Bicyclic aza compounds as muscarinic M1 receptor agonists.

Abstract

To provide compounds which are agonists of muscarinic M1 receptors and / or M4 receptors and are useful in treating muscarinic M1 / M4 receptor-mediated diseases. Also provided are pharmaceutical compositions containing the compounds, and therapeutic uses of the compounds. Compounds include those according to Formula 1, or salts thereof, wherein Q, R 1 , R 2 , R 3 and R 4 is as defined herein. The present invention provides compounds that exhibit selectivity for the M1 and / or M4 receptors over the M2 and M3 receptor subtypes. TIFF2023073504000236.tif3991

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 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 found 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. Five mAChR subtypes, M1 to M5, have been cloned. M1mAChRs are primarily expressed in postsynaptic membranes in the cortex, hippocampus, striatum, and thalamus; M2mAChRs 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, M2mAChR is expressed on cardiac tissue (where it They mediate vagal innervation of the heart and are also peripherally expressed in smooth muscle and exocrine glands. M3mAChR is expressed at relatively low levels in the CNS, but is expressed in smooth muscle tissue and It is widely expressed in glandular tissues such as sweat glands and salivary glands (Langmead et al., 2008). J Pharmacol).

[0003] Muscarinic receptors in the central nervous system, particularly M1mAChR, mediate higher cognitive processing. Diseases associated with cognitive impairment, such as Alzheimer's disease, This is accompanied by loss of cholinergic neurons in the basal brain (Whitehouse et al., 1999). 82 Science). Schizophrenia also has cognitive dysfunction 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. Although it has been shown to be effective as a symptomatic treatment for decreased gastrointestinal function, it can also cause abnormal gastrointestinal motility, bradycardia, nausea, and It has been shown to cause dose-limiting adverse events due to stimulation of peripheral M2 and M3 mAChRs, including vomiting and nausea. Wake up (http: / / www.drugs.com / pro / donepezil. html;http: / / www.drugs.com / pro / rivastigmi ne.html).

[0004] Directly to induce selective improvements in cognitive function with a favorable adverse effect profile Further discovery efforts have been directed at identifying M1 mAChR agonists. As a result of such efforts, xanomelin, AF267B, sabcomelin, miramelin, and A series of agonists have been identified, exemplified by compounds such as benzodiazepine and cevimeline. Many of the compounds are highly effective in preclinical models of cognition in both rodent and / or non-human primate models. Miramelin has been shown to be effective in working and spatial memory in rodents. It has shown efficacy against scopolamine-induced disorders; Xanomeline has shown efficacy in visual discrimination tasks and has been shown to improve cognitive performance in a passive avoidance paradigm. The compound reversed mAChR antagonist-induced impairment in performance.

[0005] Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting elderly people (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 primarily the formation of amyloid plaques composed of amyloid-β peptide (Aβ). Two types of tau protein are involved: aggregation and neurofibrillary tangles formed by hyperphosphorylated tau protein. It is characterized by characteristic brain pathology. Accumulation of Aβ is considered to be a central feature of the progression of AD. Therefore, many putative therapeutics for the treatment of AD currently target the inhibition of Aβ production. Aβ is derived from the proteolytic cleavage of membrane-bound amyloid precursor protein (APP). APP is expressed via two pathways: the non-amyloidogenic pathway and the amyloidogenic pathway. APP is processed by the γ-secretase pathway. In the former case, APP is cleaved by α-secretase to produce soluble APPα However, in the amyloidogenic pathway, APP is converted to β-secretase APPβ is cleaved by mAb to give soluble APPβ and also Aβ. ChR agonists promote APP processing to the soluble, non-amyloidogenic pathway In vivo studies have shown 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., 2014). 006 Neuron). The mAChR agonist cevimeline has been shown to be effective in patients with 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 mAChR agonist, Kampo, may exhibit a similar profile to other anti-inflammatory drugs. Sanomelin inhibits many dopamine-mediated behaviors, such as amphetamine-induced steroids 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 reverses A but not A9 in rats. inhibited the firing of 10 dopamine cells and conditioned avoidance, and c- These data also show that fos expression is induced in the striatum but not in the striata. All suggest an atypical antipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev. Muscarinic receptors are also implicated in the neurobiology of addiction. The reinforcing effects of cocaine and other addictive substances are thought to be mediated by the mesolimbic dopamine system. mediated by cholinergic muscarinic receptor subunits, where behavioral and neurochemical studies have demonstrated 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 cocaine exposure. showed reward-driven behaviors (Schmidt et al., Psychopharmacolog y(2011)Aug;216(3):367-78). Furthermore, xanomeline It has been demonstrated to block the effects of cocaine in these models.

[0007] Muscarinic receptors are also involved in the control of movement and are a key factor in Parkinson's disease, ADHD, and huntington syndrome. Dopaminergic pathways as underlying pathogenic factors inducing Parkinson's disease, Tourette's 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 are in various stages of clinical development for the treatment of schizophrenia. Phase II clinical trials of the drug have shown that it can improve various aspects of Alzheimer's disease, including behavioral disturbances and hallucinations. Its validity for cognitive symptom domains has been demonstrated (Bodick et al., 1997 Arc h Neurol) This compound was also evaluated in a small Phase II study in patients with schizophrenia. , significantly reduced positive and negative symptoms compared to placebo control (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. , gastrointestinal pain, irregular bowel movements (diahorrhea), sweating (excessive sweating), excessive salivation (saliva showed an unacceptable safety margin 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 inflammation and pain. It is caused by the action of pathogenic 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 diseases such as HIV and herpes. Muscarinic receptors are also common in cancer due to both the side effects of chemotherapy and the effects of muscarinic receptors. Activation of the agonist induces many pain reactions 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. Increased endogenous levels of cetylcholine, agonists or allosteric modulators Direct activation of muscarinic receptors by benzodiazepines has been shown to have analgesic activity. , blocking muscarinic receptors by using antagonists or knockout mice , and increased pain sensitivity. For evidence regarding the role of M1 receptors in pain, see DF As reviewed by Fiorino and M. Garcia-Guzman, 2012 are.

[0010] Recently, the M1mAChR subtype has been shown to be more prevalent than the peripherally expressed mAChR subtype. A few compounds have been identified that show improved selectivity for 08 Bioorg Med Chem Lett;Johnson et al., 2010 Bi oorg Med Chem Lett;Budzik et al., 2010 ACS Med Chem Lett.) The level of selectivity for the M3 mAChR subtype is increasing. Despite this, some of these compounds are specific to this subtype and M2mACh. It retains significant agonist activity in both R subtypes. Surprisingly, M1 and / or M4 mAChRs are more likely to be involved than M2 and M3 receptor subtypes. 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 explanation 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 (oral). The effect at 30 mg / kg was similar to that produced by the positive control cholinesterase inhibitor donepezil (0.1 mg / kg, intraperitoneal). [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 assessed by inhibiting d-amphetamine-induced hyperlocomotion (or increased locomotor activity). Data are shown for Examples 1-21 Isomer 2, 1-32 Isomer 2, 1-33 Isomer 2, 2-7 Isomer 2, and 2-17 Isomer 2. [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 assessed by inhibiting d-amphetamine-induced hyperlocomotion (or increased locomotor activity). Data are shown for Examples 1-21 Isomer 2, 1-32 Isomer 2, 1-33 Isomer 2, 2-7 Isomer 2, and 2-17 Isomer 2. 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 receptor and / or the M4 receptor. DETAILED DESCRIPTION OF THE INVENTION

[0014] Thus, in one embodiment (embodiment 1.1), the present invention provides a compound of formula (1): [ka] or a salt thereof, wherein Q has 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 SO2R 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. an optionally substituted 5- or 6-membered ring containing a heteroatom; R 2 is hydrogen; fluorine; chlorine; bromine; cyano; hydroxy; 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 SO2R 5 ;C 1-6 or R is selected from non-aromatic hydrocarbon groups; 1 and R 2 are joined together capable of forming a fused six-membered aromatic ring; R 3 is hydrogen; fluorine; cyano; hydroxy; amino; and 1 to 6 fluorine atoms. optionally substituted C 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 may be optionally replaced by a heteroatom selected from the oxidized forms of 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 separated by 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 several fluorine atoms 1-4 a hydrocarbon group; or formula C H2N(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 alkyl, heterocycloalkyl, aryl or heteroaryl groups 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 5R 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 SO2R 5 ; C optionally substituted with 1 to 6 fluorine atoms 1-6 Non-aromatic hydrocarbon groups (here In which one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, and S. and their oxidized forms, optionally replaced by heteroatoms selected from and 0, 1, 2 or more selected from O, N and S and their oxidized forms. optionally substituted 5- or 6-membered rings containing 3 heteroatoms; ; R 2 is hydrogen; fluorine; chlorine; bromine; cyano; hydroxy; 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 5and SO2R 5 ;C 1-6 or R is selected from non-aromatic hydrocarbon groups; 1 and R 2 are joined together capable of forming a fused six-membered aromatic ring; R 3 is hydrogen; fluorine; cyano; hydroxy; amino; and 1 to 6 fluorine atoms. optionally substituted C 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 may be optionally replaced by a heteroatom selected from the oxidized forms of 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 separated by 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 several fluorine atoms 1-4 a hydrocarbon group; or formula C H2N(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 alkyl, heterocycloalkyl, aryl or heteroaryl groups 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 has 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; hydroxy; amino; and 1 to 6 fluorine atoms. optionally substituted C 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 may be optionally replaced by a heteroatom selected from the oxidized forms of 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 separated by 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 aromatic heterocycle contains an additional ring member.

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

[0022] 1.6 Embodiment 1, wherein 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 compound is linked to a ring.

[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 Embodiment 1. 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 wherein Q is a six-membered ring containing one or more nitrogen atoms The compound described in

[0031] 1.15 Q is pyridyl, pyrazyl or a compound containing 0-2 C—C unsaturated bonds (c 2-oxo-3N(3-piperidin-2-one) ring. The compound according to 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 wherein Q is 5-pyrollidinyl The compound described in .16.

[0034] 1.18 In embodiment 1.1, 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 1and / or R 2 may be selected from R 1 and R 2 are 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 a CH group; R 10 , R 11 and R 12 are hydrogen; fluorine; chlorine; bromine; cyano; oxo; 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 R 16 ;SR 15 ;SOR 15 and SO2R 15 C optionally substituted with 1 to 6 fluorine atoms; 1-6 Non Aromatic hydrocarbon groups (where one or two, but not all, of the carbon atoms in 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 COO 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 SO2R 5 and 1 to 6 fluorines C optionally substituted with atoms 1-6 Non-aromatic hydrocarbon groups (1 or 2, but Some, but not all, of the carbon atoms of the hydrocarbon group may be O, N, and S, and their oxidized forms. and a group R consisting of 8 mosquito Selected from; R 15 , R 16 and R 17 are the same or different, or join together to form a ring each 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 group) of the carbon atoms are substituted by heteroatoms selected from O, N and S and their oxidized forms. or a group of formula CHN(R a )COOR b the basis of; is the formula (L)-R 18 where L is a bond or a CH group and R 18 If O, N and S and any of the oxidized forms thereof containing 0, 1, 2 or 3 heteroatoms selected from an optionally substituted 5- or 6-membered ring; Optional substituents on the optionally substituted 5- or 6-membered ring are groups R 8 Choose from The compound according to embodiment 1.1b, wherein

[0036] 1.20 R 1 but 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 O2R 5 C optionally substituted with 1 to 6 fluorine atoms; 1-6 Non-aromatic hydrocarbons Hydrocarbon groups (where one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, and 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. and optionally substituted 5- or 6-membered rings containing 1 or 3 heteroatoms. 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 COO 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 SO2R 5 and 1 to 6 fluorines C optionally substituted with atoms 1-6 Non-aromatic hydrocarbon groups (1 or 2, but Some, but not all, of the carbon atoms of the hydrocarbon group may be O, N, and S, and their oxidized forms. and a group R consisting of 8 mosquito The compound according to any one of embodiments 1.1 to 1.19, selected from:

[0037] 1.21 R 1 but 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 R6 ; NR 7 CONR 5 R 6 ;NR 7 COOR 5 ;OCONR 5 R 6 ;SR 5 ;SOR 5 and S O2R 5 C optionally substituted with 1 to 6 fluorine atoms; 1-5 Non-aromatic hydrocarbons Hydrocarbon groups (where one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, and 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; 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 SO2R 5 and 1 to 6 fluorine atoms Optionally substituted C 1-4 Non-aromatic hydrocarbon groups (one or two, but not all) the carbon atoms of the hydrocarbon group that are not selected from O, N and S and their oxidized forms a group R consisting of a heteroatom selected from 8 Choose from The compound of embodiment 1.20, wherein

[0038] 1.22 R 1 but 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 O2R 5 C optionally substituted with 1 to 6 fluorine atoms; 1-4 Non-aromatic hydrocarbons Hydrocarbon groups (where one or two, but not all, of the carbon atoms of the hydrocarbon group are O, N, and 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 containing two heteroatoms or is selected from heteroaryl rings; to the optionally substituted 5- or 6-membered aryl or heteroaryl ring Optional substituents include fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ;NR5 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 SO2R 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, optionally replaced by heteroatoms selected from A group R consisting of 8 The compound of embodiment 1.21, selected from:

[0039] 1.23 R 1 but 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 ;SO2R 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 their oxidized forms. and optionally substituted 5- or 6-membered rings having 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 SO2R 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 a group R consisting of: 8 The compound according to any one of embodiments 1.1 to 1.19, selected from:

[0040] 1.24 R 1but hydrogen; fluorine; chlorine; cyano; 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 ;SO2R 5 and 1 to 6 fluorine atoms C optionally substituted with 1-4 Non-aromatic hydrocarbon groups (one or two, 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 of formula 1.23.

[0041] 1.25 R 1 but hydrogen; fluorine; chlorine; cyano; 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 ;SO2R 5 and optionally substituted with 1 to 6 fluorine atoms C 1-4 The compound of embodiment 1.24, wherein the aromatic hydrocarbon group is selected from the group consisting of: thing.

[0042] 1.26 R 1 But 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 group The compound of embodiment 1.25, selected from:

[0043] 1.27 R 1 But hydrogen; fluorine; chlorine; cyano; NH2, COR 5 ;COOR 5 and C optionally substituted with 1 to 6 fluorine atoms 1-4 Saturated non-aromatic hydrocarbon group The compound of embodiment 1.26, selected from:

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

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

[0046] 1.30 R 1 However, hydrogen, methyl, ethyl and COOR 5 Embodiment 1, wherein The compound described in .29.

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

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

[0049] 1.33 R 1 COOMe;COOEt;COMe;COEt;CONH2;CF 3;CONHMe;CON(Me)2;COCF3;CO-cyclopropyl;CO-cyclopropyl Embodiments 1.20 to 1.30, wherein: The compound described in

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

[0051] 1.35 R 2 but hydrogen; fluorine; hydroxy; methoxy; and C 1-6 Non-aromatic carbonization The compound of embodiment 1.34, wherein R is selected from hydrogen groups.

[0052] 1.36 R 2 but hydrogen; fluorine; methoxy; and C 1-4 saturated hydrocarbon groups The compound of embodiment 1.35, wherein

[0053] 1.37 R 2 but hydrogen; fluorine; methoxy; and C 1-4 alkyl groups , the compound according to embodiment 1.36.

[0054] 1.38 R 2But hydrogen and C 1-3 In embodiment 1.37, an alkyl group is selected from the group consisting of: 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. A compound according to any one of claims 1 to 1.40.

[0059] 1.43 R 3 but hydrogen; fluorine; cyano; hydroxy; 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 according to embodiment 1.42.

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

[0061] 1.45 R 3 but hydrogen; fluorine; cyano; hydroxy; amino; C 1-4 Alkyl and and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4 Alkoxy is The compound of 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 of 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 A compound described in any one of .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 of 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 of embodiment 1.52, wherein is methyl.

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

[0071] 1.55 Nonaromatic C 1-4 The hydrocarbon group is saturated C 1-4 a hydrocarbon group, 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 of any one of embodiments 1.1 to 1.53.

[0074] 1.58 Saturation C 1-4 The hydrocarbon group is C 1-4 Embodiment 1.55, wherein the alkyl group is Or the compound of embodiment 1.56.

[0075] 1.59 Saturation C 1-4 The hydrocarbon group is C 1-3 Embodiment 1.58, wherein the alkyl group The compound described in

[0076] 1.60 C 1-3 the alkyl group is selected from methyl, ethyl and isopropyl; The compound of 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 embodiment, wherein 1. The compound according to any one of claims 1 to 9.

