Nicotinic acetylcholine receptor ligand

Abstract

Compounds of general formula (I), pharmaceutical compositions comprising the compounds, uses of the compositions, and methods for producing the compounds are disclosed. The compounds are nicotinic acetylcholine receptor (nAChR) ligands and can be used for the prevention and / or suppression of cough. 【Chemical 1】 JPEG2025517086000066.jpg5242

Description

Background Art

[0001] Nicotinic acetylcholine receptors (nAChRs) have been extensively characterized for their functions in peripheral and central neurons involved in the regulation of neurotransmission. nAChRs typically associated with the central nervous system (CNS) have been shown to occur in several subtypes. The most common nAChR subtypes are the α4β2 and α7 subtypes. The α7 nAChR belongs to a family of acetylcholine-dependent cation channels and exhibits a distinct biophysical and pharmacological profile compared to other nAChR subtypes.

[0002] These receptors are mainly expressed in neuronal tissue, but some types of immune cells also express α7 nAChR mRNA. Examples of immune cells that express α7 nAChR mRNA include macrophages, T cells, B cells, microglia, monocytes, and dendritic cells. The immunological response to protect against excessive inflammation can be regulated by the CNS via the cholinergic anti-inflammatory pathway in which acetylcholine is released from the vagus nerve. As a result, acetylcholine activates postsynaptic α7 nAChRs in intrinsic tissues including the splenic nerve after stimulation, and then inhibits inflammatory cytokines.

[0003] Various nicotinic compounds are known to interact with the α7 nAChR and have thus been proposed for therapy. However, the drawback of these known nicotinic compounds is that they are associated with various unwanted side effects, for example, by stimulating muscle and ganglionic receptors.

[0004] There is a need for compounds, compositions, and methods for preventing or treating various conditions or disorders, such as CNS disorders, including alleviating the symptoms of these disorders without associated side effects. More specifically, there is a need for compounds, compositions, and methods that affect CNS function without significantly affecting nicotinic receptor subtypes that can induce undesirable side effects such as significant activity in the cardiovascular and skeletal muscle sites. SUMMARY OF THE INVENTION

[0005] According to an aspect of the invention, there is provided a compound of general formula (I),

Chemical formula

[0006] According to an aspect of the invention, there is provided a compound of general formula (I),

Chemical formula

[0007] According to another aspect of the present invention, a compound of general formula (II),

Chemical formula

[0008] Also provided are pharmaceutical compositions containing a compound of general formula (I) or (II), the use of a compound of general formula (I) or (II), the use of a composition containing a compound of general formula (I) or (II), and methods for producing compounds of general formula (I) and (II) as defined in the appended independent claims to be referred to herein. Preferred or advantageous features of the present invention are described in the dependent claims and further explained below.

[0009] The compounds of general formula (I) and (II) of the present invention advantageously act on the central nervous system without inducing potentially undesirable side effects of nicotinic receptor subtypes. These potentially undesirable side effects can include significant activity in the cardiovascular and skeletal muscle sites.

[0010] More specifically, the compounds of general formula (I) and (II) of the present invention are α7 nAChR agonists, which provide a novel non-narcotic approach to therapy in patients with acute and chronic cough. As described below, the potential application of selective α7 nAChR agonists as antitussives according to the present invention was demonstrated in in vivo experiments by inhibiting the cough response in guinea pigs induced by citric acid.

[0011] Furthermore, the α7 nAChR agonists described herein may be beneficial for the treatment of the causes of cough. In preclinical trials of lung diseases, α7 nAChR agonists have shown anti-inflammatory effects in models of acute lung injury, allergen challenge, and gram-negative bacterial infection.

