease, Illness-related dementia, multi-infarct dementia, alcoholic dementia, thyroid function (hypo Other dementing conditions such as dementia associated with cerebellar atrophy and amyotrophic cerebellar atrophy (AMA) Dementia associated with other degenerative disorders such as amyotropic lateral sclerosis; cognitive decline Other acute or subacute conditions that may cause depression, such as delirium or depression (pseudodementia state) )Trauma, head trauma, age-related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxicity Sexual drugs, age-related cognitive impairment, autism-related cognitive impairment, Down syndrome, cognitive impairment-related Psychosis and associated cognitive impairment following electroconvulsive therapy; nicotine, cannabis, amphetamines, cocaine Cognitive impairment due to drug abuse or withdrawal, including from drugs of abuse, attention deficit hyperactivity disorder (ADHD) and movement disorders, e.g., Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesia. Skenesia, schizophrenia, schizophreniform disorders, psychotic depression, mania, acute mania, delusional disorder , hallucinatory and delusional disorders, personality disorders, obsessive-compulsive disorder, schizophrenic disorder, delusional disorder, malignant Tumor-related psychosis, metabolic disorders, endocrine disorders or narcolepsy, drug abuse or withdrawal psychosis due to withdrawal, bipolar disorder and schizoaffective disorder, The compound for use according to embodiment 2.18, resulting from or related thereto.

[0209] 2.20 Embodiments 1.1 to 1.1 for use in the treatment of Alzheimer's disease 80. The compound according to any one of claims 1 to 80.

[0210] 2.21 The compound of any one of embodiments 1.1 to 1.180 for use in the treatment of schizophrenia The compound according to any one of the preceding claims.

[0211] 2.22 Cognitive impairment targets (human or other mammalian patients, e.g., those in need of such treatment) The method comprises the step of treating a subject having a disease in a human subject having a disease in which a therapeutically effective amount of the method of any one of the embodiments 1.1 to 1. The method comprises administering a compound described in any one of .180.

[0212] 2.23 The cognitive impairment includes or results from a condition defined in embodiment 2.19; Or the method according to embodiment 2.20 related thereto.

[0213] 2.24 Embodiments in which the cognitive impairment results from or is associated with Alzheimer's disease 2.23. The method according to claim 2.23.

[0214] 2.25 The method of embodiment 2.24, wherein the cognitive disorder is schizophrenia.

[0215] 2.26 Embodiments 1.1 to 1.18 for the manufacture of a medicament for the treatment of cognitive disorders 13. Use of a compound according to any one of claims 1 to 0.

[0216] 2.27 Cognitive impairment includes, or may result from, a condition as defined in embodiment 2.11. or in connection with the use according to embodiment 2.26.

[0217] 2.28 The embodiment in which the cognitive impairment results from or is associated with Alzheimer's disease Use as described in 2.27.

[0218] 2.29 The use according to embodiment 2.29, wherein the cognitive disorder is schizophrenia.

[0219] 2.30 Acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal Forehead neuralgia, herpes neuralgia, generalized neuralgia, visceral pain, osteoarthritis pain, post-herpetic pain Menstrual pain, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, Treating severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain or to reduce the severity of any one of the embodiments 1.1 to 1.180. The compound described.

[0220] 2.31 Acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal Forehead neuralgia, herpes neuralgia, generalized neuralgia, visceral pain, osteoarthritis pain, postherpetic neuralgia , diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or to treat intractable pain, nociceptive pain, breakthrough pain, postoperative pain or cancer pain; A method for reducing the severity of such a condition, comprising administering to a subject a therapeutically effective amount of any one of embodiments 1.1 to 1.180 of the present invention. The method comprises administering a compound according to any one of claims 1 to 5.

[0221] 2.32 Treating peripheral disorders such as lowering intraocular pressure in glaucoma and Sjogren's disease Embodiments 1.1 to 1.180 for treating dry eye and dry mouth, including symptoms 2. The compound according to claim 1 ,

[0222] 2.33 Treating peripheral disorders such as lowering intraocular pressure in glaucoma and Sjogren's disease Methods for Treating Dry Eye and Dry Mouth Including Symptoms, comprising a Therapeutically Effective Amount The method comprises administration of a compound according to any one of 1.1 to 1.180.

[0223] 2.34 Acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal Forehead neuralgia, herpes neuralgia, generalized neuralgia, visceral pain, osteoarthritis pain, post-herpetic pain Menstrual pain, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, Treating severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain or to reduce their severity, or to treat peripheral disorders, such as reducing intraocular pressure in glaucoma For treating dry eye and dry mouth, including Sjogren's syndrome The compound according to any one of embodiments 1.1 to 1.180 for the manufacture of a medicament according to Use of.

[0224] 2.35 Embodiments 1.1 to 1.18 for Treating Addiction 13. Use of a compound according to any one of claims 1 to 0.

[0225] 2.36 Parkinson's disease, ADHD, Huntington's disease, Tourette's syndrome and disorders Other syndromes associated with dopaminergic dysfunction as underlying pathogenetic factors The compound according to any one of embodiments 1.1 to 1.180 for treating movement disorders of Use of things.

[0226] Process for preparing compounds of formula (1), (1a) or (1b) Compounds of formula (1), (1a) or (1b) are well known to those skilled in the art and are described herein. It can be prepared according to the synthetic methods described.

[0227] Therefore, in another embodiment (embodiment 3.1), the present invention relates to the method of embodiment 1.1-1. 180, comprising the steps of: (A) Formula (10) [ka] and a compound of formula (11): [ka] under reductive amination conditions with a compound of formula: 1 , R 2 , R 3 , R 4 and Q is defined in any one of embodiments 1.1 to 1.180; or (B) Equation (12): [ka] and the compound of formula Cl-C(=O)-CH 2 -R 4 in the presence of a base; or (C) Formula (10) [ka] and a compound of formula (13): [ka] under nucleophilic substitution conditions with a compound of formula 1 , R 2 , R 3 , R 4 and Q is the real As defined in any one of embodiments 1.1 to 1.180; and optionally: (D) reacting a compound of formula (1), (1a) or (1b) with a compound of formula (1), (1a) or (1 b) converting said compound to another compound of formula (I).

[0228] In process variant (A), the piperidine heterocycle (10) is reductively reacted with a substituted ketone (11). The reaction is carried out under amino conditions. The reductive amination reaction is carried out in dichloromethane or The solvent is dichloroethane, and the borohydride is sodium triacetoxyborohydride. It is typically carried out at ambient temperature using a primary reducing agent.

[0229] In process variant (C), the piperidine heterocycle (10) is reacted neat, i.e. No solvent or solvent such as tetrahydrofuran, acetonitrile, or dimethylacetamide Either in any suitable solvent at a mild (e.g., temperature of about 40° C. to about 70° C.) In a nucleophilic substitution reaction typically carried out with heating, a sulfonate ester (13, R = methyl, trifluoromethyl or 4-methylphenyl).

[0230] The intermediate compound of formula (12) can be prepared by the reaction sequence shown in Scheme 1 below. This can be done. [ka]

[0231] In reaction scheme 1, piperidine heterocycle (10) is reacted with Boc-protected spiroketone (14). The reductive amination reaction is carried out using a dichloromethane containing acetic acid. Cyanoborohydride in combination with zinc chloride in a solvent such as methane or dichloroethane Sodium triacetoxyborohydride in combination with sodium or titanium isopropoxide Mild heating (e.g., to a temperature of about 40° C. to about 70° C.) in the presence of either thorium or sodium This is typically carried out with heat to give the intermediate piperidine compound (15). Removal of the Boc group by treatment with an acid (e.g., trifluoroacetic acid in dichloromethane) Deprotection by evaporation gives compound (12).

[0232] Compounds of formula (12) can also be prepared by the reaction sequence shown in Scheme 2 below. Cut. [ka]

[0233] In Scheme 2, the Boc-protected spiroketone (14) is reacted with sodium borohydride in methanol. The alcohol (16) is then reduced to alcohol (17) using triethylammonium chloride. in the presence of a tertiary amine such as N,N-diisopropylethylamine or N,N-diisopropylethylamine, The sulfonate ester (17, R = 1) was synthesized using the corresponding sulfonyl chloride in dichloromethane. methyl, trifluoromethyl or 4-methylphenyl). The acid ester (17) was reacted with the piperidine heterocycle (10) either neat, i.e., without a solvent, or with tetrahydrofuran. in a suitable solvent such as tetrahydrofuran, acetonitrile or dimethylacetamide Typically, the reaction is carried out with gentle warming (e.g., to a temperature of about 40° C. to about 70° C.). In a nucleophilic substitution reaction carried out in the presence of an acid, compound (15) is obtained. Removal of the Boc group by treatment with (e.g., trifluoroacetic acid in dichloromethane) Deprotection with the aid of gives compound (12).

[0234] Once formed, a compound of formula (1), (1a) or (1b), or The protected derivatives can be prepared by reaction of the formula (1), (1a) or (1b) using methods well known to those skilled in the art. can be converted into another compound. Examples of synthetic methods are given in Advanced Organic Chemistry and O rganic Syntheses (see references above) or Fiese rs' Reagents for Organic Synthesis, Volumes 1-17 ,Edited by John Wiley,Mary Fieser (ISBN:0-471- These conversion examples are given in standard manuals such as Amie 58283-2. bond formation, urea formation, carbamate formation, alkylation reactions, N-arylation reactions and C -C bond coupling reactions are included.

[0235] In many of the reactions listed above, one or more amines are added to prevent reaction from occurring at undesirable locations on the molecule. It may be necessary to protect multiple groups or groups. Examples of protecting groups and procedures for protecting and deprotecting functional groups are given below. The method to protect is Protective Groups in Organic Synthe hesis (T. Greene and P. Wuts; 3rd ed.; John Wiley and Sons, 1999).

[0236] The compounds made by the above methods may be synthesized by any of a variety of methods well known to those of skill in the art. Examples of such methods include recrystallization and chromatographic techniques. techniques such as column chromatography (e.g., flash chromatography) and H Includes PLCs.

[0237] Pharmaceutical preparations While it is possible for the active compound to be administered alone, it may also be presented as a pharmaceutical composition (e.g., a formulation). It is preferable to do so.

[0238] Therefore, in another embodiment of the present invention (embodiment 4.1), 80, wherein at least one of formula (1), (1a) or (1b) is defined in any one of A pharmaceutical composition is provided comprising the compound together with at least one pharma- ceutical acceptable excipient. do.

[0239] In one embodiment (embodiment 4.2), the composition is a tablet composition.

[0240] In another embodiment (embodiment 4.3), the composition is a capsule composition.

[0241] The pharma- ceutically acceptable excipient(s) include, for example, a carrier (e.g., a solid carrier, a liquid carrier, solid or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or extenders and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, etc. release control agents (e.g., retarding or delaying polymers or waxes), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents. Antibacterial agents, antioxidants, buffers, isotonicity agents, thickening agents, flavors, sweeteners, colorants, plasticizers, flavoring agents , stabilizers or any other excipient conventionally used in pharmaceutical compositions. This can be done.

[0242] As used herein, the term "pharmaceutical acceptable" refers to a compound, material, composition, The composition and / or dosage form is, within the scope of sound medical judgment, deemed to be undue toxicity, irritation, allergy and the tissue of a subject (e.g., a human subject) without adverse reactions, reactions, or other problems or complications. is suitable for use in contact with the skin and is commensurate with a reasonable benefit / risk ratio Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. It won't happen.

[0243] Pharmaceutical compositions containing compounds of formula (1), (1a) or (1b) can be prepared according to known techniques. Thus, the compositions can be formulated, for example, as disclosed in Remington's Pharmaceuticals. utical Sciences,Mack Publishing Company, See Easton, PA, USA.

[0244] The pharmaceutical compositions may be administered orally, parenterally, topically, intranasally, intrabronchially, sublingually, ophthalmically, otically, rectally, or vaginally. The formulation may be in any form suitable for intradermal or transdermal administration.

[0245] Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules, and capsules. Capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions tablets, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches, Examples include buccal patches.

[0246] Tablet compositions generally comprise a unit dose of the active compound together with an inert diluent or carrier, e.g., sugar or glycerin. or a sugar alcohol, such as lactose, sucrose, sorbitol or mannitol and / or non-sugar diluents, such as sodium carbonate, calcium phosphate, calcium carbonate cellulose or its derivatives, such as microcrystalline cellulose (MCC); Methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, and Starch, such as corn starch, may be included. Tablets may contain binders and granulating agents. , e.g., polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers, e.g., crosslinked Carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., Raben), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), buffers), and foaming agents, such as citrate / bicarbonate mixtures, as standard components. Such excipients are well known and need not be discussed at length here.

[0247] Tablets may be designed to release the drug on contact with gastric juices (immediate release tablets) or for extended periods. They may be designed to release in a controlled manner over time or in specific areas of the gastrointestinal tract ( (controlled release tablets).

[0248] Pharmaceutical compositions typically contain from about 1% (w / w) to about 95%, preferably % (w / w) active and 99% (w / w) to 5% (w / w) of a pharma- ceutically acceptable excipient (e.g., As defined above) or a combination of such excipients. It is made up of about 20% (w / w) to about 90% (w / w) active ingredient and 80% (w / w) to 10% pharmaceutical agent. Pharmaceutical compositions contain from about 1% to about 95%, preferably from about 1% to about 95% by weight of an excipient or combination of excipients. The pharmaceutical composition according to the present invention preferably contains about 20% to about 90% of an active ingredient. Samples, vials, suppositories, pre-filled syringes, dragees, powders, tablets or capsules The dosage form may be in the form of a unit dose, such as

[0249] Tablets and capsules may contain, for example, 0 to 20% disintegrant, 0 to 5% lubricant, 0 to 5% Flow aids and / or 0-99% (w / w) of fillers and / or extenders (depending on drug dose) They may contain 0-10% (w / w) of polymeric binders, 0-5% (w / w) of They may also contain 0-5% (w / w) of an antioxidant and 0-5% (w / w) of a dye. Slow release tablets are typically , and 0-99% (w / w) of a release-controlling (e.g., delayed) polymer (depending on dose). The film coat for tablets or capsules will typically contain 0-10% (w / w) polymer, 0-3% (w / w) pigment, and / or 0-2% (w / w) plasticizer. Contains the agent.

[0250] Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) Co-solvents and / or 0-99% (w / w) water for injection (WFI) (depending on dose and (if lyophilized); formulations for intramuscular depot preparations contain 0-99% (w / w) The oil may also contain

[0251] Pharmaceutical preparations are “patient-specific” formulations that contain the entire course of treatment in a single package, usually a blister pack. The composition may be provided to the patient as a "patient pack."

[0252] The compounds of formula (1), (1a) or (1b) will generally be presented in unit dosage form. Thus, typically, the formulation contains sufficient compound to provide the desired level of biological activity. For example, a formulation may contain between 1 nanogram and 2 grams of active ingredient, e.g. Within these ranges, specific subranges of the compound may be used. The range is 0.1 milligrams to 2 grams of active ingredient (more commonly 10 milligrams to 1 gram). (e.g., 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams grams (e.g., 1 microgram to 10 milligrams, e.g., 0.1 milligrams to 2 milligrams) (the active ingredient in Liglam)

[0253] For oral compositions, the unit dosage form is typically from 1 milligram to 2 grams, more typically 10 milligrams. 1 g to 1 g, e.g., 50 mg to 1 g, e.g., 100 mg to It may contain 1 gram of active compound.

[0254] The active compound provides the desired treatment to a patient (e.g., a human or animal patient) in need thereof. It will be administered in an amount sufficient to achieve the desired effect (an effective amount). The amount may be determined by the attending physician according to standard procedures. EXAMPLES

[0255] The present invention is illustrated, but not limited to, by reference to specific embodiments described in the following examples. It is not something that can be achieved.

[0256] Examples 1-1 to 5-2 The compounds of Examples 1-1 to 5-2 shown in Table 1 below were prepared. The properties of S and the methods used for their preparation are listed in Table 3. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0257] General Procedure Where no preparative route is included, the intermediates are commercially available. Commercially available reagents include, but are not limited to, The product was used without further purification. Room temperature (rt) refers to approximately 20-27 °C. 1 H NMR spectrum The vectors were recorded at 400 MHz using either Bruker or Jeol equipment. Chemical shifts are expressed in parts per million (ppm), i.e., (δ:) values. NM The following abbreviations are used for the multiplicity of R signals: s = singlet, br = broad, d = doublet. t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=triplet of triplet triplet, qd=quadruple of doublet, ddd=double of doublet of doublet, ddt=double of triplet m = doublet of doublets, m = multiplet. Coupling constants are reported as J values ​​measured in Hz. NMR spectroscopy The results of chromatography and mass spectrometry were corrected taking into account background peaks. The filter is performed using 60-120 mesh silica gel and nitrogen pressure (flash clean). This refers to column chromatography carried out under conditions that monitor the reaction. The TLC for ring elution was performed using a prescribed mobile phase and silica gel F254 (Merlite) as the stationary phase. ck) and TLC testing. Microwave-mediated reactions are performed using Biotage Initiator Microwave Reactor or CEM Discover Microwave Reactor It was held at.

[0258] LCMS experiments are typically performed using electrospray conditions specified for each compound. The experiment was carried out under the following conditions:

[0259] LCMS Methods A and B Instruments: Waters Alliance 2795, Waters 2996 PDA Detector: Micromass ZQ; Column: Waters X-Bridge C-1 8, 2.5 micron, 2.1 x 20 mm or Phenomenex Gemini-N X C-18, 3 micron, 2.0 × 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, 9.4 0 / 95, 9.50 / 2, 10.00 / 2; Solvent: Solvent C=2.5LH 2 O+2.5m L ammonia solution; Solvent D = 2.5L MeCN + 135mL H 2 O+2.5mL Anne monia solution); injection volume 3 μL; UV detection 230-400 nM; column temperature 45 °C; flow rate 1 .5mL / min.

[0260] LCMS method C Instrument: Agilent 1260 Infinity LC Diode Array Detector; Agilent 6120B single quadrupole MS (API-ES source); Column: Ph enomenex Gemini-NX C-18, 3 microns, 2.0×30mm; Distribution [time (min) / solvent B in A (%)]: Method: 0.00 / 5, 2.00 / 95, 2.50 / 95, 2.60 / 5, 3.00 / 5; Solvent: Solvent A = 2.5LH 2 O+2.5mL (H 2 28%NH in O 3 );Solvent B=2.5L MeCN+129mL H 2 O+2.7 mL (H 2 28%NH in O 3 ); injection volume 0.5 μL; UV detection 190-400 nM; Ram temperature 40°C; flow rate 1.5 mL / min.

[0261] LCMS Methods D and E Instrument: HP1100 G1315A DAD, Micromass ZQ; Column: W aters X-Bridge C-18, 2.5 micron, 2.1 x 20 mm or henomenex Gemini-NX C-18, 3 microns, 2.0 × 30 mm; Gradient [time (min) / solvent D in C (%)]: Method D: 0.00 / 2, 0.10 / 2, 2.5 0 / 95, 3.50 / 95, 3.55 / 2, 4.00 / 2 or Method E: 0.00 / 2, 0.10 / 2, 8.40 / 95, 9.40 / 95, 9.50 / 2, 10.00 / 2; Solvent : Solvent C = 2.5LH 2 O+2.5mL H 2 28% ammonia solution in O; solvent D=2 .5L MeCN+135mL H 2 O+2.5mL H 2 (28% ammonia solution in O) Injection volume 1 μL; UV detection 230-400 nM; Mass detection 130-800 AMU (+ve and -ve electrospray); column temperature 45°C; flow rate 1.5 mL / min.

[0262] LCMS method F: Equipment: Waters Acquity H Class, Photodiode Array, S Q detector; Column: BEH C18, 1.7 microns, 2.1 x 50 mm; Gradient [time ( min) / solvent A in B (%): 0.00 / 5, 0.40 / 5, 0.8 / 35, 1.20 / 5 5, 2.50 / 100, 3.30 / 100 4.00 / 5; Solvents: Solvent A = 5 mM acetate ammonium acetate and H 2 Solvent B = 0.1% formic acid in O; 0.1% formic acid in MeCN; injection volume 2 μL; UV detection 200-400 nM; mass detection 100 ~1200 AMU (+ve electrospray); column temperature is ambient; flow rate 0.5 m L / min.

[0263] LCMS method G: Equipment: Waters 2695, photodiode array, ZQ-2000 detector; Ram: X-Bridge C18, 5 micron, 150 x 4.6 mm; Gradient [Time (min) / Solvent A in B (%): 0.00 / 10, 5.00 / 90, 7.00 / 100, 11.0 0 / 100, 11.01 / 10 12.00 / 10; Solvent: Solvent A=H 2 0.1% in O Solvent B = 0.1% ammonia in MeCN; injection volume 10 μL; UV detection 200 400nM; Mass detection 60-1000AMU (+ve electrospray); Column temperature is ambient temperature; flow rate 1.0 mL / min.

[0264] LCMS method H: Equipment: Waters 2695, photodiode array, ZQ-2000 detector; Ram: X-Bridge C18, 5 micron, 150 x 4.6 mm; Gradient [Time (min) / Solvent A in B (%): 0.00 / 100, 7.00 / 50, 9.00 / 0, 11.00 / 0, 11.01 / 100, 12.00 / 100; Solvent: Solvent A=H 2 0.1% ammonium nitrate in O ammonia; solvent B = 0.1% ammonia in MeCN; injection volume 10 μL; UV detection 200-4 00nM; mass detection 60-1000AMU (+ve electrospray); column temperature Ambient temperature; flow rate 1.0 mL / min.

[0265] LCMS method I: Equipment: Waters 2695, photodiode array, ZQ-2000 detector; RAM: X-Bridge C18, 3.5 microns, 150 x 4.6 mm; Gradient [Time ( min) / solvent A in B (%): 0.00 / 5, 5.00 / 90, 5.80 / 95, 10 / 9 5; Solvent: Solvent A = H 2 Solvent B = 0.1% ammonia in O; Solvent B = 0.1% ammonia in MeCN A; injection volume 10 μL; UV detection 200-400 nM; mass detection 60-1000 AMU (+ ve electrospray); column temperature was ambient; flow rate was 1.0 mL / min.

[0266] LCMS method J: Equipment: Waters 2695, photodiode array, ZQ-2000 detector; Ram: X-Bridge C18, 5 micron, 150 x 4.6 mm; Gradient [Time (min) / Solvent A in B (%): 0.01 / 10, 5.00 / 90, 7.00 / 100, 11.0 0 / 100, 11.01 / 10, 12.00 / 10; Solvent: Solvent A=H 2 20 mM vinegar in O Ammonium acetate; Solvent B = MeOH; Injection volume 10 μL; UV detection 200-400 nM; Quantitative detection: 60-1000 AMU (+ve electrospray); column temperature: ambient temperature; flow rate: Speed ​​1.0mL / min.

[0267] LCMS method K: Equipment: Waters 2695, photodiode array, ZQ-2000 detector; RAM: X-Bridge C18, 3.5 microns, 50 x 4.6 mm; Gradient [Time (min ) / solvent A in B (%): 0.01 / 0, 0.20 / 0, 5.00 / 90, 5.80 / 9 5, 7.20 / 95, 7.21 / 100, 10.00 / 100; Solvent: Solvent A=H 2 During O 0.1% ammonia; Solvent B = 0.1% ammonia in MeCN; Injection volume 10 μL; UV detection Output 200~400nM; Mass detection 60~1000AMU(+ve electrospray); Column temperature was ambient; flow rate was 1.0 mL / min.

[0268] LCMS method L Instruments: Waters Acquity UPLC, Waters 3100 PDA detector Extractor: SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1× 100 mm; gradient [time (min) / solvent B (%) in A]: 0.00 / 2, 2.00 / 2, 7 .00 / 50, 8.50 / 80, 9.50 / 2, 10.0 / 2; Solvents: Solvent A = 5m in water M ammonium acetate; solvent B = acetonitrile; injection volume 1 μL; detection wavelength 214 nm; Ram temperature 30°C; flow rate 0.3mL / min.

[0269] LCMS method M Instrument: Agilent 1260 Infinity Series UHPLC; ELS D: Agilent 1260 infinity; Column: Acquity C-18 , 1.7 microns, 2.1 x 50 mm; gradient [time (min) / % B in solvent A]: 0.0 0 / 10, 1.00 / 10, 2.00 / 15, 4.50 / 55, 6.00 / 90, 8.0 0 / 90, 9.00 / 10, 10.00 / 10; Solvent: A = 5 mM ammonium acetate in water , B = acetonitrile; injection volume: 1 μL; detection by ELSD; column temperature: 40 °C; flow rate: Speed: 0.6mL / min.

[0270] LCMS method N Instruments: Waters Acquity UPLC, Waters 3100 PDA detector Extractor: SQD; Column: Acquity BEH C-18, 1.7 micron, 2.1× 100 mm; Gradient [time (min) / solvent B (%) in A]: 0.00 / 2, 0.50 / 2, 1 .50 / 20, 4.00 / 92, 5.00 / 92, 5.50 / 50, 6.00 / 2; Solvent Solvent A = 5 mM ammonium acetate in water; Solvent B = acetonitrile; Injection volume 1 μL; Detection Wavelength 214 nm; column temperature 35°C; flow rate 0.6 mL / min.

[0271] LCMS method Instruments: Waters Acquity UPLC, Waters 3100 PDA detector Extractor: SQD; Column: Acquity HSS-T3, 1.8 microns, 2.1 x 10 0 mm; Gradient [time (min) / solvent B (%) in A]: 0.00 / 10, 1.00 / 10, 2 .00 / 15, 4.50 / 55, 6.00 / 90, 8.00 / 90, 9.00 / 10, 1 0.00 / 10; Solvents: Solvent A = 0.1% trifluoroacetic acid in water; Solvent B = acetonitrile injection volume 1 μL; detection wavelength 214 nm; column temperature 30°C; flow rate 0.3 mL / min.

[0272] LCMS data in the experimental section are presented in the format of mass ion, retention time, and UV activity.

[0273] Abbreviation AcOH = acetic acid CDI = 1,1'-carbonyldiimidazole d=days (number) DAST = diethylaminosulfur trifluoride DCE = dichloroethane DCM = dichloromethane DIPEA = diisopropylethylamine DIAD = diisopropyl azodicarboxylate DMF = Dimethylformamide DMP = Dess-Martin periodinane DMSO = dimethyl sulfoxide ES = electrospray ionization EtOAc = ethyl acetate h=hours (number) HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ 4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC = High Performance Liquid Chromatography LC = Liquid Chromatography LiAlH 4 / LAH=Lithium aluminum hydride MeCN = acetonitrile MeOH = methanol min=minute(number) MS=mass spectrometry Et 3 N = triethylamine NMR=nuclear magnetic resonance rt=room temperature sat.=saturated sol.=solution STAB = sodium triacetoxyborohydride THF = tetrahydrofuran TLC = Thin Layer Chromatography The prefixes n-, s-, i-, t- and tert- stand for their usual meaning: normal, second There are tricyclic, isocyclic, and tertiary.

[0274] Synthesis of intermediates: Intermediate 2, Ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate Procedure for preparing the [ka] 6-Boc-2-oxo-6-azaspiro[3.4]octane (3.37 g, 15 mm ol) was added in small portions to hydrogen chloride (4 M in dioxane, 50 mL, 210 mmol). CAUTION: Foaming. After 24 h, the reaction was concentrated in vacuo and the remaining solid was washed with Et 3 N(4.18mL The mixture was dissolved in a mixture of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether, 30 mmol) and DCM (66 mL). was immediately cooled to 0 °C and then ethyl chloroformate (1.57 mL, 16.5 mmol) was added. ) was added dropwise. After 18 h, the mixture was diluted with dichloromethane (100 mL) and NaHCO 3 ( The organic layer was collected and saturated with 100 mL of ethyl acetate. Wash with saturated saline (20 mL) and MgSO 4 The residue after evaporation was then dried with a column. Chromatography (normal phase, [Biotage SNAP cartridge KP-sil 1 00g, 40-63μm, 60Å, 50mL / min, gradient: 0%-4% MeOH in DCM] ) to obtain intermediate 2, ethyl 2-oxo-6-azaspiro[3.4]octane. The title compound was obtained as a colorless oil (2.47 g, 83%). Data regarding the compounds are given in Table 2.

[0275] Intermediate 3, methyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate Procedure for preparing the [ka] 6-Boc-2-oxo-6-azaspiro[3.4]octane (5.00 g, 22.2 mmol) in dichloromethane (5 mL) with hydrogen chloride (4 M in dioxane, 45 mL, 180 mmol). Caution: foaming. After 2 h, the reaction was concentrated in vacuo and 1 The remaining solid was dissolved in triethylamine (2.23 mL, 16.0 mmol) and dichloromethane. The mixture was dissolved in methane (10 mL). Upon complete dissolution, the solution was immediately cooled to 0 °C. The mixture was cooled, and then methyl chloroformate (0.68 mL, 8.83 mmol) was added dropwise. After a short while, the mixture was poured into dichloromethane (50 mL) and added NaHCO 3 (aqueous solution)(2× The organic layers were combined and washed with saturated brine (5 0 mL), passed through a Biotage phase separator, the solvent removed in vacuo, and the residue The column chromatography (normal phase, Biotage SNAP Cartridge KP-s il 50g, 40-63μm, 60Å, 40mL / min, gradient: 0%-10% M in DCM 3, which was purified by ethanol (pH 7.5) to give intermediate 3, methyl 2-oxo-6-azaspiro[3.4]oxo[3.5]phenyl The crude product was obtained as an orange oil (0.93 g, 66%). Data for the above compounds are provided in Table 2.