[0079] 1.63 Nonaromatic C 1-4 The hydrocarbon group is saturated C 1-4 a hydrocarbon group, The compound described in 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 described in

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

[0083] 1.67 R 7 When present, non-aromatic C1-4 The preceding embodiment, wherein 1. The compound according to any one of claims 1 to 9.

[0084] 1.68 Nonaromatic C 1-4 The hydrocarbon group is saturated C 1-4 a hydrocarbon group, 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, The compound of any one of embodiments 1.1 to 1.66.

[0087] 1.71 Saturation C 1-4 The hydrocarbon group is C 1-4 Embodiment 1.68, wherein the alkyl group is Or the compound of embodiment 1.70.

[0088] 1.72 Saturation C 1-4 The hydrocarbon group is C 1-3 Embodiment 1.71, wherein the alkyl group is The compound described in

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

[0090] 1.74 R 1 When is an optionally substituted 5- or 6-membered ring, it is 0, 1, 2 or 3 hetero atoms selected from N and S and their oxidized forms. 10. 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 0, 1, 2 or 3 hetero atoms selected from N and S and their oxidized forms. In any one of embodiments 1.1 to 1.73, a non-aromatic ring containing 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 five-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 0 , 1, 2 or 3 substituents R 8

[0037] As described in any one of the preceding embodiments, Compound.

[0099] 1.83 0, 1 or 2 substituents R 8 The compound of 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 SO2R 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 groups) carbon atoms are bounded by heteroatoms selected from O, N and S and their oxidized forms; Optionally, the embodiments 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 SO2R5 and 1 to 6 fluorine atoms, optionally 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. Embodiment 1.87 is selected from: The compound described in

[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 of embodiment 1.89, wherein the alkyl is selected from:

[0107] 1.91 part: [ka] However, the following groups AAA~ACB: [ka] [ka] any one of embodiments 1.1 to 1.40 and 1.42 to 1.53 selected from 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 equation (2a) [ka] wherein Q is an optionally substituted 5, 6 or 7 alkyl 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 1.48-1.53; Compounds relating to

[0109] 1.93 Compounds according to formula (2) or formula (2a), wherein Q is one or It has multiple substituents, for example, 1, 2 or 3 substituents, which can be (L)-R 10 , (L )-R 11 and (L)-R 12 where L is a bond or a CH group and;R 10 , R 11 and R 12 are hydrogen; fluorine; chlorine; bromine; cyano; oxo; Droxy; 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 ;CSNR15 R 16 ;NR 17 CONR 15 R 16 ;R 17 COOR 15 ;OCONR 15 R 16 ;SR 15 ;SOR 15 and SO2R 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 separated by heteroatoms selected from O, N and S and their oxidized forms. 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 COO 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 SO2R 5 and 1 to 6 fluorine atoms C optionally replaced by a child 1-6Non-aromatic hydrocarbon groups (1 or 2, but Not all of the carbon atoms of the hydrocarbon group are O, N, and S and their oxidized forms. and a group R consisting of 8 from Selected; R 15 , R 16 and R 17 are the same or different, or joined together to form a ring each 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 substituted by heteroatoms selected from O, N and S and their oxidized forms. or a group of formula CHN(R a )COOR b The basis of or formula (L)-R 18 where L is a bond or a CH2 group. 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 on 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 five-membered ring containing one or two nitrogen ring members. The compound according to any one of embodiments 1.1 to 1.93, wherein the heterocyclic or heteroaryl ring is

[0111] 1.95 Embodiments in which Ring A is a 5-membered heteroaryl ring containing two nitrogen ring members The compound described in 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 R 4 are embodiments 1.1 to 1.40 and 1.42 to 1.9 The compound of 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 are 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 4are 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 wherein 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 are 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 of embodiment 1.101, selected from:

[0120] 1.104 Equation (8): [ka] wherein R 1 , R 2 and R 4 are 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 of embodiment 1.101, selected from:

[0122] 1.106 Q is a ring of 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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 2

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

[0124] 1.108 Q is a ring of 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 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 2

[0125] 1.109 part: [ka] However, the following groups EAA to EAB: [ka] The compound of 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. .1. The compound described in

[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, 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 Embodiment 1.115 or embodiment 1.115, wherein the salt is a pharmaceutically 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). phytophylactic) treatment, and measurable or detectable symptoms of the disease or disorder The term "anticoagulant" encompasses 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 is sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete elimination of pain or a reduction in 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)) is defined as a group consisting 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. Therefore, they are called non-aromatic hydrocarbons. The terms include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Cycloalkylalkyl, cycloalkenylalkyl and the like are included.

[0137] "Alkyl", "alkenyl", "alkynyl", "cycloalkyl", aryl, hetero The terms "cycloaryl" and "cycloalkenyl" refer to their respective substituents unless otherwise indicated. and the like 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 a hydrocarbon group that does not contain carbon-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 elementary groups include C 1-4 The alkyl groups cyclopropyl, cyclobutyl and cyclopropyl Contains methyl.

[0139] As used herein, the term "cycloalkyl" refers to a group having a specified number of carbon atoms. Where permitted, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexyl It includes both monocyclic cycloalkyl groups such as chloroheptyl, and bicyclic and tricyclic groups. Bicyclic cycloalkyl groups include bicycloheptane, bicyclooctane, and adamantane. Any bridged ring system is 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 may be O, N, and S, and (R 1 and R 4 optionally replaced by a heteroatom selected from its oxidized form (in the case of When a carbon atom is replaced by a heteroatom, the atom of the heteroatom may be A lower valence means that the atom is less likely to be bonded to the carbon atom than would have been bonded to the carbon atom being replaced. It will be understood that this means that fewer atoms may be bonded to the heteroatom. For example, replacing a carbon atom (valence 4) in a CH2 group with an oxygen (valence 2) results in This means that the resulting molecule may contain two fewer hydrogen atoms, and the carbon atom of the CH2 group Replacing a carbon atom (valence 4) with a nitrogen atom (valence 3) 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 ethers -CH2-O-CH2- or -CH2-C with oxygen or sulfur to give the thioether -CH2-S-CH2- Substitution of a carbon atom in the H2-CH2- chain to give a nitrile (cyano) group CH2-C≡N Replacement of a carbon atom in the group CH2-C≡CH by nitrogen in the ketone -CH2-C(O)-C Substitution of a carbon atom in the group -CH2-CH2-CH2- by C=O to give H2-, Sulfoxide -CH2-S(O)-CH2- or sulfone -CH2-S(O)2-CH2 of the carbon atom in the group -CH2-CH2-CH2- by S=O or SO2 to give Substitution of -C by C(O)NH to give the amide -CH2-CH2-C(O)-NH- Substitution of carbon atoms in the H2-CH2-CH2- chain to give the amine -CH2-NH-CH2- Substitution of a carbon atom in the -CH2-CH2-CH2- chain by nitrogen for esters ( or carboxylic acid) by C(O)O to give -CH2-CH2-C(O)-O- Substitution of carbon atoms in the CH2-CH2-CH2- chain. , at least one carbon atom of the hydrocarbon group must remain.

[0142] salt Many 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 not intended to be limiting unless otherwise specified. For compounds of formula (1a), (1b), or (1c), see embodiments 1.114 to 1.116. This includes salt forms of the compounds as defined herein.

[0143] The salts are typically acid addition salts.

[0144] The salts of the present invention are those listed 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 combining 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 Alternatively, a non-aqueous medium such as 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 Phar-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, glucoside Propionate, 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 hydrobromic 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, Pyruvate, 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-acid formed with an acylated amino acid and a cation exchange resin. or di-salts.

[0146] When compounds of formula (1), (1a) or (1b) contain an amine functional group, they , a 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 pharmaceutically acceptable salts, Examples of salts that can be prepared are described in Berge et al., 1977, "Pharmaceutically A cceptable Salts,” J.Pharm.Sci.,Vol.66,pp. However, pharmaceutically unacceptable salts are prepared as intermediates. The compound may be prepared by the steps of: 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 Rotational isomerism around existing bonds, or cis and cis rings around rings such as cycloalkane rings Trans isomerism is due to different arrangements of atoms or groups around the double bond.

[0151] Therefore, in another embodiment (embodiment 1.121), the present invention provides the method of embodiment 1.1 to 1.116 provides a geometric isomer of a compound according to any one of the preceding claims.

[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 shall include its 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 containing 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 d and l isomers, or d and l isomers), or they are The absolute stereochemistry 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, and Cahn, Ingold & Prelog,Angew.Chem.Int.Ed.Engl.,1966,5, 385-415. Optical isomers can be separated by chiral chromatography (using chiral supports) They can be separated by several techniques, including chromatography on solids. Such techniques are well known to those skilled in the art. As an alternative to chiral chromatography, (+) -Tartaric acid, (-)-pyroglutamic acid, (-)-ditoluoyl-L-tartaric acid, (+)- Chiral acids such as mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid Form the stereoisomeric salts, separate the diastereoisomers by preferential crystallization, and then desalt 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 more than one optically isomeric form, it may be a pair of enantiomers. - one enantiomer has advantages 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 containing 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 total isomers are single enantiomers (e.g., The compositions are provided in which the compounds exist as either an anantiomer or a diastereoisomer.

[0157] In one general embodiment (embodiment 1.134), the compound of embodiment 1.132 ( or compounds for use) are 99% or more (e.g., substantially all) of the total amount of a single optical It exists as an isomer.

[0158] For example, in one embodiment (embodiment 1.135), the compound is a single enantiomer. 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 all isotopic substitutions 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] Similarly, 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 refers to one isotopic variation within the group. one or more hydrogen atoms are in the form of a deuterium or tritium isotope; For example, the ethyl group (perdeuteroethyl) has all five hydrogen atoms deuterium isotopes. Variations such as aryl groups are also included.

[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 settings. It can be useful in this respect.

[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 present invention. The state structure (e.g., crystalline structure) is dissolved in a non-toxic, pharmaceutically 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 dimethyl sulfoxide. Solvates are compounds of the present 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. This can be determined by analyzing the crystals. Particularly preferred solvates are hydrates, and hydrates 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 make 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, ISB See N 0-967-06710-3.

[0171] Alternatively, the compounds of the present invention may be anhydrous rather than existing as hydrates. Thus, in another embodiment (embodiment 1.153), the present invention provides an anhydrous form (e.g., The compound as defined in any one of embodiments 1.1 to 1.141 is provided in anhydrous crystalline form. To 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 (X The crystal structure can be easily determined by standard techniques such as RPD. has been analyzed 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) Various water vapor sorption gravimetric tests and XRPD have been used to characterize 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 book ,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 single crystal X-ray diffraction. In amorphous solids, the crystalline form is usually present. There is no three-dimensional structure to be determined, and the relative positions of molecules to each other in the 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, 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 1.1 to 1.153, which is 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 compounds of 1b) may exist in the form of prodrugs. 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 that is converted in vivo into a biologically active compound of formula 1b).

[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 by, for example, removing any hydroxy groups present in the parent compound. They may be formed by esterification of hydroxyl groups, where appropriate, in addition to 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 compounds are compounds that become active compounds upon a chemical reaction (e.g., ADEPT, GDEPT, For example, prodrugs may be sugar derivatives or other glycosides. It may be a conjugate or may be an amino acid ester derivative.

[0180] Therefore, in another embodiment (embodiment 1.170), the present invention provides the method of embodiment 1.1 to A prodrug of a compound as defined in any one of 1.170, wherein the compound is a human Contains a functional group that can be converted under physiological conditions to form a hydroxyl group or an amino group The present invention provides such a prodrug.

[0181] Complexes and clathrates Formula (1), (1a), or (1b) in embodiments 1.1 to 1.170 includes the formula (1), (1a), or (1b) in embodiment 1. Complexes of compounds of 1 to 1.170 (e.g., inclusion complexes with compounds such as cyclodextrins) 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 embodiments 1.1 to 1.170 is provided in the form of a hydroxybenzoate. .

[0183] Biological Activities 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 bind to M receptor subtypes compared to M2 and M3 receptor subtypes. The compounds of the present invention are highly selective for M2 and M3 receptors. For example, the compounds of the present invention are not agonists of the functional agonists described in Example 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 less than 20% E 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 present 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 The compound of 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 compound according to any one of claims 1 to 4.

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

[0192] 2.5 E of at least 95 for M1 receptors max In embodiment 2.3, is the compound described in 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 4.

[0194] 2.7 pEC in the range of 6.5-9.0 50 Muscarinic M4 receptor agonists having The compound of embodiment 2.6, wherein

[0195] 2.8 E of at least 95 for M4 receptors max Embodiment 2.6 also has is the compound of embodiment 2.7.

[0196] 2.9 Muscarinic M1 and / or M4 receptors compared to M2 and M3 receptors The compound of any one of embodiments 2.3 to 2.8, wherein the compound 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 of any one of embodiments 2.3 to 2.5, wherein

[0200] 2.13 Selective for muscarinic M4 receptors compared to M1, M2, and M3 receptors The compound of 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 of any one of embodiments 2.3 to 2.8, wherein

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

[0203] 2.16 pEC5 of less than 4.5 for muscarinic M2 and M3 receptor subtypes 0 and / or E less than 30 max The compound of 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 described in

[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 treating a cognitive or psychotic disorder 1. A compound according to any one of claims 1 to 1.180.

[0208] 2.19 Cognitive or psychotic disorders include cognitive impairment, mild cognitive impairment, frontal lobectomy, Cephalic dementia, vascular dementia, Lewy body dementia, presenile dementia, senile dementia, Friedrich- Richie'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 or multi-infarct dementia, alcoholic dementia, thyroid dysfunction (hypo Other dementia conditions, such as dementia associated with cerebellar atrophy and amyotrophic cerebellar atrophy, (amyotropic) Dementia associated with other degenerative disorders such as lateral sclerosis; cognitive decline Other acute or subacute conditions that may cause depression, such as delirium or depression (pseudodementia state) ) Trauma, head injury, age-related cognitive decline, stroke, neurodegeneration, drug-induced conditions, neurotoxicity Sexual drugs, age-related cognitive impairment, autism-related cognitive impairment, Down syndrome, cognitive impairment-related Psychosis and associated cognitive impairment after electroconvulsive therapy; nicotine, cannabis, amphetamines, cocaine Cognitive impairment due to drug abuse or drug withdrawal, including attention deficit hyperactivity disorder (ADHD) and movement disorders, e.g., Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesia Skenesia, schizophrenia, schizophrenia-like illness, 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 drug withdrawal psychosis resulting from withdrawal, bipolar disorder and schizoaffective disorder, The compound for use according to embodiment 2.18, resulting from or related thereto.

[0209] 2.20 Embodiments 1.1-1.1 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 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 (e.g., in mammalian patients, such as humans, in need of such treatment) The method comprises the step of treating a subject in a human subject with a therapeutically effective amount of any one of embodiments 1.1 to 1. The method comprises administering a compound described in any one of .180.

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

[0213] 2.24 Embodiments Wherein the cognitive impairment results from or is associated With Alzheimer's disease The method described in 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 10. Use of a compound according to any one of claims 1 to 9.

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

[0217] 2.28 Embodiments 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 pain 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 embodiments 1.1 to 1.180. The compound described.

[0220] 2.31 Acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal pain Femoral neuralgia, herpes neuralgia, generalized neuralgia, visceral pain, osteoarthritis pain, post-herpetic 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; or a method for reducing the severity thereof, comprising administering a therapeutically effective amount of any one of embodiments 1.1 to 1.180. The method comprises administering a compound according to any one of the preceding claims.

[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 syndromes 1. The compound according to any one of claims 1 to 9.

[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 syndromes, comprising a therapeutically effective amount of The method comprises administering 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 pain 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 lowering 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 10. Use of a compound according to any one of claims 1 to 9.

[0225] 2.36 Parkinson's disease, ADHD, Huntington's disease, Tourette's syndrome and other disorders Other syndromes associated with dopaminergic dysfunction as the underlying pathogenic factor 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 provides a method for manufacturing a semiconductor device according to embodiments 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 , R4 and Q is defined in any one of embodiments 1.1 to 1.180; or (B) Formula (12): [ka] Compounds of the formula Cl-C(=O)-CH2-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 are real As defined in any one of embodiments 1.1 to 1.180; and optionally: (D) A compound of formula (1), (1a) or (1b) is reacted with a compound of formula (1), (1a) or (1b). b) converting the compound of formula (1) to another compound of formula (2).

