Oxadiazoles as agonists of muscarinic m1 and / or m4 receptors

Abstract

To provide a compound which is an agonist of muscarinic M1 and / or M4 receptors and is useful for treating diseases mediated by muscarinic M1 and M4 receptors.SOLUTION: Also provided are pharmaceutical compositions containing the compounds, and therapeutic uses of the compounds. The compounds provided are of formula (I) wherein X1; X2; X3; X4; R1, R2 and R4 are as defined herein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a class of novel heterocyclic compounds, their salts, and pharmaceutical compositions containing them. and their use in the treatment of the human body. In particular, the present invention relates to muscarinic M1 The present invention is directed to a class of compounds that are agonists of the M4 receptor and / or M5 receptor, Therefore, Alzheimer's disease, schizophrenia, cognitive impairment, and muscarinic M1 / M4 receptors It is useful in the treatment of other body-mediated diseases, as well as in the treatment or alleviation of pain. [Background technology]

[0002] Muscarinic acetylcholine receptors (mAChRs) are present in both the central and peripheral nervous systems. G protein-coupled receptors that mediate the action of the neurotransmitter acetylcholine in It is a member of the mAChR superfamily. There are five mAChR subtypes, namely M1 to M 5 has been cloned. M1mAChR is expressed in the cortex, hippocampus, striatum, and thalamus. M2mAChRs are primarily expressed postsynaptically in the brainstem and thalamus. However, they are also located in the cortex, hippocampus, and striatum, where M2mAChRs are involved in present in phosphorylated synaptic terminals (Langmead et al., 2008 Br J Ph However, M2mAChRs are also expressed in the periphery and on the cardiac tissue surface (M2 mAChRs mediate vagal innervation of the heart, as well as in smooth muscle and exocrine glands. M3mAChR is expressed at relatively low levels in the CNS, but is expressed in smooth muscle , and is widely expressed in glandular tissues such as sweat glands and salivary glands (Langmead et al., Br J Pharmacol 2008).

[0003] Muscarinic receptors in the central nervous system, particularly M1mAChR, are involved in higher cognitive processing. It plays an important role in mediating cognitive decline, especially in diseases associated with cognitive impairment such as Alzheimer's disease. is accompanied by loss of cholinergic neurons in the basal forebrain (Whitehouse (Science, 1982). In schizophrenia, which is also characterized by cognitive impairment, mA ChR density is reduced in the prefrontal cortex, hippocampus, and caudate putamen of schizophrenic subjects (D ean et al., 2002, Mol Psychiatry). Furthermore, in animal models, Blockade or lesion of central cholinergic pathways results in severe cognitive deficits and nonselective mA ChR antagonists have been shown to induce psychotomimetic effects in psychiatric patients. Cholinergic replacement therapy prevents the breakdown of endogenous acetylcholine, The treatment of steroids has been based mainly on the use of esterase inhibitors. These compounds are widely used in outpatient clinics to treat steroid-resistant steroids. It has been shown to be effective against symptomatic cognitive decline, but it also causes gastrointestinal motility disorders, bradycardia, nausea, and vomiting. It causes dose-limiting side effects due to stimulation of peripheral M2 and M3 mAChRs, including Rubbing (http: / / www.drugs.com / pro / donepezil.ht ml;http: / / www.drugs.com / pro / rivastigmine .html).

[0004] Further discovery efforts should focus on direct M1mAChR agonists targeted to enhance cognitive function. These efforts have focused on identifying the causes of steroids, such as xanomeline, AF267, and B, sabcomeline, miramelin, and cevimeline, among other compounds. Many of these compounds have been shown to be effective in rodent and / or has shown high efficacy in preclinical models of cognition in both human and non-human primates. Melin inhibits scopolamine-induced deficits in working and spatial memory in rodents. Subcomelin has been shown to be effective against visual object recognition defects in marmosets. Xanomeline demonstrated efficacy in the passive avoidance paradigm, demonstrating a significant reduction in cognitive performance. It reversed ChR antagonist-induced defects.

[0005] Alzheimer's disease (AD) is the most common neurological disorder affecting older adults (2006 26.6 million people worldwide in 2019, and can cause severe memory loss and cognitive impairment. The etiology of the disease is complex, but it has two prominent features: amyloidosis and encephalopathy. Aggregation of amyloid plaques, primarily composed of β-peptides (Aβ), and hyperphosphorylation It is characterized by neurofibrillary tangles formed by tau protein. Accumulation of Aβ contributes to the progression of AD. It is considered a central feature of AD and therefore has many implications for its treatment. Current therapeutic strategies target the inhibition of Aβ production, which is a membrane-bound amyloid precursor. It results from the proteolytic cleavage of the endogenous protein (APP). APP can be cleaved by two pathways: It is processed in both non-amyloidogenic and amyloidogenic ways. Cleavage of APP by α-serotonin is common to both pathways, but in the former, APP is cleaved by α-serotonin. The cleavage site is located within the Aβ sequence. However, in the amyloidogenic pathway, APP is cleaved by β-secretase to produce soluble APPβ and also Aβ In vitro studies have shown that mAChR agonists produce soluble, non-amyloid forms of It has been shown that ATP can promote the processing of APP towards the proliferative pathway. In vivo studies have demonstrated that the mAChR agonist AF267B inhibits the progression of Alzheimer's disease. In 3xTgAD transgenic mice, a model of various components of the disease It has been shown to modify neuropathology (Caccamo et al., 2006, Neuron). In addition, cevimeline, an mAChR agonist, inhibits Aβ in the brain in Alzheimer's patients. It has been shown to cause a small but significant decrease in spinal fluid levels, thus reducing the potential demonstrated significant disease-modifying efficacy (Nitsch et al., 2000, Neurol).

[0006] Furthermore, preclinical studies have demonstrated that mAChR agonists are effective in a range of preclinical paradigms. These results suggest that mAChR agonists may exhibit an atypical antipsychotic profile. Xanomeline inhibits amphetamine-induced locomotion in rats and apomorphine in mice. Dopamine agonist-promoted tree climbing induced by steroids in unilateral 6-OH-DA-lesioned rats rotational movement in monkeys and amphetamine-induced hyperlocomotion in monkeys (without EPS loading) In rats, it improves several dopamine-driven behaviors, including In the prefrontal cortex and nucleus accumbens, but not in A9, A10, dopamine cells It has also been shown to inhibit firing and conditioned avoidance and induce c-fos expression. All of these data suggest an atypical antipsychotic-like profile (M irza et al., 1999 CNS Drug Rev). Muscarinic receptors also play a role in addiction. The reinforcing effects of cocaine and other addictive substances are mediated by the mesolimbic system. It is mediated by the dopamine system, and in this case, behavioral and neurochemical studies have shown that Cholinergic muscarinic receptor subtypes play a key role in regulating dopaminergic neurotransmission. For example, M(4)(- / -) mice demonstrated that exposure to cocaine resulted in a significant enhancement of reward-driven behavior ( Schmidt et al. Psychopharmacology (2011) August;216 (3): pp. 367-78). Furthermore, xanomeline inhibited the It has been demonstrated to block the action of ketones.

[0007] Muscarinic receptors are also involved in the control of movement and potentially in Parkinson's disease, ADHD, and , Huntington's disease, Tourette's syndrome, and dysplasia as potential pathogenic factor-driven disorders The present invention is targeted for novel treatment of movement disorders, including other syndromes associated with paminergic dysfunction. do.

[0008] Xanomeline, sabcomeline, miramelin, and cevimeline are all used to treat Alzheimer's disease are in various stages of clinical development for the treatment of idiopathic pulmonary edema and / or schizophrenia. Phase II clinical trials using Nomelin have demonstrated improved behavioral and neurological symptoms associated with Alzheimer's disease It has been demonstrated to be effective in various cognitive symptom domains, including hallucinations (Bodi ck et al., 1997, Arch Neurol). This compound is also used as an antipsychotic (schizophrenia drug). It has also been evaluated in a small Phase II study of chizophrenic drugs, Compared with controls, the study resulted in a significant reduction in both positive and negative symptoms (S Hekhar et al., 2008, Am J Psych. However, in all clinical studies Xanomeline and other related mAChR agonists have been shown to reduce nausea, gastrointestinal pain, and diarrhea. Cholinergic symptoms, including diarrhea, diaphoresis (excessive sweating), hypersalivation (excessive salivation), fainting, and bradycardia It presents an unacceptable margin of safety with regard to sexual side effects.

[0009] Muscarinic receptors are involved in central and peripheral pain. Pain can be mediated by three different Types: Can be classified as acute, inflammatory, and neuropathic. Acute pain results in tissue damage. It plays an important role in protecting the organism from harmful stimuli, but also plays a role in managing postoperative pain. Inflammatory pain is caused by a variety of factors, including tissue injury, autoimmune responses, and pathogen invasion. Neuropeptides and neurotransmitters can occur for a number of reasons, leading to neuronal inflammation and pain. It is triggered by the action of inflammatory mediators such as steroids and prostaglandins. Neuropathic pain is associated with abnormal pain sensations in response to non-painful stimuli. Spinal cord injury, multiple sclerosis, diabetes (diabetic neuropathy), viral infection (HIV or Hepatitis C) Neuropathic pain is also associated with several different diseases / injuries, such as: Both are also common in cancer, either as a result of the disease or as a side effect of chemotherapy. Activation of phospholipid receptors in the spinal cord and in the highest pain centers in the brain is due to receptor activation. It has been shown to have analgesic properties in several pain conditions. Increase in endogenous levels of acetylcholine by enzyme inhibitors, agonists or allosteric Direct activation of muscarinic receptors by modulators can have analgesic activity. In contrast, blocking muscarinic receptors with antagonists, or knocking them out, The use of mice with M1 receptors increases pain sensitivity. Evidence on this is found in D.F. Fiorino and M. Garcia-Guzman, 201 It is outlined by 2.

[0010] More recently, the M1 mAChR subtype has been compared with peripherally expressed mAChR subtypes. A few compounds have been identified that show improved selectivity for one type of methionine (Bridges et al., 2008, Bioorg Med Chem Lett; Johnson et al., 2010 2010, Bioorg Med Chem Lett; Budzik et al., 2010, ACS Med Chem Lett.) The effect on the M3 mAChR subtype appears to be reduced. Despite the increased selectivity levels, some of these compounds are still limited to this subtype and M It maintains significant agonist activity at both mAChR subtypes. In the specification, the inventors describe the M1 and / or M2 receptor subtypes compared to the M3 and M4 receptor subtypes. or describe a series of compounds that unexpectedly exhibit high levels of selectivity for M4 mAChRs. do. Summary of the Invention [Means for solving the problem]

[0011] The present invention The present invention relates to a compound having activity as a muscarinic M1 and / or M4 receptor agonist. More specifically, the present invention provides compounds that inhibit the activity of M2 and M3 receptor subtypes. The present invention provides compounds that exhibit selectivity for M1 and / or M4 receptors. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Compounds of formula (1): [ka] or a salt thereof (wherein X 1 and X 2 is a saturated hydrocarbon group containing, taken together, a total of 5 to 9 carbon atoms and 0 or 1 oxygen atoms, and is selected from the group consisting of the following moieties: [ka] are saturated hydrocarbon groups linked together to form a monocyclic or bicyclic ring system; X 3 and X 4 is a saturated hydrocarbon group containing a total of 3 to 6 carbon atoms when taken together, and is selected from the following moieties: [ka] are saturated hydrocarbon groups linked together to form a monocyclic or bicyclic ring system; R 1 is NR 5 R 6 ;CONR 5 R 6 ;COOR 7 an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and their oxidized forms, or R 1 is R 2 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, R 2 is hydrogen; fluorine; cyano; hydroxy; amino; and C optionally substituted by 1 to 6 fluorine atoms. 1~3 a hydrocarbon group, one of the carbon atoms of which may be replaced by a heteroatom selected from O, N and S and their oxidized forms, or R 2is R 1 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, R 4 H, halo, OH, CN, C 1~6 Alkyl group or C 3~6 is a cycloalkyl group, wherein the alkyl group and the cycloalkyl group are optionally substituted by one or more fluorine atoms, and any one of the atoms of the alkyl group or the cycloalkyl group may be replaced by an O heteroatom; R 5 is hydrogen, COCH3, non-aromatic C 1~10 a hydrocarbon group (which may be substituted with one or more fluorine atoms, C 1~10 Any one of the atoms of the hydrocarbon group may be replaced by a heteroatom selected from O, N and S), the group -(CH2) n -aryl (n is 0 to 3), or R 5 is R 6 and may be joined together to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and their oxidized forms, R 6 is hydrogen, non-aromatic C 1~10 a hydrocarbon group (which may be substituted with one or more fluorine atoms, C 1~10 Any one of the atoms of the hydrocarbon group may be replaced by a heteroatom selected from O, N and S), the group -(CH2) n -aryl (n is 0 to 3), or R 6 is R 5 and may be joined together to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and their oxidized forms, R 7 is a non-aromatic C optionally substituted with one or more fluorine atoms; 1~6 (It is a hydrocarbon group). (Item 2) Compounds of Formula 1a: [ka] Item 1, wherein the compound or a salt thereof is X 1 and X 2 is a saturated hydrocarbon group containing, taken together, a total of 5 to 9 carbon atoms and 0 or 1 oxygen atoms, and is selected from the group consisting of the following moieties: [ka] are saturated hydrocarbon groups linked together to form a monocyclic or bicyclic ring system; X 3 and X 4 is a saturated hydrocarbon group containing a total of 3 to 5 carbon atoms when taken together, and is selected from the following moieties: [ka] are saturated hydrocarbon groups linked together to form a monocyclic or bicyclic ring system; R 1 is NR 5 R 6 ;CONR 5 R 6 ;COOR 7 an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and their oxidized forms, or R 1 is R 2 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, R 2 is hydrogen; fluorine; cyano; hydroxy; amino; and C optionally substituted by 1 to 6 fluorine atoms. 1~3a hydrocarbon group, one of the carbon atoms of which may be replaced by a heteroatom selected from O, N and S and their oxidized forms, or R 2 is R 1 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof, R 4 is H or C 1~3 is an alkyl group, R 5 is hydrogen, COCH3, non-aromatic C 1~6 a hydrocarbon group (optionally substituted with one or more fluorine atoms), or R 5 is R 6 and may be joined together to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and their oxidized forms, R 6 is hydrogen, non-aromatic C 1~6 a hydrocarbon group (optionally substituted with one or more fluorine atoms), or R 6 is R 5 and may be joined together to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and their oxidized forms, R 7 is a non-aromatic C optionally substituted with one or more fluorine atoms; 1~6 (It is a hydrocarbon group). (Item 3) R 1 But NR 5 R 6 ;CONR 5 R 6 ;COOR 7 an optionally substituted 5- or 6-membered ring containing 0, 1, or 2 nitrogen heteroatoms, or R 1 is R 2The compound according to item 1 or 2, wherein: (Item 4) R 1 But R 2 and R are linked to form an optionally substituted monocyclic or bicyclic ring containing 0, 1 or 2 heteroatoms selected from O or N. (Item 5) R 1 But R 2 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1 or 2 heteroatoms selected from O or N, the optional substituents being C1-C6 alkyl, C1-C3 alkoxy, halogen, cyano, oxo, hydroxyl, amino or a group -(CH2) n -aryl (n is 0 to 3). (Item 6) R 1 But NR 5 R 6 ;CONR 5 R 6 ; or COOR 7 The compound according to item 1 or 2, selected from: (Item 7) R 1 is an optionally substituted 5- or 6-membered ring containing 0, 1 or 2 nitrogen heteroatoms, the optional substituents being C1-C3 alkyl, C1-C3 alkoxy, CONR 5 R 6 , halogen, cyano, oxo, hydroxyl, amino, or an optionally substituted heterocyclic ring containing 1 or 2 heteroatoms selected from O or N, wherein the optional substituents are C1-C3 alkyl. (Item 8) R 2 is H or cyano. (Item 9) R1 But NR 5 R 6 ;CONR 5 R 6 ; or COOR 7 Selected from R 5 , COCH3, non-aromatic C 1~6 or R 5 R 6 and may be bonded to each other to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof. (Item 10) R 5 , COCH3, non-aromatic C 1~6 or R 5 R 6 and can be linked together to form an optionally substituted monocyclic ring, the optional substituents being selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, oxo, hydroxyl or amino. (Item 11) R 6 But hydrogen, non-aromatic C 1~6 or R 6 R 5 and can be bonded to each other to form an optionally substituted monocyclic ring, the optional substituents being selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, oxo, hydroxyl, or amino, and the C1-C3 alkyl group or the C1-C3 alkoxy group can have an optional substituent selected from halogen, cyano, oxo, hydroxyl, or amino. (Item 12) R 1 But COOR 7 and R 7 is C1-C3 alkyl. (Item 13) R 1 but, [ka] Item 1. The compound according to item 1, selected from: (Item 14) R 1 R 2 Concatenated with: [ka] 6. The compound according to claim 4 or 5, which forms a moiety selected from: (Item 15) R 4 is methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl. (Item 16) The following part: [ka] The ring system formed by [ka] 16. The compound according to any one of items 1 to 15, selected from: (Item 17) The following part: [ka] The ring system formed by [ka] 17. The compound according to any one of items 1 to 16, selected from: (Item 18) Formula (2): [ka] The compound according to item 1, or a salt thereof, wherein X 1 , X 2 , R 1 , R 2 and R4 is as defined in any one of items 1 to 16). (Item 19) Formula (3): [ka] The compound according to item 1, or a salt thereof, wherein X 1 , X 2 , R 1 , R 2 and R 4 is as defined in any one of items 1 to 16). (Item 20) Formula (4): [ka] The compound according to item 1, or a salt thereof, wherein X 1 , X 2 , R 1 , R 2 and R 4 is as defined in any one of items 1 to 16). (Item 21) below: 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane; 6-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane; 1-[6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-2-yl]-4-phenylpiperidine-4-carbonitrile; Ethyl (1R,5S,6r)-3-[6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]oct-2-yl]-3-azabicyclo[3.1.0]hexane-6-carboxylate; 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.4]octane; 1'-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(1H-pyrazol-1-yl)-1,4'-bipiperidine; 3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-3-azabicyclo[3.1.1]heptane; 8-(3-methyl-1,2,4-oxadiazol-5-yl)-3-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane; 8-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2,8-diazaspiro[4.5]decan-3-one; 8-[8-(3-ethyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]-2,8-diazaspiro[4.5]decan-3-one; 8-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; N-(1-methylcyclobutyl)-1-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxamide; 2-(3-methyl-1,2,4-oxadiazol-5-yl)-5-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azabicyclo[2.2.2]octane; 9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-9-azabicyclo[3.3.1]nonane; 8-[9-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]non-3-yl]-2,8-diazaspiro[4.5]decan-3-one; 8-[9-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]non-3-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; N-(1-methylcyclobutyl)-1-[9-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]non-3-yl]piperidine-4-carboxamide; 9-(3-methyl-1,2,4-oxadiazol-5-yl)-7-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-3-oxa-9-azabicyclo[3.3.1]nonane; (1R,5S,6r)-N,N-diethyl-3-[9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]non-7-yl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-[4-(1H-pyrazol-1-yl)piperidin-1-yl]azepane; 8-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]-2,8-diazaspiro[4.5]decan-3-one; 8-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 4-ethyl-8-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 4,4-dimethyl-8-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 1'-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]spiro[indole-3,4'-piperidin]-2(1H)-one; [(2R,4R)-4-fluoro-1-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidin-2-yl]methanol; [(2R)-4,4-difluoro-1-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidin-2-yl]methanol; (5S)-5-ethyl-1-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidin-2-one; 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{4-[2-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]piperidin-1-yl}azepane; N-ethyl-N-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}acetamide; (2S)-N-methyl-2-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxamide; 6-(3-methyl-1,2,4-oxadiazol-5-yl)-3-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-6-azabicyclo[3.2.1]octane; 8-[6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]oct-3-yl]-2,8-diazaspiro[4.5]decan-3-one; 8-[6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]oct-3-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-(8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; (1R,5S,6r)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)-N-(1-methylcyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-(trifluoromethyl)cyclobutyl)piperidine-4-carboxamide; N-(1-ethylcyclobutyl)-1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide; N-(1-isopropylcyclobutyl)-1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide; 1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-methylcyclopentyl)piperidine-4-carboxamide; 1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-((1-methylcyclobutyl)methyl)piperidine-4-carboxamide; (1R,5S,6r)-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-methylcyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; N-(1-methylcyclobutyl)-1-(8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine-4-carboxamide; 1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-N-(1-methylcyclobutyl)piperidine-4-carboxamide; 1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-N-((1-methylcyclobutyl)methyl)piperidine-4-carboxamide; N-(1-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)piperidin-4-yl)-N-((1-methylcyclobutyl)methyl)acetamide; N-(1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-N-((1-methylcyclobutyl)methyl)acetamide; N-(1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)piperidin-4-yl)-N-((1-methylcyclobutyl)methyl)acetamide; N-benzyl-N-(1-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)piperidin-4-yl)acetamide; ((1R,5S,6r)-3-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexan-6-yl)(1-azaspiro[3.3]heptan-1-yl)methanone; (1R,5S,6r)-N-Isopropyl-N-methyl-3-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-Diethyl-3-(9-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; N,N-Diethyl-1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)piperidine-4-carboxamide;8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.6]undecan-3-one; 8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.6]undecan-2-one; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-2,8-diazaspiro[4.6]undecan-3-one; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-1-oxa-3,8-diazaspiro[4.6]undecan-2-one; 8-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.6]undecan-3-one; 8-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.6]undecan-2-one; ((1R,5S,6r)-3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl)(1-azaspiro[3.3]heptan-1-yl)methanone; (1R,5S,6r)-N,N-diethyl-3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-isopropyl-3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-Isopropyl-N-methyl-3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)azepan-4-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)azepan-4-yl)-2,8-diazaspiro[4.6]undecan-3-one; 8-(1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl)-2,8-diazaspiro[4.6]undecan-3-one; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)azepan-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)azepan-4-yl)-1-oxa-3,8-diazaspiro[4.6]undecan-2-one; 8-(1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl)-1-oxa-3,8-diazaspiro[4.6]undecan-2-one; 8-(8-(3-ethyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-(6-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 4-methyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; (1R,5S,6r)-3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octan-2-yl)-N-(1-methylcyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; N-(1-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octan-2-yl)piperidin-4-yl)-N-((1-methylcyclobutyl)methyl)acetamide; (1R,5S,6r)-N,N-dimethyl-3-(9-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-Isopropyl-N-methyl-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 8-(1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-(8-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(8-(3-isopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decan-3-one; 4-benzyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 1-Isopropyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decan-3-one; 4-Isopropyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 1-Cyclopropyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(8-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-(8-(3-isopropyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; N-benzyl-N-(1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)acetamide; (1R,5S,6r)-N,N-diethyl-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; ((1R,5S,6r)-3-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octan-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)(1-azaspiro[3.3]heptan-1-yl)methanone; Azepan-1-yl(1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)methanone; 1-(cyclopropylmethyl)-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decan-3-one; 4-(cyclopropylmethyl)-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 4-Cyclopropyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 1-benzyl-8-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro[3.4]octan-2-yl)-2,8-diazaspiro[4.5]decan-3-one; 4-benzyl-8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3.3]heptan-6-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 1-benzyl-8-(1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl)-2,8-diazaspiro[4.5]decan-3-one; 1-benzyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decan-3-one; (1R,5S,6r)-3-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-(trifluoromethyl)cyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-3-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl)-N-(1-(trifluoromethyl)cyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Item 1. The compound according to item 1, or a salt thereof, selected from (Item 22) 22. A compound according to any one of items 1 to 21 for use in medicine. (Item 23) 22. A pharmaceutical composition comprising a compound according to any one of items 1 to 21, and a pharmaceutically acceptable excipient. (Item 24) Items 1 to 21, which have muscarinic M1 and / or M4 receptor agonist activity The compound according to any one of claims 1 to 4. (Item 25) 22. A compound according to items 1 to 21 for use in the treatment of a cognitive or psychotic disorder, or for treating or reducing the severity of acute, chronic, neuropathic or inflammatory pain. (Item 26) 26. The compound for use according to item 25, wherein the cognitive disorder is Alzheimer's disease. (Item 27) 26. The compound for use according to item 25, wherein the cognitive disorder is dementia with Lewy bodies.