[0276] Intermediate 4, 2-fluoroethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate Procedure for preparing carboxylates [ka] tert-Butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate The ester (5 g, 22.19 mmol) was dissolved in 25 mL of HCl in 1,4-dioxane. The reaction mixture was concentrated in vacuo and triturated with acetone (3 x 50 mL). 6-Azaspiro[3.4]octan-2-one (2.77 g, 55.4%) was added to brown The residue was dissolved in dry DCM (20 mL) and diluted with Et 3 N(0.7m The reaction mixture was cooled to 0° C. and 2-fluoroethylcarbamate was added. Bonochloridate (0.45 g, 3.6 mmol) was added. The reaction mixture was stirred at 30° C. for 5 h. The mixture was stirred for 1 h, then diluted with water (50 mL) and extracted with DCM (2×100 mL). The layers were combined and dried (Na 2 SO 4 ), and the solvent was removed in vacuo. The residue was HPLC (normal phase, 60-120 mesh silica, 0-10% EtOAc in hexane) The intermediate 4, 2-fluoroethyl 2-oxo-6-azaspiro[3.4]oxo The product was solubilized to give methacrylate-6-carboxylate (0.2 g, 38.8%) as a brown gum. Data for this compound are given in Table 2.

[0277] Intermediates 20 and 21, respectively, 4-(5-chloro-1-methyl-1H-imidazole-2 -yl)piperidine trifluoroacetate and 4-(4,5-dichloro-1-methyl-1H Procedure for preparing (-imidazol-2-yl)piperidine trifluoroacetate [ka] 4-(1-Methylimidazol-2-yl)piperidine hydrochloride (1g, 4.96mmol l) in anhydrous DCM (20 mL) and Et 3 A mixture of N (2.1 mL, 15.1 mmol) The mixture was suspended in and cooled in an ice-water bath. (BOC) 2 O (1.19 g, 5.45 mmol) The mixture was added in portions over 5 min and the mixture was allowed to warm to room temperature and stirred for 48 h. Dilute with saturated NaHCO 3 Wash with aqueous solution (×2) and saturated saline (×1), then , passed through a phase separator, concentrated in vacuo, and purified with tert-butyl 4-(1-methyl-1H -imidazol-2-yl)piperidine-1-carboxylate (1.34 g, quantitative) Obtained as a solid. LCMS (Method C): m / z 266 (M+H) + (ES + ), 1.43 minutes, UV activity .

[0278] tert-Butyl 4-(1-methyl-1H-imidazol-2-yl)piperidine-1 -carboxylate (0.250 g, 0.942 mmol) in MeCN (7.5 mL) The mixture was dissolved in 100 ml of 10 ... The reaction mixture was concentrated in vacuo onto flash silica (approximately 15 mL). Column chromatography (normal phase, Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 40 mL / min, gradient: D over 15 column volumes 2%–10% solvent A in CM, where solvent A is 10% (7M NH 3 / M tert-Butyl 4-(5-chloro-1-methylphenyl)propanediol (EtOH) was used to purify the compound. -1H-imidazol-2-yl)piperidine-1-carboxylate and tert- 4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidine A mixture containing -1-carboxylate and succinimide (0.495 g) was obtained. LCMS (Method C): Monochloro: m / z 300 / 302 (M+H) + (ES + ), 1 .68 min, UV activity; dichloro: m / z 334 / 336 / 338 (M+H) + (ES + ), UV activity at 1.87 min. The ratio of monochloro to dichloro is approximately 16 by LC-UV. :1.

[0279] tert-Butyl 4-(5-chloro-1-methyl-1H-imidazol-2-yl)pyridine Peridine-1-carboxylate and tert-butyl 4-(4,5-dichloro-1-methyl (1H-imidazol-2-yl)piperidine-1-carboxylate and succinic acid The mixture containing the imide (0.495 g) was dissolved in DCM (5 mL) and TFA (5 mL The reaction mixture was concentrated in vacuo and the residue was azeotroped with toluene ( × 2) to obtain intermediate 20, 4-(5-chloro-1-methyl- 1H-imidazol-2-yl)piperidine trifluoroacetate and intermediate 21, 4-( 4,5-Dichloro-1-methyl-1H-imidazol-2-yl)piperidine trifluoride A crude mixture of 1,2-diacetate salts was obtained. The yield was assumed to be quantitative and was used without further purification. Data for the above compounds are provided in Table 2.

[0280] Intermediates 22 and 25, respectively, 4-(5-chloro-1H-imidazol-2-yl)piperidine Lysine dihydrobromide and 4-(4,5-dichloro-1H-imidazol-2-yl) Procedure for preparing piperidine dihydrobromide [ka] Ethyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate(0 Dissolve NCS (0.40 g, 1.79 mmol) in MeCN (12 mL) and add NCS (0.360 g The reaction mixture was treated with 1,2-dichlorophenyl ether (2.70 mmol) and stirred at room temperature for 5.5 h. The resulting powder was purified by column chromatography ( Phase, [Biotage SNAP Cartridge KP-sil 50g, 40-63μm, 60 Å, 40 mL / min, gradient: 0% to 5% solvent A in DCM over 15 column volumes; Then 5% solvent A in DCM over 5 column volumes, where solvent A is 10 % (7M NH 3 / MeOH), both of which are succinimide Mixed with isolated ethyl 4-(5-chloro-1H-imidazol-2-yl)piperidin Peridine-1-carboxylate and ethyl 4-(4,5-dichloro-1H-imidazolate Each of the two was dissolved in DCM and T, H 2 The mixture was washed with 2× O, passed through a phase separator, and concentrated in vacuo to give succinimide. The do was removed. Ethyl 4-(5-chloro-1H-imidazol-2-yl)piperidine-1-carboxylate Yield (0.12 g, 26%), LCMS (Method C): m / z 258 / 260 (M+H ) + (ES + ), 1.34 min, UV activity. Ethyl 4-(4,5-dichloro-1H-imidazol-2-yl)piperidine-1-carboxylate Carboxylate (0.24 g, 45%), LCMS (Method C): m / z 292 / 294 / 296(M+H) + (ES + ), 1.24 min, UV activity.

[0281] Ethyl 4-(5-chloro-1H-imidazol-2-yl)piperidine-1-carboxylate The silane (0.12 g, 0.47 mmol) was dissolved in AcOH (2 mL) and diluted with 48% HB. The reaction mixture was treated with r water (2 mL) and heated to reflux at about 120° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was azeotroped with toluene (×1) and concentrated in vacuo to give a solid. 2,4-(5-chloro-1H-imidazol-2-yl)piperidine dihydrobromide salt It was assumed that it was. It was used immediately.

[0282] Ethyl 4-(4,5-dichloro-1H-imidazol-2-yl)piperidine-1-carboxylate The carboxylate (0.24 g, 0.82 mmol) was dissolved in AcOH (2 mL) and 48 % HBr (2 mL) and heated at about 120° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was azeotroped with toluene (x1) and concentrated in vacuo to give a solid. 25. 4-(4,5-dichloro-1H-imidazol-2-yl)piperidine dihydrogen It was assumed to be romide and used immediately. Data for the title compound are in Table 2.

[0283] Intermediate 46, tert-butyl 4-(4-(trifluoromethyl)-1H-imidazole -2-yl)piperidine-1-carboxylate and intermediate 33, 4-[4-(trifluoromethyl)piperidine-1-carboxylate Procedure for the preparation of (1H-imidazol-2-yl)piperidine [ka] tert-Butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.4 (mmol) in MeOH (10 mL), and then 7 M methanolic ammonia was added at 0 °C. and add 3,3-dibromo-1,1,1-trifluoropropane for 30 minutes. 1H-2-one (5.07 g, 18.5 mmol) was added in small portions. The resulting reaction mixture The mixture was stirred at 25° C. for 2 h, the solvent was removed in vacuo, and the residue was diluted with H 2 O (80 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc (2×50 mL), and the organic layers were combined. Dry (Na 2 SO 4), the solvent was removed in vacuo, and the residue was purified by column chromatography (DC The mixture was purified by elution with 0.5% MeOH in 1M (basic activated alumina) to give intermediate 46, te rt-Butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine Lysine-1-carboxylate (1.80 g, 60%) was obtained as a white solid. Data for the title compounds are in Table 2.

[0284] tert-Butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl ) Piperidine-1-carboxylate (1g, 3.13mmol) in 1,4-dioxane (5 mL) and then add HCl in 1,4-dioxane (20 mL, 3 M solution) dropwise. The resulting reaction mixture was stirred at 30° C. for 16 h, the solvent was removed in vacuo, and the residue was dissolved in dichloromethane. Purification by trituration with ethyl ether (3×5 mL) gave intermediate 33, 4-(4 -(Trifluoromethyl)-1H-imidazol-2-yl)piperidine hydrochloride (650 mg, 95%) as a white solid. Data for the title compound are in Table 2.

[0285] Intermediate 37, 4-[1-methyl-4-(trifluoromethyl)-1H-imidazole-2 Procedure for preparing [-yl]piperidine hydrochloride [ka] tert-Butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl ) Piperidine-1-carboxylate (200 mg, 0.63 mmol) was dissolved in THF (5 ml L) and 60% sodium hydride (74 mg, 1.88 mmol) was added at 0° C. The reaction mixture was stirred at 0 °C for 10 min, then methyl iodide (0.06 mL, 0.96 mL) was added. mol) was added and the resulting reaction mixture was stirred at 25° C. for 2 h. 2 Partition between O (60 mL) and EtOAc (45 mL) and the aqueous layer is diluted with EtOAc (2 × 45 mL). The organic layers were combined and dried (Na 2 SO 4 ) and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase silica, mesh size: 60–120 in DCM, 0%~2.0%~3.5% MeOH) to purify tert-butyl 4-(1-methyl 4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate The carboxylate (190 mg, 91%) was obtained as a yellow gum. LCMS (Method F): m / z 334 (M+H) + (ES + ), 2.31 minutes, UV activity

[0286] tert-Butyl 4-(1-methyl-4-(trifluoromethyl)-1H-imidazolium (200 mg, 0.6 mmol) piperidine-1-carboxylate ,4-dioxane (5 mL), followed by HCl in 1,4-dioxane (20 mL, The resulting reaction mixture was stirred at 30° C. for 16 h and the solvent was removed in vacuo. The residue was purified by trituration with diethyl ether (3×5 mL) to give the intermediate 37, 4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl ]Piperidine hydrochloride (140 mg, 86.8%) was obtained as a white solid. Relevant data are in Table 2.

[0287] To prepare intermediate 43, 4-(1,3,4-oxadiazol-2-yl)piperidine Steps to follow [ka] Ethyl piperidine-4-carboxylate (3.0 g, 19.1 mmol) was dissolved in THF ( 15mL) and Cs 2 CO 3 (7.4 g, 22.9 mmol) was added at 0°C. The resulting reaction mixture was stirred at 0-5°C for 10 min, and then added with benzyl chloroformate (3.2 g, 19.1 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. , H 2 Partition between O (100 mL) and EtOAc (200 mL), and the aqueous layer is diluted with EtOAc (2× The organic layers were combined and dried (Na 2 SO 4 ), and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase silica, mesh size: 60-120, hexane Purify with 0% to 10% EtOAc in water to obtain 1-benzyl 4-ethylpiperidine The -1,4-dicarboxylate (4.2 g, 76.4%) was obtained as a yellow solid. LCMS (Method F): m / z 292 (M+H) + (ES + ), 2.35 minutes, UV active sex

[0288] 1-Benzyl 4-ethylpiperidine-1,4-dicarboxylate (4.2 g, 14. 43 mmol) in EtOH (10 mL) and hydrazine monohydrate (10 mL, 5. 41 mmol) was added and the resulting reaction mixture was stirred at 90° C. overnight. The solvent was removed in vacuo. The crude product was triturated with pentane and hexane to give benzyl 4-(hydrazinylcarbamate). To this was obtained (3.8 g, 95%) of (methylenedioxy)piperidine-1-carboxylate as a white solid. LCMS (Method H): m / z 278 (M+H) +(ES + ), 1.76 minutes, UV active sex

[0289] Benzyl 4-(hydrazinylcarbonyl)piperidine-1-carboxylate (0.5 g, 1.79 mmol) was dissolved in triethyl orthoformate (8 mL) and then TFA (0 1 mL) was added. The resulting reaction mixture was stirred at 80° C. overnight. The reaction mixture was 2 Partition between 2×O (50 mL) and EtOAc (100 mL), and the aqueous layer is diluted with EtOAc (2×100 The organic layers were combined and dried (Na 2 SO 4 ) and the solvent was removed in vacuo. The residue was separated by column chromatography (normal phase silica, mesh size: 60-120, hexa 50%~60% EtOAc in methanol) to give benzyl 4-(1,3,4-oxadiazonium chloride). Diazol-2-yl)piperidine-1-carboxylate (0.19 g, 38%) in yellow Obtained as a coloured solid. LCMS (Method H): m / z 288 (M+H) + (ES + ), 2.03 minutes, UV active sex

[0290] Benzyl 4-(1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate The sylate (0.15 g, 0.52 mmol) was dissolved in MeOH (10 mL). 0% palladium on carbon catalyst (20 mg) was added and the reaction mixture was diluted with H 2 Gas is used at room temperature The reaction mixture was heated to 300° C. 2 The mixture was stirred at room temperature for 12 hours under atmospheric conditions. The reaction mass was then washed with celite. Filtration through 4-(1,3,4-oxadiazo)-2-phenylpropanediol and removal of the solvent in vacuo afforded intermediate 43, 4-(1,3,4-oxadiazo)-2-phenylpropanediol. The title compound (2-phenyl-2-ylpiperidine) (0.078 g, 99%) was obtained as a colorless gum. Data regarding the compounds are given in Table 2.

[0291] Intermediate 44, 4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine Procedure for preparation [ka] Acetonitrile (40.0 mL) and 50% aqueous hydroxylamine (4.20 mL) ) was heated to reflux at 90° C. for 24 hours. The reaction mixture was cooled to 0° C. and filtered. The residue was After drying, (Z)-N-hydroxyethanimidamide (2.1 g, >100%) was obtained It was obtained as a coloured crystalline solid. LCMS (Method H): m / z 74 (M+H) + (ES + ), 1.86 minutes, UV inactive sex

[0292] (Z)-N-hydroxyethanimidamide (0.50 g, 6.75 mmol) and Tyl piperidine-4-carboxylate (1.17 g, 7.42 mmol) in ethanol (20 mL). Dissolved in 21% sodium ethoxide solution in ethanol (0.92 mL , 13.4 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 30 min, then heated to 100° C. The mixture was stirred for 16 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (normal phase silica, Purification by 0-12% methanol in DCM gave intermediate 44, 4-(3-methyl-1 ,2,4-Oxadiazol-5-yl)piperidine (380 mg, 34%) as a yellow gum Data for the title compounds are in Table 2.

[0293] Prepare intermediate 47, 4-(1H-imidazol-2-yl)piperidin-4-ol hydrochloride. Steps for making [ka] Dissolve 1H-imidazole (8.0 g, 117.5 mmol) in DMF (100 mL). Then sodium hydride (4.7 g, 117.5 mmol, 60% in oil) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours and 2-(trimethylsilyl)ethoxymethyl chloride ( 20.5 g, 123.38 mmol) was added dropwise to the reaction mixture at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was poured onto ice-cold water (1000 mL) and EtO The aqueous layer was extracted with EtOAc (2×500 mL) and the extract was concentrated. The layers were combined and dried (Na 2 SO 4 The solvent was removed in vacuum. The residue was purified by column chromatography. The resulting mixture was purified by chromatography (normal phase silica, 0-1% methanol in DCM) to give 1-((2 -(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (16.2 g, 68. 6%) as a pale green gum. LCMS (Method F): m / z 199 (M+H) + (ES + ), 1.73 minutes, UV active sex

[0294] 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole(5.0 g, 25.0 mmol) was dissolved in THF (50 mL) and cooled to -78 °C. Lithium (19.0 mL, 30 mmol, 1.6 M in hexane) was added dropwise at -78°C. The reaction mixture was then stirred at -78°C for 1 h. A solution of 4-oxopiperidine-1-carboxylate (5.53 g, 27 mmol) was The reaction mixture was added dropwise at -78°C. The reaction mixture was allowed to warm to room temperature over 2 hours. Saturate the mixture with NH 4 Quench with Cl solution (100 mL) and extract with EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL), and the organic layers were combined and dried (Na 2 SO 4 ) and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase silica, Purify with 0-20% EtOAc in hexane to obtain tert-butyl 4-hydroxyethyl ester. -4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole- 2-yl)piperidine-1-carboxylate (8 g, 80.0%) was obtained as a pale yellow gum. I got it. LCMS (Method F): m / z 398 (M+H) + (ES + ), 2.16 minutes, UV active sex

[0295] tert-Butyl 4-hydroxy-4-(1-((2-(trimethylsilyl)ethoxy) )Methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2. 0 g, 5.0 mmol) was dissolved in 4 M HCl in 1,4-dioxane (20 mL), The reaction mixture was stirred at room temperature for 10 h. The solvent was removed in vacuo and the residue was dissolved in acetone (3×20 ml L) to give intermediate 47, 4-(1H-imidazol-2-yl)piperidine-4- The product was obtained as a brown gum (0.5 g, 60.2%). are in Table 2.

[0296] Intermediate 48, 4-(1H-imidazol-2-yl)-4-methoxypiperidine hydrochloride Procedure for preparation [ka] tert-Butyl 4-hydroxy-4-(1-((2-(trimethylsilyl)ethoxy) )Methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (2. 0 g, 5.0 mmol) was dissolved in DMF (20 mL). The solution was 2 Cool to 0℃ under Then, NaH (0.24 g, 10.0 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min. Then methyl iodide (1.07 g, 7.5 mmol) was added and the reaction mixture was allowed to stand at room temperature. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL) and diluted with water. The aqueous layer was further extracted with EtOAc (3×100 mL) and the organic layer was The layers were combined and dried (Na 2 SO 4 The solvent was removed in vacuo. The residue was HPLC (normal phase, 60-120 mesh silica, 0-10% EtOAc in hexane) and tert-butyl 4-methoxy-4-(1-((2-(trimethylsilyl) )Ethoxy)methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate The compound (1.5 g, 75.0%) was obtained as a yellow gum.

[0297] tert-Butyl 4-methoxy-4-(1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-imidazol-2-yl)piperidine-1-carboxylate(1.5 g, 3.6 mmol) was dissolved in 4 M HCl in 1,4-dioxane (20 mL) and reacted. The mixture was stirred at room temperature for 10 h. The solvent was removed in vacuo and the residue was dissolved in acetone (3×20 mL). Trituration with 4-(1H-imidazol-2-yl)-4-methoxypiperidine affords intermediate 48, The compound was obtained as a brown solid (0.5 g, 76.0%). It is located at 2.

[0298] Intermediate 49, 4-(1-methyl-1H-imidazol-2-yl)piperidin-4-ol Procedure for preparing ethyl ketone hydrochloride [ka] 1-Methylimidazole (6.0 g, 73.0 mmol) was dissolved in THF (100 mL). The reaction mixture was cooled to -78 °C under nitrogen and dissolved in n-butyllithium in hexane. (45.4 mL, 73.0 mmol) was added slowly. The reaction mixture was gently heated to 40°C. The mixture was warmed slightly and stirred for 4 h, then cooled to -78 °C. ert-Butyl 4-oxopiperidine-1-carboxylate (14.56 g, 73.0 The reaction mixture was gently warmed to 40° C. and stirred for 10 h, then The reaction mixture was quenched with water (50 mL). The reaction mixture was diluted with EtOAc (200 mL) and water (150 The aqueous layer was extracted with EtOAc (2×200 mL), and the organic layers were combined and dried. (Na 2 SO 4 The solvent was removed in vacuo, and the residue was washed with methanol to give tert- Butyl 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)piperidine This gave the 1-carboxylate (14.0 g, 68.1%) as a solid, which was then purified crude. was used in the subsequent reaction. LCMS (Method F): m / z 282 (M+H) + (ES + ), 2.05 minutes, UV active sex

[0299] tert-Butyl 4-hydroxy-4-(1-methyl-1H-pyrrol-2-yl)pyridine Peridine-1-carboxylate (0.5 g, 1.7 mmol) was dissolved in 1,4 dioxane (3 The reaction mixture was cooled to 0 °C under nitrogen and diluted with HCl ( The reaction mixture was stirred at room temperature for 6 hours and the solvent was then evaporated to dryness. The mixture was then triturated with pentane (10 mL) and diethyl ether (10 mL). The residue was purified to give intermediate 49, 4-(1-methyl-1H-imidazol-2-yl ) Piperidin-4-ol (0.2 g, 62.5%) was obtained as a brown solid. Data on materials are in Table 2.

[0300] Intermediate 50, 4-Methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidin Procedure for preparing azidopropyl phosphate hydrochloride [ka] tert-Butyl 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl) ) Piperidine-1-carboxylate (3.0 g, 10.6 mmol) was dissolved in DMF (50 ml) The reaction mixture was cooled to 0° C. under nitrogen and added NaH (0.64 g, 16 L) at room temperature. The reaction mixture was stirred at 0°C for 1 h and then added iodine. Methyl fluoride (1.8 g, 128 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and The reaction mixture was stirred for 2 h and then quenched with water (50 mL). The reaction mixture was diluted with EtOAc (3×20 0 mL), the organic layers were combined and dried (Na 2 SO 4 The solvent was removed in vacuo. The residue was purified by column chromatography (normal phase, silica, 60-120 mesh, gradient: hex Purification by 0% to 50% EtOAc in methanol gave tert-butyl 4-methoxy-4- (1-Methyl-1H-imidazol-2-yl)piperidine-1-carboxylate(1 The compound was obtained (3.3 g, 41.3%) as a pale yellow solid. LCMS (Method F): m / z 296 (M+H) + (ES + ), 2.36 minutes, UV activity

[0301] tert-Butyl 4-methoxy-4-(1-methyl-1H-imidazol-2-yl) Piperidine-1-carboxylate (1.3 g, 3.3 mmol) was dissolved in 1,4 dioxane ( The reaction mixture was cooled to 0° C. under nitrogen and diluted with HCl in dioxane. (15 mL, 4 M solution) was added slowly. The reaction mixture was stirred at room temperature for 6 h and the solvent was removed. Remove in vacuo and triturate from pentane (10 mL) and diethyl ether (10 mL). The residue was purified by HPLC to give intermediate 50, 4-methoxy-4-(1-methyl-1H-imidazolium chloride). The resulting product was 2-(2-phenyl-2-yl)piperidine (0.80 g, 94.1%) as an off-white solid. Data for the above compounds are provided in Table 2.

[0302] Intermediate 111, benzyl 4-[(2S,4R)-1-(tert-butoxycarbonyl)

[0036] Preparing [4-hydroxypyrrolidin-2-yl]piperidine-1-carboxylate Steps to follow [ka] (2S,4R)-1-Boc-4-hydroxypyrrolidine-2-carboxylate methyl ester tert-butyl ether (25 g, 101.93 mmol) and imidazole (34.687 g, 509.5 (mmol) was dissolved in DMF (100 mL) and the reaction was cooled to 0 °C. rt-Butyldimethylsilyl chloride was added (36.86 g, 244.56 mmol), The reaction was allowed to warm to room temperature and stirred for 18 h. Volatiles were removed by rotary evaporation. The mixture was removed and diluted with DCM (250 mL). 2 The combined aqueous layers were washed with DCM (250 mL) and the combined aqueous layers were washed with HO (2 × 250 mL). The organic layer was washed with saturated NH 4 Cl (水溶液) (250mL) and saturated saline (250mL) The volatiles were removed under vacuum to give (2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidine To obtain 35.812 g (99%) of methyl 2-propane-2-carboxylate, LCMS (Method D): m / z 260 (M+H-Boc) + (ES+), 2.64 minutes, UV inert

[0303] (2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidone Diazine-2-carboxylic acid methyl ester (42.7 g, 118.76 mmol) was dissolved in THF ( The reaction mixture was cooled to 0° C. Then, lithium aluminum hydride was added. (120 mL of a 1.0 M solution in THF, 120.0 mmol) was added and the reaction was allowed to stand at 0 °C. The reaction was stirred for 1 h. 2 O (4.5 mL), 15% NaOH solution (4.5 mL) and BiH 2 Quench with O (13.5 mL) and filter through a plug of Celite. Volatiles The amine was removed under vacuum to give (2S,4R)-1-Boc-4-tert-butyldimethylsilyl To the obtained solution, 30.320 g (77%) of pyrrolidine-2-hydroxymethyl ether was obtained. LCMS (Method D): m / z 232 (M+H-Boc) + (ES+), 2.00 min. , UV inert

[0304] (2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidone Diazine-2-hydroxymethyl (10.050 g, 30.362 mmol) was dissolved in DCM (10 0 mL) and dissolved in Dess-Martin periodinane (15.371 g, 36.253 mmol). l) was added. The reaction was stirred at room temperature for 2 h and then the volatiles were removed by rotary evaporation. The crude product was then directly loaded onto a Biotage SNAP column (100 g). The (2S,4R)-1- Boc-4-tert-butyldimethylsilyl ether-pyrrolidine-2-carbaldehyde The obtained compound (2.150 g, 22%) was

[0305] Sodium hydride (135 mg of 60% oil dispersion, 3.3 mL) in THF (8 mL) at 0 °C A suspension of triethyl phosphonoacetate (0.665 mL, 3.338 mmol) was After 10 min, (2S,4R)-1-Boc-4-t was added in THF (2 mL). ert-Butyldimethylsilyl ether-pyrrolidine-2-carbaldehyde (1.002 g, 3.034 mmol) was added and the reaction was stirred at 0° C. for 30 min. Volatiles were removed by The solvent was removed on a tumble evaporator and the reaction mixture was diluted with DCM (20 mL). H 2The combined aqueous layers were washed with DCM (20 mL) and the combined aqueous layers were washed with HO (2 × 20 mL). The organic layer was washed with saturated brine (20 mL) and passed through a Biotage phase separator. The volatiles were removed under vacuum and the crude mixture was passed through a Biotage SNAP column (100 g) and purified by column chromatography (0-30% EtOAc in hexane). After purification, tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl] 2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]oxy}- pyrrolidine-1-carboxylate as a colorless oil (545 mg, 45%) Got it. LCMS (Method D): m / z 300 (M+H-Boc) + (ES+), 2.85 minutes , UV inert.

[0306] Potassium tert-butoxide (421 mg, 3.753 mmHg) in EtOH (5 mL) ol) and ethyl cyanoacetate (0.399 mL, 3.753 mmol), t-Butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}- 2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine- 1-carboxylate (500 mg, 1.251 mmol) was added and the reaction was heated to 78 °C for 1 The mixture was stirred for 8 h. AcOH was added (0.200 mL) and the volatiles were removed by rotary evaporation. The reaction mixture was diluted with DCM (50 mL) and 2 O (2 x 50 mL) The combined aqueous layers were washed with DCM (50 mL), and the combined organic layers were washed with saturated brine ( The mixture was washed with 50 mL of ethyl acetate and passed through a Biotage phase separator. The volatiles were removed under vacuum. The crude mixture was loaded onto a Biotage SNAP column (100 g) and column cleaved. Purification by chromatography (0-30% EtOAc in hexanes) afforded diethyl 3- [(4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl silyl)oxy}pyrrolidin-2-yl]-2-cyanopentanedioate (cy anopentanedioate) was obtained as a yellow oil (567 mg, 89%) .

[0307] H 2 Sodium chloride (71 mg, 1.212 mmol) in O (3 mL) and DMSO (0.040 mL, 2.204 mmol) was added to a solution of diethyl 3-[(4R)-1-(te rt-Butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy} Pyrrolidin-2-yl]-2-cyanopentanedioate (565 mg, 1.102 mm ol) was added and the reaction was stirred at 145° C. for 2 h. Ice water was added (50 mL), then E Add tOAc (50 mL) and extract the organic layer with H 2 The combined precipitate was washed with 2×50 mL of HCl. The layer was washed with saturated brine (50 mL) and passed through a Biotage phase separator. The volatiles were removed under vacuum and the crude mixture was applied to a Biotage SNAP column (50 g). It was packed and purified by column chromatography (0-30% EtOAc in hexanes). tert-Butyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy }-2-(1-cyano-4-ethoxy-4-oxobutan-2-yl)pyrrolidine-1- The carboxylate was obtained as a yellow oil (351 mg, 72%). LCMS (Method D): m / z 341 (M+H-Boc) +(ES+), 2.77 minutes , UV inert

[0308] To a flask containing NiEnCat™ (65 g wet beads, approximately 0.25 eq.) tert-Butyl(4R)-4-{[tert-butyl(diphenylphosphine)} methyl)silyl]oxy}-2-(1-cyano-4-ethoxy-4-oxobutane-2- yl)pyrrolidine-1-carboxylate (8.700 g, 19.7 mmol), The reaction was stirred at 78° C. under a hydrogen balloon atmosphere for 96 h. The reaction mixture was poured onto a Celite pad. The mixture was filtered through a filter, the volatiles were removed under vacuum, and the crude mixture was loaded onto a Biotage SNAP column. (340 g) and subjected to column chromatography (2.5-10% MeOH in DCM). tert-Butyl(4R)-4-{[tert-butyl(dimethyl) Silyl]oxy}-2-(2-oxopiperidin-4-yl)pyrrolidine-1-carboxylate The sylate was obtained as a yellow oil (4.665 g, 59%). LCMS (Method D): m / z 399 (M+H) + (ES+), 1.90 minutes, no UV Activity

[0309] tert-Butyl(4R)-4-{[tert-butyl(dimethyl)silyl]oxy} -2-(2-oxopiperidin-4-yl)pyrrolidine-1-carboxylate (1.8 50 g, 4.648 mmol) in THF (30 mL) C. (9.3 mL of a 1.0 M solution in THF, 9.300 mmol) was added at 0.degree. C. and the reaction was The reaction was stirred at 60° C. for 30 min. The reaction was cooled to room temperature and quenched with MeOH (10 mL). The reaction mixture was diluted with DCM (100 mL) and the volatile materials were removed on a rotary evaporator. L) and dilute with 1M NaOH (水溶液) (2×100 mL) and the combined aqueous layer Wash with DCM (100 mL), and then wash the combined organic layers with saturated brine (250 mL). The volatiles were removed under vacuum and the tert -Butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2 1.8-(Piperidin-4-yl)pyrrolidine-1-carboxylate was reacted with 1.8 Obtained as 30 g, >99%). LCMS (Method D): m / z 285 (M+H-Boc) + (ES+), 3.00 min. , UV inert

[0310] tert-Butyl (2S,4R)-4-{[tert-butyl (Dimethyl)silyl]oxy}-2-(piperidin-4-yl)pyrrolidine-1-carbo A solution of diisopropyl ethyl amine (1.830 g, 4.766 mmol) was added to the solution. (1.814 mL, 10.484 mmol) and benzyl chloroformate (0.816 mL , 5.719 mmol) was added at 0° C. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL) and diluted with 1 M NaOH (水溶液) (2×100m The combined aqueous layers were washed with DCM (100 mL) and the combined organic layers were washed with saturated sodium chloride solution (100 mL). Washed with brine (250 mL) and passed through a Biotage phase separator. Volatiles The was removed under vacuum and the crude mixture was loaded onto a Biotage SNAP column (100 g) Purification by column chromatography (10–40% EtOAc in hexane) gave 4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-{[ter t-Butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl]piperidine-1-carboxamide The carboxylate was obtained as a colorless oil (700 mg, 28%).