[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 solvents used are dichloroethane and borohydrides such as sodium triacetoxyborohydride. It is typically carried out at ambient temperature using a basic reducing agent.

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

[0230] The intermediate compound of formula (12) can be prepared by the series of reactions 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 Gentle heating (e.g., to a temperature of about 40°C to about 70°C) in the presence of either thorium or 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 spiro ketone (14) was reacted with natrium borohydride in methanol. The alcohol (16) is then reduced to the alcohol (17) using triethyl ammonium chloride. in the presence of a tertiary amine such as ethylamine or N,N-diisopropylethylamine, The sulfonate ester (17, R = 1) was prepared 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 solvent, or with the 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). This is then reacted with the acid in a nucleophilic substitution reaction to give compound (15). Removal of the Boc group by treatment with (e.g., trifluoroacetic acid in dichloromethane) Deprotection by the formula (12) gives compound (12).

[0234] Once formed, a compound of formula (1), (1a) or (1b), or The protected derivatives can be prepared by reacting the compounds of formula (1), (1a) or (1b) with the compounds of formula (1), (1a) or (1b) by methods well known to those skilled in the art. It can be converted into another compound. Examples of synthetic methods are given in Advanced Organic Chemistry and O Organic Syntheses (see references above) or Fiese rs' Reagents for Organic Synthesis, Volumes 1-17 , John Wiley, edited by Mary Fieser (ISBN: 0-471- Examples of these transformations include the Bond formation, urea formation, carbamate formation, alkylation reaction, N-arylation reaction and C -C bond coupling reactions are included.

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

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

[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 comprising the compound in combination with at least one pharmaceutically acceptable excipient is provided. 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] Pharmaceutically acceptable excipient(s) include, for example, carriers (e.g., solid carriers, liquid carriers, 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, coatings controlled-release agents (e.g., retarding or delaying release) polymers or waxes), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents Antibacterial agents, antioxidants, buffers, isotonicity agents, thickeners, 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 "pharmaceutically acceptable" refers to a compound, material, composition, or The composition and / or dosage form is, within the scope of sound medical judgment, deemed to be excessively toxic, irritating, or allergenic. and tissue of a subject (e.g., a human subject) without adverse reactions or other problems or complications. 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. and can be formulated accordingly, for example, by 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. It can 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 oral patches.

[0246] Tablet compositions comprise a unit dose of active compound together with an inert diluent or carrier, such as sugar or or a sugar alcohol, such as lactose, sucrose, sorbitol or mannitol and / or non-sugar diluents, such as sodium carbonate, calcium phosphate, calcium carbonate sodium or 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 cross-linked polymers, e.g., cross-linked Carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., paprika anti-oxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), Standard ingredients such as buffers, and foaming agents, e.g., citrate / bicarbonate mixtures 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 to release the drug after extended periods of time. They may be designed to release in a controlled manner over time or in specific regions 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 pharmaceutically acceptable excipient (e.g., as defined above) or a combination of such excipients. It contains about 20% (w / w) to about 90% (w / w) of the active ingredient and 80% (w / w) to 10% of the pharmaceutical ingredient. The pharmaceutical composition may comprise from about 1% to about 95%, preferably from about 1% to about 95%, of a pharmaceutical 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 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 / or extenders (depending on drug dose) They may contain 0-10% (w / w) polymer binder, 0-5% (w / w) 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 the dose). The film coating of a tablet or capsule 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 the 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 drug 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, they typically contain sufficient compound to provide the desired level of biological activity. For example, the formulation may contain between 1 nanogram and 2 grams of active ingredient, e.g., 1 nanogram 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 milligram to 2 milligrams) (the active ingredient in Liglam).

[0253] For oral compositions, the unit dosage form is from 1 milligram to 2 grams, more typically 10 milligrams. 100 mg to 1000 mg, e.g., 50 mg to 1000 mg 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 (effective amount). The amount may be determined by the attending physician according to standard procedures. [Example]

[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 done.

[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 to prepare them 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 shift values ​​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 doublet, tt = triplet of triplet triplet, qd = quadruple of doublet, ddd = quadruple of doublet, ddt = triplet doublet m = doublet of multiplets, m = multiplet. Coupling constants are reported as J values ​​measured in Hz. NMR spectra The results of chromatography and mass spectrometry were corrected taking into account background peaks. The filtering is performed using 60-120 mesh silica gel and nitrogen pressure (flash clean). This refers to column chromatography performed under conditions to monitor the reaction. TLC for elution is performed using a predetermined mobile phase and silica gel F254 (Mer ck) and TLC test. Microwave-mediated reactions are performed using Biotage Initiator microwave reactor or CEM Discover microwave reactor I went there.

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

[0259] LCMS Methods A and B Equipment: 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 = 2.5L H2O + 2.5m L ammonia solution; Solvent D = 2.5 L MeCN + 135 mL H2O + 2.5 mL ammonia Monomer 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; Mixture [time (min) / solvent B in A (%)]: Method: 0.00 / 5, 2.00 / 95, 2.50 / 95, 2.60 / 5, 3.00 / 5; Solvents: Solvent A = 2.5L HO + 2.5mL (28%NH3 in H2O); Solvent B=2.5L MeCN+129mL H2O+2.7 mL (28% NH3 in HO); 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 P 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 = 2.5 L H2O + 2.5 mL 28% ammonia solution in H2O; Solvent D = 2 0.5L MeCN + 135mL H2O + 2.5mL 28% ammonia solution in H2O) 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 micron, 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 0.1% formic acid in H2O; solvent B = 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; Solvents: Solvent A = 0.1% Al in H2O ammonia; 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 Solvents: Solvent A = 0.1% ammonium hydroxide in H2O 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; Solvents: Solvent A = 0.1% ammonia in H2O; Solvent B = 0.1% ammonia in MeCN 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; Solvents: Solvent A = 20 mM vinegar in HO Ammonium chloride; Solvent B = MeOH; Injection volume 10 μL; UV detection 200-400 nM; Quantity 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 = in H2O 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 A in B (%)]: 0.00 / 2, 2.00 / 2, 7 0.00 / 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 × 50 mm; gradient [time (min) / solvent B (%) in 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; 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 A in B (%)]: 0.00 / 2, 0.50 / 2, 1 0.50 / 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 micron, 2.1 x 10 0 mm; Gradient [time (min) / solvent A in B (%)]: 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 form 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 = number of hours 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 LiAlH4 / LAH = Lithium Aluminum Hydride MeCN = acetonitrile MeOH = methanol min=minutes (number) MS=mass spectrometry Et3N = 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- have their usual meaning: normal, second It has tertiary, iso, and tertiary classes.

[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 (3.37g, 15mm ol) was added in small portions to hydrogen chloride (4 M solution in dioxane, 50 mL, 210 mmol). CAUTION: Foaming. After 24 h, the reaction was concentrated in vacuo and the remaining solid was washed with Et3N (4.18 mL) The solution was dissolved in a mixture of 1,2-dimethyl-3-propanol (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 NaHCO3 ( The organic layer was collected and extracted (2 x 100 mL). The residue after evaporation was then washed with saturated brine (20 mL), dried over MgSO4, and then 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 on the compounds are 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 solution in dioxane, 45 mL, CAUTION: FOAMING. After 2 hours, the reaction was concentrated in vacuo and 1 The remaining solid was dissolved in triethylamine (2.23 mL, 16.0 mmol) and dichloromethane. The solution was dissolved in a mixture of methane (10 mL). Once dissolution was complete, 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 while, the mixture was poured into dichloromethane (50 mL) and added NaHCO3 (aq) (2× The organic layers were combined and washed with saturated brine (5 0 mL), passed through a Biotage phase separator, and the solvent removed in vacuo. Column chromatography (normal phase, Biotage SNAP Cartridge KP-s il 50 g, 40–63 μm, 60 Å, 40 mL / min, gradient: 0%–10% M in DCM methyl 2-oxo-6-azaspiro[3.4]o[4 ... The methacrylate-6-carboxylate 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 phosphate (5 g, 22.19 mmol) in 25 mL of HCl solution 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 EtN (0.7 mL). The reaction mixture was cooled to 0°C and 2-fluoroethyl carboxymethyl methyl ketone was added. Benzyl chloride (0.45 g, 3.6 mmol) was added, and the reaction mixture was heated at 30° C. for 5 hours. The mixture was stirred for 1 hour, then diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The layers were combined, dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography. elution with chromatograph (normal phase, 60-120 mesh silica, 0-10% EtOAc in hexane). and purified to obtain intermediate 4, 2-fluoroethyl 2-oxo-6-azaspiro[3.4]o Citrate-6-carboxylate (0.2 g, 38.8%) was obtained as a brown gum. Data for the compounds are 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 (1 g, 4.96 mmol) l) in a mixture of anhydrous DCM (20 mL) and EtN (2.1 mL, 15.1 mmol). The mixture was suspended in water and cooled in an ice-water bath. The mixture was added in small portions over 5 minutes, and the mixture was allowed to warm to room temperature and stirred for 48 hours. Dilute with M, wash with saturated aqueous NaHCO3 (x2) and saturated brine (x1), then , passed through a phase separator, concentrated in vacuo, and purified by 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 HCl, treated with NCS (0.314 g, 2.35 mmol), and stirred at room temperature overnight. 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% to 10% solvent A in CM, where solvent A is 10% (7M NH3 / M tert-butyl 4-(5-chloro-1-methylpropional) -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 active; dichloro: m / z 334 / 336 / 338 (M+H) + (ES + ), UV activity at 1.87 min. The ratio of monochloro to dichloro was 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-methylpropional) (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 prepare 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 acetic acid 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)piperazine 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 The reaction mixture was treated with 2.70 mmol) and stirred at room temperature for 5.5 hours. The resulting powder was purified by column chromatography (SEQ ID NO: 1). 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% in MeOH % (7M NH3 / MeOH) Mixed with isolated ethyl 4-(5-chloro-1H-imidazol-2-yl)piperidin Peridine-1-carboxylate and ethyl 4-(4,5-dichloro-1H-imidazoline) Each of these was dissolved in DCM to give (2-yl)piperidine-1-carboxylate. The extract was washed with H2O (x3), 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 Dissolve the silane (0.12 g, 0.47 mmol) in AcOH (2 mL) and add 48% HB The reaction mixture was treated with r aqueous solution (2 mL) and heated to reflux at about 120° C. for 2 hours. 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 to be. It was used immediately.

[0282] Ethyl 4-(4,5-dichloro-1H-imidazol-2-yl)piperidine-1-carboxylate 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 hours. The reaction mixture was concentrated in vacuo. The residue was azeotroped with toluene (×1) 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)-2-yl]piperidine-1-carboxylate Procedure for preparing (1H-imidazol-2-yl)piperidine [ka] tert-Butyl 4-formylpiperidine-1-carboxylate (2.0 g, 9.4 (mmol) was dissolved in MeOH (10 mL), and then 7 M methanolic ammonia was added at 0°C. After cooling, 3,3-dibromo-1,1,1-trifluoropropane was added for 30 minutes. HCl (5.07 g, 18.5 mmol) was added in small portions. The mixture was stirred at 25 °C for 2 h, the solvent was removed in vacuo, and the residue was diluted with H2O (80 mL) and EtOAc (50 mL), the aqueous layer was extracted with EtOAc (2 x 50 mL), and the organic layers were combined. After drying (Na2SO4), the solvent was removed in vacuo and the residue was purified by column chromatography (DC Purification by basic activated alumina in 0.5% MeOH in M ​​gave intermediate 46, te rt-Butyl 4-(4-(trifluoromethyl)-1H-imidazol-2-yl)piperazine 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 (1 g, 3.13 mmol) in 1,4-dioxane (5 mL), followed by dropwise addition of HCl in 1,4-dioxane (20 mL, 3 M solution) The resulting reaction mixture was stirred at 30° C. for 16 h, the solvent was removed in vacuo, and the residue was dissolved in distilled water. 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 m 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, and then methyl iodide (0.06 mL, 0.96 m mol) was added and the resulting reaction mixture was stirred at 25 °C for 2 h. Partition between 200 (60 mL) and EtOAc (45 mL), and the aqueous layer is diluted with EtOAc (2 × 45 mL). The organic layers were combined, dried (Na2SO4) and the solvent 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 tert-butyl 4-(1-methylpropional) 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-imidazoline (200 mg, 0.6 mmol)piperidine-1-carboxylate ,4-dioxane (5 mL), followed by HCl in 1,4-dioxane (20 mL, A 4M solution of HCl was added dropwise. 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 ( 15 mL) and Cs2CO3 (7.4 g, 22.9 mmol) was added at 0°C. The resulting reaction mixture was stirred at 0-5°C for 10 minutes, and then benzyl chloroformate (3.2%) was added. g, 19.1 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. Partition between HO (100 mL) and EtOAc (200 mL), and the aqueous layer was diluted with EtOAc (2× 200 mL), the organic layers were combined, dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase silica, mesh size: 60-120, hexane Purify by 0% to 10% EtOAc in water to obtain 1-benzyl 4-ethylpiperidine -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 (methyl)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 0.1 mL) was added. The resulting reaction mixture was stirred at 80° C. overnight. Partition between HClO (50 mL) and EtOAc (100 mL), and the aqueous layer was diluted with EtOAc (2 × 100 The organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by column chromatography (normal phase silica, mesh size: 60-120, hexahydrate) Purification by 50%-60% EtOAc in hexane gave benzyl 4-(1,3,4-oxa-1,4-diol). 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 perfused with H2 gas at room temperature. The reaction mixture was stirred under H2 atmosphere at room temperature for 12 hours. The reaction mass was then filtered through a pad of Celite. Filtration through HCl and removal of the solvent in vacuo afforded intermediate 43, 4-(1,3,4-oxadiazo- The title compound (2-amino-2-yl)piperidine (0.078 g, 99%) was obtained as a colorless gum. Data on the compounds are 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) The mixture was heated to reflux at 90°C for 24 hours. The reaction mixture was cooled to 0°C and filtered. The residue was Upon drying, (Z)-N-hydroxyethanimidamide (2.1 g, >100%) was obtained. Obtained as a colored 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). 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 minutes, 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 compound are in Table 2.

[0293] Intermediate 47, 4-(1H-imidazol-2-yl)piperidin-4-ol hydrochloride, was prepared. Steps for manufacturing [ka] 1H-imidazole (8.0 g, 117.5 mmol) was dissolved 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 hours. 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 organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by column chromatography. Chromatography (normal phase silica, 0-1% methanol in DCM) gave 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 hour. A solution of 4-oxopiperidine-1-carboxylate (5.53 g, 27 mmol) The reaction mixture was added dropwise at -78°C. The reaction mixture was allowed to warm to room temperature over 2 hours. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), and the combined organic layers were dried (Na The residue was purified by column chromatography (normal phase silica, Purification by 0-20% EtOAc in hexanes to give tert-butyl 4-hydroxybenzoate -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 x 20 ml L) to give intermediate 47, 4-(1H-imidazol-2-yl)piperidine-4- The product (0.5 g, 60.2%) was obtained as a brown gum. are listed 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 cooled to 0 °C under N2. Then, NaH (0.24 g, 10.0 mmol) was added. The reaction mixture was stirred at 0° C. for 30 minutes. Then methyl iodide (1.07 g, 7.5 mmol) was added and the reaction mixture was stirred at room temperature. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (3 x 100 mL) and the organic layer The layers were combined, dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography. elution with chromatograph (normal phase, 60-120 mesh silica, 0-10% EtOAc in hexane). and purified as 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 x 20 mL). Trituration with 4-(1H-imidazol-2-yl)-4-methoxypiperidine afforded intermediate 48, 4-(1H-imidazol-2-yl)-4-methoxypiperidine. The compound was obtained as a brown solid (0.5 g, 76.0%). It's in 2.

[0298] Intermediate 49, 4-(1-methyl-1H-imidazol-2-yl)piperidin-4-ol Procedure for preparing benzoyl 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 added to the solution of 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 hours, 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 hours, 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 x 200 mL), and the organic layers were combined and dried. The solvent was removed in vacuo and the residue was washed with methanol and 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. It was then 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)pyrrolidine Peridine-1-carboxylate (0.5 g, 1.7 mmol) was dissolved in 1,4-dioxane (3 0 mL) at room temperature, the reaction mixture was cooled to 0 °C under nitrogen, and HCl ( The reaction mixture was stirred at room temperature for 6 hours and the solvent was evaporated. The solution was removed and triturated from 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 the items are in Table 2.