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

[0013] [ka] or a salt thereof (wherein X 1 and X 2 The total number of carbon atoms is 5-9 and the number of oxygen atoms is 0 or 1. A saturated hydrocarbon group containing the following moieties:

[0014] [ka] are linked together to form a monocyclic or bicyclic ring system, and X 3 and X 4 are saturated hydrocarbon groups containing a total of 3 to 6 carbon atoms when taken together. So, the following part:

[0015] [ka] are linked together to form a monocyclic or bicyclic ring system, and R 1 is NR 5 R 6 ;CONR 5 R6 ;COOR 7 O, N and S and their oxidized forms and optionally substituted heteroatoms containing 0, 1, 2 or 3 heteroatoms selected from the group consisting of R 1 is R 2 and connect with O, N and and S and their oxidized forms. forming an optionally substituted monocyclic or bicyclic ring having R 2 is hydrogen; fluorine; cyano; hydroxy; amino; and 1 to 6 fluorine atoms C optionally substituted 1~3 a hydrocarbon group, one of the carbon atoms of the hydrocarbon group is replaced by a heteroatom selected from O, N and S and their oxidized forms. Or R 2 is R 1 and linked to a group selected from O, N and S and their oxidized forms. an optionally substituted monocyclic ring containing 0, 1, 2 or 3 heteroatoms selected from the group consisting of forming a cyclic or bicyclic ring, R 4 H, halo, OH, CN, C 1~6 Alkyl group or C 3~6 Cycloalkyl groups The alkyl and cycloalkyl groups are substituted with one or more fluorine atoms. Any one of the atoms of the alkyl or cycloalkyl group may be an O heteroatom. may have been replaced by a child, R 5 is hydrogen, COCH3, non-aromatic C 1~10 Hydrocarbon group (one or more fluorine may be substituted by atoms, C 1~10 Any one of the atoms in the hydrocarbon group is O, N and S), the group -(CH) n -aryl (n is 0 to 3), or R 5 is R 6 and bonded to each other and 0, 1, 2 or 3 selected from O, N and S and their oxidized forms. and forming an optionally substituted monocyclic or bicyclic ring containing a heteroatom of Can, R 6 is hydrogen, non-aromatic C 1~10 Hydrocarbon group (substituted with one or more fluorine atoms) It may be replaced by C 1~10 Any one of the atoms in the hydrocarbon group can be selected from O, N, and S. (which may be replaced by a selected heteroatom), the group -(CH) n -aryl( n is 0 to 3), or R 6 is R 5 and bond to each other to form O, N and 0, 1, 2 or 3 heteroatoms selected from S and its oxidized forms can form an optionally substituted monocyclic or bicyclic ring containing R 7 is a non-aromatic C optionally substituted with one or more fluorine atoms; 1~6 charcoal (hydrogen radical) to provide.

[0016] In a further embodiment (embodiment 1.2), the present invention provides a compound of formula (1a):

[0017] [ka] or a salt thereof (wherein X 1 and X 2The total number of carbon atoms is 5-9 and the number of oxygen atoms is 0 or 1. A saturated hydrocarbon group containing the following moieties:

[0018] [ka] are linked together to form a monocyclic or bicyclic ring system, and X 3 and X 4 are saturated hydrocarbon groups containing a total of 3 to 5 carbon atoms when taken together. So, the following part:

[0019] [ka] are saturated hydrocarbon groups linked together to form a monocyclic or bicyclic ring system; can be, R 1 is NR 5 R 6 ;CONR 5 R 6 ;COOR 7 O, N and S and their oxidized forms and optionally substituted heteroatoms containing 0, 1, 2 or 3 heteroatoms selected from the group consisting of R 1 is R 2 and connect with O, N and and S and their oxidized forms. forming an optionally substituted monocyclic or bicyclic ring having R 2 is hydrogen; fluorine; cyano; hydroxy; amino; and 1 to 6 fluorine atoms C optionally substituted 1~3 a hydrocarbon group, one of the carbon atoms of the hydrocarbon group is replaced by a heteroatom selected from O, N and S and their oxidized forms. Or R 2 is R 1 and linked to a group selected from O, N and S and their oxidized forms. an optionally substituted monocyclic ring containing 0, 1, 2 or 3 heteroatoms selected from the group consisting of forming a cyclic or bicyclic ring, R 4 is H or C 1~3 is an alkyl group, R 5 is hydrogen, COCH3, non-aromatic C 1~6 Hydrocarbon group (one or more fluorine atoms) or R 5 is R 6 and bonded to each other and 0, 1, 2 or 3 selected from O, N and S and their oxidized forms. It is possible to form an optionally substituted monocyclic or bicyclic ring containing a heteroatom. tree, R 6 is hydrogen, non-aromatic C 1~6 Hydrocarbon group (substituted with one or more fluorine atoms) or R 6 is R 5 and bond to each other to form O, N and and 0, 1, 2 or 3 heteroatoms selected from S and their oxidized forms. can form an optionally substituted monocyclic or bicyclic ring containing R 7 is a non-aromatic C optionally substituted with one or more fluorine atoms; 1~6 charcoal (hydrogen radical) to provide.

[0020] Specific and preferred compounds of formula (1) are described in embodiments 1.3 to 1.42 below. As defined: 1.3 R 1is 0, 1, 2 or 3 selected from O, N and S and their oxidized forms; an optionally substituted 5- or 6-membered ring containing one or three heteroatoms; A compound according to embodiment 1.1 or 1.2.

[0021] 1.4 The optionally substituted ring is phenyl, pyrazolyl, pyrrolidinyl or pyrrolidinyl. The compound according to embodiment 1.3, which is lysinonyl.

[0022] 1.5 The optional substituents of the 5- or 6-membered ring are C1-C3 alkyl, C1-C3 Alkoxy, CONR 5 R 6 , halogen, cyano, oxo, hydroxyl, amino, or may be substituted containing one or two heteroatoms selected from O or N The compound according to any of embodiments 1.3 or 1.4, wherein the heterocyclic ring is selected from:

[0023] 1.6 Optionally substituted pyrazoles in which the optional substituents on the 5- or 6-membered ring are The compound according to any of embodiments 1.3 or 1.4, wherein R is a ring.

[0024] 1.7 Embodiment 1 wherein the optional substituent on the pyrazole ring is C1-C3 alkyl Compound by .6.

[0025] 1.8 R 1 But NR 5 R 6 ;CONR 5 R 6 ;COOR 7 an embodiment selected from Compounds according to 1.1 or 1.2.

[0026] 1.9 R 1 But the following:

[0027] [ka] The compound according to embodiment 1.1 or 1.2, selected from:

[0028] 1.10 R 1 But R 2 and linked to a group selected from O, N and S and their oxidized forms. Optionally substituted monocyclic rings containing 0, 1, 2 or 3 heteroatoms or forming a bicyclic ring, a compound according to embodiment 1.1 or 1.2.

[0029] 1.11 R 1 and R 2 is linked to form pyrrolidinonyl and oxazolidinonyl Compounds according to embodiment 1.10, forming a selected optionally substituted monocyclic ring .

[0030] 1.12 R 1 and R 2 are linked to form an indolinonyl ring, Compound by 0.

[0031] 1.13 Monocyclic or bicyclic rings are:

[0032] [ka] The compound according to embodiment 1.10, selected from:

[0033] 1.14 Optional substituents on the monocyclic or bicyclic ring are C1-C6 alkyl, C1 ~C3 alkoxy, halogen, cyano, oxo, hydroxyl, amino or the group -(CH 2) n -aryl (n is 0 to 3), in embodiments 1.10 to 1.13. Compounds by either.

[0034] 1.15 Optional substituents on the monocyclic or bicyclic ring are methyl or ethyl , a compound according to any of embodiments 1.10 to 1.14.

[0035] 1.16 R 5 However, hydrogen, COCH3, non-aromatic C 1~10 Hydrocarbon group (one or may be substituted with a plurality of fluorine atoms, C 1~10 Any one of the atoms of the hydrocarbon group one of which may be replaced by a heteroatom selected from O, N and S), the group - (CH2) n -aryl (n is 0 to 3), or R 5 But R 6 and 0, 1, 2 or 3 selected from O, N and S and their oxidized forms, Forming an optionally substituted monocyclic or bicyclic ring containing one or three heteroatoms The optional substituents may be C1-C3 alkyl, C1-C3 alkoxy, selected from halogen, cyano, oxo, hydroxyl or amino, C1-C3 alkyl The alkyl group or C1-C3 alkoxy group is selected from the group consisting of halogen, cyano, oxo, hydroxyl, and In embodiment 1.5 or 1, optionally substituted amino Compounds with either .8.

[0036] 1.17 R 6 But hydrogen, non-aromatic C 1~10 Hydrocarbon group (one or more fluorine may be substituted by atoms, C 1~10 Any one of the atoms in the hydrocarbon group is O, N and S), the group -(CH) n -aryl (n is 0 to 3), or R 6 But R 5 and bonded to each other and 0, 1, 2 or 3 selected from O, N and S and their oxidized forms. and forming an optionally substituted monocyclic or bicyclic ring containing a heteroatom of The optional substituents may be C1-C3 alkyl, C1-C3 alkoxy, halogen, silyl, or the like. C1-C3 alkyl group or C The 1-C3 alkoxy group is selected from halogen, cyano, oxo, hydroxyl, and amino. Any of embodiments 1.5 or 1.8 may have optional substituents selected from Compounds by.

[0037] 1.18 R 5 and R 6 However, hydrogen, COCH3 and C 1~6 Independently of the alkyl A compound according to any of embodiments 1.1 to 1.17, selected.

[0038] 1.19 R 5 and R 6 is independently methyl, ethyl or methylcyclobutyl A compound according to embodiment 1.18, wherein:

[0039] 1.20 R 5 is COCH3. Compound.

[0040] 1.21 R 7 The compound according to embodiment 1.1, wherein is C1-C3 alkyl.

[0041] 1.22 R 7 The compound according to embodiment 1.1, wherein is ethyl.

[0042] 1.23 R 2 hydrogen; fluorine; cyano; hydroxy; amino; and 1 to 6 fluorines C optionally substituted by fluorine atoms 1~3 The carbon of the hydrocarbon group is selected from the group one of the atoms is substituted by a heteroatom selected from O, N and S and their oxidized forms May be replaced or R 2 But R 1 and O, N and S and their acids substituted aryl groups containing 0, 1, 2 or 3 heteroatoms selected from the following: According to any of embodiments 1.1 to 1.22, a monocyclic or bicyclic ring may be formed. A compound.

[0043] 1.24 R 2 is hydrogen or cyano. Compounds by.

[0044] 1.25 R 2 A compound according to any of embodiments 1.1 to 1.24, wherein is hydrogen.

[0045] 1.26 R 2 is cyano. .

[0046] 1.27 R 2 But R 1 and form an optionally substituted spirocyclic group; A compound according to any of embodiments 1.1 to 1.23.

[0047] 1.28 R 4 is hydrogen or C 1~6 Alkyl group or C 3~6 Cycloalkyl groups and the alkyl and cycloalkyl groups are substituted with one or more fluorine atoms. Any one of the atoms of the alkyl or cycloalkyl group may be an O heteroatom. The compound according to embodiment 1.1, optionally replaced by a child.

[0048] 1.29 R 4 The compound according to embodiment 1.1, wherein is hydrogen.

[0049] 1.30 R 4 The compound according to embodiment 1.1, wherein is methyl.

[0050] 1.31 R 4 The compound according to embodiment 1.1, wherein is ethyl.

[0051] 1.32 R 4 A compound according to embodiment 1.1, wherein is halo, OH or CN.

[0052] 1.33 R 4 is methyl, trifluoromethyl, ethyl, isopropyl or cyclo The compound according to embodiment 1.1, wherein the aryl group is propyl.

[0053] 1.34 X 1 and X 2 The ring system formed by Octane, 9-azabicyclo[3.3.1]nonane, 6-azabicyclo[3.2.1]octane octane, 7-azaspiro[3.4]octane, 2-azaspiro[3.4]octane, 6- Azaspiro[3.3]heptane, 3-azabicyclo[3.1.1]heptane, 3-oxa -9-azabicyclo[3.3.1]nonane, 2-azabicyclo[2.2.2]octane, In any one of embodiments 1.1 to 1.33, Compounds by.

[0054] 1.35 X 1 and X 2The ring system formed by

[0055] [ka] The compound according to any one of embodiments 1.1 to 1.33, selected from:

[0056] 1.36 X 3 and X 4 The ring systems formed by The compound according to embodiment 1.1, selected from azabicyclo[3.1.0]hexanes.