[0311] Benzyl 4-[(2S,4R)-1-(tert-butoxycarbonyl) (4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-2-yl To a solution of 1.5-difluoropiperidine-1-carboxylate (0.780 g, 1.504 mmol) , tetrabutylammonium fluoride (1.800 mL of a 1.0 M solution in THF, 1. 800 mmol) was added and the reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (100 mL) and diluted with H 2 The combined aqueous layers were washed with DCM (100 mL). The combined organic layer was washed with saturated saline (250 mL) and then washed with Biotage Filter. The volatiles were removed under vacuum to give intermediate 111, benzyl 4 -[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine [Benzyl-2-yl]piperidine-1-carboxylate was obtained as a colorless oil (500 mg, 8 2%). Data for the title compound are in Table 2.

[0312] Intermediate 112, tert-butyl(2S,4S)-4-fluoro-2-(piperidine-4 Procedure for preparing (-yl)pyrrolidine-1-carboxylate [ka] Benzyl 4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydrogen [0.24-xypyrrolidin-2-yl]piperidine-1-carboxylate (100 mg, 0.24 7 mmol) was dissolved in DCM (1 mL) at -40°C, and DAST (0.049 m The reaction was allowed to warm to room temperature and stirred for 2 hours. Dilute with CM (25 mL) and add saturated NaHCO 3(水溶液) (2 × 25 mL) and combined The combined aqueous layer was washed with DCM (25 mL) and the combined organic layer was washed with saturated brine (25 mL). The volatiles were removed under vacuum to give Benzyl 4-[(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro Pyrrolidin-2-yl]piperidine-1-carboxylate (0.090 g, 90%) Got it. LCMS (Method D): m / z 307 (M+H-Boc) + (ES+), 2.31 min. , UV inert

[0313] Benzyl 4-[(2S,4S)-1-(tert-butoxy)phenyl]-1,2-dihydro-1,3-dimethyl-2,4-dihydro-1,3-dimethyl-2,4-dimethyl-1,5 ... (oxycarbonyl)-4-fluoropyrrolidin-2-yl]piperidine-1-carboxylate A solution of 10% Pd / C (10 mg) and 1,4 cyclohexadiene (0.147 mL, 1.530 mmol) was added and the reaction was brought to 7 Stirred for 1 h at 0° C. The reaction was filtered through a plug of Celite and the volatiles were removed in vacuo. to give intermediate 112, tert-butyl(2S,4S)-4-fluoro-2-(pyridinyl) To obtain 55 mg (92%) of 3-(peridin-4-yl)pyrrolidine-1-carboxylate. Data for the title compounds are in Table 2.

[0314] Intermediate 113, tert-butyl(2S)-4,4-difluoro-2-(piperidine-4 Procedure for preparing (-yl)pyrrolidine-1-carboxylate [ka] Dissolve oxalyl chloride (0.065 mL, 0.741 mmol) in DCM (1 mL) -78 After 5 minutes, benzyl 4- [(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine -2-yl]piperidine-1-carboxylate (200 mg, 0.494 mmol) In DCM (2 mL), triethylamine (0.345 mL, 2.47 mmol) was added. l) was added after a further 5 min at −78° C. The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was diluted with DCM (25 mL) and saturated NaHCO 3(水溶液) (2×25mL ), the combined aqueous layers were washed with DCM (25 mL), and the combined organic layers were washed with saturated brine ( (25 mL) and passed through a Biotage phase separator. The volatiles were removed in vacuo Benzyl 4-[(2S)-1-(tert-butoxycarbonyl)-4- oxopyrrolidin-2-yl]piperidine-1-carboxylate (0.170 g, 85 %) was obtained. LCMS (Method D): m / z 303 (M+H-Boc) + (ES+), 2.15 minutes , UV inert

[0315] Benzyl 4-[(2S)-1-(tert-butoxycarbonyl)-4-oxopyrrolidin 170 mg, 0.422 mmol ) was dissolved in DCM (1 mL) at -78 °C, and DAST (0.167 mL, 1.2 The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with DCM ( 5mL) and dilute with saturated NaHCO 3(水溶液) (2×25 mL) and combined with water The layers were washed with DCM (25 mL) and the combined organic layers were washed with saturated brine (25 mL). The volatiles were removed in vacuo to give benzyl 4-[(2S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine To obtain 1-methyl-2-yl]piperidine-1-carboxylate (0.070 g, 39%), LCMS (Method D): m / z 325 (M+H-Boc) + (ES+), 2.41 min. UV inert

[0316] Benzyl 4-[(2S)-1-(tert-butoxy)phenyl]-2-(2-methyl-2-propanediol) dissolved in EtOH (2 mL) Carbonyl)-4,4-difluoropyrrolidin-2-yl]piperidine-1-carboxy A solution of 10% Pd / C (10 mg) and and 1,4 cyclohexadiene (0.105 mL, 1.105 mmol) were added and the reaction mixture was cooled to 10°C. Stirred for 1 h at 70° C. The reaction was filtered through a plug of Celite and the volatiles were removed in vacuo. Removal under reduced pressure affords intermediate 113, tert-butyl(2S)-4,4-difluoro-2-( piperidin-4-yl)pyrrolidine-1-carboxylate (30 mg, 65%) was obtained. Data for the title compounds are given in Table 2.

[0317] Intermediate 125, tert-butyl (2S)-4,4-difluoro-2-methylpyrrolidine Procedure for preparing 1-carboxylate [ka] 1-tert-Butyl 2-methyl(2R)-4,4-difluoroacetate in THF (20 mL) 1,2-pyrrolidine-1,2-dicarboxylate (2 g, 7.5 mmol) in THF Lithium borate solution (2.0 M, 7.5 mL, 15 mmol) was added at 0° C., and the reaction mixture was cooled to room temperature. Warm to room temperature and stir for 2 h. The reaction is diluted with saturated NaHCO 3 Add the aqueous solution little by little Once the effervescence had ceased, the mixture was concentrated to remove the THF. The aqueous mixture was diluted with saturated NaHCO 3 Partition between aqueous and DCM (x2) and separate the organic phase. The mixture was filtered through a separator and concentrated to give crude tert-butyl(2R)-4,4-difluoro-2- (Hydroxymethyl)pyrrolidine-1-carboxylate (1.98 g, >100%) Obtained as an oil. LCMS (Method C): m / z 260 (M+Na) + (ES+), 1.09 min, UV Inert.

[0318] tert-Butyl (2R)-4,4-difluoro-2- A solution of (hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.2 mmol) Solution and triethylamine (1.5 mL, 11 mmol) were added to MsCl (0.42 mL, 5. 4 mmol) was added in small portions. The mixture was stirred at 0 °C for 100 min and then cooled to 100 °C with ice-cold saturated N aHCO 3 Partition between aqueous and ice-cold DCM (x2) and pass the organic phase through a phase separator. The crude tert-butyl (2R)-4,4-difluoro-2-{[(methylsulfonyl) (phenyl)oxy]methyl}pyrrolidine-1-carboxylate (1.55g, over 100%) ) was obtained as an oil. LCMS (Method C): m / z 338 (M+Na) + (ES + ), 1.28 minutes, no UV Active.

[0319] tert-Butyl (2R)-4,4-difluoro-2- {[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate(1.5 5 g, 4.9 mmol) in THF (1.0 M, 9.8 mL, 9.8 mmol). LiBHEt 3 The solution was added in portions over a period of 10 minutes. The mixture was then stirred for 3 days. The mixture was cooled back to 0° C. and the cooling bath was allowed to expire. 2 By adding O The mixture was quenched and then concentrated to remove THF. The aqueous mixture was diluted with saturated NaHCO 3 Aqueous solution and Partition with DCM (x2) and pass the organic phase through a phase separator and concentrate to give crude intermediate 12. 5. tert-Butyl (2S)-4,4-difluoro-2-methylpyrrolidine-1-carboxylate The resulting carboxylate (0.89 g, 82%) was obtained as an oil. The data are in Table 2.

[0320] Intermediate 126, tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl) Procedure for preparing pyrrolidine-1-carboxylate [ka] (R)-1-tert-Butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxamide The silane (1.00 g, 4.111 mmol) was dissolved in DCM (10 mL) at -78 °C. DAST was then added (1.629 mL, 12.332 mmol). The reaction was allowed to warm to room temperature. The reaction mixture was diluted with DCM (100 mL) and saturated NaHCO 3( 水溶液) (2×100 mL), and the combined aqueous layers were washed with DCM (100 mL). The combined organic layers were washed with saturated brine (25 mL) and then filtered through a Biotage phase separator. The solvent was removed in vacuo to give an orange oil (0.957 g, 90 %) was obtained.

[0321] (R)-1-tert-Butyl 2-methyl-4,4-difluoropyridinium chloride in THF (5 mL) Rolidin-1,2-dicarboxylate (500 mg, 1.885 mmol) in THF Lithium borohydride as a 2.0 M solution in (1.90 mL, 3.80 mmol) C., the reaction was allowed to warm to room temperature and stirred for 1 h. The solvent was removed in vacuo and the reaction mixture was Dilute with DCM (50 mL) and add saturated NaHCO 3(水溶液) (2 × 50 mL), The combined aqueous layers were washed with DCM (50 mL) and the combined organic layers were washed with saturated brine (50 mL). The mixture was washed with ethyl acetate and passed through a Biotage phase separator. The volatiles were removed under vacuum. Intermediate 126, tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl) To obtain ethyl)pyrrolidine-1-carboxylate (452 ​​mg, 92%).

[0322] Intermediate 132, 3-(piperidin-4-yl)-1,3-oxazinan-2-one hydrochloride Procedure for preparation [ka] tert-Butyl 4-oxopiperidine-1-carboxylate (0.796 g, 4. 00mmol) and 3-aminopropan-1-ol (0.330g, 4.4mmol) CH 2 Cl 2 (20 mL) at room temperature and mixed with AcOH (0.68 mL, 12.0 mm ol) was added and stirred for 3 hours. STAB (2.34 g, 10.0 mmol) was added, The reaction mixture was stirred overnight at room temperature under nitrogen. 3 (Saturated aqueous solution)( 40 mL) and quench with CH 2 Cl 2 (4 × 45 mL) and the combined organic phase The layer was washed with saturated brine and then with MgSO 4 The solvent was removed in vacuo to give Crude tert-butyl 4-[(3-hydroxypropyl)amino]piperidine-1-carboxamide The xylate (1.03 g, 4.00 mmol) was obtained, which was used without purification. LCMS (Method B): m / z 259 (M+H) + (ES+), 0.24 min, UV inactive sex.

[0323] tert-Butyl 4-[(3-hydroxypropyl)amino]piperidine-1-carboxamide Xylate (1.03 g, 4.00 mmol), CDI (1.36 g, 8.4 mmol) and DBU (0.24 mL, 1.60 mmol) were dissolved in THF (40 mL), and the mixture The mixture was heated to reflux and maintained for 72 hours. The solvent was removed in vacuo and the residue was purified by column chromatography. [Biotage SNAP Cartridge KP-sil 25g, 40-63μm, 60 Å, 50 mL / min, gradient: 0% to 10% MeOH in DCM) to give tert -Butyl 4-(2-oxo-1,3-oxazinan-3-yl)piperidine-1-carbo The xylate (0.60 g, 53%) was obtained as a colorless oil. LCMS (Method B): m / z 307 (M+Na) + (ES+), 0.16 min, UV Inert.

[0324] tert-Butyl 4-(2-oxo-1,3-oxazinan-3-yl)piperidine 1-Carboxylate (0.60 g, 2.11 mmol) was dissolved in CH 2 Cl 2 (21mL) Dissolve and add 4M hydrogen chloride in dioxane (2.64 mL, 10.5 mmol) to the reaction mixture. The mixture was stirred at room temperature overnight. The precipitate was collected by filtration and diluted with CH 2 Cl 2 (2 x 20 mL) and drying to give intermediate 132, 3-(piperidin-4-yl)-1,3-oxadiazole. Dinan-2-one hydrochloride (0.352 g, 76%) was obtained as a colorless solid. Data on materials are in Table 2.

[0325] Intermediate 151, ethyl 2-(4-oxopiperidin-1-yl)-6-azaspiro[3. 4] Procedure for preparing octane-6-carboxylate hydrochloride [ka] Ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0. 985 g, 5.00 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.715 g, 5.00 mmol) was dissolved in CH at room temperature. 2 Cl 2 (50 mL) and mixed with Ac OH (0.31 mL, 5.50 mmol) was added and stirred for 3 h. STAB (2.65 g, 12.5 mmol) was added and the reaction mixture was stirred overnight at room temperature under nitrogen. NaHCO 3Quench with the addition of (sat. aq.) (40 mL) and CH 2 Cl 2 (4×4 5 mL), and the combined organic layers were washed with saturated brine and then with MgSO 4 Dry with The solvent was removed in vacuo to give crude ethyl 2-(1,4-dioxa-8-azaspiro[4 .5]dec-8-yl)-6-azaspiro[3.4]octane-6-carboxylate Obtained as a mixture of diastereomers which was used without further purification. LCMS (Method D): m / z 325 (M+H) + (ES+), 1.11 min and 1.1 6 minutes, UV inactive.

[0326] Crude ethyl 2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6- Azaspiro[3.4]octane-6-carboxylate (1.62 g, 5.00 mmol) ) was dissolved in THF (10 mL), water (10 mL) and concentrated hydrochloric acid (10 mL) were added, and the mixture was mixed. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with Et 2 Trituration from O gave intermediate 15 1. Ethyl 2-(4-oxopiperidin-1-yl)-6-azaspiro[3.4]octadecane The compound was obtained as a colorless solid, 1.30 g (82%) of 1,2-diphenyl-6-carboxylate hydrochloride. Data for this compound are given in Table 2.

[0327] Prepare intermediate 164, 4-(1,3-thiazol-4-yl)piperidine hydrobromide Steps to follow [ka] Both aqueous sodium carbonate (2M) and 1,4-dioxane were placed in a fritted glass tube. A stream of nitrogen was passed through the liquid through a fritted glass tube for 15 minutes. Benzyl 4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxy tetrabromo-1,3-thiazole (119 mg, 0.73 mmol), g, 0.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dic Palladium(II) (32 mg, 0.044 mmol), degassed aqueous sodium carbonate solution (2 M, 1.1 mL, 2.2 mmol) and degassed 1,4-dioxane (3 mL) were poured into a flask containing 10 mL of nitrogen Place in a flushed tube, seal and heat under pressure at 90° C. for 2.5 hours. The reaction mixture was 2 The mixture was diluted with 200 mL of ethyl acetate and extracted with EtOAc. The organic phase was passed through a phase separator. The resulting powder was purified by column chromatography. Chromatography (normal phase, [Biotage SNAP cartridge KP-sil 50g, 4 0–63 μm, 60 Å], 40 mL / min, 65% Et in isohexane 2 O, isocrate The product was purified by HPLC to give benzyl 4-(1,3-thiazol-4-yl)-3,6- Dihydropyridine-1(2H)-carboxylate (173 mg, 79%) was obtained. LCMS (Method C): m / z 301 (M+H) + (ES + ), 1.46 minutes, UV activity .

[0328] Benzyl 4-(1,3-thiazol-4-yl)-3,6 in EtOAc (10 mL) -Dihydropyridine-1(2H)-carboxylate (150 mg, 0.50 mmol) The solution was heated at 100 bar pressure, 50 °C, and a flow rate of 1 mL / min over 10% palladium on carbon. The solution was concentrated to give benzyl 4-(1,3-thiazolidinyl) To this was obtained (143 mg, 95%) aryl-4-ylpiperidine-1-carboxylate. LCMS (Method A): m / z 303 (M+H) + (ES + ), 1.92 minutes, UV activity .

[0329] Benzyl 4-(1,3-thiazole) in AcOH (1 mL) and 48% aqueous HBr (1 mL) Azole-4-yl)piperidine-1-carboxylate (127 mg, 0.42 mmol) The solution of l) was stirred at room temperature overnight. The mixture was then concentrated and the residue was azeotroped with toluene to give , Intermediate 164, 4-(1,3-thiazol-4-yl)piperidine hydrobromide (160 mg, >100%). Data for the title compounds are given in Table 2.

[0330] Intermediate 172, (1R,5S)-3-phenyl-2,4-dioxa-3-borabicyclo[ 3.3.1] Procedure for the preparation of nonan-7-one [ka] (1S,3S,5S)-Cyclohexane-1,3,5-triol (1.0 g, 6.0 1 mmol) and phenylboronic acid (0.72 g, 6.0 mmol) in toluene (35 mL The reaction mixture was concentrated to give crude (1R,5S ,7R)-3-phenyl-2,4-dioxa-3-borabicyclo[3.3.1]nonane- The 7-ol (1.43 g, 87%) was obtained as a solid, which was used immediately. 5S,7R)-3-phenyl-2,4-dioxa-3-borabicyclo[3.3.1]nona N-7-ol (1.4 g, 6.4 mmol) was dissolved in DCM (50 mL). Thorium (1.31 g, 16 mmol) and pyridinium chlorochromate (12.9 g, 11 mmol) was added and the reaction mixture was stirred for 16 hours. The crude product was extracted with DCM:hexane (1:4) and then filtered, and the filtrate was concentrated to give the crude product. Crystallization afforded intermediate 172, (1R,5S)-3-phenyl-2,4-dioxa-3-borate. Rabicyclo[3.3.1]nonan-7-one (0.65 g, 38%) was obtained as a solid. Data for the title compounds are in Table 2.

[0331] Intermediate 174, 4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidine Procedure for preparing 1-phenyl-1-ylpiperidine trifluoroacetate [ka] tert-Butyl (2R)-4,4-difluoro-2-(hydro) (oxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.63 mmol) The liquid was cooled in ice water and dissolved in 60% sodium hydride in mineral oil (30 mg, 0.75 mmol). The mixture was stirred in ice for 30 minutes, then at room temperature for 1.5 hours. Then, methyl iodide (0.118 mL, 1.9 mmol) was added, and the mixture was stirred at room temperature overnight. Add a drop of H 2 The mixture was quenched with 200 mL of ethyl acetate and then concentrated to remove THF. The residue was diluted with saturated N aHCO 3 Partition between aqueous solution and DCM (x2) and pass the organic phase through a phase separator. Concentrate and obtain crude tert-butyl (2R)-4,4-difluoro-2-(methoxymethyl) Pyrrolidine-1-carboxylate (110 mg, 69%) was obtained as an oil. LCMS (Method C): m / z 274 (M+Na) + (ES + ), 1.35 minutes, no UV Active.

[0332] Crude tert-butyl (2R)-4,4-dihydro-3H-pyridine in DCM (2 mL) and TFA (2 mL) Fluoro-2-(methoxymethyl)pyrrolidine-1-carboxylate (110 mg, 0 A solution of 1.44 mmol) was stirred at room temperature for 40 min, then diluted with toluene and concentrated. The residue was azeotroped with toluene (×2) to give crude (2R)-4,4-difluoro-2-(methoxyphenyl)- Methyl)pyrrolidine trifluoroacetate was obtained as an oil (172 mg, >100%). Ta. LCMS (Method C): m / z 152 (M+H) + (ES + ), 0.73 minutes, no UV Active.

[0333] Crude (2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidine trifluoroacetate The acid salt (172 mg, assumed 0.44 mmol) was dissolved in DMF (5 mL). IPEA (0.38mL, 2.2mmol), AcOH (0.038mL, 0.66mm ol), tert-butyl 4-oxopiperidine-1-carboxylate (0.087g , 0.44 mmol) and STAB (0.278 g, 1.3 mmol) were added in that order. The mixture was stirred at room temperature for 2 days and then concentrated to remove DMF. The residue was washed with saturated NaHC O 3 Partition between aqueous solution and DCM (x2) and pass the organic phase through a phase separator and concentrate. Crude tert-butyl 4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidone Lysine-1-yl]piperidine-1-carboxylate (0.241 g, >100%) Obtained as an oil. LCMS (Method C): m / z 335 (M+H) + (ES + ), 1.43 minutes, no UV Active.

[0334] Crude tert-butyl 4-[(2R)-4, 4-Difluoro-2-(methoxymethyl)pyrrolidin-1-yl]piperidine-1-carboxamide A solution of the carboxylate (0.241 g, assumed 0.44 mmol) was stirred at room temperature for 45 min. The mixture was then diluted with toluene and concentrated. The residue was azeotroped with toluene (×2) to give crude intermediate 17. 4,4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidine-1-yl The obtained product was trifluoroacetate as an oil. Data for the title compounds are in Table 2.

[0335] Intermediate 179, 1-[(2R)-4,4-difluoro-1-(piperidin-4-yl)piperidin] Procedure for preparing [roridin-2-yl]ethanol trifluoroacetate [ka] tert-Butyl (2R)-4,4-difluoro-2-(hydro) (oxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.63 mmol) The solution was cooled in ice water and dissolved in Dess-Martin periodinane (402 mg, 0.95 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 3 h. Saturated NaHCO 3 aqueous solution (5 mL), saturated aqueous sodium thiosulfate (5 mL) and EtOAc (10 mL) were added. The mixture was then stirred vigorously for 30 min, the phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic phase was passed through a phase separator and concentrated to give the crude aldehyde. was immediately dissolved in THF (5 mL), cooled to -78 °C, and added to ether (3 M, 0.42 ml). The mixture was cooled to 100° C. and treated with methylmagnesium bromide in 1 mL of 1.3 mmol. Remove and stir for 2.75 h, then add saturated NH 4 It was quenched by addition of aqueous Cl. The mixture was concentrated to remove THF and then washed with saturated NH 4 Partitioned between Cl and DCM (x2). The organic phase was passed through a phase separator and concentrated onto flash silica (10 mL). The resulting powder was purified by column chromatography (normal phase, Biotage SNAP column) Trudge KP-sil 25g, 40-63μm, 60Å, 30mL / min, isohexa 20-50% EtOAc in hexane to give tert-butyl (2R)-4,4- Difluoro-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (0.1 The product was obtained (0.06 g, 67%) as an oil. LCMS (Method C): m / z 152 (M-BOC+H) + , 196(M-tBu+H ) + (ES + ), 1.24 minutes, UV inert.

[0336] tert-Butyl (2R)-4,4-difluorophenyl ether in DCM (2 mL) and TFA (2 mL) Fluoro-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (102 mg A solution of 0.41 mmol) was stirred at room temperature for 30 minutes and then diluted with toluene and concentrated. The residue was azeotropically distilled with toluene to give crude 1-[(2R)-4,4-difluoropyrrolidine- The 2-yl]ethanol trifluoroacetate was obtained as a gum and was used immediately. LCMS (Method C): m / z 152 (M+H) + (ES + ), 0.27 minutes, UV inactive sex.

[0337] Crude 1-[(2R)-4,4-difluoropyrrolidin-2-yl]ethanol from above The trifluoroacetate salt (estimated 0.41 mmol) was dissolved in DMF (5 mL). , DIPEA (0.38mL (mLm), 2.0mmol), AcOH (0.035mL , 0.61mmol), tert-butyl 4-oxopiperidine-1-carboxylate (0.081 g, 0.41 mmol) and STAB (0.258 g, 1.2 mmol). The mixture was stirred at room temperature for 3 days and then concentrated to remove DMF. The residue was azeotroped with toluene, dissolved in MeOH and concentrated onto flash silica (5 mL). The resulting powder was purified by column chromatography (normal phase, Biotage SNAP Cartridge) Ridge KP-sil 25 g, 40-63 μm, 60 Å, 30 mL / min, 0- 15% Solvent A, where Solvent A is 10% in MeOH (7M NH3 / MeOH) ) and purified by tert-butyl 4-[(2R)-4,4-difluoro-2-(1 -hydroxyethyl)pyrrolidin-1-yl]piperidine-1-carboxylate (0. The product was obtained as an oil (301 g, >100%). LCMS (Method C): m / z 335 (M+H) + (ES + ), 1.41 minutes, no UV Active.

[0338] tert-Butyl 4-[(2R)-4,4 -Difluoro-2-(1-hydroxyethyl)pyrrolidin-1-yl]piperidine-1- A solution of carboxylate (0.301 g, assumed 0.41 mmol) was stirred at room temperature for 30 min. The residue was azeotroped with toluene to give crude intermediate 179, 1-[(2R)-4,4-difluoro-1-(piperidin-4-yl)pyrrolidine-2- The trifluoroacetate salt of 1,3-diylethanol was obtained as an oil (0.553 g, >100%). Data for the title compounds are in Table 2.

[0339] To prepare intermediate 215, 4-(1H-tetrazol-1-yl)piperidine hydrochloride Steps [ka] Triethyl orthoformate (3.5 g, 23 mmol), tert-butyl 4-aminopiperidine Lysine-1-carboxylate (0.80 g, 3.9 mmol) and sodium azide ( 1.52 g, 23 mmol) was dissolved in acetic acid (50 mL). The mixture was stirred at 100° C. for 6 h and then cooled to room temperature. The volatiles were removed by concentration. The residue is H 2 The mixture was partitioned between O (100 mL) and ethyl acetate (150 mL). (2 × 100 mL) and the combined organic layers were dried (Na 2 SO 4 ),solvent The crude product was obtained by concentration, which was triturated with diethyl ether to give tert -Butyl 4-(1H-tetrazol-1-yl)piperidine-1-carboxylate(0 0.51 g, 9%) as a solid. LCMS (Method F): m / z 254 (M+H) + (ES + ), 1.92 minutes, weak UV Active.

[0340] tert-Butyl 4-(1H-tetrazol-1-yl)piperidine-1-carboxylate The rate (0.51 g, 2.0 mmol) was dissolved in 1,4-dioxane (10 mL). A solution of HCl in 1,4-dioxane (4 M, 5 mL, 20 mmol) was added dropwise to the resulting The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed by concentration, and the residue was diluted with diethyl ether. The mixture was purified by trituration with ether (3×10 mL) to give intermediate 215, 4-(1H-tetrahydrofuran)- The compound was obtained as a solid, 0.30 g (97%) of 1-pyrazol-1-ylpiperidine hydrochloride. Data for this compound are given in Table 2.

[0341] Intermediate 218, 4-(1-cyclopropyl-1H-tetrazol-5-yl)piperidine Procedure for preparing the hydrochloride salt [ka] 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.0 g, 8. 7 mmol) and cyclopropylamine (0.6 mL, 8.7 mL) in DMF (45 mL HATU (3.3 g, 8.7 mmol) was added at room temperature, followed by DIPEA (3.1 mL, 17 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with cold water (250 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated to obtain a crude product. Graphy (normal phase, neutral silica gel, 60-120 mesh, 0-35% Et in hexane) OAC) to obtain tert-butyl 4-(cyclopropylcarbamoyl)piperidine. Lysine-1-carboxylate (1.5 g, 64%) was obtained as a solid. LCMS (Method F): m / z 269 (M+H) + (ES + ), 1.80 minutes, weak UV activation sex.

[0342] tert-Butyl 4-(cyclopropylcarbamoyl)piperidine-1-carboxylate phosphate (1.5 g, 5.6 mmol) and triphenylphosphine (2.9 g, 11 mmol). l) was dissolved in THF (160 mL). DIAD (2.26 g, 11 mmol) was added at room temperature. Trimethylsilyl azide (1.3 g, 11 mmol) was added over 15 min. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (250 mL) and EtOAc was added. The combined organic layers were dried (Na 2 SO 4 ), concentrated The crude product was obtained by column chromatography (normal phase, neutral silica gel, 60-1 20 mesh, 0-30% EtOAC in hexane) to give tert-butyl 4 -(1-Cyclopropyl-1H-tetrazol-5-yl)piperidine-1-carboxy The rate (400 mg, 24%) was obtained as a solid. LCMS (Method F): m / z 294 (M+H) + (ES + ), 1.96 minutes, weak UV Active.

[0343] tert-Butyl 4-(1-cyclopropyl-1H-tetrazol-5-yl)piperidine Diazine-1-carboxylate (400 mg, 1.4 mmol) in dioxane (5 mL) A solution of HCl in dioxane (4 M, 5 mL, 20 mmol) was added at 0° C. The mixture was stirred at room temperature for 5 h. The solvent was removed by concentration, and the residue was dissolved in diethyl ether (1 0 mL) to give intermediate 218, 4-(1-cyclopropyl-1H-tetrazole- 5-yl)piperidine hydrochloride (260 mg, 98%) was obtained as a solid. Relevant data are in Table 2.