[0300] Intermediate 50, 4-Methoxy-4-(1-methyl-1H-imidazol-2-yl)piperidin Procedure for preparing benzodiazepine 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 L) at room temperature, the reaction mixture was cooled to 0°C under nitrogen, and NaH (0.64 g, 16 The reaction mixture was stirred at 0°C for 1 hour, then iodized. 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 The organic layers were combined and dried (Na2SO4). The solvent was removed in vacuo. The residue was purified by column chromatography (normal phase, silica, 60-120 mesh, gradient: hexamethyl Purification by 0% to 50% EtOAc in hexane gave tert-butyl 4-methoxy-4- (1-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate(1 0.3g, 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 ( 30 mL) at room temperature, the reaction mixture was cooled to 0°C under nitrogen, and the resulting solution was diluted with HCl in dioxane. (15 mL, 4 M solution) was added slowly. The reaction mixture was stirred at room temperature for 6 hours, and the solvent was removed. Remove in vacuo and triturate from pentane (10 mL) and diethyl ether (10 mL). The residue was purified by HCl to give intermediate 50, 4-methoxy-4-(1-methyl-1H-imidazoline). (2-azol-yl)piperidine (0.80 g, 94.1%) was obtained 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)

[0043] Preparing [4-hydroxypyrrolidin-2-yl]piperidine-1-carboxylate Steps to follow [ka] (2S,4R)-1-Boc-4-hydroxypyrrolidine-2-carboxylic acid 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 hours. Volatiles were removed by rotary evaporation. The mixture was removed and diluted with DCM (250 mL). The combined aqueous layers were washed with DCM (250 mL) and the combined aqueous layers were washed with HClO (250 mL). The organic layer was washed with saturated NH4Cl (水溶液) (250mL) and saturated saline (250mL) The volatiles were removed under vacuum and the resulting mixture was washed and passed through a Biotage phase separator. (2S,4R)-1-Boc-4-tert-butyldimethylsilyl ether-pyrrolidine To obtain methyl ketone-2-carboxylate (35.812 g, 99%). 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. (120 mL of a 1.0 M solution in THF, 120.0 mmol) was added and the reaction was heated to 0°C. The reaction was stirred for 1 hour. The reaction mixture was diluted with H2O (4.5 mL), 15% NaOH solution (4.5 mL) and The reaction mixture was quenched with HO (13.5 mL) and filtered through a plug of Celite. The HCl was removed under vacuum to give (2S,4R)-1-Boc-4-tert-butyldimethylsilyl To the obtained solution, 30.320 g (77%) of 2-hydroxymethyl-pyrrolidine 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 Diazin-2-hydroxymethyl (10.050 g, 30.362 mmol) was dissolved in DCM (10 Dissolve Dess-Martin periodinane (15.371 g, 36.253 mmol) in 100 mL of HCl. l) was added. The reaction was stirred at room temperature for 2 hours, 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 product was 2.150 g (22%).

[0305] Sodium hydride (135 mg of a 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 in THF (2 mL) was added. 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. The mixture was removed on a tubby evaporator and the reaction mixture was diluted with DCM (20 mL). Wash with HO (2 x 20 mL), and the combined aqueous layers with DCM (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 loaded onto a Biotage SNAP column (100 g) and purified by column chromatography (0-30% EtOAc in hexane). Purify and obtain tert-butyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl] aryl]oxy}-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl [Isopropyl]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 After stirring for 8 hours, AcOH (0.200 mL) was added and the volatiles were removed by rotary evaporation. The reaction mixture was diluted with DCM (50 mL) and washed with H2O (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 ethanol 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) gave diethyl 3- [(4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl methyl)silyl]oxy}pyrrolidin-2-yl]-2-cyanopentanedioate (cy anopentanedioate) was obtained as a yellow oil (567 mg, 89%) .

[0307] Sodium chloride (71 mg, 1.212 mmol) and DMSO in HO (3 mL) (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), followed by E tOAc (50 mL) was added and the organic layer was washed with H2O (2 x 50 mL). The organic 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). 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(di- 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 hours. 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). and purified by tert-butyl(4R)-4-{[tert-butyl(dimethyl) Silyl]oxy}-2-(2-oxopiperidin-4-yl)pyrrolidine-1-carboxamide 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 To a solution of 50 g (4.648 mmol) of borane in 30 mL of THF was added tetrahydrofuran. HCl (9.3 mL of a 1.0 M solution in THF, 9.300 mmol) was added at 0°C and the reaction 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 volatiles were removed on a rotary evaporator. L) diluted with 1M NaOH (水溶液) (2 x 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 obtained as a yellow oil (1.8 Obtained as 30g, >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 methylpropane (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 hours. 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 hydroxide solution. Washed with brine (250 mL) and passed through a Biotage phase separator. 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 the vector 4-[(2S,4R)-1-(tert-butoxycarbonyl)-4-{[ter t-Butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl]piperidine-1-carboxylate The carboxylate was obtained as a colorless oil (700 mg, 28%).

[0311] Benzyl 4-[(2S,4R)-1-(tert-butoxycarbonyl)methyl] ... (tert-butyl(dimethyl)silyl)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidin-2-yl To a solution of [chloro]piperidine-1-carboxylate (0.780 g, 1.504 mmol) , tetrabutylammonium fluoride (1.800 mL of a 1.0 M THF solution, 1. 800 mmol) was added and the reaction was stirred at room temperature for 1 hour. The combined aqueous layers were diluted with DCM (100 mL) and washed with HO (2 × 100 mL). The combined organic layer was washed with saturated brine (250 mL) and then washed with Biotage The volatiles were removed under vacuum to give intermediate 111, benzyl 4 -[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine [Benzene-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 [pyrrolidin-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 x 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 and the resulting mixture was washed and passed through a Biotage phase separator. 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-butanoate)-2-yl]-4-( ... (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 heated to 7 Stirred for 1 hour 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)-2-methyl-4-oxo-2-(pyridinyl)-2-methyl-4-oxo-2-methyl-2-oxo-2-methyl-4 ... To obtain 55 mg (92%) of (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] Oxalyl chloride (0.065 mL, 0.741 mmol) in DCM (1 mL) -78 After 5 minutes, the benzyl 4- [(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine -2-yl]piperidine-1-carboxylate (200 mg, 0.494 mmol) DCM (2 mL) was added followed by triethylamine (0.345 mL, 2.47 mmol). 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 x 25 mL ), and 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. Volatiles were removed in vacuo The reaction mixture was removed under reduced pressure to give 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-oxopyrrolidone] [Zin-2-yl]piperidine-1-carboxylate (170 mg, 0.422 mmol ) was dissolved in DCM (1 mL) at -78 °C, and DAST (0.167 mL, 1.2 67 mmol). The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was diluted with DCM (2 5 mL) and saturated NaHCO 3(水溶液) (2 x 25 mL) and combined 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 under vacuum to give the benzyl 4-[(2S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine To this was obtained [benzo-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)benzyl]- ... Carbonyl)-4,4-difluoropyrrolidin-2-yl]piperidine-1-carboxy A solution of 10% Pd / C (10 mg) and 10% palladium / carbon (10 mg) was added to the solution. and 1,4-cyclohexadiene (0.105 mL, 1.105 mmol) were added, and the reaction mixture was Stirred for 1 hour 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 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-difluoromethylpropional in THF (20 mL) 1,2-dicarboxylate (2 g, 7.5 mmol) in THF Lithium borohydride solution (2.0 M, 7.5 mL, 15 mmol) was added at 0°C, and the reaction mixture was The reaction was allowed to warm to room temperature and stirred for 2 hours. Once the effervescence had ceased, the mixture was concentrated to remove the THF. The aqueous mixture was partitioned between saturated aqueous NaHCO3 and DCM (x2), and the organic phase was The mixture was passed through a separator and concentrated to give crude tert-butyl(2R)-4,4-difluoro-2- (Hydroxymethyl)pyrrolidine-1-carboxylate (1.98g, >100%) Obtained as an oil. LCMS (Method C): m / z 260 (M+Na) + (ES+), 1.09 minutes, UV Inert.

[0318] tert-Butyl (2R)-4,4-difluoro-2- (hydroxymethyl)pyrrolidine-1-carboxylate (1 g, 4.2 mmol) Solution and triethylamine (1.5 mL, 11 mmol) in MsCl (0.42 mL, 5. 4 mmol) was added in small portions. The mixture was stirred at 0 °C for 100 min, then cooled to 100 °C with ice-cold saturated N Partition between aqueous aHCO3 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 A solution of 5 g of HCl (4.9 mmol) in THF (1.0 M, 9.8 mL, 9.8 mmol) The LiBHEt solution was added in small portions over a period of 10 minutes. The mixture was then stirred for 3 days. The mixture was cooled back to 0°C and cooled by the addition of H2O. The mixture was quenched and then concentrated to remove THF. The aqueous mixture was diluted with saturated aqueous NaHCO3 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 carboxylate (0.89 g, 82%) was obtained as an oil. The data is 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-dicarboxil The silane (1.00 g, 4.111 mmol) was dissolved in DCM (10 mL) at -78 °C. DAST was 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 x 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-difluoropyridinone in THF (5 mL) To loridine-1,2-dicarboxylate (500 mg, 1.885 mmol), THF Lithium borohydride as a 2.0 M solution in 0 mL (1.90 mL, 3.80 mmol) The reaction was allowed to warm to room temperature and stirred for 1 hour. The solvent was removed in vacuo and the reaction mixture was Dilute with DCM (50 mL) and saturated NaHCO 3(水溶液) (2 x 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 volatiles were removed under vacuum and the column was then washed with HCl and passed through a Biotage phase separator. , Intermediate 126, tert-butyl(2R)-4,4-difluoro-2-(hydroxymethyl) To obtain 452 mg (92%) of pyrrolidine-1-carboxylate,

[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) was mixed in CH2Cl2 (20 mL) at room temperature and AcOH (0.68 mL, 12.0 mmHg) mol) was added and stirred for 3 hours. STAB (2.34 g, 10.0 mmol) was added, and The reaction mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with NaHCO3 (saturated aqueous solution) The mixture was quenched with the addition of 40 mL of HCl and extracted with CH2Cl2 (4 x 45 mL). The layer was washed with saturated brine, then dried over MgSO4 and filtered. The solvent was removed in vacuo to give Crude tert-butyl 4-[(3-hydroxypropyl)amino]piperidine-1-carbohydrate The xylate (1.03 g, 4.00 mmol) was obtained and used without further 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-carbohydrate 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) in CHCl (21 mL) 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 CH2Cl2 (2 x 20 mL). and dried to give intermediate 132, 3-(piperidin-4-yl)-1,3-oxa Dinan-2-one hydrochloride (0.352 g, 76%) was obtained as a colorless solid. Data on the items are in Table 2.

[0325] Intermediate 151, ethyl 2-(4-oxopiperidin-1-yl)-6-azaspiro[3. Procedure for preparing 4]octane-6-carboxylate hydrochloride [ka] Ethyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (0. 985g, 5.00mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.715 g, 5.00 mmol) was mixed with CH2Cl2 (50 mL) at room temperature and OH (0.31 mL, 5.50 mmol) was added and stirred for 3 hours. g, 12.5 mmol) was added and the reaction mixture was stirred overnight at room temperature under nitrogen. The mixture was quenched by the addition of NaHCO3 (saturated aqueous solution) (40 mL) and CH2Cl2 (4 × 4 5 mL), and the combined organic layers were washed with saturated brine and then dried over MgSO4. 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), and water (10 mL) and concentrated hydrochloric acid (10 mL) were added and mixed. The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was triturated from EtO to give intermediate 15. 1. Ethyl 2-(4-oxopiperidin-1-yl)-6-azaspiro[3.4]octadecanoate The compound was obtained as a colorless solid. Data for the compounds are 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 thiazole (119m 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 added under nitrogen Place in a flushed tube, seal and heat under pressure at 90°C for 2.5 hours. The reaction mixture was diluted with H2O 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% Et2O in isohexane, 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 with H The solution was concentrated to give benzyl 4-(1,3-thiazolidin-2-yl)-4-(2-methyl- ... To this was obtained (143 mg, 95%) of (4-amino-4-yl)piperidine-1-carboxylate. LCMS (Method A): m / z 303 (M+H) + (ES + ), 1.92 minutes, UV activity .

[0329] Benzyl 4-(1,3-thiazolinone) in AcOH (1 mL) and 48% aqueous HBr (1 mL) Azol-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 compound are in Table 2.

[0330] Intermediate 172, (1R,5S)-3-phenyl-2,4-dioxa-3-borabicyclo[ 3.3.1] Procedure for preparing nonan-7-one [ka] (1S,3S,5S)-cyclohexane-1,3,5-triol (1.0 g, 6.0 phenylboronic acid (0.72 g, 6.0 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- 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 NaCl-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 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 [benzo-1-yl]piperidine trifluoroacetate [ka] tert-Butyl (2R)-4,4-difluoro-2-(hydrogen) (oxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.63 mmol) The solution was cooled with 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. The mixture was quenched with a drop of H2O and then concentrated to remove THF. The residue was diluted with saturated N Partition between aqueous aHCO3 and DCM (x2), pass the organic phase through a phase separator, Concentrate to 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-dihydrobenzoate in DCM (2 mL) and TFA (2 mL) Fluoro-2-(methoxymethyl)pyrrolidine-1-carboxylate (110 mg, 0 A solution of 0.44 mmol) was stirred at room temperature for 40 minutes, 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, over 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 trifluoroacetic acid 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 this order. The mixture was stirred at room temperature for 2 days and then concentrated to remove DMF. The residue was diluted with saturated NaHC1 Partition between aqueous O3 and DCM (x2), pass the organic phase through a phase separator, concentrate, Crude tert-butyl 4-[(2R)-4,4-difluoro-2-(methoxymethyl)pyrrolidone] Lysin-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 carboxylate (0.241 g, assumed 0.44 mmol) was stirred at room temperature for 45 minutes. The residue 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)pyrrolidin-1-yl] [I]piperidine trifluoroacetate was obtained as an oily substance. Data for the title compounds are in Table 2.

[0335] Intermediate 179, 1-[(2R)-4,4-difluoro-1-(piperidin-4-yl)piperidin-4-yl] Procedure for preparing [roridin-2-yl]ethanol trifluoroacetate [ka] tert-Butyl (2R)-4,4-difluoro-2-(hydrogen) (oxymethyl)pyrrolidine-1-carboxylate (150 mg, 0.63 mmol) The solution was cooled in ice water and treated with Dess-Martin periodinane (402 mg, 0.95 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. (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 phases were 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 m The mixture was then cooled to 100°C and treated with methylmagnesium bromide in 100% CO₂O (1.3 mmol). Removed and stirred for 2.75 h, then quenched by addition of saturated aqueous NH4Cl. The mixture was concentrated to remove THF and then partitioned between saturated NH4Cl 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, Isohex Purification by 20-50% EtOAc in hexane gave tert-butyl (2R)-4,4- Difluoro-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (0.1 0.06g, 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-difluoromethane in DCM (2 mL) and TFA (2 mL) Fluoro-2-(1-hydroxyethyl)pyrrolidine-1-carboxylate (102 mg A solution of (2, 0.41 mmol) was stirred at room temperature for 30 minutes, then diluted with toluene and concentrated. The residue was azeotropically distilled with toluene to give crude 1-[(2R)-4,4-difluoropyrrolidine- 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 , 0.61 mmol), 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. 301 g, >100%) was obtained as an oil. LCMS (Method C): m / z 335 (M+H) + (ES + ), 1.41 minutes, no UV Active.