[0012] According to another aspect of the present invention, a compound of general formula (I),

Chemical formula

[0013] According to an aspect of the present invention, a compound of general formula (I),

Chemical formula

[0014] According to a further aspect of the present invention, a compound of general formula (II),

Chemical formula

[0015] As shown in Figure 1A, the pharmacological active element of α7 nAChR is adjacent to a cationic central hydrogen bond receptor and contains a hydrophobic moiety considered essential for π interaction. The quinuclidine basic nitrogen occupies the bridgehead position within the azabicyclic system and provides the maximum electrostatic interaction with minimal steric requirements. Due to the strong basicity of the quinuclidine derivative (pKa ~ 10 - 11), α7 nAChR ligands exist in the physiological condition of the cationic form with a clearly defined proton orientation. A small aliphatic group (e.g., methyl) or a larger group (e.g., benzyl) at the 2-position of the azabicyclic ring may reduce the binding to nAChR.

[0016] The compounds of the present invention incorporate a (pyridin-3-yl)methyl moiety that improves the pharmacological profile, resulting in better selectivity (especially higher than that of the 5-HT3 receptor), increased α7 nAChR affinity, and elimination of the inhibition of the hERG (human ether-à-go-go related gene) channel.

[0017] As used herein, the term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine, or iodine.

[0018] As used herein, the term aryl refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 - 14 carbon atoms in the ring. Common aryl groups include C 6 ~C 14 aryl, for example C 6 ~C 10 aryl. C 6 ~C 14Non-limiting examples of aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylylenyl, and fluorenyl. Optionally substituted aryl groups may include substituents described herein.

[0019] As used herein, the term heteroaryl refers to an aromatic group having 5 to 14 ring atoms (e.g., 5 to 10 ring atoms), containing carbon atoms, and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms. Examples of heteroaryl groups include thienyl (thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl (pyridinyl) including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl. When a heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom may be in the form of an N-oxide, e.g., pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide. An "optionally substituted heteroaryl" group may include substituents described herein.

[0020] Optionally, one or both of the aryl groups of general formula (I) and general formula (II), and each aryl or heteroaryl of general formula (I) are monocyclic. For example, one or both of the aryl groups of general formula (I) and general formula (II), and each aryl or heteroaryl of general formula (I) may be independently selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. In one embodiment, R

[0021] Optionally, one or both of the aryl groups of general formula (I) and general formula (II), and each aryl or heteroaryl of general formula (I) is monocyclic. For example, one or both of the aryl groups of general formula (I) and general formula (II), and each aryl or heteroaryl of general formula (I) may be independently selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. In one embodiment, R 1 does not contain phenyl.

[0022] Optionally, one or both of the aryl groups of general formula (I) and general formula (II), and each aryl or heteroaryl of general formula (I) are polycyclic. For example, one or both of the aryl groups of general formula (I) and general formula (II), each aryl or heteroaryl of general formula (I) may be independently selected from the group consisting of naphthalenyl, anthracenyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzodioxolanyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, purinyl, thienopyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and azulenyl.