[0344] Intermediate 193, 1-(piperidin-4-yl)pyrrolidine-2,5-dione trifluoro Procedure for preparing acetate salt [ka] Succinimide (0.099 g, 1.0 mmol), tert-butyl 4-hydroxy Piperidine-1-carboxylate (0.221 g, 1.10 mmol and triphenyl Phosphine (0.314 g, 1.20 mmol) was dissolved in THF (5 mL) and then Treat with diisopropyl azodicarboxylate (0.236 mL, 1.20 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated onto flash silica (5 mL). The powder was purified by column chromatography (normal phase, Biotage SNAP cartridge KP-sil 25g, 40-63μm, 60Å], 30mL / min, 20 in isohexane % to 100% EtOAc) to obtain tert-butyl 4-(2,5-dioxo Pyrrolidin-1-yl)piperidine-1-carboxylate (0.253 g, 90%) Obtained as a solid. LCMS (Method C): m / z 305 (M+Na) + (ES +), 1.11 minutes, UV inert

[0345] tert-Butyl 4-(2,5-dioxopropyl)acetate in DCM (3 mL) and TFA (3 mL) Pyrrolidin-1-yl)piperidine-1-carboxylate (0.141 g, 0.50 m The solution of (mol) was stirred at room temperature for 30 minutes, then diluted with toluene and concentrated. Azeotropic distillation with toluene afforded intermediate 193, 1-(piperidin-4-yl)pyrrolidine-2,5 The 4-dione trifluoroacetate was obtained as a gum and was used immediately. The relevant data are in Table 2.

[0346] Intermediate 229, Ethyl 2-([2,4'-bipiperidine]-1'-yl)-6-azaspipri Procedure for preparing b[3.4]octane-6-carboxylate [ka] 2-Bromopyridine (10.0 g, 63.3 mmol) in dry THF (60 mL) To the solution, n-butyllithium (79.1 mL, 2.5 M in hexane, 126 mmol) was added. The mixture was added slowly at -78°C. After stirring at this temperature for 30 min, tert-Butyl 4-oxopiperidine-1-carboxylate (13.8 g, 69.6 The reaction temperature was gradually raised to room temperature and stirred for 2 hours. After cooling to 0° C., the reaction mixture was carefully quenched with ice-cold water (50 mL). After removing the material, the aqueous layer was extracted with ethyl acetate (3×50 mL). The organic layers were combined and saturated. Wash with saline and dry (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was Column chromatography [normal phase, silica gel (100-200 mesh), gradient: 0% to 30% ethyl acetate in xanthan gum to obtain tert-butyl 4-hydroxyethyl ester. -4-(pyridin-2-yl)piperidine-1-carboxylate (11.4 g, 65%) ) was obtained as a yellow oil. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.48(s, 9H), 1.56 - 1.63(m,2H), 1.90 - 2.0(m, 2H), 3.25 - 3.46( m, 2H), 4.05- 4.22(m, 2H), 5.29(br.s., 1H), 7. 20 - 7.25(m, 1H), 7.32(d, J = 8.0, Hz, 1H), 7.73 (dt, J = 1.6,8.4 Hz, 1H), 8.53(d, J = 4.8 Hz, 1H ).

[0347] tert-Butyl 4-hydroxy-4-(pyridine-2- To a solution of 11.4 g (41.0 mmol) of 1,2-diphenyl-2,4-diphenyl-1,3 ... POCl 3 (5.7 mL, 61.5 mmol) was added and the mixture was stirred at room temperature for 20 hours. After removing the amine in vacuo, the reaction mixture was quenched with aqueous NaOH (10%, 30 mL) and The mixture was extracted with chloroform (2×30 mL). The organic layers were combined, dried (Na 2 SO 4 ) The residue was purified by flash column chromatography [normal phase, silica gel Purified with hexane (100-200 mesh), gradient: 0%-30% ethyl acetate in hexane tert-Butyl 3',6'-dihydro-[2,4'-bipyridine]-1'(2 The resulting product was the 'H)-carboxylate (2.3 g, 21%) as a yellow oil. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.48(s, 9H), 2.61 - 2.70(m,2H), 3.60 - 3.70(m, 2H), 4.10 - 4.19 (m, 2H), 6.58- 6.62(m, 1H), 7.11 - 7.19(m, 1H) , 7.36(d, J = 7.88Hz, 1H), 7.62 - 7.66(m, 1H), 8.55(d, J= 4.4 Hz, 1H).

[0348] CH 2 Cl 2 tert-Butyl 3',6'-dihydro-[2,4'- Bipyridine-1'(2'H)-carboxylate (2.3 g, 8.84 mmol) In the liquid, PtO 2 (200 mg, 0.88 mmol) was added and the reaction mixture was incubated at room temperature for 2 days with H 2 The reaction mixture was filtered through a pad of Celite and washed with MeOH. The residue was purified by flash column chromatography [normal phase, silica gel ( 100-200 mesh), gradient: 0% to 1 in DCM with 0.1% aqueous ammonia 5% MeOH] to give tert-butyl[2,4'-bipiperidine]-1' -carboxylate (1.05 g, 44%) was obtained as a colorless oil. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.30 - 1.40(m,1H) ,1.48(s,9H),1.60 - 1.91(m,8H),2.45- 2.55( m,2H),2.58 - 2.75(m,4H),3.24- 3.31(m,1H), 4.14 - 4.24(m,2H).

[0349] tert-Butyl[2,4'-bipiperidine]-1'-carboxylate in THF (5 mL) A solution of the sylate (1.05 g, 3.91 mmol) in THF (5 mL) was Su (975 mg, 3.91 mmol) was added and the mixture was stirred at room temperature for 2 hours. (20 mL) and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). It was then washed with saturated saline and dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Flash column chromatography [normal phase, silica gel (100-200 mesh), Gradient: 0% to 20% ethyl acetate in hexanes] to give 1-benzyl 1'-(t ert-butyl) [2,4'-bipiperidine]-1,1'-dicarboxylate (840 mg, 53%) as a colorless oil. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.44(s, 9H), 1.50 - 1.63(m,2H), 1.68 - 1.92(m, 4H), 1.95 - 2.14 (m, 2H), 2.55- 2.80(m, 2H), 2.81 - 2.95(m, 4H) , 2.98 - 3.10(m,1H), 3.75 - 4.24(m, 3H), 5.11( s, 2H), 7.34- 7.37(m, 5H)].

[0350] CH 2 Cl 2 1-Benzyl 1'-(tert-butyl) [2,4'- Solution of 1,1'-bipiperidine dicarboxylate (840 mg, 2.1 mmol) HCl in dioxane (10 mL, 4 M) was slowly added at 0° C., and the reaction mixture was allowed to stand at room temperature. The reaction mixture was stirred at rt for 2 h. 3 (20 mL) and the aqueous layer was CH 2 Cl 2 (2×20 mL). The organic layers were combined, dried (Na 2 SO 4 ) The residue was purified by flash column chromatography [normal phase, silica gel 100-200 mesh, gradient: 0% in DCM with 0.1% aqueous ammonia ~15% MeOH] to obtain benzyl[2,4'-bipiperidine]-1-carboxamide. The xylate (570 mg, 90%) was obtained as a colorless sticky solid. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.35 - 1.70(m, 6H ), 1.71 -1.98(m, 4H), 2.46 - 2.63(m, 2H), 2.68 - 2.73(m,1H), 3.03 - 3.18(m, 1H), 3.65 - 3.80 (m, 2H), 3.86- 4.16(m, 2H), 5.11(s, 2H), 7.34 - 7.37(m,5H).

[0351] CH 2 Cl 2 Benzyl[2,4'-bipiperidine]-1-carboxylate in (15 mL) ethyl 2-oxo-6-azaspiro[3. 4] A solution of octane-6-carboxylate (305 mg, 1.55 mmol) was added to Ti (O i P) 4(1.6 mL, 5.16 mmol) was added and stirred at 0°C for 40 minutes. Add NaBH to the reaction mixture. 4 (1.1 g, 5.16 mmol) was added and stirred at this temperature for 2 hours. Stirring was continued. The reaction mixture was quenched with water (20 mL) and the aqueous layer was washed with CH 2 Cl 2 (2×20 The organic layers were combined, dried (Na 2 SO 4 ), filtered and concentrated in vacuo The residue was purified by preparative HPLC (reverse phase, XBRIDGE, C-18, 19×250 mm, 5μ, Gradient: 0.1%NH 4 68%-90% ACN in water containing OH, 214 nm, room temperature: The isomers were purified by isomer-1 at 7.45 min and isomer-2 at 8.37 min. Ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate isomer 1 , (120 mg, 15%) and ethyl 2-oxo-6-azaspiro[3.4]octane- 6-Carboxylate isomer-2, (160 mg, 19%) as a colorless sticky solid Got it. Isomer-1: LCMS (Method L): m / z 484 (M+H) + (ES+), 5.70 minutes, UV active sex. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.10 - 1.32(m, 6H) , 1.36 - 1.95(m,14H), 2.00 - 2.18(m, 2H), 2.52 - 3.05(m,4H), 3.20 - 3.45(m, 4H), 3.87 - 4.18 (m, 4H), 5.11(s,2H), 7.30 - 7.35(m, 5H). Isomer-2: LCMS (Method L): m / z 484 (M+H)+ (ES+), 5.81 minutes, UV active sex. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.10 - 1.32(m, 6H) , 1.35 - 1.53(m,5H), 1.62 - 1.80(m, 5H), 1.81 - 1.97(m,4H), 2.00 - 2.18(m, 2H), 2.52 - 3.00 (m, 4H), 3.18- 3.52(m, 4H), 3.88 - 4.20(m, 4H) , 5.11(s, 2H), 7.32- 7.37(m, 5H).

[0352] Ethyl 2-oxo-6-azaspiro[3.4]octane-6 in MeOH (20 mL) -A solution of the mixture of isomers of carboxylate (1.0 g, 2.06 mmol) was added at 10% Palladium on charcoal (320 mg, 50% wet) was added and the reaction mixture was incubated at room temperature for 16 h. 2 Atmosphere The reaction mixture was filtered through a pad of Celite, washed with MeOH, Concentration in vacuo and trituration with pentane afforded intermediate 229, ethyl 2-([2,4'-bipiperidinyl]

[44] -1'-yl)-6-azaspiro[3.4]octane-6-carboxylate 5 mg, 92%) was obtained as a colorless liquid. Data for the title compound are in Table 2.

[0353] Intermediate 243, tert-Butyl 1-(piperidin-4-yl)-1,3-dihydro-2 Procedure for preparing H-isoindole-2-carboxylate [ka] Isoindoline-1-carboxylic acid hydrochloride (5.0 g, 25 mL) in methanol (60 mL) 0.0 mmol) solution, 2 (2.7mL, 37.5mmol) was slowly heated at 0℃. The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was concentrated in vacuo. The residue was triturated with diethyl ether to give methyl isoindoline-1-carboxylate hydrochloride. The salt (4.9 g, 92%) was obtained as an off-white solid. The residue was carried on to the next step without further purification. Used for tepp. 1 H-NMR (400 MHz; DMSO-d 6 ) δ: 3.81(s, 3H), 4. 52 - 4.63(m, 2H), 5.70(s, 1H), 7.44 - 7.50(m, 4) H), 9.77(br.s.,2H).

[0354] Methyl isoindoline-1-carboxylate hydrochloride (4.9 mL) in DCM (50 mL) g, 23.0 mmol) was added to a solution of Et 3 N (9.9 mL, 69.0 mmol) and (B oc) 2 O (8.0 mL, 34.0 mmol) was added sequentially at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was stirred for 12 hours. The reaction mixture was quenched with water (20 mL). The organic layer was separated and then The aqueous layer was separated into CH 2 Cl 2 (3×15 mL). The organic layers were combined and washed with saturated saline. , dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography. HPLC [normal phase, silica gel (100-200 mesh), gradient: 10% in hexane ~30% ethyl acetate] to obtain 2-(tert-butyl) 1-methylisopropyl Doline-1,2-dicarboxylate (6.5 g, 90%) was obtained as a colorless liquid. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.52(s, 9H), 3.75( s, 3H), 4.65- 4.85(m, 2H), 5.45(s, 1H), 7.25 - 7.43(m, 4H).

[0355] 2-(tert-Butyl)1-methylisoindoline-1,2 in THF (60 mL) A solution of LAH (2M, 11. 5mL, 23.0mmol) was added slowly at 0°C and stirred for 30 minutes. After completion, the reaction The mixture is saturated with Na 2 SO 4 The reaction mixture was quenched with aqueous solution (20 mL). Filter through a pad, wash with ethyl acetate (100 mL), dry (Na 2 SO 4 ) , concentrated in vacuo to give tert-butyl 1-(hydroxymethyl)isoindoline-2-carboxylate. The crude residue was purified further to give the carboxylate (5.2 g, 91%) as an off-white solid. was used in the next step without any 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.52(s, 9H), 3.70 - 3.78(m,1H), 3.98 - 4.03(m, 1H), 4.60 - 4.69 (m, 1H), 4.70- 4.85(m, 2H), 5.22(br.s., 1H), 7 .25 - 7.40(m, 4H).

[0356] tert-Butyl 1-(hydroxymethyl)isoindoline in DCM (100 mL) A solution of 1,2-dicarboxylate (5.2 g, 20.0 mmol) was added to Dess-Martin periodontate. Add azinan (27 g, 62.0 mmol) in small portions at 0° C., and stir at room temperature for 48 hours. Upon completion, the reaction mixture was filtered through a pad of Celite and washed with diethyl ether (3×20 The filtrate was washed with saturated NaHCO 3 Wash with aqueous solution and saturated saline, then dry ( Na 2 SO 4 ), concentrated in vacuo to give tert-butyl 1-formylisoindoline-2-carboxylate. The crude residue was purified further to give the carboxylate (4.5 g, 88%) as a brown liquid. was used in the next step without any 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.48(s, 9H), 4.65 - 4.90(m,2H), 5.29 - 5.35(s, 1H), 7.25 - 7.35 (m, 4H), 9.51(s,1H).

[0357] A solution of NaH (874 mg, 18.2 mmol) in THF was added to trimethyl phosphonoacetate. After stirring at -78°C for 1 h, the mixture was cooled to -78°C and then cooled to -78°C for 1 h. , tert-butyl 1-formylisoindoline-2-carboxylate (4.5 g, 1 8.2 mmol) was slowly added and the reaction mixture was allowed to warm to 0° C. Upon completion, the reaction mixture Saturated NH 4 Quench with aqueous Cl (10 mL) and dilute the aqueous layer with ethyl acetate (3×20 mL). The organic layers were combined and dried (Na 2 SO 4 ), concentrated in vacuum, and (E)-1-(3-methoxy-3-oxoprop-1-en-1-yl)isoindoline Phosphorus-2-carboxylate (5.2 g, 92%) was obtained as a brown liquid. Used in the next step without further purification. MS(ESI+ve):304

[0358] tert-Butyl (E)-1-(3-methoxy-3-oxo) prop-1-en-1-yl)isoindoline-2-carboxylate (5.2 g, 17 0.2mmol) solution of Cs 2 CO 3 (11.1g, 34.4mmol) at room temperature in small amounts After stirring for 20 minutes, methyl cyanoacetate (3.0 mL, 34.4 mmol) was added. Slowly added and the reaction mixture was stirred at 70° C. for 16 hours. The filtrate was filtered through a pad of ethyl acetate and washed thoroughly with hexane (3×20 mL). Concentrate in vacuum to obtain dimethyl 3-(2-(tert-butoxycarbonyl)isoindoline- 1-yl)-2-cyanopentanedioate) (5.5 g, crude (cr)) was dissolved in brown sticky water. The crude residue was used in the next step without further purification. MS(ESI+ve):403

[0359] Dimethyl 3-(2-(tert-butoxycarbonyl)isopropyl) To a solution of (indolin-1-yl)-2-cyanopentanedioate (1.6 g, crude), LiCl (500 mg, 11.7 mmol) was added, followed by water (0.1 mL, catalyst). The reaction mixture was stirred at 135° C. for 16 h. Upon completion, the reaction mixture was diluted with water (20 mL). The mixture was quenched with 10 mL of ethyl acetate and the aqueous layer was extracted with diethyl ether (3×20 mL). Dry (Na 2 SO 4 ), concentrated in vacuo to give tert-butyl 1-(1-cyano-4-methyl Tox-4-oxobutan-2-yl)isoindoline-2-carboxylate (1.5 g, crude) as a brown semi-solid. The crude residue was used in the next step without further purification. Used. MS(ESI+ve):345

[0360] tert-Butyl 1-(1-cyano-4-methoxy-4-oxo) xobutan-2-yl)isoindoline-2-carboxylate (300 mg, 0.8 m To a solution of 1.2 mmol of ethyl acetate, Raney nickel (0.30 g, wet) was added and the reaction mixture was heated to 50°C. H 2 The mixture was heated under 50 psi for 2 hours. The reaction temperature was then increased to 70° C. Stirred for 3 h. Upon completion, the reaction mixture was filtered through a pad of Celite and diluted with MeOH(2 The residue was triturated with diethyl ether (30 mL) and concentrated in vacuo. ert-Butyl 1-(2-oxopiperidin-4-yl)isoindoline-2-carboxylate The sylate (0.21 g, 76%) was obtained as a brown solid. MS(ESI+ve):317

[0361] tert-Butyl 1-(2-oxopiperidin-4-yl)isocyanate in THF (5 mL) A solution of indoline-2-carboxylate (210 mg, 0.60 mmol) was added to BH 3 -DMS (0.5 mL, 6.60 mmol) was added slowly at 0 °C, and the reaction mixture was cooled to 78 °C. After cooling at 0° C., the reaction mass was dissolved in methanol (0.5 mL), followed by Quenched with water (1 mL). To the crude reaction mass was added 5% MeOH / DCM (30 mL) The filtrate was concentrated in vacuo. The residue was triturated with diethyl ether (20 mL) to give ert-butyl 1-(piperidin-4-yl)isoindoline-2-carboxylate, Intermediate 243 (200 mg, 99%) was obtained as a brown solid. The data are in Table 2.

[0362] Preparation of intermediate 247, 4-(2H-1,2,3-triazol-2-yl)piperidine Steps to take [ka] tert-Butyl 4-hydroxypiperidine-1-carboxylate (0.500 g, 2.4mmol) in CH 2 Cl 2 and then dissolved in DMAP (0.302 g, 2.4 mm ol) and methanesulfonyl chloride (0.284 g, 2.48 mmol) were added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 6 h and then 2 O (70 mL) and C H 2 Cl 2 (70 mL), and the aqueous layer was separated into CH 2 Cl 2 (2 x 70 mL) The organic layers were combined and dried (Na 2 SO 4 ), filtered, and the solvent removed in vacuo to give crude tert t-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate(0 The product was obtained as a white solid (0.520 g, 75.0%), which was used directly without further purification. Used. 1 H-NMR(400 MHz;DMSO) δ: 1.23(d, J = 9.38 H z, 2H)1.54- 1.69(m, 4H)1.86 - 1.96(m, 2H)2.3 5(s, 1H)2.85- 3.00(m, 2H)3.18(d, J = 5.42 Hz, 5H)3.54 - 3.67(m, 4H)4.83(s, 1H).

[0363] 1H-1,2,3-triazole (0.098 g, 1.4 mmol) was dissolved in DMF (5 mL ), NaH (0.037 g, 1.5 mmol) was added, and the mixture was stirred at 0° C. for 30 minutes. tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate The reaction mixture was stirred at 150° C. for 1 hour. H 2 Partition between 2×O (50 mL) and EtOAc (50 mL), and the aqueous layer is diluted with EtOAc (2×50 The organic layers were combined and dried (Na 2 SO 4 ), filtered, and the solvent was removed. After removal of the solvent, crude tert-butyl 4-(2H-1,2,3-triazol-2-yl)piperidin was obtained. Peridine-1-carboxylate (0.350 g, 97.0%) was obtained as a colorless gum. This was used directly without further purification. LCMS (Method F): m / z 253 (M+H) + (ES+), 1.95 minutes, UV active .

[0364] tert-Butyl 4-(2H-1,2,3-triazol-2-yl)piperidine-1 -carboxylate (0.500 g, 1.9 mmol) in 1,4-dioxane (10 mL ), followed by the dropwise addition of HCl in 1,4-dioxane (5 mL, 4 M). The resulting reaction mixture was stirred at 25° C. for 16 h, the solvent was removed in vacuo, and the residue was dissolved in diethyl ether. The mixture was purified by trituration with ethanol (3 × 10 mL) to give 4-(2H-1,2,3-trimethylsilyl) (2-(2-phenyl-2-yl)piperidine hydrochloride, intermediate 247, (0.290 g, 96.3%) Obtained as a pale white solid. Data for the title compound are in Table 2.

[0365] Intermediate 255, 4-(5-methyl-1H-tetrazol-1-yl)piperidine hydrochloride Procedure for preparation [ka] 5-Methyl-2H-tetrazole (0.500 g, 5.9 mmol) and tert-butyl Add 4-bromopiperidine-1-carboxylate (1.29 g, 4.8 mmol) to D Dissolved in MF. 2 CO 3 (1.64 g, 11.8 mmol) was added to the resulting reaction mixture. The reaction mixture was stirred at 100° C. for 6 h and then H 2 O (100 mL) and ethyl acetate (150 The aqueous layer was further extracted with ethyl acetate (2×100 mL) and the organic layers were combined. Then, it was dried (Na 2 SO 4 ), filtered and the solvent removed in vacuo. The residue was purified by CombiFlash. Column chromatography (normal phase, neutral silica gel, 60-120 mesh, in hexane 10~20% EtOAc) to obtain tert-butyl 4-(5-methyl-1H -tetrazol-1-yl)piperidine-1-carboxylate (0.280 g, 34. 6%) as a white solid. 1 H-NMR(400 MHz, DMSO) δ: 1.43(s, 9H), 1.73 - 1.88(m, 2H),2.01(br.s., 2H), 2.68 - 2.75(m, 3H), 2.88- 2.91(m, 2H), 4.03 - 4.10(m, 2H), 4. 60 - 4.70(m, 1H).

[0366] tert-Butyl 4-(5-methyl-1H-tetrazol-1-yl)piperidine-1 -carboxylate (0.280 g, 1.04 mmol) in 1,4-dioxane (10 ml L) and then HCl in 1,4-dioxane (5 mL, 4 M) was added dropwise. The resulting reaction mixture was stirred at 25° C. for 16 h, the solvent was removed in vacuo, and the residue was dissolved in diethyl ether. The mixture was purified by trituration with ethanol (3 × 10 mL) to give 4-(5-methyl-1H-tetrahydrofuran). (1-phenyl-1-yl)piperidine hydrochloride, intermediate 255 (0.170 g, 97.6%) Data for the title compound is in Table 2.

[0367] Intermediate 258, (R)-2-(4,4-difluoro-1-(piperidin-4-yl)pyrrolidin Procedure for obtaining and preparing lysine-2-yl)propan-2-ol hydrochloride [ka] 1-(tert-butyl) 2-methyl (R)-4,4-dichlorophenyl ether in dioxane (15 mL) Fluoropyrrolidine-1,2-dicarboxylate (500 mg, 1.89 mmol) To the solution, HCl in dioxane (4 M, 15 mL) was slowly added at 0° C. and then stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was triturated with hexane (10 mL). Saturate the residue with NaHCO 3 The crude reaction mass was basified with aqueous solution (10 mL) and concentrated. The filtrate was concentrated in vacuo to give methyl (R)-4,4-difluoroacetate. The resulting mixture was treated with 1,3-dihydropyrrolidine-2-carboxylate (2,320 mg, 84%) as a brown liquid. The crude residue was used in the next step without further purification. 1 H-NMR (400 MHz, CDCl3 ) δ:1.40 - 1.51(m, 1H), 2.58 - 2.84(m, 3H), 3.52 - 3.62(m, 1H), 3.84( s, 3H), 4.40- 4.52(m, 1H).

[0368] Methyl (R)-4,4-difluoropyrrolidine-2-carboxylate in methanol (20 mL) carboxylate (200 mg, 1.21 mmol) and tert-butyl 4-oxopiperi A solution of 10% paradiazine-1-carboxylate (240 mg, 1.21 mmol) was added to the solution. Carbon carbide (300 mg, 50% wet) was added and the reaction mixture was heated to 50° C. 2 (1 atm) at room temperature After stirring for 24 hours, the reaction mixture was filtered through a pad of celite and diluted with methanol. and concentrated in vacuo to give tert-butyl (R)-4-(4,4-difluoro -2-(Methoxycarbonyl)pyrrolidin-1-yl)piperidine-1-carboxylate The compound (400 mg, 95%) was obtained as a colorless liquid. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.32 - 1.45(m, 1H ), 1.45(s,9H), 1.61 - 1.80(m, 4H), 2.39 - 2.49 (m, 1H), 2.50- 2.83(m, 2H), 3.19(s, 3H), 3.35 - 3.49(m,2H), 3.61 - 3.82(m, 3H), 3.94 - 4.05 (m, 1H).

[0369] tert-Butyl (R)-4-(4,4-difluoro-2-( Methoxycarbonyl)pyrrolidin-1-yl)piperidine-1-carboxylate (37 A solution of MeMgBr (3M, 1.07 mL, 3.21 m mol) was added slowly at 0° C. and stirred at room temperature for 4 h. After completion, the reaction mixture was diluted with saturated N H 4 Quench with aqueous Cl (10 mL) and extract the aqueous layer with ethyl acetate (3 × 10 mL). The organic layers were combined and dried (Na 2 SO 4 The crude residue was extracted with HF. Column chromatography [normal phase, silica gel (100-200 mesh), gradient 10% to 30% ethyl acetate in hexane] to obtain tert-butyl (R)- 4-(4,4-difluoro-2-(2-hydroxypropan-2-yl)pyrrolidine-1 -yl)piperidine-1-carboxylate (240 mg, 64%) as a colorless liquid Got it. 1 H-NMR (400 MHz, CDCl 3 ) δ: 1.11(s, 3H), 1.21 (s, 3H), 1.21- 1.40(m, 2H), 1.46(s, 9H), 1.61 - 1.80(m,2H), 2.15 - 2.30(m, 3H), 2.50 - 2.83 (m, 3H), 3.02- 3.23(m, 2H), 4.09 - 4.30(m, 2H) No OH was observed.

[0370] (R)-4-(4,4-difluoro-2-(2-hydroxyphenyl)-2,4-difluoropropanediol in dioxane (10 mL) Cypropan-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (2 A solution of 40 mg, 0.69 mmol) was added to HCl in dioxane (4 M, 10 mL) at 0 °C. The mixture was slowly added with 100 ml of water and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in hexane ( The crude reaction mass was triturated with CH 2 Cl 2 (30 mL) was added and filtered. was concentrated in vacuo to give (R)-2-(4,4-difluoro-1-(piperidin-4-yl)piperidin-4-yl) Roridin-2-yl)propan-2-ol hydrochloride, intermediate 258 (150 mg, 87%) ) was obtained as a brown liquid. Data for the title compound are in Table 2.

[0371] Intermediate 282, tert-butyl(2R)-2-(dimethylcarbamoyl)piperidine- Procedure for preparing 1-carboxylates [ka] (R)-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (0.500 g, 2.18 mmol) was dissolved in anhydrous DCM (8 mL) and the reaction mixture was brought to 0 °C under nitrogen. Cooled at 100°C. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl (0.628g, 3.275mmol), hydroxybenzotriazole (0.334g , 2.183mmol), N-methylmorpholine (1.104g, 10.915mmol l) and dimethylamine hydrochloride (0.356 g, 4.36 mmol) were added to the reaction mixture. The mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with DCM (20 mL) and saturated NaH CO 3 The solution was washed with saturated NaCl(aq) (20 mL) and saturated NaCl(aq) (20 mL). The organic layer was passed through a Biotage phase separator cartridge and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase, Biotage SNAP Cartridge KP- Sil 25g 40-63μm, 60Å, 25mL / min, gradient: 0%-10% MeOH / DCM]) to obtain tert-butyl (2R)-2-(dimethylcarbamoyl (1-methyl) piperidine-1-carboxylate, intermediate 282, (0.241g, 43%) Obtained as an orange oil. Data for the title compound are in Table 2.

[0372] Intermediate 295, tert-butyl(2R)-2-(fluoromethyl)pyrrolidine-1-carboxylate Procedure for preparing carboxylates [ka] (2R)-(+)-1-Boc-2-pyrrolidinemethanol (0.300 g, 1.49 N,N-Diphenylmethane (1 mmol) was dissolved in DCM (8 mL) and cooled to -78 °C under nitrogen. Add ethylaminosulfur trifluoride (0.360g 2.24mmol) dropwise to the reaction mixture. The reaction mixture was stirred under nitrogen at -78°C for 4 hours and then allowed to warm to room temperature overnight. The reaction mixture was saturated with NaHCO 3 Quench by addition of DCM (aq) (20 mL). (2 x 15 mL), and the organic layers were combined and placed on a Biotage phase separator cartridge. The residue was dried by passing it through a ridge and the solvent was removed in vacuum. (normal phase, [Biotage SNAP Cartridge KP-sil 10g 40~6 Purification was performed by HPLC using a 3 μm column, 60 Å column, 12 mL / min gradient: 0% to 4% MeOH / DCM. tert-Butyl (2R)-2-(fluoromethyl)pyrrolidine-1-carboxylate The product was obtained as an amber oil, intermediate 295 (0.104 g, 34%). Data for this compound are given in Table 2.