[0057] 1.37 X 3 and X 4 The ring system formed by

[0058] [ka] The compound according to embodiment 1.1, selected from: 1.38 X 3 and X 4 is piperidine. Compound with 6.

[0059] 1.39 Equation (2):

[0060] [ka] A compound according to any of embodiments 1.1 to 1.38, or a salt thereof, wherein X 1 , X 2 , R 1 , R 2 and R 4 In any one of embodiments 1.1 to 1.38 (as defined in

[0061] 1.40 Equation (3):

[0062] [ka] A compound according to any of embodiments 1.1 to 1.38, or a salt thereof, wherein X 1 , X 2 , R 1 , R 2 and R 4 In any one of embodiments 1.1 to 1.38 (as defined in

[0063] 1.41 Equation (4):

[0064] [ka] A compound according to any of embodiments 1.1 to 1.38, or a salt thereof, wherein X 1 , X 2 , R 1 , R 2 and R 4 In any one of embodiments 1.1 to 1.38 (as defined in

[0065] 1.42 and below: 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyridyl) [2-azaspiro[3.3]heptane; 6-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(1H-pyridyl) [(razol-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane; 1-[6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azaspiro [3.4]Oct-2-yl]-4-phenylpiperidine-4-carbonitrile; Ethyl (1R,5S,6r)-3-[6-(3-methyl-1,2,4-oxadiazole] -5-yl)-6-azaspiro[3.4]oct-2-yl]-3-azabicyclo[3. 1.0]hexane-6-carboxylate; 2-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyridyl) [2-azaspiro[3.4]octane; 1'-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(1H-pyrazoline) (1-yl)-1,4'-bipiperidine; 3-(3-methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyridyl) [(3-azabicyclo[3.1.1]hepta[4-azol-1-yl]piperidin-1-yl)] hmm; 8-(3-methyl-1,2,4-oxadiazol-5-yl)-3-[4-(1H-pyridyl) [(1-azolyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octa hmm; 8-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] 2,8-diazaspiro[4.5]decane-3-ol hmm; 8-[8-(3-ethyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[4.2.1.2]heptyl] 2,8-diazaspiro[4.5]decane-3-ol hmm; 8-[8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] Iso[3.2.1]octan-3-yl]-1-oxa-3,8-diazaspiro[4.5] Decane-2-one; N-(1-methylcyclobutyl)-1-[8-(3-methyl-1,2,4-oxadiazo (5-yl)-8-azabicyclo[3.2.1]oct-3-yl]piperidine-4 -carboxamides; 2-(3-methyl-1,2,4-oxadiazol-5-yl)-5-[4-(1H-pyridyl) [2-azabicyclo[2.2.2]octa(2-azol-1-yl)piperidin-1-yl]- hmm; 9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-[4-(1H-pyridyl) [(razol-1-yl)piperidin-1-yl]-9-azabicyclo[3.3.1]nonane ; 8-[9-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[4.2.1.2]heptyl] Bis[3.3.1]non-3-yl]-2,8-diazaspiro[4.5]decan-3-one ; 8-[9-(3-methyl-1,2,4-oxadiazol-5-yl)-9-azabicyclo[4.2.1.2]heptyl] 1-oxa-3,8-diazaspiro[4.5]deca[3.3.1]non-3-yl]-1-oxa-3,8-diazaspiro[4.5]deca n-2-on; N-(1-methylcyclobutyl)-1-[9-(3-methyl-1,2,4-oxadiazo (5-yl)-9-azabicyclo[3.3.1]non-3-yl]piperidine-4- Carboxamides; 9-(3-methyl-1,2,4-oxadiazol-5-yl)-7-[4-(1H-pyridyl) 3-oxa-9-azabicyclo[3.3 .1] Nonane; (1R,5S,6r)-N,N-diethyl-3-[9-(3-methyl-1,2,4-oxo- sadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1]non-7-yl yl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-[4-(1H-pyridyl) razolo-1-yl)piperidin-1-yl]azepane; 8-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]azepan-4-yl le]-2,8-diazaspiro[4.5]decan-3-one; 8-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl]azepan-4-yl yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 4-Ethyl-8-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepam Pan-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 4,4-dimethyl-8-[1-(3-methyl-1,2,4-oxadiazol-5-yl] )azepan-4-yl]-1-oxa-3,8-diazaspiro[4.5]decan-2-ol hmm; 1'-[1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4- yl]spiro[indole-3,4'-piperidin]-2(1H)-one; [(2R,4R)-4-fluoro-1-{1-[1-(3-methyl-1,2,4-oxa diazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-2- yl]methanol; [(2R)-4,4-difluoro-1-{1-[1-(3-methyl-1,2,4-oxa diazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-2- yl]methanol; (5S)-5-Ethyl-1-{1-[1-(3-methyl-1,2,4-oxadiazole -5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidin-2-one; 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{4-[2-(1 -methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]piperidin-1-yl }Azepan; N-ethyl-N-{1-[1-(3-methyl-1,2,4-oxadiazol-5-yl )azepan-4-yl]piperidin-4-yl}acetamide; (2S)-N-methyl-2-{1-[1-(3-methyl-1,2,4-oxadiazole -5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxamide Mido; 6-(3-methyl-1,2,4-oxadiazol-5-yl)-3-[4-(1H-pyridyl) [(1-azolyl)piperidin-1-yl]-6-azabicyclo[3.2.1]octa hmm; 8-[6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[2.2.1.2]heptyl] 2,8-diazaspiro[4.5]decane-3-ol hmm; 8-[6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[2.2.1.2]heptyl] 1-oxa-3,8-diazaspiro[4.5]decanoate Can-2-On; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[4.2.1.2]heptyl] (2.2.2)octan-5-yl)-2,8-diazaspiro[4.5]decane-3- on; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[4.2.1.2]heptyl] (2.2.2)octan-5-yl)-1-oxa-3,8-diazaspiro[4.5] Decane-2-one; 8-(8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) -8-Azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4. 5]decane-3-one; 8-(8-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) -8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diaza spiro[4.5]decane-2-one; (1R,5S,6r)-3-(2-(3-methyl-1,2,4-oxadiazole-5- yl)-2-azaspiro[3.4]octan-6-yl)-N-(1-methylcyclobutyl (I)-3-azabicyclo[3.1.0]hexane-6-carboxamide; 1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[4.2.1.2]heptyl] (2-[3.2.1]octan-3-yl)-N-(1-(trifluoromethyl)cyclobutyl) r) piperidine-4-carboxamide; N-(1-ethylcyclobutyl)-1-(8-(3-methyl-1,2,4-oxadiazo (5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidine- 4-carboxamide; N-(1-isopropylcyclobutyl)-1-(8-(3-methyl-1,2,4-oxa Diazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin Zin-4-carboxamide; 1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[4.2.1.2]heptyl] (2)[3.2.1]octan-3-yl)-N-(1-methylcyclopentyl)piperidine -4-carboxamide; 1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[4.2.1.2]heptyl] (2-[3.2.1]octan-3-yl)-N-((1-methylcyclobutyl)methyl)pyridin Peridine-4-carboxamide; (1R,5S,6r)-3-(8-(3-methyl-1,2,4-oxadiazole-5- (yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-methylcyclo[3.2.1]octan-3-yl) (tributyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; N-(1-methylcyclobutyl)-1-(8-(3-(trifluoromethyl)-1,2, 4-Oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl r) piperidine-4-carboxamide; 1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[4.2.1.2]heptyl] (2.2.2)octan-5-yl)-N-(1-methylcyclobutyl)piperidine- 4-carboxamide; 1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[4.2.1.2]heptyl] (2.2.2)octan-5-yl)-N-((1-methylcyclobutyl)methyl)pyridin Peridine-4-carboxamide; N-(1-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxo (9-azabicyclo[3.3.1]nonane-7-yl)piperidin-4-yl)-N- ((1-methylcyclobutyl)methyl)acetamide; N-(1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-aza Bicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-N-((1-methyl- (Cyclobutyl)methyl)acetamide; N-(1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-aza Bicyclo[2.2.2]octan-5-yl)piperidin-4-yl)-N-((1-methyl- (Cyclobutyl)methyl)acetamide; N-benzyl-N-(1-(9-(3-methyl-1,2,4-oxadiazole-5-yl) (yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)piperidine-4 -yl)acetamide; ((1R,5S,6r)-3-(9-(3-methyl-1,2,4-oxadiazole-5 -yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-aza Bicyclo[3.1.0]hexan-6-yl)(1-azaspiro[3.3]heptane-1 -Il)methanone; (1R,5S,6r)-N-isopropyl-N-methyl-3-(9-(3-methyl-1, 2,4-Oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3.1] Nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(9-(3-(trifluoromethyl)- 1,2,4-Oxadiazol-5-yl)-3-oxa-9-azabicyclo[3.3. 1]nonan-7-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamine Do; (1R,5S,6r)-N-ethyl-N-methyl-3-(8-(3-methyl-1,2,4 -oxadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl )-3-Azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(8-(3-methyl-1,2,4-oxo) Sadiazol-5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-3 -Azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(2-(3-methyl-1,2,4-oxo) Sadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)-3-aza Bicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(2-(3-methyl-1,2,4 -oxadiazol-5-yl)-2-azaspiro[3.4]octan-6-yl)-3 -Azabicyclo[3.1.0]hexane-6-carboxamide; N,N-diethyl-1-(2-(3-methyl-1,2,4-oxadiazol-5-yl) )-2-Azaspiro[3.4]octan-6-yl)piperidine-4-carboxamide; 8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] (2,8-diazaspiro[4.6]undecane-(2,3-diyl)-[3.2.1]octan-3-yl)-2,8-diazaspiro[4.6]undecane- 3-on; 8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] (3.2.1)octan-3-yl)-1-oxa-3,8-diazaspiro[4.6] undecane-2-one; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[4.2.1.2]heptyl] (2.2.2)octan-5-yl)-2,8-diazaspiro[4.6]undecane- 3-on; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[4.2.1.2]heptyl] (2.2.2)octan-5-yl)-1-oxa-3,8-diazaspiro[4.6] undecane-2-one; 8-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[4.2.1.2]heptyl] (2,8-diazaspiro[4.6]undecane-(2,3-diyl)-[3.2.1]octan-3-yl)-2,8-diazaspiro[4.6]undecane- 3-on; 8-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-azabicyclo[4.2.1.2]heptyl] (3.2.1)octan-3-yl)-1-oxa-3,8-diazaspiro[4.6] undecane-2-one; ((1R,5S,6r)-3-(6-(3-methyl-1,2,4-oxadiazole-5 -yl)-6-azabicyclo[3.2.1]octan-3-yl)-3-azabicyclo[ 3.1.0]hexan-6-yl)(1-azaspiro[3.3]heptan-1-yl)methyl Tanon; (1R,5S,6r)-N,N-diethyl-3-(6-(3-methyl-1,2,4-oxo) Sadiazol-5-yl)-6-azabicyclo[3.2.1]octan-3-yl)-3 -Azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-isopropyl-3-(6-(3-methyl-1, 2,4-Oxadiazol-5-yl)-6-azabicyclo[3.2.1]octane-3 -yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-isopropyl-N-methyl-3-(6-(3-methyl-1, 2,4-Oxadiazol-5-yl)-6-azabicyclo[3.2.1]octane-3 -yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(9-(3-methyl-1,2,4 -oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-yl) -3-Azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N,N-diethyl-3-(9-(3-methyl-1,2,4-oxo) Sadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) Azepan-4-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) Azepan-4-yl)-2,8-diazaspiro[4.6]undecan-3-one; 8-(1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl r)-2,8-diazaspiro[4.6]undecan-3-one; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) Azepan-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one ; 8-(8-(3-ethyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] (3.2.1)octan-3-yl)-1-oxa-3,8-diazaspiro[4.5] Decane-2-one; 8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[4.2.1.2]heptyl] (2.2.2)octan-5-yl)-1-oxa-3,8-diazaspiro[4.5] Decane-2-one; 8-(6-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) -6-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diaza spiro[4.5]decane-2-one; 4-methyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8 -Azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspirillum b[4.5]decane-2-one; (1R,5S,6r)-3-(6-(3-methyl-1,2,4-oxadiazole-5- yl)-6-azaspiro[3.4]octan-2-yl)-N-(1-methylcyclobutyl (I)-3-azabicyclo[3.1.0]hexane-6-carboxamide; N-(1-(6-(3-methyl-1,2,4-oxadiazol-5-yl)-6-aza spiro[3.4]octan-2-yl)piperidin-4-yl)-N-((1-methylsilyl) (Cibromobutyl)methyl)acetamide; N-(1-(9-(3-methyl-1,2,4-oxadiazol-5-yl)-3-oxo (9-azabicyclo[3.3.1]nonane-7-yl)piperidin-4-yl)-N- ((1-methylcyclobutyl)methyl)acetamide; N-(1-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-aza Bicyclo[3.2.1]octan-3-yl)piperidin-4-yl)-N-((1-methyl- (Cyclobutyl)methyl)acetamide; (1R,5S,6r)-N-isopropyl-N-methyl-3-(8-(3-methyl-1, 2,4-Oxadiazol-5-yl)-8-azabicyclo[3.2.1]octane-3 -yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(2-(3-methyl-1,2,4 -oxadiazol-5-yl)-2-azabicyclo[2.2.2]octan-5-yl )-3-Azabicyclo[3.1.0]hexane-6-carboxamide; (1R,5S,6r)-N-ethyl-N-methyl-3-(9-(3-methyl-1,2,4 -oxadiazol-5-yl)-9-azabicyclo[3.3.1]nonan-3-yl) -3-Azabicyclo[3.1.0]hexane-6-carboxamide; 8-(1-(3-methyl-1,2,4-oxadiazol-5-yl)azepan-4-yl yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) Azepan-4-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(1-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl) Azepan-4-yl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one ; 8-(8-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-a Zabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]deca n-3-on; 8-(8-(3-isopropyl-1,2,4-oxadiazol-5-yl)-8-aza Bicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5]decane -3-on; 8-(8-(3-ethyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] (3.2.1)octan-3-yl)-1-oxa-3,8-diazaspiro[4.5] Decane-2-one; 4-benzyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)- 8-Azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diaza Pyro[4.5]decane-2-one; 1-Isopropyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl) )-8-Azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4 .5]decane-3-one; 4-Isopropyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl) )-8-Azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazo Zaspiro[4.5]decane-2-one; 1-Cyclopropyl-8-(8-(3-methyl-1,2,4-oxadiazole-5-yl) (yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[ 4.5]decane-3-one; 8-(8-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-a Zabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[ 4.5]decane-2-one; 8-(8-(3-isopropyl-1,2,4-oxadiazol-5-yl)-8-aza Bicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-diazaspiro[4 .5]decane-2-one; N-benzyl-N-(1-(8-(3-methyl-1,2,4-oxadiazole-5-yl) (yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl Cetoamide; (1R,5S,6r)-N,N-diethyl-3-(2-(3-methyl-1,2,4-oxo) (sadiazol-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-aza Bicyclo[3.1.0]hexane-6-carboxamide; ((1R,5S,6r)-3-(6-(3-methyl-1,2,4-oxadiazole-5 -yl)-6-azaspiro[3.4]octan-2-yl)-3-azabicyclo[3.1 1-Azaspiro[3.3]heptan-1-yl)methanone ; Azepan-1-yl(1-(8-(3-methyl-1,2,4-oxadiazol-5-yl) (yl)-8-azabicyclo[3.2.1]octan-3-yl)piperidin-4-yl)methyl Tanon; 1-(cyclopropylmethyl)-8-(8-(3-methyl-1,2,4-oxadiazolium) (5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-2,8-diazomethane Zaspiro[4.5]decane-3-one; 4-(cyclopropylmethyl)-8-(8-(3-methyl-1,2,4-oxadiazolium) (5-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa- 3,8-diazaspiro[4.5]decan-2-one; 4-Cyclopropyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl) (yl)-8-azabicyclo[3.2.1]octan-3-yl)-1-oxa-3,8-di Azaspiro[4.5]decane-2-one; 1-benzyl-8-(6-(3-methyl-1,2,4-oxadiazol-5-yl)- 6-Azaspiro[3.4]octan-2-yl)-2,8-diazaspiro[4.5]deca n-3-on; 4-benzyl-8-(2-(3-methyl-1,2,4-oxadiazol-5-yl)- 2-Azaspiro[3.3]heptan-6-yl)-1-oxa-3,8-diazaspiro[ 4.5]decane-2-one; 1-benzyl-8-(1-(3-methyl-1,2,4-oxadiazol-5-yl)a zepan-4-yl)-2,8-diazaspiro[4.5]decan-3-one; 8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] (2,8-diazaspiro[4.6]undecane-(2,3-diyl)-[3.2.1]octan-3-yl)-2,8-diazaspiro[4.6]undecane- 3-on; 1-benzyl-8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)- 8-Azabicyclo[3.2.1]octan-3-yl)-2,8-diazaspiro[4.5 ]Decan-3-one; 8-(8-(3-methyl-1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1.2]heptyl] (3.2.1)octan-3-yl)-1-oxa-3,8-diazaspiro[4.6] undecane-2-one; (1R,5S,6r)-3-(8-(3-methyl-1,2,4-oxadiazole-5- yl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(1-(trifluoromethyl) (O-methyl)cyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carbox Samid; (1R,5S,6r)-3-(2-(3-methyl-1,2,4-oxadiazole-5- yl)-2-azabicyclo[2.2.2]octan-5-yl)-N-(1-(trifluoromethyl) (O-methyl)cyclobutyl)-3-azabicyclo[3.1.0]hexane-6-carbox Samid A compound according to any of embodiments 1.1 to 1.41, selected from:

[0066] 1.43 Embodiment 1.1 as defined in any one of Examples 1-1 to 18-2 Compounds by.

[0067] 1.44 Having a molecular weight of less than 550, for example less than 500, or less than 450, A compound according to any one of Forms 1.1 to 1.43.

[0068] 1.45 A compound according to any one of embodiments 1.1 to 1.44 in the form of a salt.

[0069] 1.46 The compound according to embodiment 1.45, wherein the salt is an acid addition salt.

[0070] 1.47 Embodiment 1.45 or embodiment 1.4, wherein the salt is a pharmaceutically acceptable salt. Compound with 6. definition In this application, the following definitions apply unless otherwise indicated.

[0071] Use of a compound of formula (1), formula (1a), formula (2), formula (3) or formula (4), The term "treatment" refers to a subject suffering from the disease or disorder in question, The compounds are administered to subjects at risk or potentially at risk of developing these diseases. It is used to describe any form of intervention in which a drug is administered. "Treatment" includes prophylactic (or preventative) measures in which measurable or detectable symptoms of a disease or disorder are indicated. It encompasses both preventative and treatment.