[0338] tert-Butyl 4-[(2R)-4,4-dimethyl-2H-pyridine] in DCM (2 mL) and TFA (2 mL) -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- [Il]ethanol trifluoroacetate was obtained as an oil (0.553 g, >100%). Data for the title compound 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 hours and then cooled to room temperature. The volatiles were removed by concentration. The residue was partitioned between H2O (100 mL) and ethyl acetate (150 mL). The aqueous layer was diluted with ethyl acetate. (2 x 100 mL), and the combined organic layers were dried (Na2SO4) and The solvent was removed by concentration to give the crude product, 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 ester (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, resulting in 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. Purification by trituration with ether (3 × 10 mL) gave intermediate 215, 4-(1H-tetrahydrofuran)-2-(4-methyl-2-propanol). (Irazol-1-yl)piperidine hydrochloride (0.30 g, 97%) was obtained as a solid. Data for the compounds are 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 hours. The mixture was diluted with cold water (250 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried (Na2SO4) and concentrated to give the crude product, which was purified by column chromatography. Graphology (normal phase, neutral silica gel, 60-120 mesh, 0-35% Et in hexane) OAC) to obtain tert-butyl 4-(cyclopropylcarbamoyl)piperazine. 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) 1) 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 minutes. 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 (Na2SO4) and concentrated. This was purified 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)piperidin Diazolin-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 hours. 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-ylpiperidine 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-hydroxybenzoate 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, and 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 Purification with 100% EtOAc to give tert-butyl 4-(2,5-dioxo-2-methyl-2-propanol) (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-dioxo-2-methyl-2-oxo-1, ... 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 2,3'-dione trifluoroacetate was obtained as a gum and was used immediately. The data are in Table 2.

[0346] Intermediate 229, ethyl 2-([2,4'-bipiperidin]-1'-yl)-6-azaspirillum 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. After stirring at this temperature for 30 minutes, 40 mL of THF was added slowly. 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 x 50 mL). The residue was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography [normal phase, silica gel (100-200 mesh), gradient: Purify by 0% to 30% ethyl acetate in xanthan gum to obtain tert-butyl 4-hydroxybenzoate. -4-(pyridin-2-yl)piperidine-1-carboxylate (11.4 g, 65%) ) was obtained as a yellow oil. 1 H-NMR(400 MHz; CDCl3) 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-) in pyridine (100 mL) To a solution of (methyl)piperidine-1-carboxylate (11.4 g, 41.0 mmol), POCl3 (5.7 mL, 61.5 mmol) was added and stirred at room temperature for 20 hours. After removing the amine in vacuo, the reaction mixture was quenched with aqueous NaOH (10%, 30 mL) Extraction was performed with chloroform (2 x 30 mL). The organic layers were combined, dried (Na2SO4) The residue was purified by flash column chromatography (normal phase, silica gel) Purified by filtration (100-200 mesh, gradient: 0% to 30% ethyl acetate in hexane). tert-butyl 3',6'-dihydro-[2,4'-bipyridine]-1'(2 (H)-carboxylate (2.3 g, 21%) was obtained as a yellow oil. 1 H-NMR(400 MHz; CDCl3) 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] tert-Butyl 3',6'-dihydro-[2,4'- bipyridine-1'(2'H)-carboxylate (2.3 g, 8.84 mmol) To the solution, PtO2 (200 mg, 0.88 mmol) was added, and the reaction mixture was heated at room temperature for 2 days under H 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; CDCl3) 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'-carboxamide in THF (5 mL) To a solution of cylate (1.05 g, 3.91 mmol) Cbz-O in THF (5 mL) 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). The residue was washed with saturated brine, dried (Na2SO4), 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; CDCl3) 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] 1-Benzyl 1'-(tert-butyl) [2,4'- bipiperidine]-1,1'-dicarboxylate (840 mg, 2.1 mmol) solution To the mixture was added HCl in dioxane (10 mL, 4 M) slowly at 0° C., and the reaction mixture was allowed to stand at room temperature. The reaction mixture was quenched with saturated NaHCO3 (20 mL) and the aqueous layer was Extraction was performed with CH2Cl2 (2 x 20 mL). The organic layers were combined and dried (Na2SO4). The residue was purified by flash column chromatography (normal phase, silica gel) Gradient: 0% in DCM with 0.1% aqueous ammonia ~15% MeOH] to obtain benzyl[2,4'-bipiperidine]-1-carbohydrate. The xylate (570 mg, 90%) was obtained as a colorless sticky solid. 1H-NMR(400 MHz;CDCl3) 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] Benzyl[2,4'-bipiperidine]-1-carboxy in CH2Cl2 (15 mL) late (520 mg, 1.72 mmol) and ethyl 2-oxo-6-azaspiro[3. 4] A solution of octane-6-carboxylate (305 mg, 1.55 mmol) was added to Ti (O i Pr)4 (1.6 mL, 5.16 mmol) was added and stirred at 0°C for 40 minutes. To the reaction mixture was added NaBH4 (1.1 g, 5.16 mmol) 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 diluted with CH2Cl2 (2 x 20 The organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (reverse phase, X-BRIDGE, C-18, 19 x 250 mm, 5 μm, Gradient: 68% to 90% ACN in water containing 0.1% NH4OH, 214 nm, room temperature: Purification by 7.45 min for isomer-1 and 8.37 min for isomer-2 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; CDCl3) 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; CDCl3) 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) -carboxylate (1.0 g, 2.06 mmol) in a solution of a mixture of isomers, Palladium on carbon (320 mg, 50% wet) was added and the reaction mixture was stirred at room temperature for 16 hours under H2 atmosphere. The reaction mixture was stirred under air, filtered through a pad of Celite, washed with MeOH, and Concentration in vacuo and trituration with pentane gave intermediate 229, ethyl 2-([2,4'-bipiperidinyl]-2-methyl-2-propanol

[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) To a solution of 1.0 mmol of HCl, add SOCl2 (2.7 mL, 37.5 mmol) and slowly add HCl (2.7 mL, 37.5 mmol) at 0°C. 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 stepping. 1 H-NMR (400 MHz; DMSO--d6) 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 EtN (9.9 mL, 69.0 mmol) and (B C. The reaction mixture was stirred at room temperature for 1 hour. The mixture was stirred for 12 hours, and the reaction mixture was quenched with water (20 mL). The organic layer was separated and then The aqueous layer was extracted with CH2Cl2 (3 x 15 mL). The organic layers were combined and washed with saturated brine. 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 give 2-(tert-butyl) 1-methylisothiazolinone Dolin-1,2-dicarboxylate (6.5 g, 90%) was obtained as a colorless liquid. 1 H-NMR (400 MHz; CDCl3) 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) -dicarboxylate (6.5 g, 23.0 mmol) in a solution of LAH (2 M, 11. 5 mL, 23.0 mmol) was added slowly at 0°C and stirred for 30 minutes. The mixture was quenched with saturated aqueous Na2SO4 (20 mL). Filter through a pad, wash with ethyl acetate (100 mL), and dry (Na2SO4) , concentrated in vacuo to give tert-butyl 1-(hydroxymethyl)isoindoline-2-carboxylate. The carboxylate (5.2 g, 91%) was obtained as an off-white solid. The crude residue was not further purified. was used in the next step without further purification. 1 H-NMR(400 MHz; CDCl3) 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 periodontal The mixture was stirred at room temperature for 48 hours. After completion, the reaction mixture was filtered through a pad of Celite and diluted with diethyl ether (3×20 The filtrate was washed with saturated aqueous NaHCO3, saturated brine, dried ( Na2SO4), concentrated in vacuo to give tert-butyl 1-formylisoindoline-2-carboxylate. The carboxylate (4.5 g, 88%) was obtained as a brown liquid. The crude residue was further purified. was used in the next step without further purification. 1 H-NMR(400 MHz; CDCl3) 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] To a solution of NaH (874 mg, 18.2 mmol) in THF was added trimethyl phosphonoacetate. After stirring at -78°C for 1 hour, the mixture was stirred at -78°C for 1 hour. , 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. The mixture was quenched with saturated aqueous NH4Cl (10 mL) and the aqueous layer was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried (Na2SO4), concentrated in vacuo, and extracted with tert-butyl ether. (E)-1-(3-methoxy-3-oxoprop-1-en-1-yl)isoindo Phosphorus-2-carboxylate (5.2 g, 92%) was obtained as a brown liquid. This was used in the next step without further purification. MS(ESI+ve):304

[0358] tert-Butyl (E)-1-(3-methoxy-3-oxo)propanol in MeCN (20 mL) prop-1-en-1-yl)isoindoline-2-carboxylate (5.2 g, 17 To a solution of Cs2CO3 (11.1 g, 34.4 mmol), add a small amount of Cs2CO3 (11.1 g, 34.4 mmol) at room temperature. After stirring for 20 minutes, methyl cyanoacetate (3.0 mL, 34.4 mmol) was added. was slowly added and the reaction mixture was stirred at 70°C for 16 hours. The filtrate was filtered through a pad of light and washed thoroughly with hexane (3 x 20 mL). Concentrate in vacuo to give dimethyl 3-(2-(tert-butoxycarbonyl)isoindoline- 1-yl)-2-cyanopentanedioate (5.5 g, crude (cr)) was added to a brown sticky The crude residue was used in the next step without further purification. MS(ESI+ve):403

[0359] Dimethyl 3-(2-(tert-butoxycarbonyl)isopropyl)isocyanate in DMSO (15 mL) 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 for 16 hours at 135° C. After completion, the reaction mixture was diluted with water (20 mL) The mixture was quenched with HCl and the aqueous layer was extracted with diethyl ether (3×20 mL). Dry (Na2SO4) and concentrate in vacuo to give tert-butyl 1-(1-cyano-4-methyl- 1.5-(4-oxobutan-2-yl)isoindoline-2-carboxylate 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)propanol in MeOH (30 mL) (2-hydroxybutan-2-yl)isoindoline-2-carboxylate (300 mg, 0.8 m To a solution of 1000 mol of HCl, Raney nickel (0.30 g, wet) was added and the reaction mixture was heated to 50°C. The reaction was heated under H2 atmosphere at 50 psi for 2 hours, and then the reaction temperature was increased to 70°C. After stirring for 3 h, the reaction mixture was filtered through a pad of Celite and The residue was triturated with diethyl ether (30 mL) and concentrated in vacuo. ert-Butyl 1-(2-oxopiperidin-4-yl)isoindoline-2-carboxamide The sylate (0.21 g, 76%) was obtained as a brown solid. MS(ESI+ve):317

[0361] tert-Butyl 1-(2-oxopiperidin-4-yl)isothiazolinone in THF (5 mL) A solution of indoline-2-carboxylate (210 mg, 0.60 mmol) was added to BH3 -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 added with 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, and the residue was triturated with diethyl ether (20 mL) to give t ert-butyl 1-(piperidin-4-yl)isoindoline-2-carboxylate, Intermediate 243 (200 mg, 99%) was obtained as a brown solid. The data is in Table 2.

[0362] Prepare intermediate 247, 4-(2H-1,2,3-triazol-2-yl)piperidine Steps to take [ka] tert-Butyl 4-hydroxypiperidine-1-carboxylate (0.500 g, 2.4 mmol) was dissolved in CH2Cl2, and then DMAP (0.302 g, 2.4 mmol) was added. 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, then diluted with H2O (70 mL) and C The mixture was partitioned into HCl (70 mL) and the aqueous layer was further extracted with CHC1 (2 x 70 mL). The organic layers were combined, dried (Na2SO4), filtered, and the solvent removed in vacuo to give crude tert-butyl ether. t-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate(0 0.520 g, 75.0%) as a white solid, 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. Partition the mixture between HO (50 mL) and EtOAc (50 mL), and the aqueous layer was diluted with EtOAc (2 × 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and the solvent was evaporated. 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 hours, the solvent was removed in vacuo, and the residue was treated with diethyl ether. The 4-(2H-1,2,3-trimethylsilyl)-2-(2H-trimethylsilyl)-2-(2H-trimethylsilyl)-1,2,3-trimethylsilyl ... (2-(2-isopropyl-2-pyridin-1-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 2H-tetrazole Add ethyl 4-bromopiperidine-1-carboxylate (1.29 g, 4.8 mmol) to D K2CO3 (1.64 g, 11.8 mmol) was added and the resulting reaction mixture was The reaction mixture was stirred at 100 °C for 6 h, then diluted with HO (100 mL) and ethyl acetate (150 mL). The aqueous layer was further extracted with ethyl acetate (2 x 100 mL) and the organic layers were combined. The residue was purified by CombiFlash chromatography. 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 m 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 hours, the solvent was removed in vacuo, and the residue was treated with diethyl ether. The mixture was purified by trituration with ethanol (3 × 10 mL) to give 4-(5-methyl-1H-tetrahydrofuran). (1-isopropyl-1-pyridinone hydrochloride), intermediate 255 (0.170 g, 97.6%) Data for the title compound are in Table 2.

[0367] Intermediate 258, (R)-2-(4,4-difluoro-1-(piperidin-4-yl)pyrrolidone Procedure for obtaining and preparing lysin-2-yl)propan-2-ol hydrochloride [ka] 1-(tert-butyl) 2-methyl (R)-4,4-dichloroisothiazolinone in dioxane (15 mL) Fluoropyrrolidine-1,2-dicarboxylate (500 mg, 1.89 mmol) To the solution, HCl in dioxane (4 M, 15 mL) was added slowly at 0°C and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was triturated with hexane (10 mL). The residue was basified with saturated aqueous NaHCO3 (10 mL) and concentrated. The crude reaction mass was treated with CDM ( The filtrate was concentrated in vacuo to give methyl (R)-4,4-difluoromethyl ... Pyrrolidine-2-carboxylate (2,320 mg, 84%) was obtained as a brown liquid. This 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-oxopiperine A solution of 10% paradiazine-1-carboxylate (240 mg, 1.21 mmol) was added to the solution. Carbon dioxide (300 mg, 50% wet) was added and the reaction mixture was heated under H2 (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, CDCl3) 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 (3 M, 1.07 mL, 3.21 m mol) was added slowly at 0°C and stirred at room temperature for 4 hours. After completion, the reaction mixture was diluted with saturated N The reaction mixture was quenched with aqueous HCl (10 mL) and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was Press column chromatography [normal phase, silica gel (100-200 mesh), gradient 10% to 30% ethyl acetate in hexanes] 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, CDCl3) 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-hydroxybenzoyl)methyl)-2,4-difluorobenzoyl methyl ... Cypropan-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (2 To a solution of 40 mg (0.69 mmol) of HCl in dioxane (4 M, 10 mL) was added at 0°C. The reaction mixture was concentrated in vacuo and the residue was dissolved in hexane ( The crude reaction mass was triturated with CH2Cl2 (30 mL) 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-carboxylate [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. 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl (0.628g, 3.275mmol), hydroxybenzotriazole (0.334g , 2.183 mmol), N-methylmorpholine (1.104 g, 10.915 mmol) l) and dimethylamine hydrochloride (0.356 g, 4.36 mmol) were added to the reaction mixture. The mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with DCM (20 mL) and saturated NaH Washed with CO3(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- Silica gel 25g 40-63μm, 60Å, 25mL / min, gradient: 0%-10% MeOH / DCM]) to give tert-butyl (2R)-2-(dimethylcarbamoyl) (I)piperidine-1-carboxylate, Intermediate 282, (0.241 g, 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-Diethylenediamine (2,2'-dichloro-2,3'-diphenyl-2,4'-diphenyl-1,4'-diphenyl-2 ... Add ethylaminosulfur trifluoride (0.360 g 2.24 mmol) 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 quenched by the addition of saturated NaHCO3 (aq) (20 mL) and DCM (2 x 15 mL), and the combined organic layers were placed on a Biotage phase separator. The residue was dried by passing it through a ridge and the solvent was removed in vacuo. Biotage SNAP Cartridge KP-sil 10g 40-6 Purification was performed by HPLC (3 μm, 60 Å, 12 mL / min, gradient: 0% to 4% MeOH / DCM). tert-butyl(2R)-2-(fluoromethyl)pyrrolidine-1-carboxylate The product, Intermediate 295 (0.104 g, 34%), was obtained as an amber oil. Data for the compounds are 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) ) was dissolved 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 water (3×20 mL) and saturated NaCl (aq) (20 mL), dried (Mg The solvent was removed in vacuo to give 3-tert-butyl-4-methyl(4S)-1,3- Thiazolidine-3,4-dicarboxylate, Intermediate 285, (0.812 g, 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 1,2-dimethyl-3,4-dichloro-2,4-dimethyl-2 ... The reaction was added dropwise to a solution of salil (0.566 g, 2.93 mmol) at −78° C. under nitrogen. The mixture was stirred under nitrogen at -78°C for 15 min, then diluted with (2R) in anhydrous DCM (4 mL). -(+)-1-Boc-2-pyrrolidinemethanol (0.600 g, 2.98 mmol) The reaction mixture was stirred under nitrogen at -78 °C for 15 min, then diluted with Et3N( 1.06 g, 11.92 mmol) was added and the reaction mixture was stirred under nitrogen at 0° C. for 1 hour. The reaction mixture was quenched with saturated NaHCO3 (aq) (20 mL) and diluted with 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 condenser 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 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, then overnight. The reaction mixture was warmed to room temperature and then cooled to room temperature by the addition of saturated NaHCO3 (aq) (20 mL). Quench and extract with DCM (2 x 15 mL), combine the organic layers and immerse in 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. Benzene-1-carboxylate, Intermediate 297, (0.217 g, 45%) as an amber oil Data for the title compound 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, CsCO (632 mg, 1.94 mmol) in dioxane: The reaction mixture was degassed for 30 minutes and then dissolved in water (10:2 mL). f (24 mg, 0.03 mmol) was added, and the reaction mixture was then stirred at 90° C. for 16 hours. The mixture was partitioned between H2O (80 mL) and EtOAc (50 mL), and the aqueous layer was diluted with EtOAc (2 × 50 mL), the organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. 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 then purified by H2 gas. The mixture was purged and stirred under H2 pressure for 8 hours at 25°C. The reaction mixture was filtered through Celite. The residue was washed with MeOH, the solvent was removed in vacuo, and the residue was purified by column chromatography ( Phase silica, mesh size: 60-120, 20%-24% EtOAc in hexane) and purified as tert-butyl 4-(1,2,4-thiadiazol-5-yl)piperidine. The resulting zinzidine-1-carboxylate (150 mg, 74.6%) was obtained 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 Carboxylate (150 mg, 0.56 mmol) was dissolved in 1,4-dioxane (5 mL). The reaction mixture was stirred at 30° C. for 16 hours, 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 x 3 mL). and purified to give intermediate 30, 5-(piperidin-4-yl)-1,2,4-thiazol-1,2,4-diol. 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 , 6.55 mmol), 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(PPh3) 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 partitioned between H2O (100 mL) and EtOAc (100 mL). The aqueous layer was further extracted with EtOAc (2 x 100 mL), and the organic layers were combined and dried (Na The residue was purified by column chromatography (normal phase silica, Purify by (shrinkage: 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) Dissolved in 1,4-dioxane (20 mL) and then in HCl (20 mL) in 1,4-dioxane mL of a 3M solution) was added dropwise. 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 x 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 on the compounds are 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 , 10.0 mmol), 3-iodo-2-methoxypyridine (8.21 g, 26.0 mm ol) and K2CO3 (4.3 g, 31.8 mmol) in 1-4 dioxane (10 mL) and water (5 mL). The reaction mixture was degassed using N2 for 15 minutes; 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 x 100 mL). The layers were combined, dried (Na2SO4), the solvent removed in vacuo and the crude product 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% Pd / C (0.2 g) and purged with H2 gas. The mixture was stirred at room temperature for 12 hours under H2. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to give tert-butyl 4-(2-methoxypyridin-3-yl)piperidine The -1-carboxylate (0.91 g, 47.9%) was obtained as a colorless 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-(piperazine-2-yl)-2-propanol. 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 , 10.0 mmol), 3-iodo-2-methoxypyridine (8.21 g, 26.0 mm ol) and K2CO3 (4.3 g, 31.8 mmol) in 1-4 dioxane (10 mL) and water (5 mL). The reaction mixture was degassed using N2 for 15 minutes; 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 x 100 mL). The layers were combined, dried (Na2SO4), the solvent removed in vacuo and the crude product 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% Pd / C (0.2 g) and purged with H2 gas. The mixture was stirred at room temperature for 12 hours under H2. The reaction mixture was filtered through Celite and the solvent was removed in vacuo to give tert-butyl 4-(2-methoxypyridin-3-yl)piperidine The -1-carboxylate (0.91 g, 47.9%) was obtained as a colorless 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 4.0 M 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. Data on this can be found in Table 2.