[0373] Intermediate 285, methyl (4S)-1,3-thiazolidine-4-carboxylate hydrochloride Procedure for preparation [ka] (S)-3-Boc-thiazolidine-4-carboxylic acid (1.00 g, 4.29 mmol) ) in anhydrous DMF (4 mL) and potassium carbonate (2.372 g, 17.16 mmol) ) and iodomethane (0.730 g, 5.14 mmol) were added. The reaction mixture was cooled under nitrogen The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc (40 mL) and diluted with water. (3×20 mL) and saturated NaCl(aq) (20 mL), dried (Mg SO 4 The solvent was removed in vacuo to give 3-tert-butyl-4-methyl(4S)-1,3- Thiazolidine-3,4-dicarboxylate, Intermediate 285, (0.812g, 77%) was obtained as a pale yellow oil. Data for the title compound are in Table 2.

[0374] Intermediate 297, tert-butyl(2R)-2-(difluoromethyl)pyrrolidine-1- Procedure for preparing carboxylates [ka] DMSO (0.698 g, 8.94 mmol) was dissolved in anhydrous DCM (12 mL) to give The reaction was added dropwise to a solution of salil (0.566 g, 2.93 mmol) under nitrogen at -78°C. The mixture was stirred under nitrogen at -78 °C for 15 min, then (2R) in anhydrous DCM (4 mL) was added. -(+)-1-Boc-2-pyrrolidinemethanol (0.600 g, 2.98 mmol) The reaction mixture was stirred under nitrogen at -78 °C for 15 min and then diluted with Et 3 N( 1.06 g, 11.92 mmol) was added and the reaction mixture was stirred under nitrogen at 0° C. for 1 h. The reaction mixture was diluted with saturated NaHCO 3 Quench with (aq) (20 mL) and DCM (2 × 2 The organic layers were combined and loaded onto a Biotage phase separator cartridge. The residue was dried by passing it through a cyclohexane distillation column and the solvent was removed in vacuo. Phase, [Biotage SNAP Cartridge KP-sil 10g 40-63μm, 60 Å, 12 mL / min, gradient: 0% to 4% MeOH / DCM]) to obtain te rt-Butyl (2R)-2-formylpyrrolidine-1-carboxylate (0.435g , 73%).

[0375] tert-Butyl (2R)-2-formylpyrrolidine-1-carboxylate (0.4 Dissolve 35 g, 2.19 mmol) in anhydrous DCM (8 mL) and cool to -78 °C under nitrogen. N,N-diethylaminosulfur trifluoride (0.528 g, 3.28 mmol) ) was added dropwise to the reaction mixture and the reaction mixture was stirred under nitrogen at -78°C for 3 hours and then overnight. The reaction mixture was allowed to warm to room temperature. 3 (aqueous) (20 mL) was added Quench and extract with DCM (2 x 15 mL), combine the organic layers and purify using Biotage The residue was dried by passing through a glass separator cartridge and the solvent was removed in vacuo. Column chromatography (normal phase, Biotage SNAP cartridge KP-sil 10g 40-63μm, 60Å, 12mL / min, gradient: 0%-4% MeOH / DCM ]) to give tert-butyl (2R)-2-(difluoromethyl)pyrrolidine. 1-Carboxylate, Intermediate 297, (0.217g, 45%) as an amber oil Data for the title compounds are in Table 2.

[0376] General procedure for the synthesis of intermediates: Route 1 Preparation of Intermediate 30, 5-(Piperidin-4-yl)-1,2,4-thiadiazole A typical example for preparing piperidines via Suzuki reaction, hydrogenation and Boc deprotection is shown in Typical Procedure [ka] 2-5-Bromo-1,2,4-thiadiazole (108 mg, 0.65 mmol), t ert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.65mmol) and Cs 2 CO 3 (632 mg, 1.94 mmol) in dioxane: The reaction mixture was degassed for 30 min and then dissolved in water (10:2 mL). 2 DPP f (24 mg, 0.03 mmol) was added, and the reaction mixture was then stirred at 90° C. for 16 hours. The mixture is H 2 Partition between 200 (80 mL) and EtOAc (50 mL), and the aqueous layer is diluted with EtOAc ( × 50 mL), the organic layers were combined and dried (Na 2 SO 4 ), and the solvent was removed by vacuum The residue was purified by column chromatography (normal phase silica, mesh size: 60-120 , 16% to 20% EtOAc in hexanes) to give tert-butyl 4-(1 ,2,4-Thiadiazol-5-yl)-3,6-dihydropyridine-1(2H)-cal The carboxylate (158 mg, 92.0%) was obtained as an off-white solid. LCMS (Method F): m / z 212 (M+H-56) + (ES+), 2.37 min, U V activity

[0377] tert-Butyl 4-(1,2,4-thiadiazol-5-yl)-3,6-dihydro Pyridine-1(2H)-carboxylate (200 mg, 0.74 mmol) in MeOH (15 mL) and 10% Pd / C (20 mg) was added. The reaction mixture was stirred at 4°C for 1 h. 2 By gas Purge and incubate at 25 °C for 8 hr. 2 The reaction mixture was stirred under pressure and filtered through Celite. The residue was washed with MeOH, the solvent was removed in vacuo, and the residue was purified by column chromatography ( Silica, mesh size: 60-120, 20%-24% EtOAc in hexane) tert-Butyl 4-(1,2,4-thiadiazol-5-yl) piperidine The resulting product was di-1-carboxylate (150 mg, 74.6%) as a dark green gum. LCMS (Method F): m / z 214 (M+H) + (ES+), 2.14 min, UV active

[0378] tert-Butyl 4-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate The carboxylate (150 mg, 0.56 mmol) was dissolved in 1,4-dioxane (5 mL). The reaction was stirred at 30° C. for 16 h, and HCl in dioxane (10 mL, 3.0 M solution) was added dropwise. The solvent was removed in vacuo and the residue was triturated with diethyl ether (3×3 mL). and purifying the intermediate 30, 5-(piperidin-4-yl)-1,2,4-thiazide. The azole (102 mg, 89.5%) was obtained as a dark green gum. The data are in Table 2.

[0379] Route 2 Intermediate 34, 4-(1,5-dimethyl-1H-imidazol-2-yl)-1,2,3, Procedure for preparing 6-tetrahydropyridine [ka] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola 2.0g , 6.55mmol), 2-bromo-1,5-dimethyl-1H-imidazole (1.13 g, 6.45 mmol) and CsF (2.9 g, 1.85 mmol) in DME:MeOH (2:1, 30 mL). The reaction mixture was degassed for 5 min and then Pd(PPh 3 ) 4 (73 mg, 0.064 mmol) was added and the resulting reaction mixture was heated at 100 °C for 5 h. The reaction mixture was stirred for 1 h. 2 Partition between O (100 mL) and EtOAc (100 mL). The aqueous layer was then further extracted with EtOAc (2×100 mL), and the organic layers were combined and dried (Na 2 SO 4 The residue was purified by column chromatography (normal phase silica, Purified by (shrink size: 60-120, 13%-17% ethyl acetate in hexane) , tert-Butyl 4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6 -Dihydropyridine-1(2H)-carboxylate (1 g, 55%) was obtained as a yellow gum. I got it. LCMS (Method F): m / z 278 (M+H) + (ES + ), 1.70 minutes, UV activity

[0380] tert-Butyl 4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6 -Dihydropyridine-1(2H)-carboxylate (1.0 g, 3.61 mmol) Dissolve in 1,4-dioxane (20 mL) and then add HCl in 1,4-dioxane (20 The resulting reaction mixture was stirred at 30° C. for 16 h and the solvent The solvent was removed in vacuo and the residue was purified by trituration with diethyl ether (3×5 mL). , Intermediate 34, 4-(1,5-dimethyl-1H-imidazol-2-yl)-1,2,3 ,6-Tetrahydropyridine hydrochloride (0.5 g, 65%) was obtained as a white solid. Data regarding the compounds are given in Table 2.

[0381] Route 3 Preparation of Intermediate 65, 3-(Piperidin-4-yl)pyridin-2(1H)-one Hydrochloride To prepare piperidines via Suzuki reaction, hydrogenation and Boc deprotection, as exemplified by Typical procedure [ka] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola 2.5g , 10.0mmol), 3-iodo-2-methoxypyridine (8.21g, 26.0mmol ol) and K 2 CO 3 (4.3 g, 31.8 mmol) in 1-4 dioxane (10 mL) and water (5 mL). The reaction mixture was diluted with N 2 Degas for 15 minutes using Pd-1 32 (0.376 g, 0.53 mmol) was added and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL), and the organic layer was The layers were combined and dried (Na 2 SO 4 The solvent was removed in vacuum, and the crude product was purified by column chromatography. Chromatography (normal phase, 60-120 mesh silica, 0-20% EtOAc in hexane) The compound was purified by tert-butyl 2-methoxy-3',6'-dihydro-[3,4'- Bipyridine-1'(2'H)-carboxylate (2.0 g, 69.0%) was obtained as an off-white solid. Got it as a body. LCMS (Method F): m / z 291 (M+H) + (ES+), 2.39 min, UV active

[0382] tert-Butyl 2-methoxy-3',6'-dihydro-[3,4'-bipyridine] 1'(2'H)-carboxylate (1.89 g, 6.51 mmol) was dissolved in MeOH (10 The reaction mixture was dissolved in 10 mL of 10% Pd / C (0.2 g) and the mixture was cooled to 37°C. 2 Purge with gas Then, incubate at room temperature for 12 hours. 2 The reaction mixture was filtered through Celite and the solvent was removed. Remove in vacuo to give tert-butyl 4-(2-methoxypyridin-3-yl)piperidine The -1-carboxylate (0.91 g, 47.9%) was obtained as a colourless gum. LCMS (Method F): m / z 293 (M+H) + (ES+), 2.50 minutes, UV active

[0383] tert-Butyl 4-(2-methoxypyridin-3-yl)piperidine-1-carboxylate The sylate (0.200 g, 0.6 mmol) was dissolved in 1,4-dioxane (4.0 mL) and water. (2.0 mL), concentrated hydrochloric acid was added, and the reaction mixture was stirred at 100° C. for 10 hours. The solvent was removed in vacuo and the residue was triturated with acetone (3×10 mL) to give intermediate 65, 3-(piperidine). Lysin-4-yl)pyridin-2(1H)-one hydrochloride (0.100 g, 82.6%) Obtained as a brown solid. Data for the title compound are in Table 2.

[0384] Route 4 Preparation of Intermediate 66, 2-Methoxy-3-(piperidin-4-yl)pyridine Hydrochloride A typical example for preparing piperidines via Suzuki reaction, hydrogenation and Boc deprotection is shown in Typical Procedure [ka] tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola 2.5g , 10.0mmol), 3-iodo-2-methoxypyridine (8.21g, 26.0mmol ol) and K 2 CO 3 (4.3 g, 31.8 mmol) in 1-4 dioxane (10 mL) and water (5 mL). The reaction mixture was diluted with N 2 Degas for 15 minutes using Pd-1 32 (0.376 g, 0.53 mmol) was added and the reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL), and the organic layer was The layers were combined and dried (Na 2 SO 4 The solvent was removed in vacuum, and the crude product was purified by column chromatography. Chromatography (normal phase, 60-120 mesh silica, 0-20% EtOAc in hexane) The compound was purified by tert-butyl 2-methoxy-3',6'-dihydro-[3,4'- Bipyridine-1'(2'H)-carboxylate (2.0 g, 69.0%) was obtained as an off-white solid. Got it as a body. LCMS (Method F): m / z 291 (M+H) + (ES+), 2.39 min, UV active

[0385] tert-Butyl 2-methoxy-3',6'-dihydro-[3,4'-bipyridine] 1'(2'H)-carboxylate (1.89 g, 6.51 mmol) was dissolved in MeOH (10 The reaction mixture was dissolved in 10 mL of 10% Pd / C (0.2 g) and the mixture was cooled to 37°C. 2 Purge with gas Then, incubate at room temperature for 12 hours. 2 The reaction mixture was filtered through Celite and the solvent was removed. Remove in vacuo to give tert-butyl 4-(2-methoxypyridin-3-yl)piperidine The -1-carboxylate (0.91 g, 47.9%) was obtained as a colourless gum. LCMS (Method F): m / z 293 (M+H) + (ES+), 2.50 minutes, UV active

[0386] tert-Butyl 4-(2-methoxypyridin-3-yl)piperidine-1-carboxylate The sylate (0.8 g, 2.7 mmol) was dissolved in HCl (4.0 mL, The mixture was stirred in 4.0M solution at room temperature for 10 hours. The solvent was removed in vacuo and the residue was dissolved in acetone (3 × 10 mL) to give intermediate 66, 2-methoxy-3-(piperidine-4-yl) The title compound was obtained as a white solid (0.135 g, 25.7%). Data on this are in Table 2.

[0387] Route 5 Via hydrogenation, exemplified by the preparation of intermediate 69, 3,4'-bipiperidin-2-one Typical procedure for preparing piperidines using [ka] 3-(piperidin-4-yl)-1,6-dihydropyridin-2-ol (0.5 g, 2.8 mmol) was dissolved in MeOH (10 mL) and PtO 2 (0.2g) was added. The reaction mixture was 2 Purge with gas and incubate at room temperature for 12 h. 2 The reaction mixture was stirred under gas. , filtered through Celite, and the solvent removed in vacuo to give intermediate 69, 3,4'-bipiperidine The compound was obtained as a brown gum (0.4 g, 78.3%). The data are in Table 2.

[0388] Route 6 Intermediate 127, Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidine-1- Diastereomers of {6-yl}-6-azaspiro[3.4]octane-6-carboxylate Pyrrolidine via reductive amination and Boc deprotection exemplified by the preparation of a mixture of Typical procedure for the preparation of [ka] (S)-tert-Butyl 2-(piperidin-4-yl)pyrrolidine-1-carboxylate ethyl 2-oxo-6-azaspiro[3. 4] Octane-6-carboxylate (1.60 g, 6.29 mmol) was dissolved in DMF (15 The reaction mixture was dissolved in 10 mL of acetic acid (0.54 mL, 9.44 mmol) at room temperature and acetic acid (0.54 mL, 9.44 mmol) was added. The mixture was stirred at room temperature for 3 hours. STAB (2.67 g, 12.6 mmol) was then added, The reaction mixture was stirred overnight at room temperature under nitrogen. The solvent was removed in vacuo and the residue was purified by column chromatography. Raffy (normal phase, [Biotage SNAP cartridge KP-sil 340g, 4 0-63 μm, 60 Å, 80 mL / min, gradient: 0%-10% 7N in DCM, MeOH NH 3 ]) to obtain ethyl 2-{4-[(2S)-1-(tert-butoxy) 3.)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3. 4] Octane-6-carboxylate (2.46 g, 90%) isomer inseparable mixture The mixture was obtained as a yellow solid. LCMS (Method D): m / z 436 (M+H) + (ES + ), 2.36 minutes, UV inactive sex.

[0389] Ethyl 2-{4-[(2S)-1-(tert-butoxycarbonyl)pyrrolidine-2 -yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxy The mixture of diastereomers of the tetrahydrofuran (0.6 g, 1.4 mmol) was dissolved in 1,4-dioxane (10 mL) and HCl in 1,4-dioxane (4 M, 15 mL, 60 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h, the solvent was removed, and the residue was The residue was purified by trituration with diethyl ether (3×10 mL) to give ethyl 2-{ 4-[(2S)-Pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3 .4] A mixture of diastereomers of octane-6-carboxylate, intermediate 127, was solidified. The compound was obtained as a 25% solid (0.45 g, 97%). Data for the title compound are given in Table 2.

[0390] Route 7 Intermediate 137, 1-(piperidin-4-yl)tetrahydropyrimidin-2(1H)-o Reductive amination, Boc-deprotection, urea formation, and hydrogenation are exemplified by the preparation of Typical Procedure for Preparing Piperidine via Solution [ka] Benzyl 4-oxopiperidine-1-carboxylate (0.932 g, 4.00 mm ol) and tert-butyl (3-aminopropyl)carbamate (0.766 g, 4. 4mmol) in CH 2 Cl 2 (20 mL) at room temperature and mixed with AcOH (0.68 mL, 1 STAB (2.59 g, 12.0 mmol) was added and stirred for 3 hours. was added and the reaction mixture was stirred at room temperature under nitrogen overnight. 3 (saturated water The mixture was quenched by the addition of CH 2 Cl 2 (4 x 45 mL), The combined organic layers were washed with saturated brine and then with MgSO 4 The mixture was dried over 1000 ml and filtered. The solvent was removed in vacuo, and the residue was purified by column chromatography [Biotage SNAP cartridge DiKP-sil 25g, 40-63μm, 60Å, 50mL / min, gradient: 0% in DCM ~10% MeOH]) to obtain benzyl 4-({3-[(tert-butoxy) Carbonyl)amino]propyl}amino)piperidine-1-carboxylate (1.54 g, 98%) as a colorless oil. LCMS (Method B): m / z 392 (M+H) + (ES+), 1.73 min, UV active .

[0391] Benzyl 4-({3-[(tert-butoxycarbonyl)amino]propyl}amino ) Piperidine-1-carboxylate (1.54 g, 3.92 mmol) in CH 2 Cl 2 (19.5 mL) and dissolved in 4 M hydrogen chloride in dioxane (4.90 mL, 19.6 mmol). l) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with CH 2 Cl 2 (2×20 mL) and dried to give crude benzyl 4-[(3-aminopropyl)amine. [0]Piperidine-1-carboxylate dihydrochloride (1.41g, 99%) Obtained as a coloured solid. LCMS (Method B): m / z 292 (M+H) + (ES+), 1.46 minutes, UV active sex.

[0392] Crude benzyl 4-[(3-aminopropyl)amino]piperidine-1-carboxylate Dihydrochloride (1.41 g, 3.88 mmol), CDI (0.778 g, 4.80 (0.24 mL, 12.0 mmol) and pyridine (0.24 mL, 12.0 mmol) were dissolved in THF (39 mL). The mixture was heated to reflux and maintained for 18 hours. The solvent was removed in vacuo and the residue was purified by column chromatography. Topography [Biotage SNAP Cartridge KP-sil 50g, 40~6 Purified by chromatography (3 μm, 60 Å, 50 mL / min, gradient: 0% to 10% MeOH in DCM). Benzyl 4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidinyl The resulting mixture was treated with 1,2-dichloro-1-phenylpropanediol (0.82 g, 65%) as a colorless solid. LCMS (Method B): m / z 318 (M+H) + (ES+), 2.62 min, UV active .

[0393] Benzyl 4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidine 1-Carboxylate (0.82 g, 2.59 mmol) was dissolved in EtOH (100 mL). Dissolve at 50 °C, 1 mL / min and 40 bar H 2 Using the H-Cube set to 10%P The eluted solution was concentrated in vacuo to give intermediate 137, 1-(piperidinediamine). Lysin-4-yl)tetrahydropyrimidin-2(1H)-one (0.470g, 99% ) was obtained as a colorless solid. Data for the title compound are in Table 2.

[0394] Route 8 Intermediate 139, (2S)-N-methyl-1-(piperidin-4-yl)pyrrolidine-2- The preparation of pyridine derivatives was exemplified by the preparation of carboxamides via reductive amination and Boc deprotection. Typical Procedure for Preparing Peridine [ka] (S)-N-methylpyrrolidine-2-carboxamide (0.5 g, 3.8 mmol), NEt 3 (1.5mL, 11.0mmol), tert-butyl 4-oxopiperidine- 1-carboxylate (0.38 g, 3.9 mmol) and ZnCl 2 (0.15g, 4 0.5 mmol) in MeOH (15 mL) under nitrogen and stirred at 50-60°C for 1 h. NaCNBH 3 (0.16g, 0.67mmol) was added in small portions at 0-10°C and mixed. The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (2×100 mL) and water (50 ml). L), and the organic layers were combined, dried and 2 SO 4 ), filtered and the solvent removed in vacuo. The crude product was purified by column chromatography (normal phase silica, 0-20% EtOAc in hexanes). ) and purified by tert-butyl (S)-4-(2-(methylcarbamoyl)pyrrolidone. Lysine-1-yl)piperidine-1-carboxylate (0.3 g, 25.0%) was added to a light brown Obtained as a coloured liquid. TLC observation: RF value: 0.5 (EA:Hex, 5:5). LCMS (Method G): m / z 312 (M+H) + (ES+), 1.61 minutes, UV deactivated sex.

[0395] tert-Butyl (S)-4-(2-(methylcarbamoyl)pyrrolidin-1-yl) Piperidine-1-carboxylate (0.3 g, 0.96 mmol) was added to 1,4-dioxo The reaction mixture was stirred in HCl (5.00 mL) in water at room temperature for 10 hours. The mixture was concentrated under high vacuum and triturated with acetone (3 x 10 mL). , Intermediate 139, (S)-N-methyl-1-(piperidin-4-yl)pyrrolidine-2- Carboxamide dihydrochloride (0.135 g, 67.16%) was obtained as a colorless solid. Data for the title compounds are in Table 2.

[0396] Route 9 Intermediate 181, 4-[2-(1H-pyrazol-5-yl)pyrrolidin-1-yl]piperidine The 4-position can be modified via reductive alkylation and deprotection, as exemplified by the preparation of lysine trifluoroacetate. General Procedure for Preparing Piperidines with N-Linked Cyclic Amines [ka] 5-(pyrrolidin-2-yl)-1H-pyrazole dihydrochloride (0.105 g, 0.50 mmol) was dissolved in DMF (5 mL). L, 2.5 mmol), AcOH (0.043 mL, 0.75 mmol), tert-butyl Chil 4-oxopiperidine-1-carboxylate (0.100g, 0.50mmol) and STAB (0.318 g, 1.50 mmol) were added in this order. The mixture was stirred at room temperature for 2 The mixture was stirred for 3 days and then concentrated to remove DMF. The residue was diluted with saturated NaHCO 3 Aqueous solution and DC M (×2), and the organic phase was passed through a phase separator and concentrated to give crude tert-butyl ether. 4-[2-(1H-pyrazol-5-yl)pyrrolidin-1-yl]piperidine-1-yl The carboxylate (0.271 g, >100%) was obtained as an oil. LCMS (Method C): m / z 321 (M+H) + (ES + ), 1.18 minutes, UV activity

[0397] Crude tert-butyl 4-[2-(1H-pyridinyl)-2-(2-methylphenyl)-2-(1H-pyridinyl)-1H-pyridinyl ...2H-pyridinyl 1H-pyridinyl 0.5-(4-pyrrolidinyl)pyrrolidin-1-yl)piperidine-1-carboxylate ( ... A solution of 271 g (assuming 0.50 mmol) was stirred at room temperature for 110 minutes and then diluted with toluene. The residue was azeotroped with toluene to give crude intermediate 181, 4-[2-(1H- Pyrazol-5-yl)pyrrolidin-1-yl]piperidine trifluoroacetate (0.5 The product was obtained as an oil (98 g, >100%) and used immediately. The data are in Table 2.

[0398] Route 10 Intermediate 184, 5-Methyl-1-(piperidin-4-yl)pyrrolidin-2-one acetate via copper catalyzed coupling to pyridine followed by hydrogenation, as exemplified by the preparation of General Procedure for the Preparation of Peridine-Containing Pyrrolidinones or Oxadiazolones [ka] 5-Methylpyrrolidin-2-one (0.050 g, 0.50 mL) in dioxane (2 mL) mmol), 4-iodopyridine (0.103 g, 0.50 mmol), (trans)- N,N'-Dimethylcyclohexane-1,2-diamine (0.016 mL, 0.10 mm ol), CuI (0.019 g, 0.10 mmol) and K 2 CO 3 (0.209g, 1 The mixture was sealed in a nitrogen-flushed glass tube and heated at 150 °C overnight. The cooled reaction mixture was concentrated onto flash silica (5 mL). The powder was purified by column chromatography (normal phase, Biotage SNAP cartridge) DiKP-sil 25 g, 40-63 μm, 60 Å, 30 mL / min, 0-5% in DCM Solvent A, where solvent A is 10% (7M NH 3 / MeOH) The product was purified as 5-methyl-1-(pyridin-4-yl)pyrrolidin-2-one (0.0 Yield: 88 g, 99%) as an oil. LCMS (Method C): m / z 177 (M+H) + (ES + ), 0.69 minutes, UV activity

[0399] 5-Methyl-1-(pyridin-4-yl)pyrrolidin-2-one (0.080 g, 0. 45 mmol) in AcOH (8 mL) and eluted at 1 mL / min using an H-Cube. The solution was then hydrogenated over 10% Pt / C catalyst at a flow rate of 100° C. and 80 bar pressure. Concentration and azeotropic distillation of the residue with toluene (×2) afforded crude intermediate 184, 5-methyl-1-(piperidine). Lysine-4-yl)pyrrolidin-2-one acetate (0.166 g, >100%) as an oil Data for the title compounds are in Table 2.

[0400] Route 11 Intermediate 199, (5R)-5-methyl-1-(piperidin-4-yl)pyrrolidine-2- 1-(piperidin-4-yl)-1-propanedione acetate, and intermediate 200, (5R)-5-ethyl-1-(piperidin-4-yl) Copper-catalyzed coupling to pyridines exemplified by the preparation of pyrrolidin-2-one acetates A typical procedure for preparing piperidines via subsequent hydrogenation [ka] Intermediate 199, (5R)-5-methyl-1-(piperidin-4-yl)pyrrolidine-2- On Acetate: (5S)-5-(hydroxymethyl)pyrrolidin-2-one ( 2.0 g, 17 mmol) and 4-methylbenzenesulfonyl chloride (5.3 g, 28 To a solution of 10 mmol of ethyl amine (12 mL, 86 mmol) was added triethylamine (12 mL, 86 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was dissolved in DCM and diluted with 1M HCl. Wash with aqueous solution (x3) and saturated saline (x1), then pass through a phase separator, Concentration gave a brown solid which was recrystallised from DCM / isohexane to give a tan solid. This was removed by filtration, washed with a DCM / isohexane mixture and air-dried. [(2S)-5-oxopyrrolidin-2-yl]methyl 4-methylbenzenesulfonyl The resulting mixture was concentrated to give 3.13 g (67%) of ethyl acetate. LCMS (Method C): m / z 270 (M+H) + (ES + ), 0.97 minutes, UV activity

[0401] [(2S)-5-oxopyrrolidin-2-yl]methyl 4-methyl- ethylbenzenesulfonate (0.50 g, 1.9 mmol) and lithium bromide (0.48 4g, 5.6mmol) was mixed with N 2 The mixture was heated at reflux overnight and then allowed to cool. The residue was removed by condensation and diluted with DCM and H 2 The mixture was partitioned between 100 ml and 200 ml of ethyl acetate and the phases were separated. The aqueous phase was diluted with DCM (x3). The organic phase was then passed through a phase separator and concentrated to give (5S)-5-(Br To this was obtained (0.284 g, 86%) of (bromomethyl)pyrrolidin-2-one as a gum. LCMS (Method C): m / z 178 / 180 (M+H) + (ES + ), 0.37 min. weak UV activity

[0402] In triethylamine (0.267 mL, 1.9 mmol) and ethanol (32 mL) (5S)-5-(bromomethyl)pyrrolidin-2-one (0.284 g, 1.6 mmol) l) solution was diluted with 10 mL of water at 50 bar pressure and room temperature using an H-Cube at a flow rate of 1 mL / min. The solution was concentrated to give crude (5R)-5-methylpyrrolidine- The 2-one (0.445 g, >100%) was obtained as a sticky solid. LCMS (Method C): m / z 100 (M+H) + (ES + ), 0.34 minutes, weak UV activation sex

[0403] Crude (5R)-5-methylpyrrolidin-2-one (0.445 g, assumed 1.5 mmol) is reacted according to Route 10 (coupling with intermediate 183) to give crude intermediate 199 , (5R)-5-methyl-1-(piperidin-4-yl)pyrrolidin-2-one acetate ( The compound was obtained as an oil (0.125 g, 46%). Data for the title compound are given in Table 2. do.

[0404] Intermediate 200, (5R)-5-ethyl-1-(piperidin-4-yl)pyrrolidine-2- On Acetate: Methyllithium (1.5 M in ether, 7.4 mL, 11 mmol) was dissolved in THF (6 mL ) was added rapidly with stirring to a suspension of copper iodide (1.06 g, 5.6 mmol) in 100 mL of water. N in ice water 2 The light brown solution was stirred in ice water for 45 min and then cooled to -20°C. The mixture was cooled to rt. [(2S)-5-oxopyrrolidin-2-yl]methylacetone (5-oxopyrrolidin-2-yl) ... A solution of ethyl 4-methylbenzenesulfonate (0.50 g, 1.9 mmol) was heated for 2 min. The resulting solution was stirred at -20°C for 45 min and then cooled in ice water. Stir overnight and allow the cooling bath to slowly expire. The mixture was diluted with NH 4 Cl saturated aqueous solution (15 The biphasic mixture was extracted with ether (×3) and the organic phase was washed with saturated brine, passed through a phase separator, and concentrated to give crude (5R)-5-ethyl Pyrrolidin-2-one (0.124 g, 59%) was obtained as an oil. LCMS (Method C): m / z 114 (M+H) + (ES + ), 0.50 minutes, weak UV activation sex

[0405] Crude (5R)-5-ethylpyrrolidin-2-one (0.124 g, 1.10 mmol) By reacting according to Route 10 (coupling with intermediate 183), crude intermediate 200, ( 5R)-5-Ethyl-1-(piperidin-4-yl)pyrrolidin-2-one acetate (0. Yield was 156 g, 72%) as a gum. Data for the title compound are in Table 2.