[0023] Optionally, one or both of the aryl groups of general formula (I) and general formula (II), each aryl or heteroaryl of general formula (I) is acenaphthylene, acephenanthrylene, acridine, anthracene, anthracene, 9,10-anthracenedione, 9(10H)-anthracenone, anthraquinone, anthrone, benz[e]acephenanthrylene, benz[c]acridine, benz[a]anthracene, 7H-benz[de]anthracen-7-one, benzanthrone, benzo[b]chrysene, benzo[c]chrysene, benzo[g]chrysene, benzo[c]cinnoline, benzo[a]dibenzothiophene, benzo[b]fluoranthene, benzo[ghi]fluoranthene, benzo[j]fluoranthene, benzo[k]fluoranthene, 11H-benzo[a]fluorene, 11H-benzo[b]fluorene, 7H-benzo[c]fluorene, benzo[h]naphtho[1,2-f]quinoline, benzo[b]naphtho[2,1-d]thiophene, benzo[rst]pentaphene, benzo[ghi]perylene, benzo[c]phenanthrene, benzo[a]pyrene, benzo[e]pyrene, benzo[f]quinoline, benzo[h]quinoline, benzo[b]triphenylene, biphenylene, 9H-carbazole, chrysene, coronene, 4H-cyclopenta[def]phenanthrene, cyclopenta[cd]pyrene, dibenz[a,h]acridine, dibenz[a,j]acridine, dibenz[c,h]acridine, dibenz[a,c]anthracene, dibenz[a,h]anthracene, dibenz[a,j]anthracene, 7H-dibenzo[a,g]carbazole, 13H-dibenzo[a,i]carbazole, 7H-dibenzo[c,g]carbazole, dibenzo[b,def]chrysene, dibenzo[def,mno]chrysene, dibenzo[def,p]chrysene, dibenzo[b,h]phenanthrene, dibenzo[a,e]pyrene, dibenzo[a,h]pyrene, dibenzo[a,i]pyrene, dibenzo[a,1]pyrene, dibenzothiophene, fluoranthene, 9H-fluorene, 9H-fluoren-9-one, indeno[1,2,3-cd]pyrene, 1H-indole, isoquinoline, naphthacene, naphthalene, naphtho[1,2,3,4-def]chrysene, naphtho[2,It may be independently selected from the group consisting of quinoline, pentaphene, perylene, 1H-phenalene, phenanthraquinone, phenanthrene, 9,10-phenanthrenium, phenanthridine, 1,10-phenanthroline, phenanthro[4,5-bcd]thiophene, phenazine, phenazon, picene, pyrene, quinoline, triphenylene, and 9H-xanthene.,

[0024] Optionally, one or both of the aryl groups of general formula (I) and general formula (II), and each aryl or heteroaryl of general formula (I) are substituted with, for example, 1, 2, or 3 substituents.

[0025] Optionally, the substituents are alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br, or I), --OR’, --NR’R’’, --CF3, --CN, --NO 2 ,--SR’, --N 3 ,--C(=O)NR’R’’, --NR’C(=O)R’’, --C(=O)R’, --C(=O)OR’, --OC(=O)R’, --O(CR’R’’), --C(=O)R’, --SO 2 R’, and --SO 2 NR’R’’ are independently selected, where R’ and R’’ are each independently hydrogen, lower alkyl. Lower alkyl may be methyl, ethyl, propyl, isopropyl, butyl, or t-butyl. For example, the substituent may be a straight-chain or branched alkyl containing C 1 ~C 8 , preferably C 1 ~C 5 , for example, methyl, ethyl, or isopropyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl).

[0026] Optionally, R’ and R’’ are joined to form a cyclic functional group.

[0027] Optionally, the substituent is independently selected from the group consisting of cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

[0028] Optionally, R in general formulas (I) and (II) 1 is selected from 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0029] Optionally, R in general formula (I) 2 is selected from indolyl, benzofuranyl, benzothiazolyl, and phenyl.

[0030] Optionally, R in general formula (I) 1 and R 2 may be fused. Thus, R in general formula (I) 1 and R 2 may be joined together to form an optionally substituted aryl group. R in general formula (I) 1 and R 2 may together form a carbocyclic or heterocyclic aromatic ring. R in general formula (I) 1 and R 2 may together form a monocyclic or polycyclic group. For example, R in general formula (I) 1 and R 2 may together form a 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, or 17-membered ring.

[0031] Optionally, one or both aryl groups in general formula (I) may contain a carbocyclic or heterocyclic aromatic ring. Optionally, one or both aryl groups in general formula (I) may be an optionally substituted carbocyclic or heterocyclic aromatic ring.

[0032] Optionally, R in general formula (I) 1 and R 2may together form an optionally substituted aryl or an optionally substituted heteroaryl. In this case, R in general formula (I) 1 and R 2 may each independently be an optionally substituted aryl or an optionally substituted heteroaryl. Therefore, R in general formula (I) 1 and R 2 may be joined together to form an optionally substituted aryl group or an optionally substituted heteroaryl group. R in general formula (I) 1 and R 2 may together form a monocyclic or polycyclic group. For example, R in general formula (I) 1 and R 2 may together form a 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring, 14-membered ring, 15-membered ring, 16-membered ring, or 17-membered ring.