[0387] Route 5 via hydrogenation exemplified by the preparation of intermediate 69, 3,4'-bipiperidin-2-one Typical Procedure for Preparing Piperidine [ka] 3-(piperidin-4-yl)-1,6-dihydropyridin-2-ol (0.5 g, 2.8 mmol) was dissolved in MeOH (10 mL) and PtO2 (0.2 g) was added. The reaction mixture was purged with H2 gas and stirred at room temperature for 12 hours under H2 gas. , filtered through Celite, and the solvent removed in vacuo to give intermediate 69, 3,4'-bipiperidine The resulting product was 1,2-dichloro-2-one (0.4 g, 78.3%) as a brown gum. The data is in Table 2.

[0388] Route 6 Intermediate 127, ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidine-1- Diastereomers of {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 preparing [ka] (S)-tert-Butyl 2-(piperidin-4-yl)pyrrolidine-1-carboxy late (1.24 g, 6.29 mmol) and 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 1 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, and then STAB (2.67 g, 12.6 mmol) was added. The reaction mixture was stirred under nitrogen at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column chromatography. Normal phase, Biotage SNAP cartridge KP-sil 340g, 4 0-63 μm, 60 Å, 80 mL / min, gradient: 0%-10% 7N in DCM, MeOH NH3]) to give ethyl 2-{4-[(2S)-1-(tert-butoxy) (carbonyl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3. 4] Octane-6-carboxylate (2.46 g, 90%) is an inseparable mixture of isomers 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 1,4-dioxane (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 hours, 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 tetrahydrofuran (0.45 g, 97%). Data for the title compound are in Table 2.

[0390] Route 7 Intermediate 137, 1-(piperidin-4-yl)tetrahydropyrimidin-2(1H)-ol Reductive amination, Boc-deprotection, urea formation, and hydrogenation are exemplified by the preparation of benzophenone. 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. 4 mmol) in CHCl (20 mL) at room temperature and STAB (2.59 g, 12.0 mmol) was added and stirred for 3 hours. The reaction mixture was stirred overnight at room temperature under nitrogen. The mixture was quenched by the addition of HCl (40 mL) and extracted with CH2Cl2 (4 x 45 mL). The combined organic layers were washed with saturated brine, then dried over MgSO4 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 CHCl (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 CH2Cl2 (2 x 20 mL) and dried to give crude benzyl 4-[(3-aminopropyl)amine] [N]piperidine-1-carboxylate dihydrochloride (1.41 g, 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. Biotage SNAP Cartridge KP-sil 50g, 40-6 Purification by HPLC (3 μm, 60 Å, 50 mL / min, gradient: 0% to 10% MeOH in DCM) Benzyl 4-(2-oxotetrahydropyrimidin-1(2H)-yl)piperidin The resulting product was tetrahydrofuran-1-carboxylate (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). The solution was dissolved in 10% P using an H-Cube set at 50 °C and 40 bar H2 at 1 mL / min. The eluted solution was concentrated in vacuo to give intermediate 137, 1-(piperazine-2-yl)-2-propanol. 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- Pi via reductive amination and Boc deprotection, as exemplified by the preparation of carboxamides. Typical Procedure for Preparing Peridine [ka] (S)-N-methylpyrrolidine-2-carboxamide (0.5 g, 3.8 mmol), NEt3 (1.5 mL, 11.0 mmol), tert-butyl 4-oxopiperidine- 1-carboxylate (0.38 g, 3.9 mmol) and ZnCl2 (0.15 g, 4 0.5 mmol) was dissolved in MeOH (15 mL) under nitrogen and stirred at 50-60°C for 1 hour. NaCNBH3 (0.16 g, 0.67 mmol) 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 x 100 mL) and water (50 ml). L), the organic layers were combined, dried (Na2SO4), 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 Lysin-1-yl)piperidine-1-carboxylate (0.3 g, 25.0%) was added to a light brown Obtained as a colored 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 a solution of HCl (5.00 mL) in water at room temperature for 10 hours. Concentrate under high vacuum and triturate 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 compound are in Table 2.

[0396] Route 9 Intermediate 181, 4-[2-(1H-pyrazol-5-yl)pyrrolidin-1-yl]piperazine 4-position 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 ethyl 4-oxopiperidine-1-carboxylate (0.100 g, 0.50 mmol) 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 1 day and then concentrated to remove DMF. The residue was diluted with saturated aqueous NaHCO3 and DC 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- 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-(4-methyl- ... razolidin-5-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (0. A solution of 271 g (assuming 0.50 mmol) of toluene was stirred at room temperature for 110 minutes. 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 is 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 Preparing 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 K2CO3 (0.209 g, 1 The mixture (0.5 mmol) 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% NH3 in MeOH (7M NH3 / MeOH) and purified to obtain 5-methyl-1-(pyridin-4-yl)pyrrolidin-2-one (0.0 88g, 99%) was obtained 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 a 10% Pt / C catalyst at a flow rate of 100°C and 80 bar pressure. Concentration and azeotroping the residue with toluene (×2) gave crude intermediate 184, 5-methyl-1-(piperazine-2-yl)-2-(2-methyl-2-propanol). Lysin-4-yl)pyrrolidin-2-one acetate (0.166 g, >100%) as an oil Data for the title compound are in Table 2.

[0400] Route 11 Intermediate 199, (5R)-5-methyl-1-(piperidin-4-yl)pyrrolidine-2- 1-(piperidin-4-yl)propanol acetate, and intermediate 200, (5R)-5-ethyl-1-(piperidin-4-yl)propanol Copper-catalyzed coupling to pyridines exemplified by the preparation of pyrrolidin-2-one acetates 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 12 mmol of methyltriethylamine (12 mL, 86 mmol) was added triethylamine (12 mL, 86 mmol). The resulting 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-methylbenzenesulfonate The resulting solution was purified by HPLC using a HPLC-MS / ... 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 A mixture of 4 g (5.6 mmol) was heated to reflux under N2 overnight and then allowed to cool. The residue was partitioned between DCM and H2O 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-(bromo-2-methyl-2-propanol). (bromomethyl)pyrrolidin-2-one (0.284 g, 86%) was obtained 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) of (5S)-5-(bromomethyl)pyrrolidin-2-one (0.284 g, 1.6 mmol) l) solution was added to the H-Cube at a flow rate of 1 mL / min at room temperature and 50 bar pressure. 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 HCl. The light brown solution was pre-cooled in ice water under N2. The 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]methylpropional in THF (6 mL) 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 minutes and then soaked in ice water. The mixture was stirred overnight and the cooling bath was allowed to slowly cool. The mixture was quenched with 2 mL of ethyl acetate and stirred for several hours. The biphasic mixture was extracted with ether (x3), 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) Reaction according to Route 10 (coupling with intermediate 183) gives crude intermediate 200, ( 5R)-5-Ethyl-1-(piperidin-4-yl)pyrrolidin-2-one acetate (0. 156 g (72%) was obtained 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 mL) in M ​​(5 mL) 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, then added in small portions. 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 Zin-2-one acetate (0.343 g, 100%) was obtained as a solid. The 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 benzo-1-ylpiperidine-1-carboxylate. Typical Procedure for Preparing Piperidine 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 under nitrogen at room temperature overnight. The solvent was removed in vacuo and the residue Partition the mixture between HO (15 mL) and EtOAc (25 mL), and the aqueous layer was diluted with EtOAc (2 × 25 mL). mL), the organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo to give t ert-butyl 4-[(2R)-2-(methoxycarbonyl)pyrrolidin-1-yl]pyridin-1-yl Peridine-1-carboxylate, intermediate 159, was obtained as a white solid (393 mg, >99%). Data for the title compound 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 NaHCO3 (aq) (10 mL). The combined organic layers were separated and extracted with DCM (2 x 10 mL). The residue was dried by passing it through a parabolic cartridge and the solvent was removed in vacuo. Normal Phase, Biotage SNAP Cartridge KP-sil 25g 40 ~63 μm, 60 Å, 25 mL / min, gradient: 0% to 10% MeOH / DCM] Purify and obtain tert-butyl 3,3-difluoro-1,4'-bipiperidine-1'-carboxylate. The carboxylate, Intermediate 271, (0.347 g, 60%) was obtained as an amber oil. Data for the title compounds are in Table 2.

[0410] Route 15 Intermediate 195, 4-(1-methyl-1H-tetrazol-5-yl)piperidine hydrochloride Preparation of piperidines via tetrazole formation followed by alkylation is exemplified by the preparation of Typical steps for manufacturing [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 (Na2SO4) and concentrated to give the crude product. Chromatography (normal phase, neutral silica gel, 60-120 mesh, 0-5% in DCM) 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 C (1.2 g, 4.7 mmol), iodomethane (2.0 g, 14 mmol) and C s2CO3 (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 added to EtOAc (3×1 The combined organic layers were dried (Na2SO4) and concentrated to give the crude product. This was purified by column chromatography (normal phase, neutral silica gel, 60-120 mesh). 0-35% EtOAc in hexane, then 45-60% EtOAc in hexane. The two regioisomers were separated by purification using the tert-butyl 4 -(1-methyl-1H-tetrazol-5-yl)piperidine-1-carboxylate ( 0.160 g, 13%) was obtained as a solid, eluting 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 allowed to stand at 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 Illustrated by the preparation of piperidinium chloride via reductive amination, amide formation, and Boc deprotection. Typical procedure for preparing acetone [ka] R-Pipecolic acid (1 g, 7.75 mmol) and tert -butyl 4-oxopiperidine-1-carboxylate (2.31 g, 11.6 mmol) ), 10% palladium on carbon (1 g, 50% wet) was added, and the reaction mixture was heated at room temperature with H2 The reaction mixture was stirred under 1 atm for 48 hours. The reaction mixture was filtered through a celite bed and filtered. The product 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. This crude residue was carried on to the next step without further purification. Used for the pool. 1 H-NMR(400 MHz; CDCl3) 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 MeNH2 ( To a solution of 2M in THF (3.2 mL, 6.41 mmol), DIPEA (1.75 mL, 9.60 mmol) was added at 0° C. After stirring for 10 minutes, 1-propanephosphonic anhydride was added. Add the product [50% ethyl acetate solution (4.07 mL, 6.41 mmol)] and let it stand at room temperature for 3 hours. After completion, the reaction mixture was quenched with saturated aqueous NaHCO3 and The organic layers were combined, washed with saturated brine, dried (Na2SO4) , concentrated in vacuo to give tert-butyl (R)-2-(methylcarbamoyl)-[1,4'- Bipiperidine]-1'-carboxylate (4, 1 g, 97%) was dissolved in a colorless, sticky liquid. This 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 HCl in dioxane (4 M, 10 mL) was slowly added to the solution at 0 °C, and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo. This was then diluted with saturated aqueous NaHCO3 (10 mL). The crude reaction mass was basified with 5% MeOH / DCM (30 mL) and concentrated. The mixture was stirred for 1 minute 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 are in Table 2.

[0416] Route 17 Preparation of Intermediate 250, 4-Ethyl-5-iodo-1-methyl-1H-pyrazole Typical procedure for preparing iodopyrazoles via Sandmeyer reaction is illustrated [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 nitrite isoacetate. A mill was added dropwise and the mixture was stirred for 2 hours at 80°C and then for 2 hours at room temperature. Partition between HO (100 mL) and EtOAc (250 mL), and the aqueous layer was diluted with EtOAc (2 × 2 50 mL), and the combined organic layers were dried (Na2SO4), filtered, and the solvent The solvent was removed under vacuum. The residue was purified by column chromatography (normal phase, neutral silica gel, 60-12 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%) The product was obtained as a pale yellowish gum. Data for the title compound are in Table 2.

[0417] Route 18 Intermediate 302, tert-Br Preparation of methyl (2R)-2-(difluoromethyl)pyrrolidine-1-carboxylate The activated carbamates are obtained via 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. EtN (3.60 g, 0.036 mol) and and 4-nitrophenylchloroformate (3.767 g, 0.0187 mol) were added to the reaction mixture. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 (aq) (30 mL). The organic layers were combined and washed with 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-methyl-4-methyl-1,4-diol) (0.700 g, 2.41 mmol) was dissolved in DMF (15 mL). 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 NaHCO3 (aq.) The aqueous layer was extracted with DCM (2 x 20 mL), and the organic layers were combined and purified by Bio Dry by passing through a phase separator cartridge and remove the solvent under 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-ol The carboxylate, intermediate 302, was obtained (0.738 g, 72%). The 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 [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 0.1 mmol) and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carbo Titanium dioxide (1.60 g, 7.1 mmol) was dissolved in DCM (60 mL) at room temperature. Phenylene isopropoxide (2.31 mL, 7.81 mmol) was added and the reaction mixture was stirred at room temperature. The reaction mixture was stirred for 1 hour. 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 RT. 0 mL), diluted with DCM, and then filtered through a pad of Celite. The layers were separated and the aqueous layer was extracted with DCM. The combined DCM layers were washed with saturated brine. The solvent was removed in vacuo and the residue was purified by column chromatography. Biotage SNAP Cartridge KP-sil 50g, 40-6 3 μm, 60 Å, 50 mL / min, gradient: 1% to 10% M in DCM with 0.5% NEt eOH]) to obtain ethyl 2-[4-(1H-imidazol-2-yl)piperazine. 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 18 mL / min using a mini-N C18 column, 150 x 21 mm Elution was performed with MeCN / H2O and fractions were collected by monitoring at 218 nm. 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]-2-methyl ... din]-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-carboxamide 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), ZnCl2 (2 mg, 0.0 1 mmol) and triethylamine (0.3 mL, 2.28 mmol) in MeOH (5 m L) and the reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to 0°C and N aBH3CN (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 dissolved in HO (50 mL) and EtO The aqueous layer was extracted with EtOAc (2×35 mL) and the organic layers were combined. 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% NH3] 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-ol Carboxylate, Example 1-3 Isomer 2, (12 mg, 6.6%) was obtained as a yellow solid Data for isomer 2 are in Table 3.