[0406] Route 12 Intermediate 205, (4R)-4-Methyl-3-(piperidin-4-yl)-1,3-oxa Carbamate formation exemplified by the preparation of zolidin-2-one acetate, copper to pyridine Typical procedure for preparing piperidines via catalytic coupling followed by hydrogenation [ka] A solution of triphosgene (0.297 g, 1.0 mmol) in DCM (5 mL) was added to DC (2R)-2-aminopropan-1-ol (0.156 mL, 2.0 A solution of 0.56 mL (4.0 mmol) and triethylamine (0.56 mL, 4.0 mmol) was added over 1 h. The mixture was stirred in ice water for another 2 hours and then cooled in ice water. Ethanol (6 mL) was added. The thick suspension was filtered through a sinter and the solid was washed with more ether. The filtrate was concentrated onto flash silica (5 mL) and the resulting The powder was purified by column chromatography (normal phase, Biotage SNAP cartridge KP-sil 25g, 40~63μm, 60Å], 30mL / min, 100%EtOAc ) to give (4R)-4-methyl-1,3-oxazolidin-2-one (19 2 mg, 95%) was obtained as a solid. LCMS (Method C): m / z 102 (M+H) + (ES + ), 0.14 minutes, UV inactive sex

[0407] (4R)-4-Methyl-1,3-oxazolidin-2-one (0.188 g, 1.9 m mol) according to Route 10 (coupling with intermediate 183) to give crude intermediate Compound 205, (4R)-4-methyl-3-(piperidin-4-yl)-1,3-oxazolidinyl The resulting compound was di-2-one acetate (0.343 g, 100%) as a solid. The relevant data are in Table 2.

[0408] Route 13 Intermediate 159, tert-butyl 4-[(2R)-2-(methoxycarbonyl)pyrrolidine Reductive amine synthesis exemplified by the preparation of 1-phenyl-1-ylpiperidine-1-carboxylate. Typical Procedure for Preparing Piperidines via Synthesis [ka] D-Proline methyl ester hydrochloride (0.200 g, 1.208 mmol) and 1-B oc-4-piperidinone (0.24 g, 1.208 mmol) in DMF (2 mL) at room temperature and diisopropylethylamine (0.209 mL, 1.208 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. STAB (0.512 g, 2.416 (mmol) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvent was removed in vacuo and the residue H 2 Partition between 200 (15 mL) and EtOAc (25 mL), and the aqueous layer is diluted with EtOAc (2 × 25 1 mL), and the organic layers were combined and 2 SO 4 Dry on a stover and remove the solvent in vacuo to give t ert-Butyl 4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]pyrrolidin Peridine-1-carboxylate, intermediate 159, was obtained as a white solid (393 mg, >99%). Data for the title compounds are in Table 2.

[0409] Route 14 Intermediate 271, tert-butyl 3,3-difluoro-1,4'-bipiperidine-1'- Preparing piperidines via reductive amination exemplified by the preparation of carboxylates Typical steps to [ka] 3,3-Difluoropiperidine hydrochloride (0.30 g, 1.90 mmol) and 1-Bo c-4-Piperidinone (0.379 g, 1.90 mmol) in DMF (8 mL) at room temperature The mixture was dissolved and diisopropylethylamine (0.246 g, 1.90 mmol) was added. The reaction mixture was stirred at 50° C. under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and then added ice Acetic acid (0.114 g, 1.90 mmol) and STAB (1.01 g, 4.76 mmol) ) was added and the reaction mixture was stirred at 50° C. under nitrogen overnight. Water (2 mL) was added to the cooled reaction mixture. The mixture was added and the solvent was removed in vacuo. The residue was diluted with saturated NaHCO 3 (aqueous solution) (10mL) The combined organic layers were separated and extracted with DCM (2 x 10 mL). The residue was dried by passing it through a palladium cartridge and the solvent was removed in vacuum. Raffy (normal phase, [Biotage SNAP Cartridge KP-sil 25g 40 ~63 μm, 60 Å, 25 mL / min, gradient: 0% to 10% MeOH / DCM] Purify and prepare tert-butyl 3,3-difluoro-1,4'-bipiperidine-1'-carbazolidine. The carboxylate, intermediate 271, (0.347 g, 60%) was obtained as an amber oil. Data for the title compounds are given in Table 2.

[0410] Route 15 Intermediate 195, 4-(1-methyl-1H-tetrazol-5-yl)piperidine hydrochloride Preparation of piperidines via tetrazole formation and subsequent alkylation is exemplified by the preparation of Typical steps for making [ka] tert-Butyl 4-cyanopiperidine-1-carboxylate (2.1 g, 10 mm ol), sodium azide (1.95 g, 30 mmol) and ammonium chloride (1.6 g, 30 mmol) was dissolved in DMF (20 mL). The reaction mixture was heated at 100 °C for 24 h. The mixture was stirred, then diluted with water (250 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated to give the crude product. Chromatography (normal phase, neutral silica gel, 60-120 mesh, 0-5% in DCM) %MeOH) to obtain tert-butyl 4-(1H-tetrazol-5-yl ) piperidine-1-carboxylate (1.25 g, 50%) as a solid. LCMS (Method F): m / z 198 (M-tBu+H) + (ES + ), 1.69 minutes, UV inert

[0411] tert-Butyl 4-(1H-tetrazol-5-yl)piperidine-1-carboxylate rate (1.2 g, 4.7 mmol), iodomethane (2.0 g, 14 mmol) and C s 2 CO 3 (9.6 g, 28 mmol) was dissolved in dry DMF (36 mL). The mixture was stirred at 100° C. for 2 h, then diluted with water (250 mL) and diluted with EtOAc (3×1 The combined organic layers were dried (Na 2 SO 4 ), concentrated and purified by crude This was purified by column chromatography (normal phase, neutral silica gel, 60-120 mesh). , 0 to 35% EtOAc in hexane, then 45 to 60% EtOAc in hexane. The two regioisomers were separated by purification using the methods described above. The desired regioisomer, tert-butyl 4 -(1-Methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate ( 0.160 g, 13%) was obtained as a solid, eluted second from the column. LCMS (Method F): m / z 212 (M-tBu+H) + (ES + ), 1.79 minutes, UV inert

[0412] tert-Butyl 4-(1-methyl-1H-tetrazol-5-yl)piperidine-1 -Carboxylate (0.160 g, 0.60 mmol) was dissolved in dioxane (3 mL). HCl in dioxane (4 M, 3 mL, 12 mmol) was added at 0° C., and the mixture was then cooled to room temperature. The mixture was stirred at rt for 5 h. The solvent was removed and the mixture was triturated with diethyl ether (5 mL) to give 4 -(1-Methyl-1H-tetrazol-5-yl)piperidine hydrochloride, intermediate 195, ( The compound was obtained as a solid (0.130 g, >100%). Data for the title compound are given in Table 2. do.

[0413] Route 16 Intermediate 223, (2R)-N-methyl-1,4'-bipiperidine-2-carboxamide Preparation of piperidinium phosphate esters via reductive amination, amide formation and Boc deprotection is exemplified by A typical procedure for preparing [ka] R-Pipecolic acid (1 g, 7.75 mmol) and tert -Butyl 4-oxopiperidine-1-carboxylate (2.31 g, 11.6 mmol) ) was added 10% palladium on charcoal (1 g, 50% wet) and the reaction mixture was incubated at room temperature for 2 h. 2 The reaction mixture was stirred under 1 atm for 48 h. The reaction mixture was filtered through a bed of Celite and filtered. The material was evaporated in vacuo. The crude residue was triturated with DCM (50 mL) to give (R)-1'-( tert-Butoxycarbonyl)-[1,4'-bipiperidine]-2-carboxylic acid (1. 2 g, 50%) as a white solid. The crude residue was carried on to the next step without further purification. It was used for the pool. 1 H-NMR (400 MHz; CDCl 3 ) δ: 1.46(s, 9H), 1.50 - 1.59(m,1H), 1.75 - 1.91(m, 4H), 1.93 - 2.05 (m, 2H), 2.10- 2.19(m, 2H), 2.35 - 2.41(m, 1H) , 2.51 - 2.69(m,3H), 3.41 - 3.49(m, 1H), 3.55 - 3.61(m,1H), 3.70 - 3.79(m, 1H), 4.25 - 4.36 (m, 2H).

[0414] (R)-1'-(tert-butoxycarbonyl)-[1,4 '-bipiperidine]-2-carboxylic acid (1.0 g, 3.20 mmol) and MeNH 2 ( To a solution of 2M in THF (3.2 mL, 6.41 mmol), DIPEA (1.75 mL, 9.60mmol) was added at 0°C. After stirring for 10 minutes, 1-propanephosphonic anhydride was added. Add 50% ethyl acetate solution (4.07 mL, 6.41 mmol) and let sit at room temperature for 3 hours. After completion, the reaction mixture was diluted with saturated NaHCO 3 Quench with aqueous DCM (3 × 3 The organic layers were combined, washed with saturated saline, dried (Na 2 SO 4 ) , concentrated in vacuo to give tert-butyl (R)-2-(methylcarbamoyl)-[1,4'- Bipiperidine]-1'-carboxylate (4, 1 g, 97%) was dissolved in water to obtain a colorless, sticky liquid. The crude residue was used in the next step without further purification. 1 H-NMR(400 MHz, DMSO) δ: 1.46(s, 9H),1.61 - 1.80(m, 4H),1.91 - 2.08(m, 4H), 2.25 - 2.33(m , 2H), 2.61 - 2.71(m,4H), 2.82(d, J = 4.8 Hz, 3 H), 3.32 -3.45(m, 2H), 4.25 - 4.36(m, 2H), 6.8 5(br.s., 1H).

[0415] tert-Butyl (R)-2-(methylcarbamoyl)- in dioxane (10 mL) [1,4'-bipiperidine]-1'-carboxylate (700 mg, 2.15 mmol ) was slowly added with HCl in dioxane (4 M, 10 mL) at 0°C and stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and then washed with saturated NaHCO 3 Aqueous solution (10mL) The crude reaction mass was basified with and concentrated. 5% MeOH / DCM (30 mL) was added and 10 The mixture was stirred for 1 min and filtered. The filtrate was concentrated in vacuo to give intermediate 223, (R)-N-methyl-[ 1,4'-bipiperidine]-2-carboxamide (400 mg, 83%) was added to a brown sticky The data for the title compound is in Table 2.

[0416] Route 17 Preparation of Intermediate 250, 4-Ethyl-5-iodo-1-methyl-1H-pyrazole A typical procedure for preparing iodopyrazoles via the Sandmeyer reaction is illustrated below. [ka] 1-Ethyl 4-methyl-1H-pyrazolamine (0.5 g, 3.932 mmol), Dissolve in diiodomethane (9.0 mL) at 0-5°C under a nitrogen atmosphere, then add isothiocyanate. A mill was added dropwise and the mixture was stirred for 2 hours at 80° C. and then for 2 hours at room temperature. H 2 Partition between O (100 mL) and EtOAc (250 mL), and the aqueous layer is diluted with EtOAc (2 × 2 The combined organic layers were dried (Na 2 SO 4 ), filtered, and the solvent The residue was purified by column chromatography (normal phase, neutral silica gel, 60-120 mL). 0 mesh, 30-50% ethyl acetate in hexane) to give 4-ethyl-5- Iodo-1-methyl-1H-pyrazole, intermediate 250 (0.5 g, 53.23%) Data for the title compound are in Table 2.

[0417] Route 18 Intermediate 302, tert-Br Preparation of ethyl (2R)-2-(difluoromethyl)pyrrolidine-1-carboxylate The activated carbamates can be prepared by deprotection, carbamate formation, and then reductive amination, as exemplified by Typical procedure for preparing mate [ka] 6-Boc-2-oxo-6-aza-spiro[3.4]octane (4.00 g, 0.0 17 mol) was dissolved in 4 M HCl in dioxane (25 mL) and stirred overnight at room temperature under nitrogen. The solvent was removed in vacuo to give an off-white solid, which was suspended in DCM (40 mL) and The reaction mixture was cooled to 0° C. under nitrogen. 3 N (3.60g, 0.036mol) and and 4-nitrophenyl chloroformate (3.767 g, 0.0187 mol) were added to the reaction mixture. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO 3 (aqueous solution) (30 mL) The organic layers were combined and purified by Biotage The residue was dried by passing through a glass separator cartridge and the solvent was removed in vacuo. Column chromatography (normal phase, Biotage SNAP cartridge KP-sil 50g 40-63μm, 60Å, 50mL / min, gradient: 0%-6% MeOH / DCM ]) to give 4-nitrophenyl 2-oxo-6-azaspiro[3.4]octanoate. Tan-6-carboxylate was obtained as a yellow solid (1.40 g, 27%). LCMS (Method C): m / z 291(M+H)+(ES+), 1.167 min.

[0418] 4-Nitrophenyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate The 4-(1 H-pyrazol-1-yl)piperidine (0.365 g, 2.41 mmol), glacial acetic acid ( 0.144g, 2.41mmol) and STAB (1.535g, 7.24mmol) The reaction mixture was stirred overnight at 50° C. under nitrogen. The reaction mixture was quenched with water (2 mL). The solvent was removed in vacuo. The residue was dissolved in DCM (20 mL) and saturated NaHCO 3 (aqueous solution)( The aqueous layer was extracted with DCM (2 x 20 mL), and the organic layers were combined and purified with Bio Dry by passing through a 2x phase separator cartridge and remove the solvent in vacuum. The residue was purified by column chromatography (normal phase, Biotage SNAP cartridge) DiKP-sil 25g 40-63μm, 60Å, 25mL / min, gradient: 0%-10% MeOH / DCM]) to give 4-nitrophenyl 2-[4-(1H-pyrazoline (1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate The carboxylate, intermediate 302, was obtained (0.738 g, 72%). The relevant data are in Table 2.

[0419] General synthetic procedure for the examples: Route A Example 1-1, Ethyl 2-[4-(1H-imidazol-2-yl)piperidin-1-yl] This is exemplified by the preparation of 6-azaspiro[3.4]octane-6-carboxylate. Preparation of piperidines via sodium triacetoxyborohydride reductive amination Typical steps to [ka] 4-(1H-imidazol-2-yl)piperidine dihydrochloride (1.43 g, 7 .1mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carbo Titanium oxide (1.60 g, 7.1 mmol) was dissolved in DCM (60 mL) at room temperature and Phenyl isopropoxide (2.31 mL, 7.81 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to -5°C and then STAB (3.01 g, 14 0.2 mmol) and acetic acid (350 μL, 4.26 mmol) were added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred overnight under nitrogen while warming at 40°C. 3 (Saturated aqueous solution)(1 0 mL), diluted with DCM and then washed through a pad of Celite. Filter. Separate the layers and extract the aqueous layer with DCM. Wash the combined DCM layers with saturated brine. Then, MgSO 4 The solvent was removed in vacuo and the residue was purified by column chromatography. (normal phase, [Biotage SNAP cartridge KP-sil 50g, 40-6 3 μm, 60 Å, 50 mL / min, gradient: 0.5% NEt 3 1% to 10% M in DCM with ethyl 2-[4-(1H-imidazol-2-yl)piperidine]) Lysine]-6-azaspiro[3.4]octane-6-carboxylate (2.645 g, An inseparable mixture of diastereomers (98.3%) was obtained as a white solid. The diastereomers were separated using LC using Phenomenex Ge 28-38% at 18mL / min using a mini-N C18 column, 150×21mm MeCN / H 2 The column was eluted with 0 and fractions were collected by monitoring at 218 nm. and isomer 1, ethyl 2-[4-(1H-imidazol-2-yl)piperidine]-6 - Azaspiro[3.4]octane-6-carboxylate (0.338g, 14%) Isomer 2, ethyl 2-[4-(1H-imidazol-2-yl)piperidinyl] 1-Diazinyl]-6-azaspiro[3.4]octane-6-carboxylate (0.369 g, 1 6%) as a colorless solid. Data for isomer 2 are in Table 3.

[0420] Route B Example 1-3, Ethyl 2-(4-(4-(trifluoromethyl)-1H-imidazole- 2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate Sodium cyanoborohydride and zinc chloride reductive acylation exemplified by the preparation of silylates. Typical Procedure for Preparing Piperidines via Monomination [ka] 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperidine(1 00mg, 0.46mmol), Ethyl 2-oxo-6-azaspiro[3.4]octane -6-carboxylate (89 mg, 0.46 mmol), ZnCl 2 (2mg, 0.0 1 mmol) and triethylamine (0.3 mL, 2.28 mmol) in MeOH (5 mL L) and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was cooled to 0° C. and N aBH 3 CN (114 mg, 1.83 mmol) was added in small portions. The mixture was stirred at 25° C. for 7 h and the solvent was removed in vacuo. The residue was 2 O (50 mL) and EtO Ac (35 mL), the aqueous layer was extracted with EtOAc (2 x 35 mL), and the organic layers were combined. Then, it was dried (Na 2 SO 4 ), and the solvent was removed in vacuo. The residue was purified by preparative HPLC [reverse phase (X- BRIDGE, C-18, 250 × 19 mm, 5 μm, 18 mL / min, gradient: MeCN / 28.0% in water (40.0 min), 100% (3.0 min), then 28.0% (5.0 min) ), 0.1%NH 3 ] to obtain ethyl 2-(4-(4-(trifluoromethyl) yl)-1H-imidazol-2-yl)piperidin-1-yl)-6-azaspiro[3. 4] Octane-6-carboxylate, Example 1-3 Isomer 1, (15 mg, 8.24% ) as a yellow solid, (2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-yl The carboxylate, Example 1-3 Isomer 2, (12 mg, 6.6%) was obtained as a yellow solid. Data for isomer 2 are given in Table 3.

[0421] Route C Example 1-4, Ethyl 2-[4-(4-cyano-1H-imidazol-2-yl)piperidinyl Preparation of 6-azaspiro[3.4]octane-6-carboxylate Conversion of trifluoromethyl-substituted imidazoles to cyano-substituted imidazoles as exemplified by Typical steps to [ka] Ethyl 2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine Peridine-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(2 00 mg, 0.50 mmol) in NH 3 Dissolve in 20 mL of water and stir at 60°C for 8 hours. The solvent was removed in vacuo and the residue was 2 Partition between O (60 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (2×40 mL) and the organic layers were combined and dried (Na 2 S O 4 The solvent was removed in vacuo, and the residue was purified by preparative HPLC [reverse phase (DURASHELL, C-1 8, 250×21.2 mm, 5 μm, 22 mL / min, gradient: MeCN / 25.0% in water ( 30.0 min), 100% (3.0 min), then 25.0% (7.0 min), 0.1% NH 3 ] to obtain ethyl 2-(4-(4-cyano-1H-imidazole-2- 1-(1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate isomer 1, Example 1-4 (26 mg, 14.6%) as a yellow solid, [4-(4-cyano-1H-imidazol-2-yl)piperidin-1-yl]-6-a Zaspiro[3.4]octane-6-carboxylate, Examples 1-4 Isomer 2, (25m g, 14.06%) as a yellow solid. Data for isomer 2 are in Table 3.

[0422] Route d Example 1-7, Ethyl 2-[4-(1-methyl-1H-imidazol-2-yl)piperidinyl Preparation of 6-azaspiro[3.4]octane-6-carboxylate Sodium triacetoxyborohydride reductive amination, Boc deprotection exemplified by Typical Procedure for Preparing Piperidine via Ethyl Carbamate Formation [ka] 4-(1-Methylimidazol-2-yl)piperidine hydrochloride (0.244 g, 1.2 1mmol) and 6-Boc-2-oxo-6-azaspiro[3,4]octane (0.2 73 g, 1.21 mmol) was dissolved in DCM (10 mL) at room temperature and Cid (0.4 mL, 2.42 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to -5°C and then STAB (0.513 g, 2.42 mmol) and acetic acid (27 μL, 480 μmol) were added, and the reaction mixture was warmed to room temperature while nitrogen The reaction mixture was stirred overnight under vacuum. 3 Addition of saturated aqueous solution (10 mL) The mixture was quenched, diluted with DCM, and then filtered through a pad of Celite. The layers were separated and the aqueous layer The mixture was extracted with DCM. The combined DCM layers were washed with brine and then with MgSO 4 Dry with The solvent was removed in vacuo and the residue was purified by column chromatography (normal phase, [Biotag e SNAP Cartridge KP-sil 25g, 40-63μm, 60Å, 50mL / 1 min, gradient: 1% to 10% MeOH in DCM]) to obtain tert-butyl 2- [4-(1-methyl-1H-imidazol-2-yl)piperidine]-6-azaspiro[ 3.4] Octane-6-carboxylate (0.330 g, 72%) isomers cannot be separated A workable mixture was obtained as a yellow gum. LCMS (Method A): m / z 374 (M+H) + (ES + ), 1.68 minutes, UV inactive sex.

[0423] Tert-Butyl 2-[4-(1-methyl-1H-imidazol-2-yl)piperidinyl] 6-azaspiro[3.4]octane-6-carboxylate (0.326 g, 0. 87 mmol) was dissolved in 4 M hydrogen chloride in dioxane (1.2 mL, 5.2 mmol). The reaction mixture was stirred at room temperature for 18 h. The volatiles were then removed in vacuo and the residue was dissolved in D Dissolved in CM (17 mL) and triethylamine (0.49 mL, 3.49 mmol) Ethyl chloroformate (125 μL, 1.31 mmol) was added dropwise and the solution was stirred at room temperature for 18 hours. The mixture was then stirred for 1 h. 3 (aqueous) (75 mL) and DCM (75 mL) The mixture was poured into 100 mL of water and extracted (2 x 75 mL). The combined DCM extracts were then poured into 100 mL of saturated L) and then washed with MgSO 4 After concentration, the residue was purified by column chromatography. - (Normal phase, [Biotage SNAP Cartridge KP-sil 25g, 40~63 1 μm, 60 Å, 50 mL / min, gradient: 1% to 10% MeOH in DCM). Ethyl 2-[4-(1-methyl-1H-imidazol-2-yl)piperidine]-6 -Azaspiro[3.4]octane-6-carboxylate was obtained as a brown oily substance. It was obtained as a mixture of asterisks (0.25 g, 83%) using preparative HPLC. The diastereomers were separated using a Phenomenex Gemini-N A C18 column, 150 x 21 mm, was used, and 38-48% MeCN / H 2 The mixture was extracted with 20 and the fractions were collected by monitoring at 218 nm. -[4-(1-methyl-1H-imidazol-2-yl)piperidine]-6-azaspiro [3.4] Octane-6-carboxylate, Example 1-7 Isomer 1, (0.044 g, 15%) as a colorless oil, ethyl 2-[4-(1-methyl-1H-imidazole -2-yl)piperidine]-6-azaspiro[3.4]octane-6-carboxylate , Examples 1-7 gave Isomer 2, (0.031 g, 10%) as a colorless oil. Data for body 2 are in Table 3.

[0424] Route e Example 1-9, Methyl 2-[4-(1,5-dimethyl-1H-imidazol-2-yl) Piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate To obtain the piperidinyl-containing compounds exemplified by the preparation, 3,6-dihydro Typical Procedure for Hydrogenating Pyridin-1(2H)-yl-Containing Compounds [ka] Methyl 2-(4-(1,5-dimethyl-1H-imidazol-2-yl)-3,6-di Hydropyridin-1(2H)-yl)-6-azaspiro[3.4]octane-6-carbo xylate (102 mg, 0.29 mmol) [synthesized via route d and intermediates 3 and 34] The resulting mixture was dissolved in MeOH (10 mL) and 10% Pd / C (25 mg) was added. The reaction mixture is 2 Purge with gas and then incubate at 25 °C for 20 h in H 2 Stirring was carried out under a balloon. The reaction mixture was filtered through Celite, washed with MeOH, and the solvent from the filtrate was removed in vacuo. The residue was then separated by preparative HPLC (X Bridge, C-18, 150×30 mm, 5 μm, 4 0 mL / min, gradient: 30% acetonitrile / water (12.00 min), 100% (14. 00 min), followed by 30% (14.01 min), 0.1% ammonia]. Methyl 2-[4-(1,5-dimethyl-1H-imidazol-2-yl)piperidine -1-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 1- 9Isomer 1, (5.6 mg, 5.8%) as a colorless gum, methyl 2-[4-(1, 5-Dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspipri b[3.4]octane-6-carboxylate, Example 1-9 isomer 2, (11.6 mg , 11.7%) was obtained as a colorless gum. Data for isomer 2 are given in Table 3.

[0425] Route F Example 1-36, Ethyl 2-[4-(1H-1,2,4-triazol-1-yl)piperidine Preparation of lysine-1-yl]-6-azaspiro[3.4]octane-6-carboxylate Sodium triacetoxyborohydride reductive amination, Boc deprotection, as exemplified by Typical Procedure for Preparing Piperidines via Protection and Ethyl Carbamate Formation [ka] 4-(1H-1,2,4-triazol-1-yl)piperidine (0.152 g, 1. 0 mmol) and 6-Boc-2-oxo-6-azaspiro[3,4]octane (0.2 22 g, 1.05 mmol) in DCM (10 mL) 2 Dissolve at room temperature under acetic acid (0. The reaction mixture was stirred at room temperature for 2 hours and STAB( 0.53 g, 2.50 mmol) was added and the reaction mixture was stirred at room temperature overnight. NaHCO 3 Quench by addition of (saturated aqueous solution) (30 mL) and add DCM (4 × 25 mL The combined DCM layers were passed through a Biotage phase separator. After removal of the empty space, tert-butyl 2-[4-(1H-1,2,4-triazol-1-yl ) Piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate A crude mixture of diastereomers was obtained which was used without purification. LCMS (Method C): m / z 362 (M+H) + (ES + ), 1.58 minutes and 1.61 minutes Minute hours, UV inert.

[0426] Crude tert-Butyl 2-[4-(1H-1,2,4-triazol-1-yl)piperidine [Diazin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (assumed 1 0.0 mmol) was dissolved in 4 M hydrogen chloride in dioxane (1.2 mL, 5.2 mmol) The reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was diluted with DCM (10 mL ) and dissolved in NEt 3 (0.70 mL, 5.0 mmol) was added. Ethyl chloroformate ( 0.14 mL, 1.5 mmol) was added dropwise and the solution was stirred at room temperature overnight. The mixture was diluted with NaH CO 3 (aq) (40 mL), extracted with DCM (4×40 mL) and combined. The DCM layer was passed through a Biotage phase separator. The solvent was removed in vacuo and the residue was Chromatography (normal phase, Biotage SNAP cartridge KP-sil 25g, 40-63μm, 60Å, 40mL / min, gradient: 0%-10% MeOH in DCM ) to obtain ethyl 2-[4-(1H-1,2,4-triazol-1-yl) Piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate An inseparable mixture of diastereomers was obtained. Preparative HPLC was used to separate the diastereomers. This was done using a Phenomenex Gemini-NX 5μm C18 A 110A Axia column, 100 x 30 mm, was used, with a flow rate of 14.4 µm at 30 mL / min. The mixture was eluted with 25-55% MeCN / solvent B [wherein solvent B is H 2 0.2% (2 8%NH 3 / H 2 O)] and fractions were collected by monitoring at 210 nm. And ethyl 2-[4-(1H-1,2,4-triazol-1-yl)piperidine -1-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 1- 36 Isomer 1, (0.026 g, 8%) as a colorless solid, ethyl 2-[4-(1H- 1,2,4-triazol-1-yl)piperidin-1-yl]-6-azaspiro[3. 4] Octane-6-carboxylate, Example 1-36 Isomer 2, (0.026 g, 8% ) was obtained as a colorless solid. Data for isomer 2 are in Table 3.

[0427] Route G Example 1-51, Ethyl 2-{4-[1-(2-methoxyethyl)-1H-imidazole -2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo The preparation of imidazole derivatives using sodium hydride in DMF is exemplified by the preparation of xylates. Typical Procedure for Alkylation of Alkyl-Containing Compounds [ka] Ethyl 2-[4-(1H-imidazol-2-yl)piperidin-1-yl]-6-a Zaspiro[3.4]octane-6-carboxylate (150 mg, 0.45 mmol) The mixture of diastereomers was dissolved in anhydrous DMF (3 mL) and 60% sodium hydride was added. % mineral oil suspension (27 mg, 0.68 mmol) and stirred at room temperature for 2 hours. Bromoethyl methyl ether (0.051 mL, 0.54 mmol) was added and the mixture was heated at room temperature. The mixture was stirred at rt overnight. The mixture was concentrated to remove DMF. The residue was dissolved in MeOH and flushed The resulting powder was purified by column chromatography (normal phase , [Biotage SNAP Cartridge KP-sil 25g, 40-63μm, 6 0 Å], 30 mL / min, 0–20% solvent A in DCM, where solvent A is 10% in MeOH (7M NH3 / MeOH) to obtain ethyl 2-{4-[1-(2 -Methoxyethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-a Diastereomers of zaspiro[3.4]octane-6-carboxylate (159 mg, 90%) This mixture was dissolved in MeOH, and the solution was subjected to preparative reverse phase HPLC. The purified product was purified using a Phenomenex Gemini-NX 5 μm C18 14.4 minutes at 30 mL / min using a 110A Axia column, 100 x 30 mm The mixture was eluted with 15-45% MeCN / solvent B [wherein solvent B is H 2 0.2% in O 28%NH 3 / H 2 O)] and collect fractions by monitoring at 210 nm. Then, ethyl 2-{4-[1-(2-methoxyethyl)-1H-imidazole-2 -yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxy Rate, Example 1-51 Isomer 1, (54 mg, 31%) and ethyl 2-{4-[1-( 2-Methoxyethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate, Examples 1-51 Isomer 2, (2 7mg, 15%) was obtained. Data for isomer 2 are in Table 3.