[0033] Optionally, the compound is selected from the group consisting of: 2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole, 3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucidine, 2-Phenyl-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole, 5-[6-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxy-3-pyridyl]-1H-indole, 5-[6-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1H-indole, 5-[5-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxypyrazin-2-yl]-1H-indole, 6-[6-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine, 2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine, 3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine, 6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline, 2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline, 3-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline, 3-(6-Imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine, and 2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0034] Advantageously, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole significantly reduces the number of citric acid-induced coughs compared to the saline control.

[0035] Advantageously, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine significantly decreases the number of citric acid-induced coughs compared to the saline control.

[0036] Advantageously, 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole significantly decreases the number of citric acid-induced coughs compared to the saline control.

[0037] Optionally, the compound is selected from the group consisting of: trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (2) trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine (4) trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole (5) cis-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (6) cis-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (7) trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine (8) trans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole (9) trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (10) trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (11) (2S,3R)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (2S,3R-11) (2R,3S)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (2R,3S-11) trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine (12) trans-tert-Butyl 2-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylate (13) trans-2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14) trans-2-Bromo-5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (15) trans-2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole (16) trans-3-[2-(3-pyridylmethyl)quinucidin-3-yl]oxyisoquinoline (17) trans-2-[2-(3-pyridylmethyl)quinucidin-3-yl]oxyquinoline (18) trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucidine (19) trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole (20)

[0038] Advantageously, trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole significantly reduces the number of citric acid-induced coughs as compared to the saline control.

[0039] Advantageously, trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinucidine significantly decreases the number of citric acid-induced coughs as compared to the saline control.

[0040] Advantageously, trans-5-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1H-indole significantly decreases the number of citric acid-induced coughs as compared to the saline control.

[0041] Furthermore, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole also showed a significant improvement in the cough latency period at a dosage about 20 to 30 times lower than that of codeine, which is regarded as a "representative" narcotic antitussive.

[0042] Accordingly, in a preferred embodiment of the present invention, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof is provided. Accordingly, in another preferred embodiment of the present invention, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof is provided. Accordingly, in another preferred embodiment of the present invention, 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole is provided.

[0043] In a preferred embodiment of the present invention, a compound of the following formula or a pharmaceutically acceptable salt thereof is provided.

Chemical formula

[0044] In a preferred embodiment of the present invention, a compound of the following formula or a pharmaceutically acceptable salt thereof is provided.

Chemical formula

[0045] In a preferred embodiment of the present invention, a compound of the following formula or a pharmaceutically acceptable salt thereof is provided.

Chemical formula

[0046] In a preferred embodiment of the present invention, a compound of the following formula or a pharmaceutically acceptable salt thereof is provided.

Chemical formula

[0047] In a preferred embodiment of the present invention, a compound of the following formula or a pharmaceutically acceptable salt thereof is provided. [Chemistry]

[0048] In a preferred embodiment of the present invention, a compound of the following formula or a pharmaceutically acceptable salt thereof is provided. [Chemistry]

[0049] Optionally, the pharmaceutically acceptable salt is selected from chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, ascorbate; salts containing acidic amino acids such as aspartate or glutamate, or one or more of hydrates or ethanol solvates.

[0050] Optionally, the compounds of general formulas (I) and (II) may exist in unsolvated forms as well as solvated forms including hydrated forms. A hydrate refers to a complex formed by the combination of water molecules with solute molecules or ions. A solvate refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Solvates are meant to include hydrates. Some examples of solvents include, but are not limited to, methanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Optionally, the compounds of general formulas (I) and (II) may exist as solid materials in, for example, multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the intended uses of the present invention and are intended to be within the scope of the present invention.

[0051] "Tautomers" mean compounds formed by the phenomenon of proton shift of one atom of a molecule to another atom (see Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992)). Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. The compounds described herein may have one or more tautomers and thus may include various isomers. All such isomeric forms of these compounds are expressly included in the present invention.