[0421] Route C Example 1-4, Ethyl 2-[4-(4-cyano-1H-imidazol-2-yl)piperidinyl] Preparation of [di-(2-methyl-1-yl)-6-azaspiro[3.4]octane-6-carboxylate Conversion of trifluoromethyl-substituted imidazoles to cyano-substituted imidazoles exemplified by Typical steps to [ka] Ethyl 2-(4-(4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin peridin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(2 00 mg, 0.50 mmol) in NH3 solution (20 mL) and stirred at 60 °C for 8 h. The solvent was removed in vacuo and the residue was partitioned between H2O (60 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (2×40 mL) and the organic layers were combined and dried (NaSO 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 / water 25.0% ( 30.0 min), 100% (3.0 min), then 25.0% (7.0 min), 0.1% NH3] to give ethyl 2-(4-(4-cyano-1H-imidazole-2- (yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate Example 1-4 Isomer 1 (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 Examples 1-7, Ethyl 2-[4-(1-methyl-1H-imidazol-2-yl)piperidinyl] Preparation of [di-(2-methyl-1-yl)-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 1 mmol) 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 titanium isopropoxide was added. Cid (0.4 mL, 2.42 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. 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 adding nitrogen. The reaction mixture was stirred overnight under nitrogen. The reaction mixture was cooled to room temperature by the addition of NaHCO3 (saturated aqueous solution) (10 mL). The mixture was quenched, diluted with DCM, and then filtered through a pad of Celite. The combined DCM layers were washed with saturated brine and then dried over MgSO4. 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 afford tert-butyl 2- [4-(1-methyl-1H-imidazol-2-yl)piperidine]-6-azaspiro[ 3.4]Octane-6-carboxylate (0.330 g, 72%) isomers inseparable 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] 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 hours. The volatiles were then removed in vacuo and the residue was 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 diluted with NaHCO3 (aq) (75 mL) and DCM (75 mL). The combined DCM extracts were poured into saturated brine (20 ml) and extracted (2 x 75 mL). L) and then dried over MgSO4. After concentration, the residue was purified by column chromatography. -(Normal phase, [Biotage SNAP Cartridge KP-sil 25g, 40-63 Purification by HPLC (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 oil. It was obtained as a mixture of asterisks (0.25 g, 83%) using preparative HPLC. The diastereomers were separated using Phenomenex Gemini-N A C18 column, 150 x 21 mm, was used, and 38-48% MeCN / H2 was measured at 18 mL / min. The mixture was extracted with 200 ml of ethyl acetate 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, Examples 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, Isomer 2, (0.031 g, 10%) was obtained as a colorless oil. Data for body 2 are in Table 3.

[0424] Route e Examples 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 of 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 hydroxylate (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 was purged with H2 gas and then stirred under a H2 balloon at 25 °C for 20 h. The reaction mixture was filtered through Celite, washed with MeOH, and the solvent from the filtrate was removed in vacuo. The residue was purified 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. 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- 9 Isomer 1, (5.6 mg, 5.8%) as a colorless gum, methyl 2-[4-(1, 5-Dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspirillum [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)piperazine] Preparation of lysin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate Sodium triacetoxyborohydride reductive amination, Boc deprotection, as exemplified by Typical Procedure for Preparing Piperidine 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) was dissolved in DCM (10 mL) at room temperature under N2, and 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. The reaction mixture was quenched by the addition of NaHCO3 (saturated aqueous solution) (30 mL) and diluted with DCM (4 × 25 mL The combined DCM layers were passed through a Biotage phase separator. After removal of the solvent, 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 min and 1.61 min Minute hours, UV inert.

[0426] Crude tert-butyl 2-[4-(1H-1,2,4-triazol-1-yl)piperidinyl] [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 NEt3 (0.70 mL, 5.0 mmol) was added. 0.14 mL, 1.5 mmol) was added dropwise and the solution was stirred at room temperature overnight. Poured into CO3 (aq) (40 mL), extracted with DCM (4 x 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 5 μm C18 column. A 110A Axia column, 100 x 30 mm, was used, with a flow rate of 14.4 mL / min. The column was eluted with 25-55% MeCN / solvent B [where solvent B is 0.2% (2 8% NH3 / H2O)] 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 Imidazole derivatives using sodium hydride in DMF as 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. Dibromoethyl 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 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 give ethyl 2-{4-[1-(2 -Methoxyethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-a Diastereoisopropyl benzoate (159 mg, 90%) This mixture was dissolved in MeOH and the solution was subjected to preparative reverse phase HPLC. This was purified using Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100 x 30 mm, 14.4 min at 30 mL / min Elution was performed with 15-45% MeCN / solvent B [where solvent B is 0.2% ( 28% NH3 / H2O)] 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 7 mg, 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 acetone. 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 diastereomeric mixture of 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 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- {yl}-6-azaspiro[3.4]octane-6-carboxylate (91 mg, 54%) This mixture was dissolved in MeOH and the solution was separated into preparative reverse phase Purification was performed by HPLC using Phenomenex Gemini-NX 5 μm C18 110A Axia column, 100 x 30 mm, at 30 mL / min. Elute with 15–45% MeCN / solvent B over 14.4 min [where solvent B is H2 0.2% in 28% NH3 / H2O], monitored 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-carboxamide Sylate, Example 1-52 Isomer 1, (8 mg, 5%) and ethyl 2-{4-[1-(silyl) (aminomethyl)-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. Procedure for preparing 4]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 solution 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-methyl-4-[(2-methyl-2-methyl-4-methyl-2 ... -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-carboxamide A mixture of diastereomers of silanes (180 mg, 0.45 mmol) was dissolved in THF (4 mL) and lithium hydroxide monohydrate (75 mg, 1.8 mmol) in HO (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 ( Approximately 0.2 g of this crude mixture of diastereomers was obtained (0.4 g, >100%). 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 minutes at 30 mL / min using a 100 x 30 mm / Elute with solvent B [where solvent B is 0.2% NH3 in H2O (28% NH3 / H2O)] Fractions were collected by monitoring at 210 nm. 6-(Ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine -4-yl}-1H-imidazol-1-yl)acetic acid, Examples 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 Diastereoisomer of {-2-yl]piperidin-4-yl}-1H-imidazol-1-yl)acetic acid The crude mixture of thiathreomers, 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 resulting powder was dissolved and concentrated on flash silica (10 mL). 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 Purification by 10% (7M NH3 / MeOH) in MeOH afforded ethyl 2- (4-{1-[2-(methylamino)-2-oxoethyl]-1H-imidazole-2- (yl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate This mixture was dissolved in MeOH and the solution was separated into diastereomers. The product was purified by phase 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 at RT [where solvent B is H 0.2% in 28% NH3 / H2O], monitored at 210 nm. The fractions were collected according to the following formula: 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] Pi via carbamate formation, 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% mineral oil suspension was added and the reaction The reaction mixture was stirred under nitrogen at room temperature for 10 minutes. 0.150 g, 2.94 mmol) was added and the reaction mixture was stirred under nitrogen at room temperature 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 saturated Partition with NaHCO3 (aq) (10 mL) and extract the aqueous layer 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 Tagage 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 0.2% NH3 in H2O (28% NH3 / H2O)] [0.01], and collect fractions by monitoring at 210 nm) do,( 2 H5) 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 H5) 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 -yl]-6-azaspiro[3.4]octane-6-carboxylate 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 The reaction was stirred for 1 hour, then cooled to 0° C. and treated with ethyl 2-(4- (Pyrrolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane of diastereomeric α-6-carboxylate hydrochloride (100 mg, 0.30 mmol) The resulting reaction mixture was stirred at 60° C. for 8 hours and adjusted to a basic pH. The reaction mixture was then partitioned between H2O (40 mL) and EtOAc (25 mL). The layer was further extracted with EtOAc (2 x 25 mL), and the organic layers were combined and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative HPLC (X Bridge, C-18, 150 x 30 mm, 5 μm, 40 mL / min, gradient: acetonitrile / water 30% (12.00 min 100% (14.00 min), then 30% (14.01 min), 0.1% The product was purified by HCl, and ethyl 2-[4-(1-formylpyrrolidin-2-yl)pyrrolidine] was obtained. 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 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 Typical procedure for preparing piperidines via amide formation 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, and the resulting The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with H2O (40 mL) and EtOAc ( The aqueous layer was further extracted with EtOAc (2 x 25 mL) and the organic layers were combined. The solvent was removed in vacuo and the residue was collected. HPLC (X Bridge, C-18, 150 x 30 mm, 5 μm, 40 mL / min, gradient Mixture: 30% 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 Glutan-6-carboxylate, Example 2-4 isomer-2 (6.2 mg, 9.7%) The data for isomer 2 are 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 hydroxylates Typical procedure for preparing acetone [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 A mixture of diastereomers (1.5 mol) was dissolved in DCM (20 mL) and triethylamine (1. 54 mL, 11.1 mmol) of methylaminoformyl chloride (Methy laminoformyl chloride) (620 mg, 6.63 mmol) was added. The solution was stirred at room temperature for 2 hours. 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%) Preparative HPLC was used to separate the diastereomers. x Gemini-NX C18 column, 100 x 30 mm, at 18 mL / min Elution with 25–35% MeCN / 0.2% ammonia (v / v) in H2O at 210 nm The fractions were collected by monitoring. -{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 preparing 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 t3 (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. The mixture was partitioned between HO (40 mL) and EtOAc (25 mL), and the aqueous layer was diluted with EtOAc (2× The organic layers were combined, dried (Na2SO4), and the solvent was removed in vacuo. 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)-2-methylpropional. -yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxy Rate, Example 2-19 Isomer-1 (Example 219 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 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 [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 (0.303 mL, 0.90 mmol) was dissolved in HO (2 mL) at 25 °C. mol) was added dropwise and the resulting mixture was stirred at 70° C. for 14 hours. The reaction mixture was quenched with HCl solution (5 mL), and then diluted with HCl (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 dried over Na2SO4. 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% NH3] to give 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%) was obtained 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 Typical procedure for preparing piperidines via amide formation 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 stirred at 0°C for 1 hour. Stir at 4°C for 10 minutes, 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 a mixture of diastereomers was added and the resulting reaction mixture The mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with H2O (50 mL) and EtOAc (35 mL). Partition, further extract the aqueous layer with EtOAc (2 x 35 mL), combine the organic layers and add Na2S The residue was dried over O4 and the solvent was removed in vacuo. Finally, the residue was purified by column chromatography (normal phase , normal basic alumina, active, in DCM 0. Purify with 5% to 1.0% MeOH to obtain ethyl 2-(4-(1-(N-((benzyl) (N-methylglycyl)pyrrolidin-2-yl)piperidine-1 -yl)-6-azaspiro[3.4]octane-6-carboxylate (130 mg, 8 0.74%) as a brown gum. (C) 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), followed by Pd / C (dry basis, 13 mg) The reaction was then purged with H2 gas and the resulting reaction mixture was stirred at 25 °C for 1 The reaction mixture was stirred for 10 hours. The reaction mixture was filtered through a plug of Celite, washed with methanol, and then The filtrate was then dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by preparative HPLC [reverse phase HPLC (X-BRIDGE, C-18, 250 x 19 mm, 5 μm, 15 mL / min, gradient Mixture: 20.0% to 35.0% in MeCN / water (30.0 min), 100.0% (3.0 min) 20.0% (2.0 min), 0.1% NH3] to give ethyl 2 -(4-(1-(methylglycyl)pyrrolidin-2-yl)piperidin-1-yl)-6 -Azaspiro[3.4]octane-6-carboxylate, Examples 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 (2 mmol) was dissolved in DCM (5 mL) and diisopropyl ethyl acetate. The mixture was dissolved in 100 mL of triphosgene (88 mg, 0. 291 mmol) was added at 0°C, and the solution was warmed to room temperature and stirred for 1 hour. The solution was diluted with DCM (50 mL) and washed with H2O (70 mL). The aqueous layer was washed with DCM (2 × 5 The combined DCM extracts were dried over Na2SO4 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 to the reaction mixture. The mixture was stirred at room temperature for 1 h. The mixture was then diluted with DCM (50 mL) and The aqueous layer was extracted with DCM (2 x 50 mL) and the combined DCM extracts were washed with N Dry with HCl and concentrate in vacuo to give ethyl 2-{4-[(2S)-1-(azetidinediamine)-4-yl]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), 0.1% ammonia in HCl and 0.1% ammonia in H2O 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 added to a colorless Example 2-27 Isomer 2 (20 mg, 16.12%) as a colorless gum Data for isomer 2 are given in Table 3.

[0440] Route r Example 2-42, Ethyl 2-(4-{(2S)-1-[ethyl(propan-2-yl)carbonyl]carbonyl}carbonyl 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)pyrrolidin-2-yl {6-azaspiro[3.4]octane-6-carboxylate} A typical method for preparing piperidines via urea formation and dehydration is illustrated by the preparation of Typical Procedures [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 (2 mmol) was dissolved in DCM (2 mL) and diisopropyl ethyl acetate. The mixture was dissolved in 1,2-dichloro-2,4-triphosgene (43 mg, 0.209 mL, 1.21 mmol). (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 NaHCO3 (aq) ( 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-carboxamide 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 hour. 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, and the solution was warmed to room temperature and stirred for 2 hours. 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 stirred for 11 minutes. 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 x 20 mL) and the combined DCM extracts were Wash with saturated brine (50 mL) and then pass through a Biotage phase separator. The residue was purified by preparative HPLC using Phenomenex A Gemini-NX C18 column, 100 × 30 mm, was used, and HO was Elute with 25-45% MeCN / 0.2% ammonia (v / v) and monitor at 210 nm. The fractions were collected by filtration. Example 2-42 Isomer 1, ethyl 2-(4 -{(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%) as a colorless oil, obtained from Example 2- 138 Isomer 2, Ethyl 2-{4-[(2S)-1-(5-methyl-1,3,4-oxa diazol-2-yl)pyrrolidin-2-yl]piperidin-1-yl}-6-azaspirate b) [3.4]octane-6-carboxylate (3.0 mg, 2%) as a colorless oil The data for isomer 2 are in Table 3.