[0428] Route h Example 1-52, Ethyl 2-{4-[1-(cyanomethyl)-1H-imidazole-2- yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate Preparation of imidazole-containing compounds using potassium carbonate in DMF, as exemplified by the preparation of acetamides. Typical Procedure for Alkylation of Compounds [ka] Ethyl 2-[4-(1H-imidazol-2-yl)piperidin-1-yl]-6-a Zaspiro[3.4]octane-6-carboxylate (150 mg, 0.45 mmol) The mixture of diastereomers was dissolved in anhydrous DMF (3 mL). Potassium carbonate (187 mg, 1.4 mmol) and bromoacetonitrile (0.114 mL, 1.6 mmol). The mixture was stirred at room temperature for two nights. The mixture was concentrated to remove DMF. The residue was diluted with Me The resulting powder was dissolved in OH and concentrated onto flash silica (5 mL). Chromatography (normal phase, Biotage SNAP Cartridge KP-sil 25g , 40–63 μm, 60 Å], 30 mL / min, 0–20% solvent A in DCM, where solvent A was purified by 10% NH3 in MeOH (7M NH3 / MeOH) 2-{4-[1-(cyanomethyl)-1H-imidazol-2-yl]piperidine-1- {6-azaspiro[3.4]octane-6-carboxylate (91 mg, 54%) This mixture was dissolved in MeOH, and the solution was separated into reverse phase Purification was performed by HPLC using Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100×30 mm, 30 mL / min. Elute with 15-45% MeCN / solvent B over 14.4 min [wherein solvent B is H 2 0.2% (28%NH 3 / H 2 O)] by monitoring at 210 nm. The fractions were collected and ethyl 2-{4-[1-(cyanomethyl)-1H-imidazole- 2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate Silane, Example 1-52 Isomer 1, (8 mg, 5%) and Ethyl 2-{4-[1-(silane) Anomethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspipri b[3.4]octane-6-carboxylate, Example 1-52 isomer 2, (5 mg, 3 %) was obtained. Data for isomer 2 are given in Table 3.

[0429] Route I Example 1-53, (2-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4 ]oct-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)acetic acid, and Example 1-54, ethyl 2-(4-{1-[2-(methylamino)-2-oxoethyl yl]-1H-imidazol-2-yl}piperidin-1-yl)-6-azaspiro[3. 4] Procedure for preparing octane-6-carboxylate [ka] Ethyl 2-[4-(1H-imidazol-2-yl)piperidin-1-yl]-6-a Zaspiro[3.4]octane-6-carboxylate (500 mg, 1.5 mmol) The mixture of diastereomers was dissolved in 60% mineral oil of sodium hydride in DMF (10 mL). (90 mg, 2.3 mmol) and methyl bromoacetate (0.171 mL, 1.8 mmol). ol) using the method of route g to give ethyl 2-{4-[1-(2-methoxyphenyl)- -2-oxoethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6- Dialysis of azaspiro[3.4]octane-6-carboxylate (393 mg, 65%) A mixture of teleomers was obtained. LCMS (Method C): m / z 405 (M+H) + (ES + ), 1.12 and 1.17 min. , weak UV activity.

[0430] Ethyl 2-{4-[1-(2-methoxy-2-oxoethyl)-1H-imidazole- 2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate A mixture of diastereomers of the silanes (180 mg, 0.45 mmol) was dissolved in THF ( mL) and H 2 Lithium hydroxide monohydrate (75 mg, 1.8 mmol) in O (1 mL) The mixture was stirred at room temperature for 5 days. The mixture was concentrated to remove THF and acidified with 1M aqueous HCl. The resulting mixture was concentrated to give (2-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4 ]oct-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)acetic acid ( A crude mixture of diastereomers (0.4 g, >100%) was obtained. Approximately 0.2 g of this The mixture was dissolved in MeOH and the solution was purified by preparative reverse phase HPLC. enomenex Gemini-NX 5μm C18 110A Axia column, 5-15% MeCN over 14.4 min at 30 mL / min using a 100 x 30 mm / solvent B [where solvent B is H 2 0.2% (28%NH 3 / H 2 O) The fractions were collected by monitoring at 210 nm, and (2-{1-[ 6-(Ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine -4-yl}-1H-imidazol-1-yl)acetic acid, Example 1-53 Isomer 1, (30 mg, 17%) and (2-{1-[6-(ethoxycarbonyl)-6-azaspiro[3. 4]Oct-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)acetic acid , Example 1-53 Isomer 2, (22 mg, 13%) was obtained. Data for isomer 2 are in Table 3.

[0431] The remaining (2-{1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]octo Diastereomeric ester of 1H-imidazol-1-yl)-2-ylpiperidin-4-yl The crude mixture of rheomers, Example 1-53, (0.2 g, assumed 0.22 mmol) was dissolved in DMF ( 3 mL) and diisopropylethylamine (0.155 mL, 0.89 mmol) and a solution of methylamine in methanol (2 M, 0.33 mL, 0.66 mmol). Then, HATU (0.127 g, 0.33 mmol) was added, and the mixture was stirred at room temperature. The mixture was concentrated to remove DMF, and the residue was dissolved in a mixture of DCM and MeOH. The mixture was dissolved and concentrated on flash silica (10 mL). The resulting powder was subjected to column chromatography. Chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25g, 4 0–63 μm, 60 Å], 30 mL / min, 0–20% solvent A in DCM, where solvent A is 10% (7M NH 3 / MeOH) to obtain ethyl 2- (4-{1-[2-(methylamino)-2-oxoethyl]-1H-imidazole-2- 6-Azaspiro[3.4]octane-6-carboxylate This mixture was dissolved in MeOH, and the solution was fractionated and reverse-isotope The product was purified by phase HPLC using Phenomenex Gemini-NX 30mL / min using 5μm C18 110A Axia column, 100×30mm The column was eluted with 15–45% MeCN / solvent B over 14.4 min at RT, where solvent B was H 2 0.2% (28%NH 3 / H 2 O)] by monitoring at 210 nm. The fractions were collected according to the above procedure. Oxoethyl]-1H-imidazol-2-yl}piperidin-1-yl)-6-azazol Pyro[3.4]octane-6-carboxylate, Example 1-54 Isomer 1, (9 mg, 4%) and ethyl 2-(4-{1-[2-(methylamino)-2-oxoethyl]-1H -imidazol-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octa The isomer 2, Example 1-54, (6 mg, 3%) was obtained. Data for 2 are in Table 3.

[0432] Route j Example 1-70, Ethyl 2-{4-[(2R)-4,4-difluoro-2-(methylcarbamate) Bamoyl)pyrrolidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4] Picobalt esters were synthesized via carbamate formation, as exemplified by the preparation of octane-6-carboxylate. Typical Procedure for Preparing Peridine [ka] 4-Nitrophenyl 2-[4-(1H-pyrazol-1-yl)piperidin-1-yl ]-6-Azaspiro[3.4]octane-6-carboxylate (0.125 g, 0.2 94 mmol) was suspended in anhydrous THF (4 mL) and sonicated to induce dissolution. Sodium hydride (0.026 g, 0.647 mmol) in a 60% suspension in mineral oil was added and the reaction The reaction mixture was stirred at room temperature under nitrogen for 10 minutes. 0.150 g, 2.94 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. Water (1 mL) was added to the reaction mixture and the solvent was removed in vacuo. The residue was diluted with DCM (20 mL) and Japanese NaHCO 3 (aqueous) (10 mL) and the aqueous layer was extracted with DCM (2 x 10 mL). The organic layers were combined and passed through a Biotage phase separator cartridge. The solvent was removed in vacuo and the residue was purified by column chromatography (normal phase, [Bio tage SNAP Cartridge KP-sil 10g 40~63μm, 60Å, 12 The residue was purified by preparative reverse phase chromatography (mL / min, gradient: 0% to 10% MeOH / DCM). HPLC(Phenomenex Gemini-NX 5μm C18 110A A xia column, 100 x 30 mm, 20-50% Me over 14.4 min at 30 mL / min Elute with CN / solvent B [where solvent B is H 2 0.2% (28%NH3 / H 2 O) [0.15% by weight], and collecting fractions by monitoring at 210 nm) do,( 2 H 5 ) Ethyl 2-[4-(1H-pyrazol-1-yl)piperidin-1-yl [3.4]octane-6-carboxylate, Examples 1-70 isomers Compound 1 (0.017 g, 17%) was obtained as a white solid ( 2 H 5 ) Ethyl 2-[4-(1H -pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane -6-carboxylate, Example 1-70 Isomer 2, (0.013 g, 13%) was obtained as a white solid The data for isomer 2 are given in Table 3.

[0433] Route k Example 2-2, Ethyl 2-[4-(1-formylpyrrolidin-2-yl)piperidine-1 3,4-Dimethyl-6-azaspiro[3.4]octane-6-carboxylate. A typical procedure for preparing piperidines via formamide formation is shown. [ka] A mixture of formic acid (2 mL) and acetic anhydride (0.1 mL, 1.43 mmol) was heated at 60 °C for 1 h. The reaction was stirred for 1 h, then cooled to 0° C. and treated with ethyl 2-(4- (Pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane of diastereomeric 6-carboxylate hydrochloride (100 mg, 0.30 mmol) The mixture was added dropwise. The resulting reaction mixture was stirred at 60° C. for 8 hours and adjusted to a basic pH. The reaction mixture is then heated to 300° C. 2The mixture was partitioned between 2H2O (40 mL) and EtOAc (25 mL). The layer was further extracted with EtOAc (2×25 mL), and the organic layers were combined and washed with Na 2 SO 4 Dry with The solvent was removed in vacuo, and the residue was purified by preparative HPLC (X Bridge, C-18, 150 × 30 mm, 5 μm, 40 mL / min, gradient: acetonitrile / 30% in water (12.00 min 100% (14.00 min), then 30% (14.01 min), 0.1% The ethyl 2-[4-(1-formylpyrrolidin-2-yl)pyridine was purified by HPLC using a 50-mL HPLC-MS / MS chromatography. peridin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate, Example 2-2 Isomer 1 (14.6 mg, 13.0%) was obtained as a yellow gum by extraction with ethyl 2-[4 -(1-formylpyrrolidin-2-yl)piperidin-1-yl]-6-azaspiro[3 .4] Octane-6-carboxylate, Example 2-2 Isomer 2 (12.5 mg, 11. 1%) as a yellow gum. Data for isomer 2 are in Table 3.

[0434] Route L Example 2-4, Ethyl 2-{4-[1-(trifluoroacetyl)pyrrolidin-2-yl ]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate A typical procedure for preparing piperidines via amide formation is exemplified by the preparation of [ka] Ethyl 2-(4-(pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro [3.4] Octane-6-carboxylate (50 mg, 0.15 mmol) and NEt 3 (0.06 mL, 0.45 mmol) was dissolved in THF (3 mL) at room temperature. ,2,2-Trifluoroacetic acid (0.03 mg, 0.22 mmol) was added dropwise to the resulting The reaction mixture was stirred at room temperature for 8 hours. 2 O (40 mL) and EtOAc ( The aqueous layer was further extracted with EtOAc (2×25 mL) and the organic layers were combined. S,Na 2 SO 4 The solvent was removed in vacuo and the residue was separated. HPLC (X Bridge, C-18, 150 x 30 mm, 5 μm, 40 mL / min, gradient Mixture: 30% in acetonitrile / water (12.00 min), 100% (14.00 min), then 30% (14.01 min), 0.1% ammonia] to give ethyl 2-{ 4-[1-(trifluoroacetyl)pyrrolidin-2-yl]piperidin-1-yl}- 6-Azaspiro[3.4]octane-6-carboxylate, Example 2-4 Isomer-1 ( 5.5 mg, 8.0%) as a yellow gum, Cetyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]o 2-4 isomer-2 (6.2 mg, 9.7%) The data for isomer 2 are given in Table 3.

[0435] Route m Example 2-17, Ethyl 2-{4-[(2S)-1-(methylcarbamoyl)pyrrolidine -2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo Piperidinylation via amide / carbamate / urea formation exemplified by the preparation of xylates A typical procedure for preparing [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (2.10 g, 5.65 m The mixture of diastereomers (1.5 mmol) was dissolved in DCM (20 mL) and triethylamine (1. 54 mL, 11.1 mmol). laminoformyl chloride) (620 mg, 6.63 mmol) was added. The solution was stirred at room temperature for 2 h. The mixture was then diluted with 1 M NaOH (aq) (50 ml The mixture was poured into a 100 mL flask, extracted with DCM (2 x 50 mL), and the combined DCM extracts were washed with saturated brine. (50 mL), then passed through a Biotage phase separator and concentrated in vacuo. and ethyl 2-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl] piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate Provided as a yellow solid and as a mixture of diastereomers (1.79 g, 82%) The diastereomers were separated using preparative HPLC. x Gemini-NX C18 column, 100 x 30 mm, at 18 mL / min H 2 Elution was performed with 25–35% MeCN / 0.2% ammonia (v / v) in O at 210 nm. The fractions were collected by monitoring. And, Examples 2-17 Isomer 1, Ethyl 2 -{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidine- 1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.78 g, 36%) as a colorless oil, Example 2-17 Isomer 2, ethyl 2-{4-[(2S )-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate (0.67 g, 31%) was dissolved in water. Obtained as an oil. Data for isomer 2 are in Table 3.

[0436] Route n Example 2-19, Ethyl 2-{4-[1-(ethylcarbamoyl)pyrrolidin-2-yl ]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate For the preparation of piperidines via urea / carbamate formation, as exemplified by the preparation of Typical Procedure [ka] Ethyl 2-(4-(pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro [3.4] Octane-6-carboxylate hydrochloride (100 mg, 0.30 mmol) Mixture of diastereomers, diethylamine (0.3 mL, 0.60 mmol) and NE t 3 (0.1 mL, 0.90 mmol) was dissolved in DCE (5 mL) at room temperature. 145 mg, 0.60 mmol) was added and the reaction mixture was stirred at room temperature for 15 hours. Mix it with H 2 Partition between 2×O (40 mL) and EtOAc (25 mL), and the aqueous layer is diluted with EtOAc (2× The organic layers were combined and dried (Na 2 SO 4 ) and remove the solvent under vacuum. The residue was purified by preparative HPLC [reverse phase HPLC (X-BRIDGE, C-18, 250×19 mm, 5 μm, 15 mL / min, gradient: 30.0% to 38.0% MeCN / water (25.0 min), 100.0% (3.0 min), then 30.0% (2.0 min), 0.1% NH 3 ] to obtain ethyl 2-(4-(1-(ethylcarbamoyl)pyrrolidine-2 -yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxy Rate, Example 2-19 Isomer-1 (Example 2-19 Isomer-1), (7.5 mg, 6.2 0%) as a yellow gum, Ethyl 2-(4-(1-(ethylcarbamoyl)pyrrolidine -2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carbo Xylate, Example 2-19 Isomer 2, (8.1 mg, 6.60%) as a yellow gum The data for isomer 2 are given in Table 3.

[0437] Route o Example 2-22, Ethyl 2-[4-(1-methylpyrrolidin-2-yl)piperidine-1 6-azaspiro[3.4]octane-6-carboxylate. Typical procedure for preparing piperidines via alkylation with [ka] Ethyl 2-(4-(pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro [3.4] Octane-6-carboxylate hydrochloride (200 mg, 0.60 mmol) Mixture of diastereomers and formaldehyde (40% solution, 1.01 mL, 3.60 (mmol) in H 2 2 mL of formic acid (0.303 mL, 0.90 mL) at 25 °C. mol) was added dropwise and the resulting mixture was stirred at 70° C. for 14 h. The reaction mixture was diluted with Na HCO 3 solution (5 mL) and the reaction mixture was then quenched with H 2 O (50 mL) and EtO The aqueous layer was further extracted with EtOAc (2×35 mL) and the organic layer was The layers were combined and Na 2 SO 4 The solvent was removed in vacuo and the residue was purified by preparative HPLC [reverse phase HPLC (X-Bridge, C-18, 250×19.0mm, 5μm, 14mL / min , Gradient: 37% MeCN / water (28.0 min), 100% (4.0 min), then 37 % (3.0 min), 0.1% NH 3 ] to obtain ethyl 2-(4-(1-methyl Pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane- 6-Carboxylate, Example 2-22 Isomer 1 (12 mg, 5.80%) as a yellow gum As ethyl 2-(4-(1-methylpyrrolidin-2-yl)piperidin-1-yl) -6-Azaspiro[3.4]octane-6-carboxylate, Examples 2-22 Isomer 2 (11 mg, 5.30%) was obtained as a yellow gum. Data for isomer 2 are given in Table 3. do.

[0438] Route p Example 2-23, Ethyl 2-{4-[1-(N-methylglycyl)pyrrolidin-2-yl ]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate A typical procedure for preparing piperidines via amide formation is exemplified by the preparation of [ka] N-[(benzyloxy)carbonyl]-N-methylglycine (73 mg, 0.33 m mol) was dissolved in acetonitrile (5 mL) and then HATU (170 mg, 0.45 The reaction mixture was cooled to 0°C for 10 min. Stir at RT for 10 min and then add ethyl 2-(4-(pyrrolidin-2-yl)piperidine-1 -yl)-6-azaspiro[3.4]octane-6-carboxylate hydrochloride (100m g, 0.30 mmol) of the diastereomeric mixture was added and the resulting reaction mixture was The reaction mixture was stirred at 25° C. for 3 h. 2 in O (50 mL) and EtOAc (35 mL). Partition, extract the aqueous layer further with EtOAc (2 x 35 mL), combine the organic layers and wash with Na 2 S O 4 The residue was then dried over 1000 ml of ethyl acetate and the solvent was removed in vacuo. Finally, the residue was purified by column chromatography (normal phase , normal basic alumina, active, 0. Purify with 5% to 1.0% MeOH to obtain ethyl 2-(4-(1-(N-((benzene (N-methyl)-2-(pyrrolidinyl)-(carbonyl)-N-methylglycyl)-pyrrolidin-2-yl)-piperidine-1 -yl)-6-azaspiro[3.4]octane-6-carboxylate (130 mg, 8 0.74%) as a brown gum. Carbonyl)-N-methylglycyl)pyrrolidin-2-yl)piperidin-1-yl )-6-Azaspiro[3.4]octane-6-carboxylate (130 mg, 0.24 (mmol) in MeOH (10 mL) and then Pd / C (dry basis, 13 mg) The reaction was then heated to 300° C. 2 The resulting reaction mixture was purged with gas and incubated at 25 °C for 1 The reaction mixture was filtered through a plug of Celite, washed with methanol, and then The filtrate was then diluted with Na 2 SO 4 The residue was dried at 4°C and the solvent was removed in vacuo. HPLC (X-BRIDGE, C-18, 250 x 19 mm, 5 μm, 15 mL / min, gradient Mixture: MeCN / water 20.0% to 35.0% (30.0 min), 100.0% (3.0 min) 0.1% NH 3 ] to obtain ethyl 2 -(4-(1-(methylglycyl)pyrrolidin-2-yl)piperidin-1-yl)-6 -Azaspiro[3.4]octane-6-carboxylate, Example 2-23 Isomer 1, ( 9.0 mg, 9.27%) as a yellow gum, ethyl 2-(4-(1-(ethylcarbamate) )pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]o Citrate-6-carboxylate, Example 2-23 Isomer 2, (8.0 mg, 8.50%) was obtained as a yellow gum. Data for isomer 2 are in Table 3.

[0439] Route Q Example 2-27, Ethyl 2-{4-[(2S)-1-(azetidin-1-ylcarbonyl )pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane Preparation of piperidines via urea formation exemplified by the preparation of 6-carboxylates. Typical steps to [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (100 mg, 0.291 The mixture of diastereomers (1 mmol) was dissolved in DCM (5 mL) and diisopropyl ethyl acetate. The mixture was dissolved in triphosgene (88 mg, 0. 291 mmol) was added at 0° C., and the solution was allowed to warm to room temperature and stirred for 1 h. Then, the mixture Dilute with DCM (50 mL) and 2The aqueous layer was washed with DCM (2 × 5 0 mL) and the combined DCM extracts were diluted with Na 2 SO 4 The residue was dried over 1000 ml and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and azetidine (0.020 mL, 0.291 mmol) and diisopropylethylamine (0.256 mL, 1.48 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (50 mL) and 2 O(70 The aqueous layer was extracted with DCM (2 × 50 mL) and the combined DCM extracts were washed with N a 2 SO 4 Dry and concentrate in vacuo to give ethyl 2-{4-[(2S)-1-(azetidinediamine -1-ylcarbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspipri b[3.4]octane-6-carboxylate as a yellow solid and diastereomers The residue was purified by preparative HPLC [reverse phase HPLC (CHIRALPAK A DH, C-18, 250 x 20 mm, 5 μm, 18.0 mL / min, gradient: acetonitrile 0% to 50% (15.0 min) in 100 mL of 0.1% ammonia and H 2 0.1% ammonia in O Purified by ethyl (S)-2-(4-(1-azetidine-1-carbonyl) Pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane- 6-Carboxylate, Example 2-27 Isomer 1 (20 mg, 16.12%) was dissolved in water to obtain a colorless gel. Example 2-27 Isomer 2 (20 mg, 16.12%) as a colorless gum The data for isomer 2 are given in Table 3.

[0440] Route r Example 2-42, Ethyl 2-(4-{(2S)-1-[ethyl(propan-2-yl)carboxylate] rubamoyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4 ]octane-6-carboxylate, and Example 2-138, ethyl 2-{4-[(2S )-1-(5-methyl-1,3,4-oxadiazol-2-yl)pyrrolidine-2-yl {6-azaspiro[3.4]octane-6-carboxylate} A typical procedure for preparing piperidines via urea formation and dehydration is illustrated by the preparation of Procedure [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (164 mg, 0.403 The mixture of diastereomers (1 mmol) was dissolved in DCM (2 mL) and diisopropyl ethyl acetate. The mixture was dissolved in triphosgene (43 mg, 0. (145 mmol) was added at 0° C., and the solution was allowed to warm to room temperature and stirred for 18 hours. tert-Butyl carbazate (108 mg, 0.82 mmol) and diisopropyl Ethylamine (0.142 mL, 0.82 mmol) was added and the reaction was stirred at room temperature for 18 hours. The mixture was then diluted with DCM (20 mL) and saturated NaHCO 3 (aqueous solution)( The aqueous layer was extracted with DCM (20 mL) and the combined DCM extracts were was washed with saturated brine (50 mL) and then passed through a Biotage phase separator; Concentrate in vacuo to obtain ethyl 2-{4-[(2S)-1-(butylcarbazoyl)pyrrolidine- 2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate The sylate as a yellow oil and a mixture of diastereomers (192 mg, 97%) was offered as. LCMS (Method D): m / z 494 (M+H) + (ES + ), 1.83 and 1.87 min. UV inactive.

[0441] The crude product was dissolved in 4 M hydrogen chloride in dioxane (2.0 mL, 8.0 mmol) and DCM ( The reaction mixture was stirred at room temperature for 1 h. The volatiles were then removed in vacuo. After evaporation, the reaction mixture was diluted with DCM (2 mL) and diisopropylethylamine (0.14 mL). Redissolved in acetyl chloride (0.031 mL, 0.428 mmol). (mmol) was added at 0° C., the solution was allowed to warm to room temperature and stirred for 2 h. The volatiles were removed in vacuo. The residue was dissolved in toluene (2 mL) and dichloromethane (1 mL) and used in the next step without further purification. Dissolve in isopropylethylamine (0.135 mL, 0.78 mmol) and cool to 0°C. Phosphoryl chloride was added (0.182 mL, 1.945 mmol) and the reaction was cooled to 11 After stirring at 0° C. for 30 min, the reaction was cooled to room temperature and quenched with ice water (20 mL). The mixture was then diluted with DCM (20 mL) and 1 M NaOH (水溶液) (2×2 The aqueous layer was extracted with DCM (3×20 mL) and the combined DCM extracts were The mixture was washed with saturated saline (50 mL) and then passed through a Biotage phase separator. The residue was purified by preparative HPLC using Phenomenex A Gemini-NX C18 column, 100 × 30 mm, was used for H at 18 mL / min. 2 O Elute with 25-45% MeCN / 0.2% ammonia (v / v) and monitor at 210 nm. The fractions were collected by elution. -{(2S)-1-[ethyl(propan-2-yl)carbamoyl]pyrrolidin-2-yl {piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate Example 2-42 Isomer 2, ethyl 2- (4-{(2S)-1-[ethyl(propan-2-yl)carbamoyl]pyrrolidine-2 -yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxy The isomer 1, ethyl acetate (1.6 mg, 1%) was obtained as a colorless oil. 2-{4-[(2S)-1-(5-methyl-1,3,4-oxadiazol-2-yl )pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane -6-carboxylate (3.9 mg, 2.5%) was obtained as a colorless oil from Example 2- 138 Isomer 2, Ethyl 2-{4-[(2S)-1-(5-methyl-1,3,4-oxa diazolidin-2-yl]pyrrolidin-2-yl]piperidin-1-yl}-6-azaspirate b) [3.4] Octane-6-carboxylate (3.0 mg, 2%) was treated as a colorless oil. The data for isomer 2 are given in Table 3.

[0442] Routes Example 2-47, Ethyl 2-(4-{(2S)-1-[(2-fluoroethoxy)carbamoyl 6-Azaspiro[3.4]octyl]pyrrolidin-2-yl}piperidin-1-yl Piperidinylation via carbamate formation exemplified by the preparation of tan-6-carboxylate Typical Procedure for Preparing Gin [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.15 g, 0.44 m mol) diastereomer mixture and diisopropylethylamine (0.152 mL , 0.89 mmol) was dissolved in DCM (5 mL) and the reaction mixture was then cooled to 0° C. Ethyl 2-fluorochloroformate (0.062 g, 0.492 mmol) was added, and the resulting mixture was The resulting reaction mixture was stirred at 25° C. for 16 hours. 2 O (70 mL) Partition with DCM (50 mL), extract the aqueous layer further with DCM (2×50 mL) and the organic layer Combined, Na 2 SO 4 The residue was dried at 40° C. and the solvent was removed in vacuo. LC(CHIRALPAK AD-H, C-18, 250×20mm, 5μm, 18.0 mL / min, gradient: 0% to 35% in acetonitrile (52 min), 0.1% ammonia and Purification with 0.1% ammonia in water gave ethyl 2-(4-{(2S)-1-[(2- Fluoroethoxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6- Azaspiro[3.4]octane-6-carboxylate, Example 2-47 Isomer-1 (1 7 mg, 8.9%) as a yellow gum, (fluoroethoxy)carbonyl]pyrrolidin-2-yl}piperidin-1-yl)-6-a Zaspiro[3.4]octane-6-carboxylate, Example 2-47 Isomer-2 (19 mg, 10%) as a yellow gum. Data for isomer 2 are in Table 3.

[0443] Route t Example 2-52, Ethyl 2-{4-[(2S)-1-(hydroxyacetyl)pyrrolidine -2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo A typical example for preparing piperidines via amide formation is illustrated by the preparation of xylates. Typical Procedure [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.2 g, 0.541 m A mixture of diastereomers of 0.152 mL of triethylamine (1.1 mmol) and mol) was dissolved in DCM (5 mL), and the reaction mixture was then cooled to 0° C. and acetochloride was added. C. Diacetyl (0.080 g, 0.591 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the residue was then dissolved in acetonitrile (25 mL) and The reaction mixture was dissolved in 20% aqueous NaOH (10 mL) and stirred at room temperature for 1 h. H 2 Partition between O (70 mL) and DCM (50 mL) and rehydrate the aqueous layer with DCM (2 × 50 mL). Further extraction was performed, and the organic layers were combined and diluted with Na 2 SO 4 The solvent was removed in vacuo and the residue was separated. HPLC [reversed phase HPLC (CHIRALPAK AD-H, C-18, 250×20m m, 5 μm, 18.0 mL / min, gradient: 0% to 30% (35.0 min), acetonitrile Ethyl (S)-2 was purified by 0.1% ammonia in water and 0.1% ammonia in water. -(4-(1-(2-hydroxyacetyl)pyrrolidin-2-yl)piperidin-1-yl 6-Azaspiro[3.4]octane-6-carboxylate, Example 2-52 isomer Compound 1 (8 mg, 8.3%) was obtained as a colorless gum, ethyl (S)-2-(4-(1-(2 -Hydroxyacetyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspipri b[3.4]octane-6-carboxylate, Example 2-52 Isomer 2 (12 mg, 1 2.24%) as a colorless gum. Data for isomer 2 are in Table 3.

[0444] Route u Example 2-53, Ethyl 2-{4-[(2S)-1-(3,3,3-trifluoropropane 6-Azaspiro[3.4]oyl)pyrrolidin-2-yl]piperidin-1-yl} Piperidine via amide formation exemplified by the preparation of butane-6-carboxylate Typical procedure for the preparation of [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.12 g, 0.36 m mol) diastereomer mixture and diisopropylethylamine (0.123 mL , 0.71 mmol) in DCM (10 mL), followed by trifluoropropanion Acid (trifluoropropanioic acid) (0.045g, 0.394 The reaction mixture was cooled to 0° C. and propylphosphonic anhydride was added ( 0.140g, 0.462mmol 50% in EtOAc), resulting reaction mixture The mixture was stirred at 25° C. for 2 h. 2Distribute in 20 mL of HO and 50 mL of DCM. The aqueous layer was then extracted further with DCM (2 x 50 mL), and the organic layers were combined and diluted with Na 2 SO 4 in After drying, the solvent was removed in vacuo. The residue was purified by preparative HPLC [reverse phase HPLC (CHIRALPA K AD-H, C-18, 250×20 mm, 5 μm, 18.0 mL / min, gradient: acetoacetate 0% to 30% in nitrile (27.0 min), 0.1% ammonia and 0.1% ammonia in water The ethyl (S)-2-(4-(1-(3,3,3-trifluoropropane) lopanoyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4 ]octane-6-carboxylate, Example 2-53 Isomer 1 (9 mg, 6.0%) Ethyl (S)-2-(4-(1-(3,3,3-trifluoropropane) Noyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]o Citrate-6-carboxylate, Example 2-53 Isomer 2 (9 mg, 6.0%) It was obtained as a gum. Data for isomer 2 are in Table 3.