[0072] The term "therapeutically effective amount" as used herein (e.g., for the treatment of a disease or condition) refers to a For example, when a condition is In the case of pain, a therapeutically effective amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete elimination of pain or a reduction in the severity of pain. This can be a reduction in the

[0073] The terms "alkyl," "heterocyclic," and "ether" are used interchangeably unless otherwise indicated. Used in its conventional sense (e.g., as defined in the IUPAC Gold Book) will be done.

[0074] The term "monocyclic," as used herein, refers to atoms arranged to form a single ring structure. The term "bicyclic" as used herein refers to a ring structure formed by two linked rings. Bicyclic compounds can be carbocyclic or heterocyclic. Furthermore, the two rings can both be aliphatic, or both can be It can be aromatic or a combination of aliphatic and aromatic.

[0075] The above X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 4 , R 5 , R 6 or R 7 In the definition of where specified, non-aromatic hydrocarbon groups or alkyl or cycloalkyl one or two but not all carbon atoms of the group are selected from O and N When the group is a single carbon (C1) group, this carbon may be replaced by a hetero atom. If a carbon atom is replaced by a heteroatom, the The lower valence compared to carbon means that fewer atoms are bonded to the replaced carbon atom. is attached to a heteroatom. The exchange of a carbon atom (with a valence of 4) in an H2 group by an oxygen (with a valence of 2) produces This means that the resulting molecule contains two fewer hydrogen atoms, and the carbon atom in the CH2 group (atom The exchange of a hydrogen atom (which has a valence of 4) with a nitrogen atom (which has a valence of 3) results in one less water molecule. It means that it contains an atomic element.

[0076] Examples of the replacement of a heteroatom for a carbon atom include the carbon atom in a -CH2-CH2-CH2- chain. Ethers -CH2-O-CH2- or thioethers by replacing atoms with oxygen or sulfur Formation of ter-CH2-S-CH2-, exchange of the carbon atom in the group CH2-C≡CH with nitrogen The reaction produces the nitrile (cyano) group CH2-C≡N, while the group -CH2-CH2-CH2- by C=O to form the ketone -CH2-C(O)-CH2-, Sulfoxylation by replacement of carbon atoms in CH2-CH2-CH2- with S=O or SO2 Synthesis of hydroxyl-CH2-S(O)-CH2- or sulfone-CH2-S(O)2-CH2- Amides are formed by replacing the carbon atoms in the -CH2-CH2-CH2- chain with C(O)NH Formation of -CH2-CH2-C(O)-NH-, carbon atom in the -CH2-CH2-CH2- chain Exchange of the molecule with nitrogen to form the amine -CH2-NH-CH2-, and -CH2-C Esters (or carboxylic acids) formed by replacing the carbon atoms in the H2-CH2- chain with C(O)O In each of these exchanges, the reaction product is -CH2-CH2-C(O)-O-. Therefore, at least one carbon atom of the hydrocarbon group must remain. salt Many compounds of formula (1), formula (1a), formula (2), formula (3) or formula (4) may be used in the form of salts, e.g. For example, acid addition salts, or in some cases, carboxylates, sulfonates and phosphates. The compounds of the present invention may exist in the form of salts of organic and inorganic bases. All such salts are within the scope of the present invention. Within the scope of the present invention, compounds of formula (1), formula (1a), formula (2), formula (3) or formula (4) are described. and includes salt forms of the compounds defined in embodiments 1.40 to 1.47.

[0077] The salts are usually acid addition salts.

[0078] The salts of the present invention are listed in Pharmaceutical Salts: Properties , Selection, and Use, P. Heinrich Stahl (ed.) , Camille G. Wermuth (ed.), ISBN:3-90639-026-8 , Hardcover, p. 388, August 2002. They can be synthesized from a parent compound that contains a basic or acidic moiety by suitable chemical methods. Generally, such salts can be prepared from the free acid in water or in an organic solvent, or in a mixture of the two. or by reacting the free base form of these compounds with an appropriate base or acid. Generally, ether, ethyl acetate, ethanol, isopropanol Alternatively, a non-aqueous medium such as acetonitrile is used.

[0079] Acid addition salts (as defined in embodiment 1.46) can be prepared from a wide range of acids, i.e. inorganic and Examples of acid addition salts falling within the scope of embodiment 1.46 include: are acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetyl Amidobenzoic acid, butanoic acid, (+)-camphoric acid, camphor-sulfonic acid, (+)-(1S )-Camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, Enoic acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfone Acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, Glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), gluta mic acids (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, Hydrohalic acids (e.g., hydrogen bromide, hydrogen chloride, hydrogen iodide), isethionic acid, lactic acid ( For example, (+)-L-lactic acid, (±)-DL-lactic acid, lactobioic acid, maleic acid, malic acid Acid, (-)-L-Malic acid, Malonic acid, (±)-DL-Mandelic acid, Methanesulfonic acid, Naphthalene-2-sulfonic acid, Naphthalene-1,5-disulfonic acid, 1-hydroxy-2 -Naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, Monocarboxylic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-amino Mino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)- L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid, etc. and an acid selected from the group consisting of acylated amino acids and cation exchange resins. The mono- or di-salts include those which are

[0080] The compound of formula (1), formula (1a), formula (2), formula (3) or formula (4) is an amine functional group When these compounds contain, for example, alkylating agents by methods well known to those skilled in the art, By the reaction of the above, a quaternary ammonium salt can be formed. The ammonium compound is within the scope of formula (1), formula (1a), formula (2), formula (3) or formula (4). do.

[0081] The compounds of the present invention may exist as mono- or di-salts depending on the pKa of the acid from which the salt is formed. It is possible.

[0082] The salt forms of the compounds of the present invention are generally pharmaceutically acceptable salts, and Examples of salts are given in Berge et al., 1977, "Pharmaceutically Accelerated "Table Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, pharmaceutically unacceptable salts may also be prepared as intermediates, and The intermediates may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be useful for preparation or isolation, are part of the present invention. is also formed. stereoisomer Stereoisomers have the same molecular formula and arrangement of bonded atoms, but differ in the spacing of their atoms. Stereoisomers are, for example, geometric isomers or isomers that differ only in their three-dimensional orientation. or optical isomers. geometric isomer In the case of geometric isomers, the isomerism is cis and trans (Z and and E) different orientations of atoms or groups about a double bond, such as isomerism, or amide bond. cis and trans isomers of methyl methyl ketones, or carbon-nitrogen double bonds (e.g., in oximes) Syn and anti isomerism about a bond (where the bond is held in a circular position) or rotational isomerism about a bond with restricted rotation or cis and trans isomerism about rings such as cycloalkane rings .

[0083] Therefore, in another embodiment (embodiment 1.48), the present invention provides the method of embodiment 1.1-1. .47 provides a geometric isomer of a compound according to any one of the above. optical isomer Unless the context requires otherwise, compounds of formula (I) contain one or more chiral centers. If a compound can exist in more than one optically isomeric form, reference to the compound includes reference to each individual optical isomer. or as a mixture (e.g., a racemic mixture), or as two or more optical isomers. and all its optical isomers (e.g., enantiomers, epimers, and diastereoisomers) ) is included.

[0084] Thus, in another embodiment (embodiment 1.49), 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 1.48,

[0085] Optical isomers are characterized by their optical activity (i.e., + and - isomers, or d and l isomers). ), or they may be characterized and identified by the Cahn, Ingol The absolute stereochemistry is determined using the "R and S" nomenclature developed by d and Prelog. It may be characterized in terms of chemistry, and is based on Advanced Chemistry by Jerry March. Organic Chemistry, 4th Edition, John Wiley & Sons, Ne w York, 1992, pp. 109-114, also by Cahn, Ingold & Co. relog, Angew.Chem.Int.Ed.Engl., 1966, vol. 5, 3 See pages 85-415. Optical isomers can be separated by chiral chromatography (using chiral supports). They can be separated by several techniques, including chromatography on a support. Such techniques are well known to those skilled in the art. Optical isomers can be separated by chiral chromatography as an alternative. (+)-Tartaric acid, (-)-pyroglutamic acid, (-)-di-toluoyl-L-tartar Acids, (+)-mandelic acid, (-)-malic acid and (-)-camphorsulfonic acid Formation of diastereoisomeric salts with chiral acids and preferential crystallization of diastereoisomers can be separated and then the salts dissociated to give the individual enantiomers, which are the free bases. .

[0086] When the compounds of the present invention exist as two or more optical isomers, One of the enantiomers may exhibit advantages over the other, e.g., in terms of biological activity. Therefore, in certain circumstances, only one of the pair of enantiomers or Only one of the diastereoisomers may be desirable for use as a therapeutic agent.

[0087] Thus, in another embodiment (embodiment 1.50), the present invention provides one or more A compound according to embodiment 1.49 having a ral center, the compound of embodiment 1.44 At least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 8 5%, 90%, or 95% of the mixture is a single optical isomer (e.g., an enantiomer or diastereomer). The present invention provides compositions containing compounds that exist as isomers (isomeric isomers).

[0088] In one general embodiment (embodiment 1.51), the compound of embodiment 1.49 (for use) 99% or more (e.g., substantially all) of the total amount of the compound (compound for the purpose of the present invention) is present as a single optical isomer exist.

[0089] For example, in one embodiment (embodiment 1.52), the compound exists as a single enantiomer. There is.

[0090] In another embodiment (embodiment 1.53), the compound is present as a single diastereoisomer: exist.

[0091] The present invention also provides mixtures of optical isomers, which can be racemic or non-racemic. Accordingly, the present invention provides: 1.54 The compound according to embodiment 1.49, in the form of a racemic mixture of optical isomers.

[0092] 1.55 The compound according to embodiment 1.49 in the form of a non-racemic mixture of optical isomers. . Isotopes The compound of the invention as defined in any one of embodiments 1.1 to 1.55 is It may contain one or more isotopic substitutions, and when a particular element is mentioned, all of that element is included. For example, when referring to hydrogen, the following is included within the scope: 1 H, 2 H( D) and 3 Similarly, when referring to carbon and oxygen, the ranges are Inside, 12 C. 13 C and 14 C, and 16 O and 18 Contains O.

[0093] Similarly, when referring to a particular functional group, it also includes within its scope, unless the context indicates otherwise. For example, when referring to an alkyl group such as an ethyl group, one or more isotopic variations of the group are included. Multiple hydrogen atoms, for example, an ethyl group in which all five hydrogen atoms are in the deuterium isotope form (perdeuteroethyl group), in the form of deuterium or tritium isotopes It also includes the body.

[0094] The isotope may be radioactive or non-radioactive. In this embodiment (embodiment 1.56), the compound of any one of embodiments 1.1 to 1.53 is , containing non-radioactive isotopes. Such compounds are preferred for therapeutic use. However, In another embodiment (embodiment 1.57), the compound of any one of embodiments 1.1 to 1.55 is The compound may contain one or more radioisotopes. Compounds having such properties may be useful in diagnostic situations. solvate Formula (1), Formula (1a) as defined in any one of embodiments 1.1 to 1.57 The compounds of formula (2), formula (3) or formula (4) may form solvates. Preferred solvates are those in which the solid state of the compounds of the invention is dissolved in non-toxic pharmaceutically acceptable solvent molecules. solvates formed by incorporation into a crystalline structure (e.g., a crystal structure) (hereinafter (These solvents are called solvating solvents.) Examples of such solvents include water, alcohols (ethanol), These include alcohols such as ethanol, isopropanol, and butanol) and dimethyl sulfoxide. Solvates are compounds of the invention dissolved in a solvent or mixture of solvents containing a solvating solvent. The solvates may be prepared by recrystallization from any of the given examples. Whether or not the crystals of the compound are formed can be determined by thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and so on. and X-ray crystallography. The solvates can be stoichiometric or non-stoichiometric. Particularly preferred solvates are hydrates, examples of which include includes the hemihydrate, monohydrate and dihydrate.

[0095] Thus, in further embodiments 1.58 and 1.59, the present invention provides: R: 1.58 The compound according to any one of embodiments 1.1 to 1.57 in solvate form. thing.

[0096] 1.59 The compound according to embodiment 1.58, wherein the solvate is a hydrate.

[0097] A more detailed discussion of solvates and methods used to prepare and characterize solvates For more information, please contact SSCI, Inc. of West Lafayette, IN, USA. Published by Bryn et al. in Solid-State Chemistry of Dr. See ugs, 2nd edition, 1999, ISBN 0-967-06710-3.

[0098] Alternatively, rather than existing as a hydrate, the compounds of the present invention may be anhydrous. Thus, in another embodiment (embodiment 1.60), the present invention provides a method for producing hydroxybenzoates in an anhydrous form (e.g., anhydrous hydroxybenzoates). The compound as defined in any one of embodiments 1.1 to 1.58 is in a crystalline form. Provide. Crystalline and amorphous forms The compound of any one of embodiments 1.1 to 1.60 may be crystalline or amorphous (e.g., Whether a compound exists in a crystalline state or not can be determined by This can be readily determined by standard techniques such as X-ray powder diffraction (XRPD). and its crystal structure have been determined by single crystal X-ray crystallography, X-ray powder diffraction (XRPD), and differential scanning calorimetry. (DSC), and infrared spectroscopy, including Fourier transform infrared spectroscopy (FTIR). Several techniques can be used to characterize the crystal behavior under various humidity conditions. can be analyzed by gravimetric vapor sorption studies and also by XRPD. The determination of the crystal structure is carried out by the methods described herein and in the Fundamentals of Crystallography, C.Giacovazzo, HLMona co, D. Viterbo, F. Scordari, G. Gilli, G. Zanott. i and M.Catti(International Union of Cry) stallography / Oxford University Press, 199 2 years ISBN 0-19-855578-4(p / b), 0-19-85579-2( X-ray diffraction can be performed according to conventional methods, such as those described in h / b)). This technique involves the analysis and interpretation of X-ray diffraction of a single crystal. In amorphous solids, the three-dimensional structure normally present in crystalline forms is absent, and In the method, the positions of the molecules relative to each other are substantially random, e.g., Hancoc See K et al. J. Pharm. Sci. (1997), Vol. 86, p. 1.

[0099] Thus, in a further embodiment, the present invention provides: 1.61 The compound according to any one of embodiments 1.1 to 1.60, in a crystalline form.

[0100] 1.62 and below: (a) 50% to 100% crystalline, more particularly at least 50% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% Crystalline, or at least 90% crystalline, or at least 95% crystalline, or At least 98% crystalline, or at least 99% crystalline, or at least 99.5 % crystalline, or at least 99.9% crystalline, for example 100% crystalline, A compound according to any one of embodiments 1.1 to 1.61.

[0101] 1.63 according to any one of embodiments 1.1 to 1.62 in amorphous form compound. Prodrug Formula (1), Formula (1a), Formula (1b), Formula (1c), Formula (1d), Formula (1e), Formula (1f ... The compounds of formula (2), formula (3) or formula (4) may exist in the form of a prodrug. "Prodrug" refers to a compound that, for example, in vivo, produces a compound according to any one of the embodiments 1.1 to 1.60. a biological compound of formula (1), formula (1a), formula (2), formula (3) or formula (4) as defined in It means any compound that can be converted into an active compound.

[0102] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable During metabolism, the ester group (-C(=O)OR) is converted to Such esters may optionally be cleaved to yield the active drug. Any reactive groups in the It may be formed by esterifying any hydroxyl groups present in the compound.

[0103] Similarly, some prodrugs are activated by enzymes to produce the active compound or further During the chemical reaction, active compounds (e.g., ADEPT, GDEPT, LIDEPT, etc.) For example, prodrugs can be used as sugar derivatives or other glycosyltransferases. It may be a hydroxyl conjugate or an amino acid ester derivative.

[0104] Therefore, in another embodiment (embodiment 1.64), the present invention provides the method of embodiment 1.1-1. 60. A prodrug of a compound as defined in any one of claims 1 to 60, contains a functional group that is convertible under physiological conditions to form a hydroxyl or amino group. Prodrugs are provided. Complexes and inclusion compounds Similarly, complexes of the compounds of embodiments 1.1 to 1.64 (e.g., cyclodextrins, etc.) or a complex with a metal) is 1.64, which is enclosed by equation (1), equation (1a), equation (2), equation (3) or equation (4) Included.

[0105] Thus, in another embodiment (embodiment 1.65), the present invention provides a complex or clathrate compound. A compound according to any one of embodiments 1.1 to 1.64 is provided in the form of a product. Biological Activities and Therapeutic Uses The compounds of the present invention have activity as muscarinic M1 and / or M4 receptor agonists. The muscarinic activity of the present compounds is measured using the phospho-ERK inhibitors described in Example A below. This can be determined using the 1 / 2 assay.

[0106] A major advantage of the compounds of the present invention is that they inhibit the M2 and M3 receptor subtypes In addition, the compounds of the present invention have high selectivity for M1 and / or M4 receptors. The compound is neither an agonist nor an antagonist of the M2 and M3 receptor subtypes. For example, compounds of the present invention typically exhibit an M1 a pEC of at least 6 (preferably at least 6.5) for the receptor 50 Value, and and E higher than 80 (preferably higher than 95) max While these compounds have when tested against M2 and M3 subtypes in the functional assay of Example A , pEC less than 550 value, and less than 20% E max It can have a value.

[0107] Some compounds of the invention have activity at both M1 and M4 receptors.

[0108] Thus, in embodiments 2.1 to 2.17, the present invention provides: 2.1 According to any one of embodiments 1.1 to 1.65 for use in medicine compound.

[0109] 2.2 For use as muscarinic M1 and / or M4 receptor agonists A compound according to any one of embodiments 1.1 to 1.65.

[0110] 2.3 Assay of Example A herein, or a substantially similar assay In the case of (i), pEC50 greater than 6.9 for M1 receptors 50 and at least 80 E max In embodiments 1.1 to 1.65, the compound is a muscarinic M1 receptor agonist having A compound of any one of the following:

[0111] 2.4 pEC greater than 7.0 50 It is a muscarinic M1 receptor agonist with , a compound according to embodiment 2.3.

[0112] 2.5 E of at least 90 for M1 receptors max Embodiments 2.3 to 2.4 or a compound according to embodiment 2.4.

[0113] 2.6 Assay of Example A herein, or a substantially similar assay In the study, the pEC values ​​for the M4 receptor ranged from 6.0 to 8.7. 50 and at least 60E max is a muscarinic M1 and / or M4 receptor agonist having the formula A compound according to any one of embodiments 1.1 to 1.65.