[0442] Routes Example 2-47, Ethyl 2-(4-{(2S)-1-[(2-fluoroethoxy)carbonyl] nyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4]octyl Piperidin via carbamate formation exemplified by the preparation of ethane-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 The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (70 mL) and Partition with DCM (50 mL), extract the aqueous layer further with DCM (2 x 50 mL) and the organic layer The mixture was combined, dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by preparative HPLC [reverse phase HP LC(CHIRALPAK AD-H, C-18, 250×20mm, 5μm, 18.0 mL / min, gradient: 0% to 35% (52 min), 0.1% ammonia in acetonitrile 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 method for preparing piperidines via amide formation is illustrated by the preparation of carboxylates. 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 1.2 mmol) and triethylamine (0.152 mL, 1.1 m 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 and the reaction mixture was stirred at room temperature for 2 hours. 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 hour. Partition the mixture between HO (70 mL) and DCM (50 mL), and the aqueous layer was washed with DCM (2 × 50 mL). After further extraction, the organic layers were combined, dried over Na2SO4, the solvent removed in vacuo, and the residue was analyzed. 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 0.1% ammonia in water and 0.1% ammonia in water to give ethyl (S)-2 -(4-(1-(2-hydroxyacetyl)pyrrolidin-2-yl)piperidin-1-yl) (Isomeric)-6-azaspiro[3.4]octane-6-carboxylate, Example 2-52 Compound 1 (8 mg, 8.3%) was obtained as a colorless gum, and was synthesized by the method of -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-trifluoropropanediol) {6-azaspiro[3.4]oyl)pyrrolidin-2-yl]piperidin-1-yl} Piperidine via amide formation exemplified by the preparation of octane-6-carboxylate Typical procedure for preparing [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) diastereomeric mixture and diisopropylethylamine (0.123 mL , 0.71 mmol) was dissolved 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% EtOAc solution), resulting reaction mixture The mixture was stirred at 25°C for 2 hours. The reaction mixture was partitioned between H2O (20 mL) and DCM (50 mL). The aqueous layer was further extracted with DCM (2 x 50 mL), and the organic layers were combined and washed with Na2SO4. 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 x 20 mm, 5 μm, 18.0 mL / min, gradient: acetonitrile 0% to 30% in nitrile (27.0 min), 0.1% ammonia and 0.1% ammonia in water Purification by nitrite gave ethyl (S)-2-(4-(1-(3,3,3-trifluoropropanediol). 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)-2-yl)- ... (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 Lawesson's reagent is exemplified by the preparation of thioamides. 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) was dissolved in THF (4 mL), and then Lawesson's reagent (0.265 g , 0.65 mmol) was added. The reaction mixture was stirred at 70°C for 24 hours. The volatiles were removed. Remove the reaction mixture in vacuo and add 1 M NaOH (水溶液) (50 mL) and DCM (30 mL) The aqueous layer was further extracted with DCM (2 x 50 mL), and the combined organic layers were diluted with 5% pyronitrile. Sodium sulfate (水溶液) The residue was washed with HCl, dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by preparative HPLC using Phenomenex Gemini- 25-45% in H2O at 18 mL / min using a NX C18 column, 100 x 30 mm Extraction with MeCN / 0.2% ammonia (v / v) and monitoring at 210 nm The fractions were collected according to the following formula: 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 is in Table 3.

[0446] Route w Example 2-61, Ethyl 2-{4-[(2S)-1-ethylpyrrolidin-2-yl]piperazine Preparation of lysin-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 (0.123 mg, 0.89 mmol) and potassium carbonate (0.89 mmol) mol) was dissolved in DMF (5 mL) and the reaction mixture was stirred at 60° C. for 2 hours. 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 partitioned between H2O (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 dried over Na2SO4. 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: 35% acetonitrile / 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 [3.4]octane-6-carboxylate, Example 2-61 Isomer 2 (26 mg, 2 3.1%) as a colorless gum. Data for isomer 2 are in Table 3.

[0447] Route x Example 2-62, Ethyl 2-(4-{(2S)-1-[3-(pyridin-2-yl)propyl]propionate (Panoyl)pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4] Piperidines can be prepared via amide formation, as exemplified by octane-6-carboxylate. Typical steps for manufacturing [ka] Oxalyl chloride (0.065 mL, 0.768 mmol) in DCM (2 mL) at 0 °C To a solution of 2-pyridinepropionic acid (106 mg, 0.704 mmol) and DMF (1 (drops) was added. Ethyl 2-{4-[(2S)-pyrrolidin-2-yl]piperidine-1- {yl}-6-azaspiro[3.4]octane-6-carboxylate hydrochloride (262 mg A mixture of diastereomers of (2, 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 hours. The mixture was then diluted with 1 M NaOH (aq) (50 mL) The mixture was poured into a glass and extracted with DCM (2 x 50 mL). The combined DCM extracts were then 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 (2-phenyl-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 dissolved in 25–45% MeCN / 0.2% ammonia (v / v) in H2O at 18 mL / min. 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 Benzene-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)propyl]propionate (Panoyl)pyrrolidin-2-yl}piperidin-1-yl)-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)carbo -β-alanyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspirillum 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 1,3-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) in CH2Cl2 (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% ethyl acetate solution) was added to the resulting reaction mixture. The mixture was stirred at 25 °C for 3 h, partitioned between H2O (70 mL) and CH2Cl2 (50 mL), and The layers were further extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were dried (Na 2SO4), 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 further treatment. LCMS (Method I): m / z 541 (M+H) + (ES+) 4.38 and 4.51 minutes , UV inert.

[0449] The residue was analyzed by 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]carbonyl]carbonyl carboxyl-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-a ranyl}pyrrolidin-2-yl]piperidin-1-yl}-6-azaspiro[3.4]o Diastereomers of octane-6-carboxylate (100 mg, 0.185 mmol) The mixture was dissolved in TFA (2.0 mL), and the resulting solution was stirred at 80°C for 3 hours. 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)pyrrolidin-2-yl)methyl) (I)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 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. Data for isomer 2 are 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 procedure for preparing piperidines via alkylation is illustrated by the preparation of alkylates. 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 A mixture of diastereomers (2 mol) was dissolved in MeCN (5 mL) and CS2CO3 (2 90 mg, 0.89 mmol) was added, followed by 2-iodo-1-fluoroethane (56 m gg, 0.32 mmol) was added and the reaction mixture was stirred at 50° C. for 16 hours. The mixture was partitioned between HO (70 mL) and ethyl acetate (50 mL), and the aqueous layer was diluted with ethyl acetate (2 × 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified by 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)piperazine Lysin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate, Example 2-68 Isomer 1 (25 mg, 25%) was obtained as a yellowish gum by the addition of 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 of DIPEA (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. The reaction mixture was diluted with HO (70 mL ) and EtOAc (50 mL), and the aqueous layer was further extracted with EtOAc (2 x 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by preparative H 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), purified by 0.1% ammonia to give 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 9 Isomer 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 is in Table 3.

[0453] Route ab Example 2-70, Ethyl 2-{4-[(2S)-1-(3,3,3-trifluoropropyl {6-azaspiro[3.4]octa(2-yl)pyrrolidin-2-yl}piperidin-1-yl} Piperidines can be prepared via alkylation, as exemplified by the preparation of benzophenone-6-carboxylates. Typical steps for manufacturing [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 0.123 g of K2CO3 (0.89 mmol) and 0.123 g of K2CO3 (0.89 mmol) l) was dissolved in MeCN (5 mL) and the reaction mixture was stirred at 60°C for 2 hours. -Trifluoro-3-iodopropane (0.066 g, 0.29 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 8 h. The reaction mixture was diluted with HO (70 mL) and E The aqueous layer was further extracted with EtOAc (2 x 50 mL) to give The organic layers were combined, dried (Na2SO4), filtered, and the solvent removed in vacuo. The residue was purified by preparative H 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), purified by 0.1% ammonia to give 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 2 (0.005 mg, 3.9%) was 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- Preparing 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 0.14 mL of DIPEA (0.87 mmol) and DIPEA (0.14 mL, 0.87 mmol) l) was dissolved in MeCN (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. C. (0.044 g, 0.29 mmol) was added dropwise and the resulting reaction mixture was heated to 100.degree. The reaction mixture was partitioned between H2O (70 mL) and EtOAc (50 mL). The aqueous layer was further extracted with EtOAc (2 x 50 mL) and the organic layers were combined and dried (Na 2SO4), 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-methylpropional)-2-hydroxybenzoate). 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 (S)-2-(4-(1-(2-methoxy-2-oxo) 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-(isopropyl methylamino)methyl]-2-(2-methyl- ... xoethyl]pyrrolidin-2-yl}piperidin-1-yl)-6-azaspiro[3.4 ] piperizinyl octane-6-carboxylate via alkylation, as exemplified by the preparation of 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 A mixture of diastereomers of NEt3 (0.087 g, 0.85 mmol) and NEt3 (0.087 g, 0.85 mmol) ) was dissolved in dioxane (5 mL) and the reaction mixture was stirred at 60°C for 30 minutes. 1H-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. The reaction mixture was diluted with HO (70 mL) and E The aqueous layer was further extracted with EtOAc (2 x 50 mL) to give The organic layers were combined, dried (Na2SO4), 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: Trinitrile / water: 20% (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))piperidin (Rolidin-2-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6 -carboxylate, Example 2-72 Isomer 1 (0.002 g, 1.6%) was added to a yellow gum 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%), 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 Pr)4 (0.40 mL, 1.34 mmol) was added at 0°C. The reaction mixture was stirred for 1 h. Na(OAc)3BH (283 mg, 1.34 mmol) was added. l) was added portionwise to the reaction mixture and stirred at 0° C. for 2 hours. After completion, the reaction mixture was diluted with saturated N The mixture was quenched with aqueous HCl and extracted with DCM (3×30 mL). The residue was washed with saturated brine, dried (Na2SO4), and concentrated in vacuo. Chromatography [normal phase, silica gel (100-200 mesh), gradient: in DCM 5% to 10% methanol] to obtain tert-butyl 1-(1-(6-(ethoxymethyl)methyl)-2-(2-methyl-2-propanol). (oxycarbonyl)-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl (I)isoindoline-2-carboxylate (35 mg, 75%) was obtained as a colorless liquid. Ta. MS(ESI+ve):484

[0457] tert-Butyl 1-(1-(6-ethoxy)methyl)-2-methyl-2-propanol in 1,4-dioxane (10 mL) (carbonyl)-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl)i A solution of diisoindoline-2-carboxylate (290 mg, 0.61 mmol) was added to HCl in hexane (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--d6) 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-ol) 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 methylcarbamic acid 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 x 20 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was flash-dried. Column chromatography [normal phase, silica gel (100-200 mesh), gradient: DC Purification was performed with 5% to 10% methanol in HCl to obtain ethyl 2-(4-(2-methylpropional)-2-methylpropional). 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-d6): 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-Preparative HPLC System - Dual Piston pumps 331 and 332, 171 diode array detector and GX-271 liquid Including 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 × 30 mm) Separation of the dimers afforded ethyl 2-(4-(2-methylcarbamoyl)-isoindolyl) (6-azaspiro[3.4]octane-6-yl)piperidin-1-yl carboxylate, Example 2-76 Isomer 1 (8.99 mg, 12.3%) was treated with PEG-400 to give a colorless gum. and ethyl 2-(4-(2-(methylcarbamoyl)-isoindolin-1-yl)pyridin-1-yl) 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 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 (2 mmol) was dissolved in DCM (5 mL) and triethylamine (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 hours and then diluted with H The aqueous layer was partitioned between HClO (70 mL) and DCM (100 mL). After further extraction, the organic layers were combined, dried (Na2SO4), the solvent removed, and the residue separated. HPLC [Reversed 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 [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 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 Complexation using cesium carbonate and copper iodide in DMF, exemplified by the preparation of hydroxylates. Typical Procedure for Arylation of Pyrrolidine-Containing Compounds with a Heterocyclic 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 a mixture of diastereomers of Cs2CO3 (0.361 g, 1.1 mmol ) 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 h. The reaction mixture was diluted with H2O (70 ml The aqueous layer was partitioned between 10 mL of ethyl acetate and 50 mL of EtOAc. The aqueous layer was further diluted with 2×50 mL of ethyl acetate. The organic layers were combined, dried (Na2SO4), and the solvent was removed by concentration. 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 ], and 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 {benzo-1-yl}-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}- Heterocyclic compounds using sodium carbonate in ethanol as exemplified by the preparation of carboxylates. 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 A mixture of diastereomers of 0.092g of Na2CO3 (0.87mmol) and 0.092g of Na2CO3 (0.87mmol) ol) was dissolved in ethanol (10 mL) and stirred at room temperature for 30 minutes. C. The resulting reaction mixture was added with 100 ml of methylparaben (0.034 g, 0.29 mmol) at 0.degree. The mixture was stirred at 80° C. for 6 hours. The reaction mixture was concentrated and dichloromethane was added. The mixture was filtered, and the filtrate was concentrated and 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-pyrrolidin-2-yl)piperidin-1-yl]pyrrolidin-2-yl}piperidin-1-yl 3.4]octane-6-carboxylate, Example 2-81 Isomer 1 (0.031 g, 2 5%) as a gum, and ethyl 2-{4-[(2S)-1-(pyrimidin-2-yl)pyrimidin-2-yl] ... 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 Data for isomer 2 are 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-carboxylates using cesium carbonate in DMF as exemplified by the preparation of 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 S2CO3 (260 mg, 0.81 mmol) was added to it, and then 2-bromothiazole To the mixture was added ethanol (58 mg, 0.29 mmol), and the reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was partitioned between H2O (70 mL) and EtOAc (50 mL). The aqueous layer was diluted with EtOAc (50 mL). The organic layers were combined, dried (Na2SO4), and 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% (21.0 min), 0.1% ammonia in water and 0.1% ammonia in water Purification was carried out to obtain 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 hydroxylates. Typical steps for manufacturing [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 hour, the solvent was removed in vacuo and the residue was subjected to further purification. It was used in the next step without 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-carboxy Dissolve diethyl ether (0.266 g, 1.26 mmol) in DMF (4 mL) at room temperature and dilute EA (0.435 mL, 2.510 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. 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 diastereomeric mixture was isolated using preparative HPLC. This was achieved by using a Phenomenex Gemini-NX C18 column, A 100 x 30 mm tube was used, with a flow rate of 18 mL / min for 25-45% MeCN / 0.2% Al in H2O. 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-(methoxycarbonyl) {6-azaspiro[3.4]octyl)pyrrolidin-1-yl]piperidin-1-yl} Benzene-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 is 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, as 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), NEt3 (0.75 mL, 5.0 m mol), 6-(ethoxycarbonyl)-2-oxo-6-azaspiro[3.4]octa A mixture of benzoyllium (0.188 g, 0.93 mmol) and ZnCl2 (30 mg, 0. Dissolve 0.02 mmol) in MeOH (15.00 mL) under nitrogen and heat at 50-60°C for 1 h. NaCNBH3 (0.069 g, 1.0 mmol) was added in small portions at 0-10°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (2 x 50 mL) and water. (30 mL), the organic layers were combined, dried (Na2SO4), filtered, and the solvent was evaporated. The crude product was purified by preparative HPLC [reverse phase HPLC (X-Bridge PREP C1 8, 250 x 19 mm, 5 μm, 15 mL / min, gradient: 30% to 100% in acetonitrile % (22 min), then 100% (2 min), 0.1% NH3, and 2-85 Isomer 1, Ethyl (S)-2-(4-(2-methylcarbamoyl)pyrrolidine -1-yl)piperidin-1-yl)-6-azaspiro[3.4]octane-6-carbo Xylate (0.09 g, 24.32%) as a white solid, Example 2-85 Isomer 2, Ethyl (S)-2-(4-(2-(methylcarbamoyl)pyrrolidin-1-yl)piperidin Zin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate(0.0 89 g, 24.10%) was obtained as a white solid. Data for isomer 2 are in Table 3.

[0467] Route AP Example 2-87, Ethyl 2-{4-[(2R)-4,4-difluoro-2-(methoxycarbonyl) (carbonyl)pyrrolidin-1-yl}-6-azaspiro[3.4]octane-6-carbox Deprotection and sodium triacetoxyborohydride reduction exemplified by the preparation of sylates Typical Procedure for Preparing Piperidines via Substitutional Amination [ka] tert-Butyl 4-[(2R)-4,4-difluoro-2-(methoxycarbonyl) pyrrolidin-1-yl]piperidine-1-carboxylate (0.36 g, 1.03 mm ol) was dissolved in 4.0 M HCl in dioxane (10 mL), and the reaction mixture was stirred at room temperature for 6 h. The solvent was removed in vacuo and the residue was used in the next step without further purification. The crude reaction mixture and ethyl 2-oxo-6-azaspiro[3.4]octane-6-carbohydrate were Dissolve hydroxylate (0.243 g, 1.233 mmol) in DCE ...

Claims

【Request 1】 【Chemistry 1】 Or a compound represented by ethyl 2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate.

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

3. A pharmaceutical comprising a compound according to claim 1 or a pharma- ceutically acceptable salt according to claim 2.

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

5. A pharmaceutical for the treatment of schizophrenia comprising a compound according to claim 1 or a pharma- ceutically acceptable salt according to claim 2.

6. A pharmaceutical for the treatment of Alzheimer's disease comprising a compound according to claim 1 or a pharma- ceutically acceptable salt according to claim 2.

7. A pharmaceutical for the treatment of bipolar disorder comprising a compound according to claim 1 or a pharma- ceutically acceptable salt according to claim 2.

Images