[0445] Route V Example 2-58, Ethyl 2-{4-[(2S)-1-propanethioylpyrrolidine-2- yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate A typical procedure for preparing thioamides via the Lawesson's reagent is illustrated by the preparation of Procedure [ka] Ethyl 2-{4-[(2S)-1-propanoylpyrrolidin-2-yl]piperidine- 1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.341g , 0.87 mmol) in THF (4 mL), and then Lawesson's reagent (0.265 g The reaction mixture was stirred at 70° C. for 24 h. The volatiles were removed. Remove the reaction mixture in vacuo and add 1M NaOH (水溶液) (50 mL) and DCM (30 mL). The aqueous layer was further extracted with DCM (2 x 50 mL) and the organic layers were combined and washed with 5% pyridine. Sodium sulfate (水溶液) Wash with Na 2 SO 4 The residue was dried at 40° C. and the solvent was removed in vacuo. The residue was purified by preparative HPLC using Phenomenex Gemini- NX C18 column, 100×30 mm, was used, and H was run at 18 mL / min. 2 25~45% in O Extraction with MeCN / 0.2% ammonia (v / v) and monitoring at 210 nm The fractions were collected according to the following procedure. Example 2-58 Isomer 1, ethyl 2-{4-[(2S)- 1-propanethioylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro [3.4] Octane-6-carboxylate (14.1 mg, 4%) was obtained as a yellow oil. Example 2-58 Isomer 2, Ethyl 2-{4-[(2S)-1-propanethioylpyrrolidone Lysin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6- The carboxylate (7.6 mg, 2%) was obtained as a yellow oil. The data are in Table 3.

[0446] Route W Example 2-61, Ethyl 2-{4-[(2S)-1-ethylpyrrolidin-2-yl]piperidine Preparation of lysine-1-yl}-6-azaspiro[3.4]octane-6-carboxylate A typical procedure for preparing piperidines via alkylation is exemplified by [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.100 g, 0.29 A mixture of diastereomers of potassium carbonate (0.123 mg, 0.89 mmol) and potassium carbonate (0.123 mg, 0.89 mmol) mol) was dissolved in DMF (5 mL) and the reaction mixture was stirred at 60° C. for 2 h. Then, Iodoethane was added (0.049 g, 0.31 mmol), and the reaction mixture was heated at 100 °C for 62 h. The reaction mixture was stirred for 1 h. 2 Partition between O (70 mL) and EtOAc (50 mL), and the aqueous layer The extract was further extracted with EtOAc (2 x 50 mL), and the organic layers were combined and washed with Na 2 SO 4 Dry in The solvent was removed in vacuo. The residue was purified by preparative HPLC (X Bridge, C-18, 150× 19 mm, 5 μm, 20 mL / min, gradient: acetonitrile / 35% in water (0.01 min) , 100% (25.01 min), then 35% (30.00 min), 0.1% ammonia ] to obtain ethyl (S)-2-(4-(1-ethylpyrrolidin-2-yl)pyridin-2-yl)pyridin-2-yl. peridin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 2-61 Isomer 1 (43 mg, 38.8%) was obtained as a colorless gum by elution with ethyl (S)- 2-(4-(1-ethylpyrrolidin-2-yl)piperidin-1-yl)-6-azaspirillum b[3.4]octane-6-carboxylate, Example 2-61 Isomer 2 (26 mg, 2 3.1%) as a colorless gum. Data for isomer 2 are given in Table 3.

[0447] Route x Example 2-62, Ethyl 2-(4-{(2S)-1-[3-(pyridin-2-yl)propionate 3.4]-6-azaspiro[3.4] Piperidines can be prepared via amide formation, as exemplified by octane-6-carboxylate. Typical steps for making [ka] Oxalyl chloride (0.065 mL, 0.768 mmol) in DCM (2 mL) at 0 °C A solution of 2-pyridinepropionic acid (106 mg, 0.704 mmol) and DMF (1 (drops) were added. Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidine-1- {6-yl}-6-azaspiro[3.4]octane-6-carboxylate hydrochloride (262 mg A mixture of diastereomers (0.640 mmol) was dissolved in DCM (1 mL) and diisopropyl Dissolve in ethylamine (0.355 mL, 2.049 mmol) and add to the above solution. It was stirred at room temperature for 2 h. The mixture was then diluted with 1 M NaOH(aq) (50 mL). The mixture was poured into a flask, extracted with DCM (2 x 50 mL), and the combined DCM extracts were washed with saturated brine (5 0 mL), then passed through a Biotage phase separator, concentrated in vacuo, and 2-(4-{(2S)-1-[3-(pyridin-2-yl)propanoyl]pyrrolidine {piperidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxamide The carboxylate was obtained as a black oil and a mixture of diastereomers (0.245 g, 8 2%). The diastereomers were separated using preparative HPLC. , using a Phenomenex Gemini-NX C18 column, 100 x 30 mm and H at 18 mL / min. 2Dissolve in 25–45% MeCN / 0.2% ammonia (v / v) in O The fractions were collected by monitoring at 210 nm. Isomer 1, ethyl 2-(4-{(2S)-1-[3-(pyridin-2-yl)propanoyl pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octa 1,2-dimethyl-2,4-triphenylphosphine-6-carboxylate (0.042 g, 14%) was obtained as a colorless oil from Example 2. -62 isomer 2, ethyl 2-(4-{(2S)-1-[3-(pyridin-2-yl)propionate 3.4]-6-azaspiro[3.4] Octane-6-carboxylate (0.030 g, 10%) was obtained as a colorless oil. Data for 2 are in Table 3.

[0448] Route y Example 2-65, Ethyl 2-{4-[(2S)-1-{N-[(benzyloxy)carbamoyl yl]-β-alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspipri 2-[3.4]octane-6-carboxylate, and Example 2-66, Ethyl 2-{4- [(2S)-1-(β-alanyl)pyrrolidin-2-yl]piperidin-1-yl}-6 amines, exemplified by the preparation of -azaspiro[3.4]octane-6-carboxylate. Typical Procedure for Preparing Piperidines via Deprotection and CBZ Deprotection [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (100 mg, 0.298 A mixture of diastereomers (0.102 mL, 0.597 mmol) and DIPEA (0.102 mL, 0.597 mmol) mol) to CH 2 Cl 2 (5 mL), cooled to 0° C., and Z-β-ara-OH(0 0.066g, 0.298mmol) was added, followed by propanephosphonic anhydride (0.12 3g, 0.388mmol, 50% in ethyl acetate) was added. The resulting reaction mixture The mixture was stirred at 25°C for 3 h and then cooled to 5°C. 2 O (70 mL) and CH 2 Cl 2 (50 mL), and water CH layer 2 Cl 2 (2×50 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and the solvent removed in vacuo to give ethyl 2-{4-[(2S)-1-{N-[ (benzyloxy)carbonyl]-β-alanyl}pyrrolidin-2-yl]piperidine- 1-yl}-6-azaspiro[3.4]octane-6-carboxylate (100 mg, This was purified for the synthesis of Example 2-66. It was used directly without any modification. LCMS (Method I): m / z 541 (M+H) + (ES+) 4.38 and 4.51 minutes , UV inert.

[0449] The residue was subjected to preparative HPLC [reversed phase HPLC (CHIRALPAK AD-H, C-18, 25 0×20 mm, 5 μm, 18.0 mL / min, gradient: 0% to 50% (15 0.0 min), 0.1% ammonia and 0.1% ammonia in water. Ethyl 2-{4-[(2S)-1-{N-[(benzyloxy)carbonyl]-β- alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4] Octane-6-carboxylate, Example 2-65 Isomer 1 (20 mg, 12.5%) Ethyl 2-{4-[(2S)-1-{N-[(benzyloxy)carbonyl] carboxy]-β-alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-aza Spiro[3.4]octane-6-carboxylate, Example 2-65 Isomer 2 (20 mg , 12.5%) was obtained as a colorless gum. Data for isomer 2 are given in Table 3.

[0450] Ethyl 2-{4-[(2S)-1-{N-[(benzyloxy)carbonyl]-β-acetate ranyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]o Diastereomers of methacrylate-6-carboxylate (100 mg, 0.185 mmol) The mixture was dissolved in TFA (2.0 mL). The resulting solution was stirred at 80° C. for 3 h. The residue was purified by preparative HPLC [reverse phase HPLC (CHIRALPAK AD-H, C -18, 250 x 19 mm, 5 μm, 13.0 mL / min, gradient: 0% to acetonitrile 30% (30.0 min), purified by 0.1% ammonia and 0.1% ammonia in water Ethyl (S)-2-(4-(1-(3-aminopropanoyl)pyrrolidine-2-yl) Piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate Example 2-66 Isomer 1 (2 mg, 2.63%) was obtained as a colorless gum by the addition of ethyl (S )-2-(4-(1-(3-aminopropanoyl)pyrrolidin-2-yl)piperidine- 1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Examples 2-6 6Isomer 2 (3 mg, 4.0%) was obtained as a colorless gum. See Table 3.

[0451] Route z Example 2-68, Ethyl 2-{4-[(2S)-1-(2-fluoroethyl)pyrrolidine -2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo A typical example for preparing piperidines via alkylation exemplified by the preparation of xylates. Typical Procedure [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (100 mg, 0.27 m The mixture of diastereomers (1.2 mmol) was dissolved in MeCN (5 mL) and CS 2 CO 3 (2 90 mg, 0.89 mmol) was added, followed by 2-iodo-1-fluoroethane (56 mg gg, 0.32 mmol) was added and the reaction mixture was stirred at 50° C. for 16 h. H 2 The mixture was partitioned between 2× ethyl acetate (50 mL) and 1× ethyl acetate (70 mL). The organic layers were combined and dried (Na 2 SO 4 ), filtered, and the solvent was removed. The residue was subjected to preparative HPLC [reverse phase HPLC (CHIRALPAK AD-H, C- 18, 250 x 19 mm, 5 μm, 15.0 mL / min, gradient: 0% to 4% in acetonitrile 0% (19 min), 0.1% ammonia and 0.1% ammonia in water]. , ethyl (S)-2-(4-(1-(2-fluoroethyl)pyrrolidin-2-yl)piperidine Lysine-1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 2-68 Isomer 1 (25 mg, 25%) was dissolved in ethyl (S)- 2-(4-(1-(2-fluoroethyl)pyrrolidin-2-yl)piperidin-1-yl )-6-Azaspiro[3.4]octane-6-carboxylate, Example 2-68 Isomer 2 (20 mg, 20.3%) was obtained as a yellowish gum. Data for isomer 2 are in Table 3.

[0452] Route aa Example 2-69, Ethyl 2-{4-[(2S)-1-(2,2,2-trifluoroethyl )pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane Preparation of piperidines via alkylation exemplified by the preparation of -6-carboxylates Typical steps to [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.100 g, 0.29 A mixture of diastereomers of 0.112 g, 0.87 mmol) and DIPEA (0.112 g, 0.87 mmol) l) was dissolved in THF (5 mL) and stirred at 60° C. for 2 hours. 2,2,2-trifluoroethyl phosphate (0.067 g, 0.29 mmol) was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 24 hours. 2 O(70mL ) and EtOAc (50 mL), and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The organic layers were combined and dried (Na 2 SO 4 The residue was purified by preparative chromatography. PLC (X Bridge, C-18, 250 x 19 mm, 5 μm, 12 mL / min, gradient : 45% in acetonitrile / water (0.01 min), 100% (30.00 min), then 45% (32.00 min), 0.1% ammonia to purify ethyl (S)-2- (4-(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)piperidine- 1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Examples 2-6 9Isomer 1 (0.003 g, 2.4%) was obtained as a colorless gum, ethyl (S)-2-(4 -(1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)piperidine-1- (yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 2-69 Isomer 2 (0.002 mg, 1.6%) was obtained as a colorless gum. The data are in Table 3.

[0453] Route ab Example 2-70, Ethyl 2-{4-[(2S)-1-(3,3,3-trifluoropropionate {6-azaspiro[3.4]octa(pyrrolidin-2-yl)piperidin-1-yl} Piperidines can be prepared via alkylation, as exemplified by the preparation of amine-6-carboxylates. Typical steps for making [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.100 g, 0.29 (mmol) diastereomeric mixture and K 2 CO 3 (0.123g, 0.89mmol l) was dissolved in MeCN (5 mL) and the reaction mixture was stirred at 60° C. for 2 h. -Trifluoro-3-iodopropane (0.066g, 0.29mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 8 hours. 2 O (70 mL) and E The aqueous layer was extracted with EtOAc (2×50 mL) and the extract was The layers were combined and dried (Na 2 SO 4 ), filtered, and the solvent was removed in vacuo. The residue was PLC (X Bridge, C-18, 250 x 19 mm, 5 μm, 15 mL / min, gradient : 60% in acetonitrile / water (0.01 min), 100% (14.01 min), then 60% (23.00 min), 0.1% ammonia to purify ethyl (S)-2- (4-(1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl)piperidine -1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 2- 70 Isomer 1 (0.005 g, 3.9%) was obtained as a colorless gum, ethyl (S)-2-( 4-(1-(3,3,3-trifluoropropyl)pyrrolidin-2-yl)piperidine- 1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Examples 2-7 Isomer 1 and isomer 2 (0.005 mg, 3.9%) were obtained as a colorless gum. Data for body 2 are in Table 3.

[0454] Route ac Example 2-72, Ethyl (S)-2-(4-(1-(2-methoxy-2-oxoethyl) Pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane- Preparation of piperidines via alkylation exemplified by the preparation of 6-carboxylates. Typical steps to [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.100 g, 0.29 A mixture of diastereomers (0.14 mL, 0.87 mmol) and DIPEA (0.87 mmol) l) was dissolved in MeCN (5 mL) and the reaction mixture was stirred at room temperature for 1 h. C. (0.044 g, 0.29 mmol) was added dropwise and the resulting reaction mixture was heated to 100.degree. The reaction mixture was stirred at rt for 3 h. 2 Partition between O (70 mL) and EtOAc (50 mL). The aqueous layer was then further extracted with EtOAc (2×50 mL) and the organic layers were combined and dried (Na 2 SO 4 ), filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC (X Bridge, C -18, 250 x 19 mm, 5 μm, 15 mL / min, gradient: acetonitrile / 48% in water (0.01 min), 100% (11.1 min), 48% (48.00 min), 0.1% ammonia] to obtain ethyl (S)-2-(4-(1-(2-methoxy-2-phenyl)-2-propanediol. xoethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4 ]octane-6-carboxylate, Example 2-72 Isomer 1 (0.012 g, 9.9% ) as a colorless gum, Ethyl)pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]o Citrate-6-carboxylate, Example 2-72 Isomer 2 (0.013 mg, 10.7%) ) was obtained as a colorless gum. Data for isomer 2 are in Table 3.

[0455] Route ad Example 2-72, Ethyl 2-(4-{(2S)-1-[2-(dimethylamino)-2-o xoethyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4 ]Piperine via alkylation, as exemplified by the preparation of octane-6-carboxylate Typical Procedure for Preparing Gin [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.100 g, 0.29 (mmol) mixture of diastereomers and NEt 3 (0.087g, 0.85mmol ) was dissolved in dioxane (5 mL) and the reaction mixture was stirred at 60° C. for 30 min. 2) N,N-dimethylacetamide (0.036 g, 0.29 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 12 hours. 2 O (70 mL) and E The aqueous layer was extracted with EtOAc (2×50 mL) and the extract was The layers were combined and dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was purified by preparative HPLC. (X Bridge, C-18, 250 × 19 mm, 5 μm, 14 mL / min, gradient: 20% in trinitrile / water (0.01 min), 40% (36.00 min), 100% (44 0.00 min), followed by 20% (52.00 min), 0.1% ammonia]. Ethyl (S)-2-(4-(1-(2-(dimethylamino)-2-oxoethyl)pyridine Rolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6 -Carboxylate, Example 2-72 Isomer 1 (0.002 g, 1.6%) was dissolved in water to give a yellow gum. As ethyl (S)-2-(4-(1-(2-(dimethylamino)-2-oxoethyl )Pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane -6-carboxylate, Example 2-72 isomer 2 (0.002 mg, 1.6%) in yellow It was obtained as a gum. Data for isomer 2 are in Table 3.

[0456] Route ae Example 2-76, Ethyl 2-{4-[2-(methylcarbamoyl)-2,3-dihydro- 1H-Isoindol-1-yl]piperidin-1-yl}-6-azaspiro[3.4] Reductive amination, Boc deprotection exemplified by the preparation of octane-6-carboxylate Typical Procedure for Preparing Piperidines via Protection and Urea / Amide Formation [ka] tert-Butyl 1-(piperidin-4-yl)isoindoline in DCM (5 mL) -2-carboxylate (135 mg, 0.45 mmol) and ethyl 3-oxo-8- Azabicyclo[3.2.1]octane-8-carboxylate (88 mg, 0.890 m mol) solution of Ti(O i P) 4 (0.40 mL, 1.34 mmol) was added at 0°C. The reaction mixture was stirred for 1 h. 3 BH (283 mg, 1.34 mmol) l) was added portionwise to the reaction mixture and stirred at 0° C. for 2 h. After completion, the reaction mixture was diluted with saturated N aHCO 3The mixture was quenched with aqueous solution of 1,2-dichloromethane and extracted with DCM (3×30 mL). The organic layers were combined and Wash with saturated saline and dry (Na 2 SO 4 The residue was purified by flash column chromatography. Chromatography [normal phase, silica gel (100-200 mesh), gradient: in DCM 5% to 10% methanol] to obtain tert-butyl 1-(1-(6-(ethyl acetate) (oxycarbonyl)-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl (35 mg, 75%) was obtained as a colorless liquid. Ta. MS(ESI+ve):484

[0457] tert-Butyl 1-(1-(6-(ethoxycarbonyl)) (carbonyl)-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl) A solution of diisoindoline-2-carboxylate (290 mg, 0.61 mmol) was added to HCl in xanthan (4 M, 5 mL) was added slowly at 0° C., and the mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo. The solid residue was triturated with diethyl ether to give ethyl 2-(4- (Isoindolin-1-yl)piperidin-1-yl)-6-azaspiro[3.4]octyl Tan-6-carboxylate hydrochloride (250 mg, cr) was obtained as an off-white solid. MS(ESI+ve):384 1 H-NMR (400 MHz; DMSO-d 6 ) δ: 1.15(t, J = 6.9 Hz, 3H),1.16 - 1.26(m, 1H), 1.70 - 1.90(m, 5H) ), 1.95 -2.28(m, 5H), 3.49 - 3.72(m, 4H), 3.60 - 3.72(m,4H), 3.98 - 4.15(m, 2H), 4.13(q, J = 6.9 Hz, 2H),4.45 - 4.59(m, 2H), 7.37 - 7.49(m, 5H), 9.54,10.19(2br.s., 2H).

[0458] Ethyl 2-(4-(isoindolin-1-yl)piperidine-1-yl) in DCM (5 mL) -yl)-6-azaspiro[3.4]octane-6-carboxylate hydrochloride (240m g, 0.40 mmol) was added to a solution of 0.5 mL of DIPEA (0.43 mL, 2.38 mmol). To this reaction mixture was added methylcarbamyl chloride. mic chloride (67 mg, 0.72 mmol) was added and stirred at room temperature for 16 hours. The reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2×20 mL). The organic layers were combined and dried (Na 2 SO 4 ), concentrated in vacuo. The residue was flashed Column chromatography [normal phase, silica gel (100-200 mesh), gradient: DC 5% to 10% methanol in 10 mL of ethyl 2-(4-(2-methylphenyl)carbamate. Bamoyl)-isoindolin-1-yl)piperidin-1-yl)-6-azaspiro[3 .4] Octane-6-carboxylate as a mixture of diastereomers (130 mg, 48 %) as a sticky liquid. LCMS (Method M): m / z 441 (M+H) + (ES+), 1.97 and 1.99 Minutes, UV activity. 1 H-NMR (400 MHz; DMSO-d 6 ):δ: 1.15(t, J = 6. 9 Hz, 3H),1.16 - 1.26(m, 4H), 1.49 - 1.90(m, 5 H), 1.91 -2.01(m, 2H), 2.62(d, J = 3.9 Hz, 3H) , 2.70 -2.90(m,2H), 3.09 - 3.25(m, 4H), 3.97( q, J = 6.8Hz, 2H), 4.45 - 4.59(m, 2H), 5.01 - 5 .09(m, 1H),6.27(br.s., 1H), 7.22 - 7.32(m, 4H) ).

[0459] Preparative HPLC (73.0 mg submitted, Gilson Semi-Prep HPLC System - Dual Piston pumps 331 and 332, 171 diode array detector and GX-271 liquid Includes head handler, Solvent: Aqueous = water + 0.2% ammonia (28% ammonia solution) and organics = acetonitrile, gradient: 20-50% organics solution in water, flow rate: 30 mL / min Column: Gemini-NX, C18, 5μ, 100×30mm) Separation of the mers gave ethyl 2-(4-(2-(methylcarbamoyl)-isoindolyl) (1-phenyl-1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxamide carboxylate, Example 2-76 Isomer 1 (8.99 mg, 12.3%) was treated as a colorless gum. Ethyl 2-(4-(2-(methylcarbamoyl)-isoindolin-1-yl)pyridinyl) peridin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 2-76 Isomer 2 (10.9 mg, 14.9%) was obtained as a colorless gum. Data for 1 and isomer 2 are given in Table 3.

[0460] Route af Example 2-77, Ethyl 2-{4-[(2S)-1-phenylpyrrolidin-2-yl]pyridin Preparation of {peridin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate A typical procedure for arylation of pyrrolidines is exemplified by [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.100 g, 0.27 The mixture of diastereomers (1 mmol) was dissolved in DCM (5 mL) and triethylamine was added. (54 mg, 0.54 mmol) was added, followed by (1R,5S)-3-phenyl-2,4 -Dioxa-3-borabicyclo[3.3.1]nonan-7-one (J. Luo et al., Tet See Rahedron Letters 54(2013), 4505-4508. The reaction mixture was stirred at room temperature for 16 h and then H 2 The aqueous layer was diluted with DCM (2×50 mL). After further extraction, the organic layers were combined and dried (Na 2 SO 4 ), remove the solvent, and separate the residue. HPLC [Reverse phase HPLC (CHIRALPAK AD-H, C-18, 250×19mm , 5 μm, 15.0 mL / min, gradient: 0% to 30% in acetonitrile (21.0 min); Purification with 0.1% ammonia and 0.1% ammonia in water gave ethyl 2-{4-[ (2S)-1-Phenylpyrrolidin-2-yl]piperidin-1-yl}-6-azaspipri b[3.4]octane-6-carboxylate, Example 2-77 Isomer 1 (10 mg, 1 3%) as a gum, and ethyl 2-{4-[(2S)-1-phenylpyrrolidine-2-yl {6-azaspiro[3.4]octane-6-carboxylate} Example 2-77 gave Isomer 2 (10 mg, 13%) as a gum. The relevant data are in Table 3.

[0461] Route ag Example 2-78, Methyl 2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidine -2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo The complexation reaction using cesium carbonate and copper iodide in DMF is exemplified by the preparation of xylates. Typical Procedure for Arylation of Pyrrolidine-Containing Compounds with a Monocyclic Ring [ka] Methyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.120 g, 0.37 (mmol) mixture of diastereomers, Cs 2 CO 3 (0.361g, 1.1mmol ) and CuI (0.105 g, 0.50 mmol) were dissolved in DMF (5 mL) and stirred at room temperature. The mixture was stirred for 30 minutes. Then, 2-bromopyridine (0.058 g, 0.37 mmol) was added. The resulting mixture was stirred at 100° C. for 18 hours. 2 O(70m The aqueous layer was partitioned between EtOAc (2×50 mL) and EtOAc (50 mL). The organic layers were combined and dried (Na 2 SO 4 ), the solvent was removed by concentration, and the residue was Preparative HPLC of the residue (X Bridge, C-18, 150 x 19 mm, 5 μm, 13 mL / min, gradient: 40% to 100% acetonitrile / water (20 min), 0.1% ammonia ] to obtain methyl 2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidine. {6-azaspiro[3.4]octane-6-yl}piperidin-1-yl}- Example 2-78 Isomer 1 (0.011 g, 2%) as a gum, 2-{4-[(2S)-1-(pyridin-2-yl)pyrrolidin-2-yl]piperidinyl {6-azaspiro[3.4]octane-6-carboxylate, Example 2 -78 Isomer 2 (0.09 mg, 2%) was obtained as a gum. Data for Isomer 2 are See Table 3.

[0462] Route ah Example 2-81, Ethyl 2-{4-[(2S)-1-(pyrimidin-2-yl)pyrrolidine {6-azaspiro[3.4]octane-6-yl}piperidin-1-yl}- The synthesis of heterocyclic carboxylates using sodium carbonate in ethanol is exemplified by the preparation of Typical Procedure for Arylation of Pyrrolidine-Containing Compounds with [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Azaspiro[3.4]octane-6-carboxylate hydrochloride (0.100 g, 0.29 (mmol) diastereomeric mixture and Na 2 CO 3 (0.092g, 0.87mm ol) was dissolved in ethanol (10 mL) and stirred at room temperature for 30 min. 3H-pyrimidine (0.034 g, 0.29 mmol) was added at 0° C. The resulting reaction mixture The mixture was stirred at 80° C. for 6 h. The reaction mixture was concentrated and dichloromethane was added. The mixture was filtered, the filtrate was concentrated, and the concentrate was purified by preparative HPLC (X Bridge, C-18, 150×19 mm, 5 μm, 15 mL / min, gradient: acetonitrile / 38% in water (0.01 min), 4 2% (15.00 min), 100% (19.00 min), then 38% (23.00 min) ), 0.1% ammonia] to obtain ethyl 2-{4-[(2S)-1-(pyridyl) 6-Azaspiro[(2-pyridinyl)pyrrolidin-2-yl]piperidin-1-yl 3.4] Octane-6-carboxylate, Example 2-81 Isomer 1 (0.031 g, 2 5%) as gum, and ethyl 2-{4-[(2S)-1-(pyrimidin-2-yl)pyrimidinyl] roridin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6 -carboxylate, Example 2-81 Isomer 2 (0.017 mg, 14%) as a gum The data for isomer 2 are given in Table 3.

[0463] Route AI Example 2-82, Ethyl 2-{4-[(2S)-1-(1,3-thiazol-2-yl) pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane 6-Carboxylate preparation using cesium carbonate in DMF. Typical Procedure for Arylation of Ring-Containing Pyrrolidine-Containing Compounds [ka] Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidin-1-yl}-6- Mixture of diastereomers of azaspiro[3.4]octane-6-carboxylate hydrochloride The product, intermediate 127, (100 mg, 0.27 mmol) was dissolved in DMF (5 mL) and C S 2 CO 3 (260mg, 0.81mmol) was added to it, and then 2-bromothiazo The reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was 2 The mixture was partitioned between 200 mL (70 mL) and EtOAc (50 mL). The organic layers were combined, dried (Na 2 SO 4 ), melt The solvent was removed by concentration, and the residue was purified by preparative HPLC [reverse phase HPLC (CHIRALPAK A DH, C-18, 250 x 19 mm, 5 μm, 15.0 mL / min, gradient: acetonitrile 0% to 30% in water (21.0 min), 0.1% ammonia and 0.1% ammonia in water The ethyl 2-{4-[(2S)-1-(1,3-thiazol-2-yl) pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane 6-Carboxylate, Example 2-82 Isomer 1 (20 mg, 18%) was treated as a colorless gum. Ethyl 2-{4-[(2S)-1-(1,3-thiazol-2-yl)pyrrolidine -2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo The xylate, Example 2-82, isomer 2 (6 mg, 6%) was obtained as a colorless gum. Data for isomer 1 and isomer 2 are given in Table 3.

[0464] Route aj Example 2-84, Ethyl 2-{4-[(2R)-2-(methoxycarbonyl)pyrrolidine -1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo Piperidines can be prepared via deprotection and reductive amination, as exemplified by the preparation of xylates. Typical steps for making [ka] tert-Butyl 4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl ]Piperidine-1-carboxylate (0.396 g, 1.26 mmol) was dissolved in DCM ( mL) and then HCl in dioxane (3 mL, 4.0 M solution) was added dropwise. The resulting reaction mixture was stirred at room temperature for 1 h, the solvent was removed in vacuo, and the residue was subjected to further purification. was used in the next step without any further purification.

[0465] Methyl 1-piperidin-4-yl-D-prolinate hydrochloride (0.358 g, 1.26 mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate Dissolve diethyl ether (0.266 g, 1.26 mmol) in DMF (4 mL) at room temperature and add DIP EA (0.435 mL, 2.510 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. STAB (0.533 g, 2.518 mmol) was then added and the reaction mixture was heated under nitrogen. The mixture was stirred overnight at room temperature under reduced pressure. The solvent was removed in vacuo and the diastereomers were isolated using preparative HPLC. This was achieved by using a Phenomenex Gemini-NX C18 column, 100×30mm, 18mL / min H 2 25-45% MeCN / 0.2% A in O The column was eluted with ammonia (v / v) and fractions were collected by monitoring at 210 nm. And Example 2-84 Isomer 1, ethyl 2-{4-[(2R)-2-(methoxycarbo 6-Azaspiro[3.4]octyl)pyrrolidin-1-yl]piperidin-1-yl} Tan-6-carboxylate (18.4 mg, 4%) was obtained as a colorless oil from Example 2 -84 Isomer 2, Ethyl 2-{4-[(2R)-2-(methoxycarbonyl)pyrrolidine -1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo The xylate (13.9 mg, 3%) was obtained as a colorless oil. The data are in Table 3.

[0466] Route ak Example 2-85, Ethyl 2-{4-[(2S)-2-(methylcarbamoyl)pyrrolidine -1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carbo To prepare piperidines via reductive amination, exemplified by the preparation of xylates. Typical procedure [ka] (S)-N-Methyl-1-(piperidin-4-yl)pyrrolidine-2-carboxamide Dihydrochloride (0.2 g, 0.94 mmol), NEt 3 (0.75mL, 5.0m ...

Claims

[Claim 1] The invention described in this specification.

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