[0114] 2.7 Assay of Example A herein, or a substantially similar assay In the study, the pEC400 activity against the M4 receptor ranged from 6.0 to 8.1. 50 and at least 90E max is a muscarinic M1 and / or M4 receptor agonist having the formula A compound according to any one of embodiments 1.1 to 1.65.

[0115] 2.8 pEC in the range of 7.5 to 8.7 50 Muscarinic M4 receptor agonists having The compound according to embodiment 2.6, wherein

[0116] 2.9 pEC in the range of 6.5-7.5 50 Muscarinic M4 receptor agonists having The compound according to embodiment 2.7, wherein

[0117] 2.10 E of at least 75 for M4 receptors max Embodiment 2.6 Or a compound according to embodiment 2.8.

[0118] 2.11 E of at least 95 for M4 receptors max Embodiment 2.7 Or a compound according to embodiment 2.9.

[0119] 2.12 Muscarinic M1 and M4 receptors compared to M2 and M3 receptors and optionally a compound according to any one of embodiments 2.3 to 2.11.

[0120] 2.13 Selective for muscarinic M1 receptors compared with M2 and M3 receptors , a compound according to embodiment 2.12.

[0121] 2.14 Selectivity for M1 receptors compared to muscarinic M2, M3, and M4 receptors Alternatively, a compound according to any one of embodiments 2.3 to 2.5.

[0122] 2.15 pEC50 of less than 5 for muscarinic M2 and M3 receptor subtypes 50 , and E below 50 max According to any one of embodiments 2.3 to 2.14, compound.

[0123] 2.16 pEC50 of less than 4.5 for muscarinic M2 and M3 receptor subtypes 50 , and / or E less than 30 max The compound according to embodiment 2.15, having the formula:

[0124] 2.17 Use in the treatment of diseases or conditions mediated by muscarinic M1 receptors Any one of embodiments 1.1 to 1.65 and embodiments 2.3 to 2.16 for use in Compounds by.

[0125] Due to their muscarinic M1 and / or M4 receptor agonist activity, the compounds of the present invention , Alzheimer's disease, schizophrenia and other psychotic disorders, cognitive impairment, and muscari It can also be used to treat other diseases mediated by M1 and / or M4 receptors. It may also be used to treat various types of pain.

[0126] Thus, in embodiments 2.18 to 2.39, the present invention provides: 2.18 Embodiment 1.1 for use in the treatment of cognitive or psychotic disorders Compounds with any one of ~1.65.

[0127] 2.19 Cognitive or psychotic disorder , cognitive impairment, mild cognitive impairment (Alzheimer's disease) Mild cognitive impairment due to Alzheimer's disease and / or prodromal Alzheimer's disease nt), frontotemporal dementia, vascular dementia, dementia with Lewy bodies, presenile dementia , senile dementia, Friederich's ataxia, Down's syndrome, Huntington's chorea, movement hyperactivity, mania, Tourette's syndrome, Alzheimer's disease (fda.gov / download s / Drugs / GuidanceComplianceRegulatoryInfo Available at rmation / Guidances / UCM596728.pdf , U.S. Food and Drug Administration's "Early Alzheimer's disease: Development As defined by the "Developing Drugs for Treatment" (including pre-Alzheimer's disease, and early stages 1, 2, and 3 of Alzheimer's disease) , progressive supranuclear palsy, attention, adaptive, learning disorders, memory (i.e., memory disorder, amnesia, amnesic disorder, transient global amnesia Syndrome and age-related memory impairment and cognitive function, including language function Impairment; as a result of stroke, Huntington's disease, or Pick's disease Cognitive impairment, AIDS-related dementia, or multi-infarct dementia Any other dementia conditions, alcoholic dementia, hypothyroidism-related dementia, as well as minor Dementia associated with brain atrophy and other degenerative disorders such as amyotrophic lateral sclerosis Delirium or depression (pseudocognitive state), trauma, head injury, age-related cognitive decline, brain Stroke, neurodegeneration, drug-induced states, neurotoxic substances, and age-related cognitive impairment mant, autism-related cognitive impairment (impairment), Down syndrome, and psychiatric disorders Associated cognitive deficits and cognitive disorders following electroconvulsive therapy Other acute or subacute conditions that may cause cognitive decline, such as: nicotine, cannabis Cognitive impairment due to drug abuse or drug withdrawal, including amphetamines and cocaine der), attention deficit hyperactivity disorder (ADHD), and movement disorders such as Parkinson's disease (d isorder), neuroleptic-induced parkinsonism, and tardive dyskinesia, Schizophrenia, schizophreniform disorders, psychotic depression, mania, acute mania, delusions, hallucinations and paranoia Disorder, personality disorder, obsessive-compulsive disorder (d schizotypal disorder, schizotypal disorder, delusional disorder r), psychosis due to malignant tumor, metabolic disorder, endocrine disorder or narcosis psychosis due to drug abuse or drug withdrawal, bipolar disorder and and schizoaffective disorder, The compound for use according to embodiment 2.18, which is a compound for use in treating or associated with these conditions.

[0128] 2.20 Embodiments 1.1 to 1.65 for use in the treatment of Alzheimer's disease A compound of any one of the following:

[0129] 2.21 Any of embodiments 1.1 to 1.65 for use in the treatment of schizophrenia A compound consisting of one of these.

[0130] 2.22 Subject (e.g., a mammalian patient, such as a human, e.g., a person in need of treatment for a cognitive disorder) A method of treating cognitive impairment in a human subject, comprising administering to said subject a therapeutically effective dose of any one of embodiments 1.1 to 1.5. 1.65. A method comprising administering a compound according to any one of claims 1 to 65.

[0131] 2.23 The method according to embodiment 2.22, wherein the cognitive impairment is Any method involving, resulting from, or relating to a condition defined in .

[0132] 2.24 Cognitive impairment is a real condition caused by or associated with Alzheimer's disease. The method according to embodiment 2.23.

[0133] 2.25 The compound according to embodiment 2.23, wherein the cognitive disorder is schizophrenia.

[0134] 2.26 Any of embodiments 1.1 to 1.65 for the manufacture of a medicament for treating cognitive disorders or the use of one of the compounds.

[0135] 2.27 This embodiment includes the condition defined in embodiment 2.19. Use according to embodiment 2.26 resulting from or relating to a condition.

[0136] 2.28 Cognitive impairment is caused by or associated with Alzheimer's disease Use according to embodiment 2.27.

[0137] 2.29 The use according to embodiment 2.28, wherein the cognitive disorder is schizophrenia.

[0138] 2.30 Acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal Menstrual pain, herpes zoster neuralgia, general neuralgia, visceral pain, osteoarthritis pain, postherpetic neuralgia pain, diabetic neuropathy, nerve root pain, sciatica, back pain, head or neck pain, severe or difficult Treating or preventing therapeutic pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain A compound according to any one of embodiments 1.1 to 1.65 for reducing the severity of:

[0139] 2.31 Acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal pain Menstrual pain, herpes zoster neuralgia, general neuralgia, visceral pain, osteoarthritis pain, postherpetic neuralgia pain, diabetic neuropathy, nerve root pain, sciatica, back pain, head or neck pain, severe or difficult Treating or preventing therapeutic pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain A method for reducing the severity of these diseases, comprising administering a therapeutically effective dose of any of embodiments 1.1 to 1.65. or one of administering the compound.

[0140] 2.32 Treatment of peripheral disorders such as lowering intraocular pressure in glaucoma, and Sjögren's disease Embodiments 1.1-1. for the treatment of dry eye and dry mouth, including rheumatoid arthritis. Compounds by any one of 65.

[0141] 2.33 Treatment of peripheral disorders such as lowering intraocular pressure in glaucoma, and Sjögren's disease 1. A method for the treatment of dry eye and dry mouth, including rheumatoid arthritis, comprising administering a therapeutically effective amount of A method comprising the administration of a compound according to any one of embodiments 1.1 to 1.65.

[0142] 2.34 Acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal Menstrual pain, herpes zoster neuralgia, general neuralgia, visceral pain, osteoarthritis pain, postherpetic neuralgia pain, diabetic neuropathy, nerve root pain, sciatica, back pain, head or neck pain, severe or difficult Treating or treating therapeutic pain, nociceptive pain, breakthrough pain, post-operative pain or cancer pain to reduce the severity of these disorders or to treat peripheral disorders such as reducing intraocular pressure in glaucoma for the treatment of dry eye and dry mouth, including Sjogren's syndrome, Use of a compound according to any one of embodiments 1.1 to 1.65 for the manufacture of a medicament.

[0143] 2.35 For example, pemphigus vulgaris, dermatitis herpetiformis, pemphigoid and other blistering skin conditions Any one of embodiments 1.1 to 1.65 for use in the treatment of skin lesions caused by Use of the compound by one.

[0144] 2.36 Functional dyspepsia, irritable bowel syndrome, gastroesophageal reflux (GER) and esophageal reflux associated with altered gastrointestinal function and motility, such as dysmotility, symptoms of gastroparesis, and chronic diarrhea Embodiments 1.1 to 1.65 for use in the treatment, prevention, amelioration or reversal of a condition Use of the compound by any one of the following:

[0145] 2.37 Bothma-Henkin-Christiansen syndrome, chemical poisoning (e.g., selenium and and silver), hypopituitarism, Kallmann syndrome, skull fractures, tumor treatment and thyroid function Any of embodiments 1.1 to 1.65 for use in the treatment of olfactory dysfunction, such as decreased Use of the compound by either one.

[0146] 2.38 A compound according to any one of embodiments 1.1 to 1.65 for the treatment of poisoning. Use of things.

[0147] 2.39 Parkinson's disease, ADHD, Huntington's disease, Tourette's syndrome, and latent Other syndromes associated with dopaminergic dysfunction as potential pathogenic factor-driven disorders which a compound according to any one of embodiments 1.1 to 1.65 for the treatment of movement disorders Use of.

[0148] 2.40 Behavioral and psychiatric symptoms of dementia (BPSD; agitation, verbal aggression) , physical aggression, depression, anxiety, abnormal motor behavior, elevated mood, irritability, apathy, disengagement clinical trials for the treatment of disorders including inhibition, impulsivity, delusions, hallucinations, sleep changes, and appetite changes. Use of a compound according to any one of embodiments 1.1 to 1.65. DETAILED DESCRIPTION OF THE INVENTION

[0149] Process for the preparation of compounds of formula (1) or formula (2) Compounds of formula (1), formula (1a), formula (2), formula (3) or formula (4) are well known to those skilled in the art. and the synthetic methods described herein.

[0150] Therefore, in another embodiment (embodiment 3.1), the present invention provides a method for manufacturing a semiconductor device according to embodiments 1.1-1. 65, comprising the steps of: Provide a method including: (A) Under reductive amination conditions, a compound of formula (10):

[0151] [ka] and, Compound of formula (11):

[0152] [ka] Reaction with (R 1 , R 2 , R 4 , X 1 , X 2 , X 3 and X 4 is embodiment 1.1 to 1.6 5); or (B) Compound of formula (1) (R 1 CONR 5 R 6 When it is necessary to prepare , Compound of formula (12):

[0153] [ka] and the formula R 5 R 6 NH amines, where R represents a suitable group such as methyl or ethyl. and R 2 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 and X 4 is embodiment 1.1 to 1.6 5); or (C) Compound of formula (1) (R 1 CONR 5 R 6 When it is necessary to prepare , Compound of formula (13):

[0154] [ka] and the formula R 5 R 6 NH amines, where R represents a suitable group such as methyl or ethyl. and R 2 , R4 , R 5 , R 6 , X 1 , X 2 , X 3 and X 4 is embodiment 1.1 to 1.6 5); or (D) Compound of formula (1) (R 1 represents an N(C=O)OR group or an N(C=O)NR2 group. When it is necessary to prepare a compound containing a 5-membered ring or a 6-membered ring, Amines of formula (14):

[0155] [ka] and a compound of formula (15) or (16):

[0156] [ka] (In the formula, R 2 , R 4 , X 1 , X 2 , X 3 and X 4 Any of the embodiments 1.1 to 1.65 LG is as defined in any one of the following: Cl, 1-imidazole, or 4-nitro or reaction with a suitable leaving group such as phenylalanine; and possibly: (E) Conversion of one compound of formula (1) into another compound of formula (1).

[0157] In variant (A), ketone (11) is reacted with amine (10) under reductive amination conditions. The reductive amination reaction is usually carried out using acetic acid (AcOH) or trifluoroacetic acid (TFA ) containing acids such as dichloromethane (DCM), dichloroethane (DCE), N,N- Tria in a solvent such as dimethylformamide (DMF) or methanol (MeOH) Sodium acetoxyborohydride (STAB) or zinc chloride in a solvent such as MeOH Sodium cyanoborohydride (NaCNBH3) in combination with (ZnCl2), is titanium tetraisopropoxide (Ti(O i Pr)4) in combination with AcOH or is a hydrogenation reaction using STAB in a solvent such as DCM or DCE containing an acid such as TFA. Use a boron reducing agent to reduce the temperature from ambient to mild heating (e.g., temperatures from about 20°C to about 70°C). Optionally, the amine (10) is optionally reacted with triethylamine (TEA ) or in the presence of a tertiary base such as N,N-diisopropylamine (DIPEA), It is present in the reaction as an acid salt such as hydrogen chloride (HCl), hydrogen bromide (HBr) or TFA salt. That's fine.

[0158] Amines of formula (10) may be commercially available or are available in the art and readily accessible to those skilled in the art. They may be prepared by a variety of different methods well known in the art.

[0159] Ketones of formula (11) can be prepared by the reaction sequence shown in Scheme 1 below: That is, the protecting group PG represents a suitable protecting group such as BOC or CBZ. The aminoketone (17) was reduced under suitable conditions to effect the formation of the N-protected amino alcohol (18). The reaction can be carried out under these conditions. Typically, such conditions are at a temperature of about -20°C to about 50°C. In the case of sodium borohydride (NaBH4) in a solvent such as MeOH, or Et Lithium borohydride in a solvent such as 2O or THF a borohydride reducing agent such as LiBH4, or Et2O or TH Aluminum hydride reagents such as lithium aluminum hydride (LAH) in solvents such as F Once the N-protected amino alcohol (18) is formed, and deprotection to give amino alcohol (19). For example, the protecting group P When G is BOC, suitable conditions for effecting its removal are 1,4-dioxane or Reaction with an acid such as HCl in a solvent such as EtO, or TFA in a solvent such as DCM Alternatively, when the protecting group PG is CBZ, a suitable method for its removal can be used. Suitable conditions are palladium supported on carbon in a solvent such as EtOH at a temperature of about 20°C to about 80°C. The amino alcohol (1) can be reacted with H2 in the presence of a Pd / C catalyst. 9), once formed, can be reacted at a temperature of about 0°C to about 50°C, optionally in the presence of water. in the presence of a suitable base such as EtN, NaHCO, NaCO or KCO, Reaction with cyanogen bromide in a suitable solvent such as DCM, MeCN, Et2O or EtOH Once formed, cyanamide (20) can be formed by and Et in the presence of a Lewis acid such as zinc chloride or zinc bromide at a temperature of about 0°C to about 25°C. in a suitable solvent such as OAc, Et2O, THF, 1,4-dioxane or EtOH, or or a mixture of the above solvents, N-hydroxyamide (22) or the corresponding N-hydroxyamide (23) A suitable N-hydroxy reagent, such as cyamidine (23), 4 is embodiment 1.1 to 1.65), and then In the presence of an aqueous acid, such as aqueous HCl, in a suitable solvent such as EtOH, at about 50° C. to about 100° C. Upon heating at temperatures up to 100°C, alcohol (21) can be formed. Alternatively, amino The alcohol (19) may be optionally reacted under a reaction pressure greater than atmospheric pressure using a sealed vessel. and optionally using conventional or microwave heating to facilitate the reaction. At a temperature of, for example, about 20°C to about 200°C, optionally EtN, DIP In the presence of a suitable base such as EA, K2CO3 or DBU, optionally THF, 1,4 of a suitable solvent such as dioxane, MeCN, EtOH, DMSO, DMF or NMP In the presence of oxadiazole (24) (R 4 Any one of embodiments 1.1 to 1.65 LG is as defined in bromide) or sulfonate esters (e.g., tosylate, mesylate, or triflate) The alcohol (21) can be reacted directly with a suitable leaving group such as methyl ester. Once formed, the hydroxybenzoate may be dissolved in a suitable solvent, such as DCM, at a temperature of, for example, about 0°C to about 25°C. By using a chromium reagent such as pyridinium chlorochromate in a suitable solvent, Using a wide range of reagents and conditions that exist in the art and are well known to those skilled in the art, ketones can be prepared. It can be oxidized to (11).

[0160] [ka] In variant (B), ester (12) is reacted with 1,2,3,4-trimethyl-2,4-trimethyl-1 ... Amine R 5 R 6 Typically, these conditions are used in a solvent such as toluene. In some cases, trimethylaluminum is reacted with the tertiary base, such as TEA or DIPEA, (Me3Al) and other reagents at temperatures between about 0°C and about 110°C. Isopropylmagnesium chloride ( i Reaction in the presence of PrMgCl Esters such as (12) and amines R 5 R 6 NH or optionally in a suitable solvent In the presence of, optionally in the presence of a suitable base such as TEA or DIPEA, the ester ( 12) and Amine R 5 R 6 Carry out amide formation by direct heating with NH Other suitable conditions will be known to those skilled in the art.

[0161] In variant (C), carboxylic acid (13) is reacted with carboxylic acid (14) under conditions suitable for effecting amide formation. , Amine R 5 R 6 NH. Carboxylic acid (13) and amine R 5 R 6 From NH amide formation, for example, at a temperature between about 0° C. and about 100° C. using DCM, THF or In a solvent such as DMF, possibly in the presence of 1-hydroxybenzotriazole (HOBt) In the presence of a tertiary base such as TEA or DIPEA, Diimide (DIC), Ethyl-(N',N'-dimethylamino)propylcarbodiimide Hydrochloride (EDC), (benzotriazol-1-yloxy)tripyrrolidinophosphonium Hexafluorophosphate (PyBOP), O-(7-azabenzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ( HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethyl Amino-morpholino-carbenium hexafluorophosphate (COMU) or 2 ,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2, A number of suitable amide coupling reagents, such as 4,6-trioxide (T3P), Those skilled in the art will be aware that suitable conditions exist in the art.