[0052] "Isomers" means compounds that have the same molecular formula but differ in the nature or sequence of the bonds between their atoms or in the arrangement of those atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". "Stereoisomers" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms when they have one or more asymmetric centers or double bonds with asymmetric substitution and can thus be produced as individual stereoisomers or mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers (mirror image isomers)". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers may be characterized by the absolute configuration of their asymmetric center, by the R and S sequence rules of Cahn and Prelog, or in the manner in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., as the (+) or (-) isomers, respectively). Chiral compounds may exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a racemic mixture. Unless otherwise indicated, this specification is intended to include individual stereoisomers as well as mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see the discussion in Chapter 4 of Advanced Organic Chemistry, 6th edition J. March, John Wiley and Sons, New York, 2007).

[0053] The present invention also encompasses isotopically labeled compounds that are identical to those recited herein but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include 2H (deuterium, D), 3 3H (tritium), 11 13C,13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I, etc., but not limited to these, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. Unless otherwise specified, when a position is specifically designated as H or hydrogen, the position is understood to have hydrogen in its natural abundance isotope composition or its isotopes, such as deuterium (D) or tritium ( 3 H). Specific isotope-labeled compounds of the present invention (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) and fluorine-18 (i.e., 18 F) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosing requirements) and may thus be preferred in some situations. The isotope-labeled compounds of the present invention can generally be prepared by substituting an isotope-labeled reagent for a non-isotope-labeled reagent according to procedures similar to those described herein.

[0054] According to the present invention, there is also provided a pharmaceutical composition comprising a compound described herein and a pharmaceutically or therapeutically acceptable excipient or carrier, e.g., a pharmaceutical composition comprising a compound of general formula (I) or (II) and a pharmaceutically or therapeutically acceptable excipient or carrier.

[0055] For example, the pharmaceutical composition may contain 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may contain 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinucidine or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may contain 5-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1H-indole.

[0056] For example, the pharmaceutical composition may contain trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may contain trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinucidine or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may contain trans-5-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1H-indole.

[0057] Pharmaceutically acceptable excipients or carriers may include fillers, binders, disintegrants, lubricants, glidants, complexing agents, solubilizing agents, and surfactants, which may be selected to facilitate the administration of the compound by a particular route. Examples of carriers include various sugars such as calcium carbonate, calcium phosphate, lactose, glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. Carriers may also include, as solvents, or for suspensions, physiologically compatible liquids such as sterile solutions of water for injection (WFI), saline, dextrose solutions, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycol, liquid paraffin, etc. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, microcrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowax C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor oil, mineral oil, polyethylene glycol (e.g., PEG400 or PEG4000 - 8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, doxate sodium, cyclodextrin (e.g., 2 - hydroxypropyl -.Delta-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, di-fatty acid esters of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan ester Tween (registered trademark)), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, e.g., sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray-dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrate, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropylmethylcellulose), HPC (hydroxypropylcellulose), hydroxyethylcellulose, etc.

[0058] According to the present invention, there are also provided compounds described herein for use in the treatment of a disease or disorder, e.g., compounds of general formula (I) or (II) for use in the treatment of a disease or disorder. For example, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder. For example, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinucidine or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder. For example, 5-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder.

[0059] For example, trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder. For example, trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder. For example, trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder.