[0162] Alternatively, the compound of formula (1) (R 1 CONR 5 R 6 ) is synthesized by the following scheme 2 The reaction sequence shown in Figure 1 affords the formation of carboxylic acid (13) and amine R 5 R 6 Obtained from NH It can be manufactured.

[0163] [ka] Thus, carboxylic acid (13) can be reacted under conditions suitable for the formation of intermediate (25). can be reacted (wherein R 2 , R 4 , X 1 , X 2 , X 3 and X 4 is an embodiment 1.1 to 1.65, and LG is chloride (Cl). , 1-imidazole or RO(C=O)O (R is ethyl or isobutyl, etc. Typically, such conditions are achieved by using a solvent such as DCM, THF or in a suitable solvent such as DMF, optionally in the presence of a catalyst such as DMF, and optionally Oxalyl chloride or thionyl chloride in the presence of a tertiary base such as TEA or DIPEA (LG=Cl), 1,1'-carbonyldiimidazole (CDI) (LG=1-imidazoline) chloroformate), or ethyl or isobutyl chloroformate (LG=RO(C=O) Once formed, intermediate (25) can be converted to amide (26). amine R 5 R 6 NH (in the formula, R 2 , R 4 , R 5 , R 6 , X 1 , X 2 , X 3 and X 4 is defined in any one of embodiments 1.1 to 1.65. Typically, such conditions are DCM, THF, or DMSO. F, optionally in the presence of a tertiary base such as TEA or DIPEA, The reaction takes place at temperatures between ℃ and about 100℃.

[0164] In variant (D), the amine of formula (14) is reacted with a suitable amine to form a compound of formula (1). reacting with a compound of formula (15) or a compound of formula (16) under conditions (R 1 is N(C= (O)OR or N(C=O)NR2 groups). Such conditions are carried out in a solvent such as DCM, THF or DMF, optionally with TEA, D in the presence of a suitable base such as IPEA or K2CO3 at a temperature between about 0°C and about 100°C This is the reaction.

[0165] In variant (E), one of the compounds of formula (1) is converted to a compound of formula ( 1) can be converted into another compound of the formula: Synthetic procedures for converting one functional group into another Examples of this are in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, Mi chael B. Smith, John Wiley, 2013 (ISBN:978- 0-470-46259-1), Organic Syntheses, Online Edition, www.orgsyn.org, (ISSN 2333-3553) and Fieser s' Reagents for Organic Synthesis, volumes 1-17, John Wiley (edited by Mary Fieser) (ISBN: 0-471-582 83-2) and other standard texts.

[0166] In many of the reactions listed above, the reaction is prevented from occurring at undesired locations on the molecule. In order to achieve this, it may be necessary to protect one or more groups. Examples of protecting groups, as well as Methods for protecting and deprotecting functional groups are described in Greene's Protective Groups. ups in Organic Synthesis, 5th Edition, edited by Peter G.M. .Wuts, John Wiley, 2014 (ISBN:978111805748 3) can be found.

[0167] The compounds made by the above methods may be synthesized by any of a variety of methods well known to those skilled in the art. Examples of such methods include recrystallization and column chromatography. chromatography (e.g. flash chromatography), HPLC and SFC, etc. This includes chromatographic techniques. Pharmaceutical preparations The active compounds can be administered alone, but may also be administered in pharmaceutical compositions (e.g., formulations). It is preferred that the solution be supplied as a single unit.

[0168] Therefore, in another embodiment of the present invention (embodiment 4.1), Formula (1), formula (1a), formula (2), formula (3) or formula (4) defined in any one of (4) At least one compound and at least one pharmaceutically acceptable excipient A pharmaceutical composition comprising the same is provided.

[0169] In one embodiment (embodiment 4.2), the composition is a tablet composition.

[0170] In another embodiment (Embodiment 4.3), the composition is a capsule composition.

[0171] A pharmaceutically acceptable excipient is, for example, a carrier (e.g., a solid, liquid, or semi-solid carrier). , adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and solvents and liquid diluents such as cosolvents), granulating agents, binders, flow aids, coatings, release control agents Modifiers (e.g., release-suppressing or retarding polymers or waxes), binders, disintegrants, buffers agents, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffering agents, tonicity adjusting agents, thickening agents , flavoring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilizers, or additives commonly used in pharmaceutical compositions The excipient may be selected from any other commonly used excipient.

[0172] As used herein, the term "pharmaceutically acceptable" means a compound that does not cause undue toxicity, irritation, allergies, or The method of the present invention provides a method for treating a subject's (e.g., a human subject's) tissue without any adverse reactions or other problems or complications. appropriate for use in contact with the body, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Each excipient also refers to a compound, substance, composition and / or dosage form that is a part of the formulation. It must be "acceptable" in the sense of being compatible with the ingredients.

[0173] Pharmaceutical compositions containing compounds of formula (1), formula (1a), formula (2), formula (3) or formula (4) The composition can be formulated according to known techniques, for example, Remington's Ph. armaceutical Sciences, Mack Publishing Co. company, Easton, PA, USA.

[0174] The pharmaceutical compositions are administered orally, parenterally, topically, intranasally, intrabronchially, sublingually, intraocularly, intraauricularly, intrarectally, It may be in any form suitable for vaginal or transdermal administration.

[0175] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules, ... Capsules (hard or soft shell), caplets, pills, lozenges, syrups tablets, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers, or These include patches such as steroids or buccal patches.

[0176] Tablet compositions may contain sugars or sugar alcohols, such as lactose, sucrose, sorbitol, ethanol or mannitol; and / or sodium carbonate, calcium phosphate, calcium carbonate non-sugar derived diluents such as calcium or microcrystalline cellulose (MCC); Cells such as methylcellulose, ethylcellulose, and hydroxypropylmethylcellulose inert diluents such as cellulose or its derivatives, and starches such as corn starch; Tablets may contain a unit dose of the active compound together with a diluent or carrier. In addition, polyvinylpyrrolidone, disintegrants (e.g., cross-linked carboxymethylcellulose, etc.) swellable cross-linked polymers), lubricants (e.g., stearates), preservatives (e.g., parabens ), antioxidants (e.g., BHT), buffering agents (e.g., phosphate or citrate buffers) as binders and granulating agents, such as PEG-14, PEG-24, PEG-34, PEG-44, PEG-45, PEG-46, PEG-47, PEG-48, PEG-49 ... Such excipients are well known and are described in detail herein. There is no need to consider this.

[0177] Tablets can be formulated to release the drug on contact with gastric juices (immediate release tablets) or over an extended period of time. or to release in a controlled manner upon contact with specific areas of the GI tract (controlled release). Tablets) can be designed.

[0178] The pharmaceutical composition generally contains about 1% (w / w) to about 95%, preferably % (w / w) of the active ingredient. ingredients, and 99% (w / w) to 5% (w / w) of pharmaceutically acceptable excipients (e.g., as defined above), or a combination of such excipients. The active ingredient is about 20% (w / w) to about 90% and the pharmaceutical agent is about 80% (w / w) to about 10%. The pharmaceutical composition comprises from about 1% to about 95%, preferably from about 1% to about 95%, of a compound selected from the group consisting of hydroxybenzoates, ... The pharmaceutical composition according to the present invention can be prepared, for example, in the form of an ampoule containing about 20% to about 90% of the active ingredient. , vials, suppositories, pre-filled syringes, dragees, powders, tablets or capsules , may be in unit dosage form.

[0179] Tablets and capsules may contain, for example, 0-20% disintegrant, 0-5% lubricant, 0-5% Flow aids and / or 0-99% (w / w) of fillers and / or extenders (depending on drug dose) Tablets and capsules may contain 0-10% (w / w) of polymers. - May contain binders, 0-5% (w / w) antioxidants, and 0-5% (w / w) pigments Slow-release tablets also typically have a controlled release of 0 to 99% (w / w) (e.g., Contains a (dose-dependent) retarding polymer. The binders are typically 0-10% (w / w) polymer, 0-3% (w / w) pigment and / or or 0 to 2% (w / w) of a plasticizer.

[0180] Parenteral formulations typically contain 0-20% (w / w) buffers and 0-50% (w / w) cosolvents. and / or 0-99% (w / w) water for injection (WFI) (depending on the dose, lyophilized Intramuscular depot formulations may also contain 0-99% (w / w) oil. stomach.

[0181] The pharmaceutical preparation contains the entire course of treatment in a single package, usually a blister pack. The patient may be provided with a "patient pack" containing:

[0182] The compounds of formula (1), formula (1a), formula (2), formula (3) or formula (4) generally contain the unit The compound is provided in a dosage form and therefore sufficient to achieve the desired level of biological activity. Typically, the formulation contains 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram The active ingredient may be present in an amount of 1000mg to 2000mg. A specific subrange of the product is 0.1 milligrams to 2 grams of active ingredient (more typically, 1 0 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams), or 1 microgram 1000mg to 20mg (e.g. 1µg to 10mg, e.g. 0.1µg 1-2 milligrams of active ingredient).

[0183] For oral compositions, the unit dosage form may be from 1 milligram to 2 grams, more typically 10 milligrams. 100mg to 1g, e.g. 50mg to 1g, e.g. 100mg to 1g It may contain the active compounds of rum.

[0184] The active compound is administered in an amount sufficient to achieve the desired therapeutic effect (effective amount), as needed. The exact amount of compound administered is determined by the patient (e.g., a human or animal patient) to be treated. This may be determined by the supervising physician in accordance with standard procedures.

[0185] The present invention is now directed to, but is not limited to, the specific embodiments described in the following examples. This is illustrated by reference to the embodiments. [Example]

[0186] Examples 1-1 to 18-2 The compounds of Examples 1-1 to 18-2 shown in Table 1 below were prepared. NMR and LCMS characterization of the compounds and some of the methods used to prepare them are given below. They are listed in Table 3. Starting materials and intermediates for some of the examples are listed in Table 2.

[0187] [Table 1-1]

[0188] [Table 1-2]

[0189] [Table 1-3]

[0190] [Table 1-4]

[0191] [Table 1-5]

[0192] [Table 1-6]

[0193] [Table 1-7] General Procedure Where preparative routes are not included, relevant intermediates are commercially available. Commercially available reagents are also available. The product was used without further purification. Room temperature (rt) refers to approximately 20-27°C. 1 H NMR Spectra were recorded at 400 MHz on either Bruker or Jeol instruments. Chemical shift values ​​are expressed in parts per million (ppm), or (δ) values. For multiplicities, the following abbreviations are used: s = singlet, br = broad, d = double lett, t=triplet, q=quartet, quint=quintet, td=double triplet of triplet, tt = triplet of triplet, qd = quartet of doublet ddd = doublet of doublet of doublet, ddt = triplet of doublet m = doublet, m = multiplet. Coupling constants are columned as J values ​​measured in Hz. NMR and mass spectroscopy results were corrected for background peaks. Chromatography is performed using 60-120 mesh silica gel and nitrogen Refers to column chromatography performed under reduced pressure (flash chromatography) TLC for reaction monitoring was performed using the indicated mobile phase and fixed column chromatography (Merck). Refers to TLC performed using silica gel F254 as the phase. Microwave-mediated Reactions are carried out using Biotage initiators or CEM Discover microwave reactors. It was. LCMS analysis LCMS analysis of compounds was performed electrochemically using the equipment and methods shown in the table below. The experiment was carried out under Rospray conditions: [Table A]

[0194] [Table B-1]

[0195] [Table B-2]

[0196] The experimental items and LCMS data in Tables 2 and 3 are in the following format: (instrument system, method Method): Mass ion, retention time, and UV detection wavelength are shown. compound purification Final purification of the compounds was performed using preparative reversed-phase HP HPLC using the equipment and methods detailed below. The analysis was carried out by LC, chiral HPLC or chiral SFC, where the data were of the following form: Formula: Purification technique: [Phase (column description, column length x inner diameter, particle size), solvent flow rate, gradient Ent - shown as % of mobile phase B in mobile phase A (time elapsed), mobile phase (A), mobile phase (B )]. Preparative HPLC purification: Shimadzu LC-20AP binary system with SPD-20A UV detector Tem Chiral HPLC purification: Shimadzu LC-20AP binary system with SPD-20A UV detector Tem Chiral SFC purification: Waters SFC200 Sepiatec 100 Berger Multigram2 Purification method A Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 15 mL / min, gradient 10% to 40% (23 min), 100% (2 Mobile phase (A): 5 mM ammonium bicarbonate in water (A): 100% acetonitrile; (B): 0.1% ammonia in water; (C): 100% acetonitrile. Purification method B Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 10% to 33% (25 min), 100% (2 min), 10% (3 minutes), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonia in water (B): 100% acetonitrile]. Purification method C Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 5 mL / min, gradient 37% to 40% (23 min), 100% (2 min), 37% ( 2 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonia in water (A); (B): 100% acetonitrile]. Purification method D Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 30% to 40% (20 min), 100% (2 min), 100% 30% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% in water ammonia; (B): 100% acetonitrile]. Purification method E Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 5% to 40% (20 min), 40% (3 min), 100% (2 min) 100% to 5% (2 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + (B): 0.1% ammonia in water; (C): 100% acetonitrile]. Purification method F Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 5 mL / min, gradient 15% to 47% (15 min), 100% (1 min) Mobile phase (A): 5 mM ammonium bicarbonate in water + 0% in water (B): 100% acetonitrile]. Purification method G Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 5% to 50% (17 min), 50% to 70% (2 min), 100% (3 min), 100% to 5% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (A): 0.1% ammonia in water; (B): 100% acetonitrile]. Purification method H Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 16 mL / min, gradient 15% to 42% (20 min), 100% (2 min), 100% 15% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% in water ammonia; (B): 100% acetonitrile]. Purification method I Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 6 mL / min, gradient 5% to 30% (19 min), 100% (3 min), 100% 5% (4 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method J Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 0 mL / min, gradient 0% to 30% (45 min), 30% to 30% (48 min), 10 0% (2 min), 100% to 0% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method K Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 5% to 38% (25 min), 100% (2 min), 100% to 5 % (5 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method L Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 6 mL / min, gradient 20% to 30% (25 min), 30% to 30% (5 min), 10 0% (3 min), 100% to 20% (5 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method M Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 15 mL / min, gradient 15% to 30% (30 min), 30% to 30% (6 min), 100% (2 min), 100-15% (4 min), Mobile phase (A): 5% in water (B): 100% acetonitrile; (C): 100% ammonium bicarbonate + 0.1% ammonia in water; (D): 100% acetonitrile [L] Purification method N Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 15 mL / min, gradient 25% to 35% (23 min), 100% (1 100-25% (4 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonia in water; (B): 100% acetonitrile]. Purification method O Chiral HPLC: [Normal phase (CHIRALPAK AD-H, 250×21mm, 5μm) , 18 mL / min, isocratic (A:B) 45:55 (45 min), mobile phase (A): in hexane (B) 0.1% diethylamine in isopropanol:methanol (30:70) 0.1% diethylamine]. Purification method P Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 3 mL / min, gradient 15% to 20% (30 min), 20% to 20% (6 min), 10 0% (1 min), 100% to 15% (6 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method Q Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 5 mL / min, gradient 5% to 17% (32 min), 17% to 17% (58 min), 10 0% (3 min), 100% to 5% (4 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method R Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 20% to 35% (25 min), 35% to 35% (3 min), 100 % (2 min), 100% to 20% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method S SFC: [(CHIRALCEL OX-H, 250×21mm, 5μm), 70mL / min, isocratic (A:B) 70:30 (8.5 min), mobile phase (A): 100% liquid CO2, (B): 0.1% diethylamine in isopropanol:methanol (50:50)]. Purification method T Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 18% to 30% (18 min), 100% (2 min), 100% 18% (2 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% in water ammonia; (B): 100% acetonitrile]. Purification method U Chiral HPLC: [Normal phase (CHIRALCEL OX-H, 250 x 21 mm, 5 μm) , 18 mL / min, isocratic (A:B) 90:10 (32 min), mobile phase (A): in hexane 0.1% diethylamine, (B): isopropanol:acetonitrile (70:30) 0.1% diethylamine in]. Purification method V Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 5 mL / min, gradient 10% to 25% (25 min), 25% to 25% (7 min), 10 0% (2 min), 100% to 10% (2 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method W Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 15 mL / min, gradient 25% to 40% (15 min), 100% (3 (min), 100% to 25% (5 min), mobile phase (A): 0.1% ammonia in water; (B ):100% acetonitrile]. Purification method X SFC: [(LUX A1, 250×21.2mm, 5μm), 50mL / min, isocratic ( A:B) 65:35, mobile phase (A): 100% liquid CO2, (B): 0 in methanol. 1% ammonia]. Purification method Y Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 8% to 20% (23 min), 20% to 20% (2 min), 100% (2 min), 100% to 8% (5 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (A): 0.1% ammonia in water; (B): 100% acetonitrile]. Purification method Z SFC: [(CHIRALPAK AD-H, 250×21mm, 5μm), 75mL / min, isocratic (A:B) 82:18 (20 min), mobile phase (A): 100% liquid CO2, ( B): 0.1% diethylamine in methanol].

[0197] Purification method AA Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 8% to 23% (17 min), 23% to 23% (2 min), 100% (2 min), 100% to 8% (4 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (A): 0.1% ammonia in water; (B): 100% acetonitrile]. Purification method AB Preparative HPLC: [Reverse phase (YMC ACTUS TRIART C-18, 250×20m m, 5 μm), 15 mL / min, gradient 15% to 30% (28 min), 100% (2 Mobile phase (A): 5 mM ammonium bicarbonate in water (A): 100% acetonitrile; (B): 0.1% ammonia in water; (C): 100% acetonitrile. Purification method AC SFC: [(CHIRALPAK AD-H, 250×21mm, 5μm), 75mL / min, isocratic (A:B) 75:25 (18 min), mobile phase (A): 100% liquid CO2, ( B): 0.1% diethylamine in methanol]. Purification method AD Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 x 50 mm, 5 μm), 9 0 mL / min, gradient 5% to 35% (20 min), 100% (2 min), 100% 5% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method AE Chiral HPLC: [Normal phase (CHIRALPAK AD-H, 250×21mm, 5μm) , 18 mL / min, isocratic (A:B) 70:30 (35 min), mobile phase (A): in hexane (B) 0.1% diethylamine in isopropanol:methanol (50:50) 0.1% diethylamine]. Refining method AF Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 13 mL / min, gradient 15% to 30% (30 min), 30% to 30% (10 min), 100% (2 min), 100%-15% (3 min), Mobile phase (A): Water (B): 5 mM ammonium bicarbonate + 0.1% ammonia in water; (C): 100% acetonitrile Trill]. Purification method AG SFC: [(CHIRALPAK AD-H, 250×21mm, 5μm), 80mL / min, isocratic (A:B) 75:25 (13 min), mobile phase (A): 100% liquid CO2, ( B): 0.1% diethylamine in isopropanol:methanol (50:50)]. Purification method AH Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 x 50 mm, 5 μm), 8 0 mL / min, gradient 5% to 18% (50 min), 18% to 18% (10 min), 10 0% (3 min), 100% to 5% (7 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method AI SFC: [(CHIRALPAK AD-H, 250×21mm, 5μm), 80mL / min, isocratic (A:B) 70:30 (20 min), mobile phase (A): 100% liquid CO2, ( B): 0.1% diethylamine in methanol]. Purification method AJ Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 0% to 27% (28 min), 27% to 27% (6 min), 100 % (4 min), 100% to 0% (2 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method AK Chiral HPLC: [Normal phase (CHIRALPAK AD-H, 250×21mm, 5μm) , 18 mL / min, isocratic (A:B) 90:10 (27 min), mobile phase (A): in hexane (B): 0.1% diethylamine in isopropanol]. Purification method AL Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 15% to 35% (20 min), 35% to 35% (3 min), 10 0% (2 min), 100% to 15% (3 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method AM SFC: [(CHIRALPAK AD-H, 250×21mm, 5μm), 80mL / min, isocratic (A:B) 65:35 (16.5 min), mobile phase (A): 100% liquid CO2 , (B): 0.1% diethylamine in methanol]. Purification method AN Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 5 mL / min, gradient 10% to 30% (20 min), 30% to 30% (5 min), 1 00% (2 min), 100% to 10% (3 min), Mobile phase (A): 5 mM bicarbonate in water (B): ammonium + 0.1% ammonia in water; (C): 100% acetonitrile]. Purification method AO Chiral HPLC: [Normal phase (CHIRALPAK AD-H, 250×21mm, 5μm) , 18 mL / min, isocratic (A:B) 85:15 (30 min), mobile phase (A): in hexane (B): 0.1% diethylamine in isopropanol]. Purification method AP Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 6 mL / min, gradient 10% to 32% (18 min), 100% (2 min), 100% ~10% (2 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% in water % ammonia; (B): 100% acetonitrile]. Purification method AQ Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 3 mL / min, gradient 20% to 25% (17 min), 25% to 25% (3 min), 1 00% (2 min), 100% to 20% (3 min), Mobile phase (A): 5 mM bicarbonate in water (B): ammonium + 0.1% ammonia in water; (C): 100% acetonitrile]. Purification method AR Chiral HPLC: [Normal phase (CHIRALCEL OX-H, 250 x 21 mm, 5 μm) , 18 mL / min, isocratic (A:B) 78:22 (37 min), mobile phase (A): in hexane (B) 0.1% diethylamine in isopropanol:methanol (50:50) 0.1% diethylamine]. Purification method AS Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 15 mL / min, gradient 25% to 38% (16 min), 100% (2 Mobile phase (A): 5 mM ammonium bicarbonate in water (A): 100% acetonitrile; (B): 0.1% ammonia in water; (C): 100% acetonitrile. Purification method AT Preparative HPLC: [Reverse phase (X SELECT PHENYL HEXYL, 250×19m m, 5 μm), 15 mL / min, gradient 5% to 35% (20 min), 100% (4 min) (A): 0.1% ammonia in water; (B): 100% to 5% (4 min); 100% acetonitrile]. Purification method AU Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 5% to 28% (18 min), 28% to 28% (2 min), 100 % (2 min), 100% to 5% (2 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method AV Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 10% to 20% (25 min), 20% to 20% (8 min), 10 0% (2 min), 100% to 10% (5 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Refining method AW Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 15 mL / min, gradient 15% to 20% (22 min), 20% to 20% (5 min), 10 0% (2 min), 100% to 15% (6 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method AX Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 10 mL / min, gradient 5% to 55% (18 min), 55% to 55% (6 min), 100 % (2 min), 100% to 5% (6 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method AY Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 5 mL / min, gradient 20% to 45% (22 min), 100% (2 min), 100% ~20% (5 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% in water % ammonia; (B): 100% acetonitrile]. Purification method AZ Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 6 mL / min, gradient 30% to 39% (14 min), 100% (2 min), 100% ~30% (4 min), Mobile phase (A): 5 mM ammonium bicarbonate in water + 0.1% in water % ammonia; (B): 100% acetonitrile]. Purification method BA SFC: [(CHIRALPAK AD-H, 250×21mm, 5μm), 80mL / min, isocratic (A:B) 85:15 (7 min), mobile phase (A): 100% liquid CO2, (B ): 0.1% diethylamine in methanol]. Purification method BB Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 13 mL / min, gradient 25% to 35% (28 min), 35% to 35% (2 min), 10 0% (2 min), 100% to 25% (5 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method BC Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 13 mL / min, gradient 25% to 40% (30 min), 40% to 40% (2 min), 10 0% (2 min), 100% to 25% (6 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method BD Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 14 mL / min, gradient 20% to 50% (20 min), 50% to 50% (5 min), 10 0% (2 min), 100% to 20% (6 min), Mobile phase (A): 5 mM bicarbonate in water (B): 100% acetonitrile]. Purification method BE Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 12 mL / min, gradient 5% to 50% (23 min), 50% to 50% (5 min), 100 % (2 min), 100% to 5% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method BF Preparative HPLC: [Reversed phase (X-BRIDGE C-8, 250 × 19 mm, 5 μm), 13 mL / min, gradient 5% to 55% (22 min), 55% to 55% (6 min), 100 % (2 min), 100% to 5% (3 min), Mobile phase (A): 5 mM ammonium bicarbonate in water (B): 100% acetonitrile]. Purification method BG Preparative HPLC: [Reversed phase (X-BRIDGE C-18, 250 × 19 mm, 5 μm), 1 4 mL / min, gradient 25% to 52% (25 min), 52% to 52% (9 min), 1 00% (2 min), 100% to 25% (4 min), Mobile phase (A): 5 mM bicarbonate in water (B): ammonium + 0.1% ammonia in water; (C): 100% acetonitrile]. Abbreviation AcOH = acetic acid aq. = aqueous DCM = dichloromethane DIPEA = diisopropylethylamine DMF = dimethylformamide DMSO = dimethyl sulfoxide ES(I) = electrospray ionization Et2O = diethyl ether EtOAc = ethyl acetate EtOH = ethanol h = time H2O = Water HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3- Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HCl = hydrogen chloride, hydrochloric acid HPLC = high-performance liquid chromatography LC = liquid chromatography MeCN = acetonitrile MeOH = methanol min(s) = minutes MS = mass spectrometry nm = nanometers NMR = nuclear magnetic resonance sat. = saturation SFC = Supercritical Fluid Chromatography STAB = sodium triacetoxyborohydride TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography The prefixes n-, s-, i-, t- and tert- have their usual meaning: norma le, secondary, iso and tertiary. Synthesis of intermediates: Route 1 Intermediate 3, 2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1.2] ... Typical preparation of ketones, exemplified by the preparation of zaspiro[3.3]heptan-6-one Typical Procedures

[0198] [ka] tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate The ester (Intermediate 1) (500 mg, 2.37 mmol) was dissolved in MeOH (10 mL), The resulting solution was cooled to 0° C. Sodium borohydride (270 mg, 7.10 mmol) l) was added in small portions and the resulting reaction mixture was stirred at 25°C for 2 hours. The residue was partitioned between H2O (80 mL) and EtOAc (60 mL). The aqueous layer was further extracted with EtOAc (2 x 60 mL) and the organic layers were combined and dried ( Na2SO4) and the solvent removed in vacuo. The residue was triturated with pentane to give te rt-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate The compound (500 mg, 99%) was obtained as a solid. LCMS (System 2, Method E): m / z 214 (M+H) + (ESI+ve), 1. 54 minutes, 202nm.

[0199] tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxamide The sylate (500 mg, 2.34 mmol) was dissolved in DCM (10 mL), and the resulting solution The solution was cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise, and the resulting reaction mixture The mixture was stirred for 6 h at 25° C. The solvent was removed in vacuo and the residue was dissolved in pentane (3×1 mL). When mixed, 2-azaspiro[3.3]heptan-6-ol trifluoroacetate (2 60 mg, 98%) was obtained as a gum. LCMS (System 2, Method E): m / z 114 (M+H) + (ESI+ve), 0. 22 minutes, 202nm.

[0200] 2-Azaspiro[3.3]heptan-6-ol trifluoroacetate (250 mg, 2 0.21 mmol) was dissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3 (1 mL). The mixture was treated with cyanogen bromide (255 mg, 2.43 mmol) and cooled to 0°C for 10 min. was added in small portions and the resulting reaction mixture was stirred at 25° C. for 5 hours. The solvent was removed in vacuo. The residue was made basic with saturated aqueous NaHCO3 solution. The precipitated solid was filtered off. The filtrate and washings were then combined and dried (NaSO 4 O4), the solvent is removed in vacuo and the crude product is purified by trituration with pentane. and 6-hydroxy-2-azaspiro[3.3]heptane-2-carbonitrile (230 mg, 75%) was obtained as a gum. LCMS (System 2, Method E): m / z 139 (M+H) + (ESI+ve), 0. 76 minutes, 202nm.

[0201] 6-Hydroxy-2-azaspiro[3.3]heptane-2-carbonitrile (180m g, 1.30 mmol) in a mixture of EtOAc:EtO (5:1) (5 mL). N-hydroxyacetamide (Intermediate 2) (125 mg, 1.69 mmol) was added. The resulting mixture was stirred at 25 °C for 5 min, and then ZnCl2( A solution of 1M, 1 mL, 1 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 20 minutes. The reaction mixture was stirred for 1 hour, during which time a white precipitate formed. The reaction mixture was diluted with EtO (3 × 10 mL The remaining solid was diluted with EtOH and the solvent was decanted off each time. (3 mL), treated with aqueous HCl (4 M, 2 mL), and heated to reflux for 6 h. The solvent was removed in vacuo and the residue was made basic with aqueous NaHCO3 and then diluted with H2O(8 The aqueous layer was partitioned between DCM (2×60 mL) and DCM (60 mL). After further extraction, the combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. Purification by triturating with pentane gave 2-(3-methyl-1,2,4- octyl (2-azaspiro[3.3]heptan-6-ol) (60m g, 24%) was obtained as a gum. LCMS (System 2, Method E): m / z 196 (M+H) + (ESI+ve), 1. 34 minutes, 202nm.

[0202] 2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azaspiro[3 .3]Heptan-6-ol (80 mg, 0.41 mmol) was dissolved in DCM (5 mL). The solution was cooled to 0°C. Pyridinium chlorochromate (132 mg, 0.62 m mol) was added in small portions and the resulting reaction mixture was stirred at 25° C. for 3 hours. The solvent was removed in vacuo and the residue was made basic with NaHCO3 solution and H2O (60 mL). The aqueous layer was partitioned between EtOAc (2×45 mL). After further extraction, the combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. When mixed with pentane, 2-(3-methyl-1,2,4-oxadiazole-5- (yl)-2-azaspiro[3.3]heptan-6-one (Intermediate 3) (60 mg, 76%) ) was obtained as a gum.

[0203] Data for intermediate 3 are in Table 2. Route 2 This is exemplified by the preparation of intermediate 6, 6-azaspiro[3.4]octan-2-ol hydrochloride. A typical procedure for the preparation of alcohols is shown.

[0204] [ka] tert-Butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate The ester (Intermediate 5) (10 g, 44.3 mmol) was dissolved in MeOH (1000 mL), The resulting solution was cooled to 0° C. Sodium borohydride (2.0 g, 53.2 mmol) ) was added in small portions and the resulting reaction mixture was stirred at 25°C for 1 hour. The residue was partitioned between H2O (250 mL) and EtOAc (250 mL). The aqueous layer was further extracted with EtOAc (2 x 150 mL) and the organic layers were combined and dried. Drying (Na2SO4) and removal of the solvent in vacuo gave tert-butyl 2-hydroxy-6 - Azaspiro[3.4]octane-6-carboxylate (9.2g, 91%) in the form of a gum obtained as an object. LCMS (System 3, Method F): m / z 228 (M+H) + (ESI+ve), 3. 09 minutes, 202nm.

[0205] tert-Butyl 2-hydroxy-6-azaspiro[3.4]octane-6-carboxylate The silane (9 g, 39.6 mmol) was dissolved in a solution of HCl in 1,4-dioxane (4 M, 90 The resulting reaction mixture was stirred at 25°C for 16 hours. Remove in vacuo and purify the residue by triturating with diethyl ether (3x50mL). Then, 6-azaspiro[3.4]octan-2-ol hydrochloride (Intermediate 6) (7 g, 9 0%) was obtained as a gum.

[0206] Data for intermediate 6 are in Table 2. Route 3 Preparation of Intermediate 27, 2-Azabicyclo[2.2.2]octan-5-ol Hydrochloride A typical procedure for the preparation of alcohols is exemplified by

[0207] [ka] tert-Butyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carbohydrate Dissolve 500 mg (2.2 mmol) of hydroxylate (Intermediate 26) in 10 mL of THF. The solution was cooled to -20°C under a nitrogen atmosphere. A solution of lithium aluminum hydride in 100 mmol) was added at −20° C., and the resulting mixture was The reaction mixture was stirred at 2° C. for 2 h. The reaction mixture was diluted with cold H2O (25 mL) and EtOAc (15 mL). ), and the aqueous layer was further extracted with EtOAc (2x15 mL). The organic layer was dried (Na2SO4) and the solvent removed in vacuo to give tert-butyl 5-hydroxybenzoate. Roxy-2-azabicyclo[2.2.2]octane-2-carboxylate (500mg 99%) was obtained as a gum. LCMS (System 2, Method E): m / z 172 (M+H-56) + (ESI+ve) , 1.60 min, 202nm. tert-Butyl 5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate Carboxylate (500 mg, 2.2 mmol) was dissolved in HCl in 1,4-dioxane at 0°C. The mixture was dissolved in 4M HCl (10 mL) and stirred at room temperature for 2 hours. The solvent was removed in vacuo. , the residue was triturated with n-pentane (2 × 10 mL) to give 2-azabicyclo[2.2. 2] Octan-5-ol hydrochloride (Intermediate 27) (280 mg, 100%) as a solid Obtained.

[0208] Data for intermediate 27 are in Table 2. Route 4 Intermediate 30, 9-azabicyclo[3.3.1]nonan-3-ol trifluoroacetic acid Typical Procedure for Preparation of Alcohols, Illustrated by Preparation of Salts

[0209] [ka] tert-Butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxamide To a solution of sylate (Intermediate 29) (6 g, 25.1 mmol) in THF (60 mL) at 0°C Lithium aluminum hydride in THF (1M, 37.6 mL, 37.6 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 4 h. Then, ice-cold water (20 mL The reaction was quenched by adding ethyl acetate (2×50 mL) and the mixture was diluted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. and tert-butyl 3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate The carboxylate (6 g, 99%) was obtained as a solid. This product was further purified or Used crude in the next step without characterization.

[0210] tert-Butyl 3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carbamate The carboxylate (6 g, 24.1 mmol) was dissolved in DCM (30 mL), and the resulting solution The mixture was cooled to 0° C. TFA (15 mL) was added and the mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was triturated with toluene (2x15mL) to give 9-azabicyclo[4.2.1]phenylalanine. Chlo[3.3.1]nonan-3-ol trifluoroacetate (Intermediate 30) (8.5 g, 100%) was obtained as a gum.

[0211] Data for intermediate 30 are in Table 2. Route 5 Intermediate 47 [(2R,4R)-4-fluoro-1-(piperidin-4-yl)pyrrolidone] of amines, as exemplified by the preparation of lysin-2-yl]methanol trifluoroacetate. Typical procedure for preparation

[0212] [ka] Methyl (2R,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloride (intermediate Compound 45) (11.3 g, 61.7 mmol) was dissolved in methanol (280 mL) and te rt-Butyl 4-oxopiperidine-1-carboxylate (Intermediate 46) (12.2 g , 61.7 mmol), triethylamine (13 mL, 92.6 mmol) and 10% Palladium on carbon catalyst (approximately 50%, wet with HO, 6 g) was added. The mixture was stirred at 25°C under 1 atmosphere of hydrogen for 18 hours, then filtered through Celite and the filtrate was evaporated in vacuo. The resulting crude product was mixed with pentane to give tert-butyl 4-[(2 R,4R)-4-Fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl]piperi The di-1-carboxylate (18 g, 89%) was obtained as a solid. LCMS (System 1, Method D): m / z 331 (M+H) + (ESI+ve), 4. 23 minutes, 210nm.

[0213] tert-Butyl 4-[(2R,4R)-4-fluoro-2-(methoxycarbonyl) pyrrolidin-1-yl]piperidine-1-carboxylate (18 g, 54.5 mmol ) was dissolved in THF (200 mL) and the resulting solution was cooled to 0° C. Then, A solution of lithium borohydride (3 M, 54 mL, 164 mmol) was added dropwise, and the The mixture was stirred for 17 h at 25° C. The solvent was removed in vacuo and the residue was diluted with saturated NaHC The mixture was made basic with aqueous HO and partitioned between HO (600 mL) and DCM (400 mL). The aqueous layer was further extracted with EtOAc (2 x 400 mL), and then the organic layer was The mixture was combined, dried (Na2SO4), and the solvent was removed in vacuo. The residue was dissolved in pentane (3x1 0 mL) to give tert-butyl 4-[(2R,4R) -4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidine-1-carboxylate The carboxylate (14.5 g, 88%) was obtained as a gum. LCMS (System 1, Method D): m / z 303 (M+H) + (ESI+ve), 3. 57 minutes, 210nm.

[0214] tert-Butyl 4-[(2R,4R)-4-fluoro-2-(hydroxymethyl)pyridinyl] roridin-1-yl]piperidine-1-carboxylate (14.5 g, 0.42 mmol) l) was dissolved in DCM (100 mL) and the resulting solution was cooled to 0°C. Acid (30 mL) was added dropwise and the reaction mixture was stirred at 25° C. for 8 hours. Purification by evaporating and triturating the residue with pentane (3x10mL) gave [ (2R,4R)-4-fluoro-1-(piperidin-4-yl)pyrrolidin-2-yl] Methanol trifluoroacetate (Intermediate 47) (9.60 g, 100%) as a colorless gum was obtained as.

[0215] Data for intermediate 47 are in Table 2. Route 6 Intermediate 51, 4-[2-(1-methyl-1H-pyrazol-4-yl)pyrrolidine- A typical example of the preparation of amines is illustrated by the preparation of 1-yl]piperidine trifluoroacetate. Typical Procedure

[0216] [ka] 1-Methyl-4-(pyrrolidin-2-yl)-1H-pyrazole (Intermediate 50) (0. 25g, 1.66mmol), tert-butyl 4-oxopiperidine-1-carboxylate ZnC ester (Intermediate 46) (0.32 g, 1.66 mmol) in diethyl ether l2 solution (1 M, 0.083 mL, 0.083 mmol) and triethylamine (0. 72 mL, 4.97 mmol) was dissolved in MeOH (10 mL), and the resulting mixture was The mixture was then cooled to 0°C and stirred at 0°C for 4 hours. Then, NaBH3CN (0.21 g The reaction mixture was stirred at room temperature for 16 hours. The residue was stirred for 1 hour, then the solvent was removed in vacuo. The residue was diluted with H2O (50 mL) and EtOAc (1 The aqueous layer was further extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo to give the crude product. This was purified by column chromatography using alumina and MeOH / DCM as the solvent. Purification by HPLC gave tert-butyl 4-(2-(1-methyl-1H-pyrazole). -4-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (0.33 g, 59%) was obtained as a gum. LCMS (System 3, Method F): m / z 335 (M+H) + (ESI+ve), 3. 23 minutes, 215nm.

[0217] tert-Butyl 4-(2-(1-methyl-1H-pyrazol-4-yl)pyrrolidine (1-yl)piperidine-1-carboxylate (0.30 g, 0.90 mmol) To the stirred DCM (3 mL) solution was added TFA (3 mL) dropwise at 0°C, and the resulting mixture was The mixture was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo and the residue was dissolved in toluene (3×5 mL ) and co-evaporated to give 4-[2-(1-methyl-1H-pyrazol-4-yl)pyrrolidine Diazin-1-yl]piperidine trifluoroacetate (Intermediate 51) (0.20 g, 95%) was obtained as a gum.

[0218] Data for intermediate 51 are in Table 2. Route 7 Intermediate 60, 8-(3-(trifluoromethyl)-1,2,4-oxadiazole- exemplified by the preparation of (5-yl)-8-azabicyclo[3.2.1]octan-3-one Typical procedure for the preparation of ketones

[0219] [ka] tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carbohydrate To a solution of 10 g (44.4 mmol) of hydroxylate (Intermediate 17) in 100 mL of DCM Trifluoroacetic acid (25 mL) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was stirred for 1 hour, then the solvent was evaporated under reduced pressure and the residue was taken up in toluene (3 x 15 mL). When mixed with crude 8-azabicyclo[3.2.1]octan-3-one trifluoro The acetate salt (16 g, 100%) was obtained and carried on to the next reaction without further purification. did. LCMS (System 4, Method B): m / z 126 (M+H) + (ESI+ve), 2. 20 minutes, 214nm.

[0220] A solution of sodium bicarbonate (26 g, 0.32 mol) in water (100 mL) was stirred vigorously. While stirring, 8-azabicyclo[3.2.1]octan-3-one trifluoroacetate ( A solution of 16 g (0.067 mol) of HCl in 150 mL of DCM was added dropwise. Add a solution of cyanogen bromide (16.3 g, 0.153 mol) in DCM (25 mL) and The resulting reaction mixture was stirred at room temperature for 16 hours until the pH was adjusted to 7. Solid sodium carbonate was added, and the mixture was then extracted with DCM (3 x 25 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Chromatography (normal phase, silica gel 60-120 mesh, 0-3% MeOH in DCM) ) to give 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxamide. Bonitrile (6.5 g, 65%) was obtained. LCMS (System 4, Method B): m / z 151 (M+H) + (ESI+ve), 4. 13 minutes, 202nm.

[0221] 3-oxo-8-azabicyclo[3.2.1]octane-8-carbonitrile (1 g, 6.65 mmol) and 2,2,2-trifluoro-N-hydroxyacetimidamide (Intermediate 59) (1 g, 7.99 mmol) was dissolved in ethanol (50 mL) and diethyl ether was added. A solution of ZnCl2 (1 M, 7.99 mL, 7.99 mmol) in diethyl ether was added, and the resulting The resulting mixture was stirred at room temperature for 16 hours. Then, aqueous HCl (4 M, 6 mL) was added, and The mixture was heated to reflux at 90° C. overnight. A saturated sodium bicarbonate solution (50 mL ) was added and the mixture was extracted with ethyl acetate (3×10 mL). The residue was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purify by normal phase, silica gel 60-120 mesh, 0-7% EtOAC in hexane When prepared, 8-(3-(trifluoromethyl)-1,2,4-oxadiazole-5-yl) (I)-8-azabicyclo[3.2.1]octan-3-one (Intermediate 60) (517 mg , 30%) was obtained.

[0222] Data for intermediate 60 are in Table 2. Route 8 Intermediate 62, (1R,5S,6r)-N-(-methylcyclobutyl)-3-azabicyclo[4.2.1.2] Illustrated by the preparation of chloro[3.1.0]hexane-6-carboxamide hydrochloride Typical procedure for the preparation of min

[0223] [ka] Ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carbohydrate Dissolve the hydroxylate (Intermediate 9) (2.0 g, 8.16 mmol) in DCM (25 mL). Triethylamine (3.45 mL, 24.5 mmol) was added, and the mixture was cooled to 0°C. Cool and stir for 20 minutes, then add di-tert-butyl dicarbonate (2.65 g, 12 0.2 mmol) was added. The resulting reaction mixture was then stirred at 25°C for 18 hours. The solvent was removed in vacuo and the residue was dissolved in H2O (80 mL) and ethyl acetate (60 mL). The aqueous layer was further extracted with ethyl acetate (2 x 60 mL) and the combined organic layers were dried. The residue was purified by column chromatography ( phase, activated Al2O3, 0% to 40% ethyl acetate in hexane) to give 3- (tert-Butyl) 6-ethyl(1R,5S,6r)-3-azabicyclo[3.1.0 ]hexane-3,6-dicarboxylate (1.70 g, 82%) was obtained as a liquid. . LCMS (System 3, Method F): m / z 241 (M-15+H) + (ESI+ve) , 4.06 min, 202nm.

[0224] 1-Methylcyclobutan-1-amine hydrochloride (Intermediate 61) (948 mg, 7.84 m mol) was suspended in toluene (10 mL) and triethylamine (1.70 mL, 11.8 The mixture was cooled to -10°C and trimethylaluminum in toluene was added. A 2M solution (5.9 mL, 11.8 mmol) was added dropwise and stirring was continued for 20 min. 3-(tert-butyl)6-ethyl(1R,5S,6r)-3-azabicyclo [3.1.0]hexane-3,6-dicarboxylate (1.0 g, 3.92 mmol) was added at -10°C, and then the reaction mixture was stirred at 70°C for 40 hours. The vacuum was removed and the residue was partitioned between H2O (80 mL) and ethyl acetate (60 mL). The aqueous layer was further extracted with ethyl acetate (2 x 80 mL) and the combined organic layers were dried (Na The residue was purified by column chromatography (normal phase, activated Al2O3, 0% to 60% ethyl acetate in hexane) to give tert-butyl (1R,5S,6r)-6-((1-methylcyclobutyl)carbamoyl)-3-aza Bicyclo[3.1.0]hexane-3-carboxylate (560 mg, 49%) was a solid was obtained as. LCMS (System 3, Method F): m / z 293 (M-H)-(ESI-ve), 3. 80 min, 202 nm.

[0225] tert-Butyl (1R,5S,6r)-6-((1-methylcyclobutyl)carbamoyl) yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (550mg , 1.87 mmol) was dissolved in 1,4-dioxane (6 mL) and the solution was cooled to 0°C. A solution of HCl in 1,4-dioxane (4 M, 10 mL) was added and the reaction mixture was The mixture was stirred for 5 hours at 25° C. The solvent was removed in vacuo and the residue was taken up in pentane (3×3 mL). Purification by mixing yielded (1R,5S,6r)-N-(1-methylcyclobutyl )-3-Azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (Intermediate 62 ) (408 mg, 95%) was obtained as a solid.

[0226] Data for intermediate 62 are in Table 2. Route 9 Intermediate 68, N-((1-methylcyclobutyl)methyl)piperidine-4-carboxylate Typical Procedure for the Preparation of Amines, Illustrated by the Preparation of Imidazole Trifluoroacetate

[0227] [ka] 1-(tert-butyl) 4-ethylpiperidine-1,4-dicarboxylate (intermediate Compound 64) (700 mg, 0.0027 mol) and (1-methylcyclobutyl)methanesulfonate Dissolve amine (Intermediate 65) (434 mg, 0.0032 mol) in toluene (3.0 mL). triethylamine (1.13 mL, 0.008 mol), followed by toluene at -20°C. Add trimethylaluminum solution (2 M, 5.44 mL, 0.0108 mol) dropwise The mixture was stirred at -20°C for 30 minutes and then heated at 80°C for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold H2O (200 mL) and DCM (100 The aqueous layer was further extracted with DCM (2 x 100 mL) and the combined extracts were The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography. Fluorescence (normal phase, 100-120 mesh silica gel, 0%-39% acetic acid in hexane) Purification with tert-butyl 4-(((1-methylcyclobutyl)methyl) gave (I)carbamoyl)piperidine-1-carboxylate (320 mg, 38%) was obtained as a solid. This was obtained. LCMS (System 2, Method H): m / z 311 (M+H) + (ESI+ve), 1. 71 minutes, 202nm.

[0228] tert-Butyl 4-(((1-methylcyclobutyl)methyl)carbamoyl)piperidin Diazolin-1-carboxylate (320 mg, 0.00103 mol) in DCM (2 mL) The solution was cooled to 0° C., TFA (1 mL) was added dropwise, and the resulting reaction mixture was then heated to room temperature. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was triturated with toluene (3 x 5 mL). Purification by filtration gave crude N-((1-methylcyclobutyl)methyl)piperidine. 4-Carboxamide trifluoroacetate (Intermediate 66) (410 mg, 100%) was obtained. This was used without further purification.

[0229] Data for intermediate 66 are in Table 2. General synthetic procedure: Route A Example 1-1, 2-(3-methyl-1,2,4-oxadiazol-5-yl)- 6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[ 3.3] Typical procedure for the preparation of amines, exemplified by the preparation of heptane

[0230] [ka] 4-(1H-pyrazol-1-yl)piperidine (Intermediate 4) (47 mg, 0.31 m mol), 2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-azazol Pyro[3.3]heptan-6-one (Intermediate 3) (60 mg, 0.31 mmol), tri Ethylamine (0.1 mL, 0.93 mmol) and ZnCl2 (4 mg, 0.03 m mol) was dissolved in MeOH (10 mL), and the resulting mixture was stirred at 65° C. for 8 hours. The mixture was then cooled to 0°C and NaBH3CN (58 mg, 0.93 mmol) was added. The reaction mixture was stirred at 25° C. for 16 hours. The solvent was evaporated in vacuo. The residue was partitioned between H2O (50 mL) and EtOAc (40 mL), and the aqueous layer The extract was further extracted with EtOAc (2 x 40 mL). The combined organic layers were dried (Na2SO4 O4), the solvent was removed in vacuo, and the residue was purified using purification method A to give 2-( 3-Methyl-1,2,4-oxadiazol-5-yl)-6-[4-(1H-pyrazoline [3.3]heptane (Example 1) -1) (17 mg, 17%) was obtained as a solid.

[0231] Data for Example 1-1 are in Table 3. Route B Example 6-5, N-(1-methylcyclobutyl)-1-[8-(3-methyl-1,2 ,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octa-3-yl A typical procedure for the preparation of amines is illustrated by the preparation of [methyl]piperidine-4-carboxamide. Procedure

[0232] [ka] 1-Methylcyclobutan-1-amine (Intermediate 25) (27 mg, 0.3 mmol) In a toluene (10 mL) solution, triethylamine (0.12 mL, 0.86 mmol) The mixture was stirred at room temperature for 15 minutes. -1,2,4-oxadiazol-5-yl)-8-azabicyclo[3.2.1]octa -3-yl]piperidine-4-carboxylate (Intermediate 24) (100 mg, 0.29 (mmol) was added and the reaction mixture was stirred at room temperature for 15 min and then cooled to 0°C. A solution of trimethylaluminum in toluene (2 M, 0.43 mL, 0.86 mmol) The mixture was added at 0° C., and then the reaction mixture was stirred at 80° C. for 16 h. (10 mL) and ethyl acetate (20 mL), and the aqueous layer was diluted with ethyl acetate (2 × 20 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. Removal of this product gives the crude product, which can be purified by purification method L to give N-(1-methylsilyl) chlorobutyl)-1-[8-(3-methyl-1,2,4-oxadiazol-5-yl)- 8-Azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxamide Example 6-5 Isomer 1 (40 mg, 24%) as a gum and N-(1-methyl Cyclobutyl)-1-[8-(3-methyl-1,2,4-oxadiazol-5-yl) -8-Azabicyclo[3.2.1]oct-3-yl]piperidine-4-carboxamide Isomer 2 of Example 6-5 (5 mg, 3%) was obtained as a solid.

[0233] Data for Isomer 2 of Examples 6-5 are in Table 3. Route C Example 10-12 is (2S)-N-methyl-2-{1-[1-(3-methyl-1,2 ,4-oxadiazol-5-yl)azepan-4-yl]piperidin-4-yl}pyrro Typical Procedure for the Preparation of Amines, Illustrated by the Preparation of Lysine-1-carboxamide

[0234] [ka] tert-Butyl(2S)-2-{1-[1-(3-methyl-1,2,4-oxadiazolium nitrate] (5-azol-5-yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxylate The carboxylate (Intermediate 54) (260 mg, 0.60 mmol) was dissolved in a stirred solution of DCM (3 ml L) solution was added dropwise with TFA (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 h. , stirring, then evaporate the solvent in vacuo and co-evaporate the residue from toluene (3 x 5 mL). When the reaction mixture is reacted with 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{4- [(2S)-Pyrrolidin-2-yl]piperidin-1-yl}azepane trifluoroacetic acid The salt (190 mg, 95%) was obtained as a gum. LCMS (System 3, Method F): m / z 334 (M+H) + (ESI+ve), 1. 95 minutes, 225nm.

[0235] 1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{4-[(2S )-pyrrolidin-2-yl]piperidin-1-yl}azepane trifluoroacetate (30 To a stirred solution of 100 mg of HCl in 3 mL of DMF was added 533 mL of K2CO3 (533 m g, 3.86 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. Carbamyl (Intermediate 55) (240 mg, 2.58 mmol) was added and the reaction mixture The reaction mixture was stirred at 80° C. for 16 hours. Then, the reaction mixture was diluted with ice-cold water (10 mL) and The aqueous layer was extracted with EtOAc (20 mL). All organic layers were then combined, dried (Na2SO4) and evaporated under reduced pressure. This gives a crude product, which is then purified by purification method AQ and then purification method AR. , (2S)-N-methyl-2-{1-[1-(3-methyl-1,2,4-oxadiazo (azepan-4-yl)piperidin-4-yl}pyrrolidine-1-carboxamide Examples 10-12 Isomer 1 of samide (11 mg, 2%) as a gum and (2S )-N-methyl-2-{1-[1-(3-methyl-1,2,4-oxadiazole-5- yl)azepan-4-yl]piperidin-4-yl}pyrrolidine-1-carboxamide Isomer 2 of Examples 10-12 (10 mg, 2%) was obtained as a gum.

[0236] Data for Isomer 1 in Examples 10-12 and Isomer 2 in Examples 10-12 are: It is in Table 3.

[0237] [Table 2-1]

[0238] [Table 2-2]

[0239] [Table 2-3]

[0240] [Table 2-4]

[0241] [Table 3-1]

[0242] [Table 3-2]

[0243] [Table 3-3]

[0244] [Table 3-4]

[0245] [Table 3-5]

[0246] [Table 3-6]

[0247] [Table 3-7]

[0248] [Table 3-8]

[0249] [Table 3-9]

[0250] [Table 3-10]

[0251] [Table 3-11]

[0252] [Table 3-12] biological activity Example A Phospho-ERK1 / 2 assay Functional assays were performed using Alphascreen Surefire phospho-ERK1 / 2 assays. Crouch & Osmond, Comb. Chem. High Throug ERK1 / 2 phosphorylation was measured using a 100-kDa IgG antibody (HuPut Screen, 2008). This is a downstream consequence of both q / 11 and Gi / o protein-coupled receptor activation, This allows for a more accurate assay than using different assay formats for different receptor subtypes. , M1, M3 (Gq / 11 coupled) and M2, M4 receptors (Gi / o coupled) , highly preferred. CHO cells were cultured in MEM-alpha + 10% dialyzed FBS in a 96-well tissue culture plate. Once cells had attached, they were plated at a rate of 25K / well. Agonist stimulation was performed by adding 5 μL of agonist to the cells. The incubation was continued for 15 minutes at 37°C. The medium was removed and 50 μL of lysis buffer was added. 4 μL of sample was transferred to a 384-well plate and 7 μL of detection mix was added. The plate was incubated for 2 hours with gentle agitation, and then PHERAST® was added. The data obtained for each receptor subtype were analyzed using a plate reader. , pEC 50 and E max The values ​​of were calculated and the results are listed in Table 4 below.

[0253] For most of the examples, at least two diastereomers are present, unless otherwise specified. Unless otherwise specified, these can be analyzed using reversed-phase HPLC, chiral HPLC, or chiral SFC techniques. The assignment of isomers (e.g., isomer 1, isomer 2) depends on the separation technique used in the final purification step. Based on the retention time of the compound using reversed-phase HPLC, chiral HPLC, C or chiral SFC retention time, which will vary from compound to compound.

[0254] Analytical data for the active isomers are reported in Table 3. For some less active compounds The relevant data is contained in Table 4, highlighting the preference with respect to absolute stereochemistry.

[0255] [Table 4-1]

[0256] [Table 4-2] equivalent The above examples are presented for the purpose of illustrating the present invention and are not intended to limit the scope of the invention in any way. Numerous modifications and variations have been made to the principles underlying this invention. It should be understood that various changes may be made to and implemented in the particular embodiments of the invention described above without departing from the spirit and scope of the invention. All such modifications and variations will be readily apparent to those skilled in the art, as exemplified in the examples. It is intended that all such applications be encompassed by this application.

Claims

[Claim 1] An object, method or system as described in this specification.

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