[0060] According to the present invention, there are also provided compounds described herein for use in the treatment of a disease or disorder mediated by the α7 nicotinic acetylcholine receptor (nAChR), for example, compounds of general formula (I) or (II) for use in the treatment of a disease or disorder mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0061] For example, trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof may be for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinucidine or a pharmaceutically acceptable salt thereof may be for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, trans-5-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof may be for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0062] Advantageously, the compounds described herein, for example, the compounds of general formulas (I) and (II), competitively inhibit the binding of radiolabeled MLA to the human α7 nAChR subtype with equilibrium constant (Ki) values of 1 to 1000 nM. Accordingly, the compounds described herein, for example, the compounds of general formulas (I) and (II), are suitable for use in the treatment of diseases or disorders mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0063] The term "mediated", e.g., "mediated by nAChR", is understood to mean linked to the activity of nAChR. For example, the term "mediated" can be understood to mean, e.g., "transcriptional control or translational control", or "transcriptional control or translational control", e.g., controlled by upregulation or downregulation. Preferably, the expression "mediated by nAChR" can be understood to be related to the activation (i.e., opening) of the nAChR ion channel. More specifically, a conformational change in the nAChR ion channel can occur upon binding of a compound that opens the hydrophobic gate and then leads to a four-fold symmetric twist of the M1-M4 domains that allows the passage of ions. For example, this process can be accompanied by permeability to monovalent Na + and K + ions, as well as Ca 2+ ions. Advantageously, the ability of nAChR to change intracellular calcium levels can lead to the activation of different downstream intracellular pathways such as neuronal signaling and plasticity.

[0064] Furthermore, the term "mediated" can be understood to include, for example, the facilitation of intracellular signaling via a G-protein binding cluster contained within the intracellular loop of the α7 subunit.

[0065] Optionally, the compounds described herein, e.g., the compounds of general formulas (I) and (II), can desensitize nAChR. Thus, the compounds described herein, e.g., the compounds of general formulas (I) and (II), can be suitable for desensitizing nAChR. Accordingly, compounds described herein, e.g., compounds of general formula (I) or (II), are also provided for use as nAChR desensitizing agents.

[0066] More specifically, nAChR can rapidly convert to a closed state followed by a desensitized state after activation. Desensitization is the loss of a biological response to agonist stimulation. Upon washout of the ligand, the receptor may return to its basal or resting allosteric state.

[0067] According to the present invention, there is also provided the use of a compound described herein in the manufacture of a medicament for the treatment of a disease or disorder, for example, the use of a compound of general formula (I) or (II) in the manufacture of a medicament for the treatment of a disease or disorder.

[0068] According to the present invention, there is also provided a method for treating a disease or disorder, the method comprising the step of administering to a patient in need thereof a compound described herein, or a pharmaceutical composition described herein. For example, there is provided a method for treating a disease or disorder comprising the step of administering to a patient in need thereof a compound of general formula (I) or (II), or a pharmaceutical composition comprising a compound of general formula (I) or (II). For example, a method for treating a disease or disorder may comprise the step of administering 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucridin-3-yl]oxy-1,3,4-thiadiazole, or a pharmaceutical composition described herein, to a patient in need thereof.

[0069] Optionally, the disease or disorder is a disease or disorder mediated by α7 nAChR.

[0070] Optionally, the disease or disorder is selected from cognitive and neurodegenerative diseases, psychotic disorders such as schizophrenia, acute nociception, neuropathic, or inflammatory pain, and mood disorders such as depression and inflammation.

[0071] For example, the disease or disorder is i) pain including one or more of acute, neuropathic, inflammatory, neuropathic, chronic pain, severe chronic pain, postoperative pain, cancer-related pain, angina, renal colic or biliary colic, menstruation, migraine, gout, arthritis, rheumatoid-like diseases, tenosynovitis, vasculitis, trigeminal neuralgia or herpes zoster neuralgia, painful diabetic neuropathy, burning pain, low back pain, causalgia syndrome, and brachial plexus avulsion; ii) metabolic syndrome, weight gain, type I diabetes, type II diabetes, or diabetic neuropathy; iii) one or more of psoriasis, asthma, atherosclerosis, idiopathic pulmonary fibrosis, chronic and acute inflammation, psoriasis, endotoxemia, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, allograft rejection, chronic graft rejection, asthma, atherosclerosis, mononuclear phagocyte-dependent lung injury, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute cholangitis, aphthous stomatitis, ileal pouchitis, glomerulonephritis, lupus nephritis, thrombosis, and graft-versus-host reaction, and / or iv) selected from the group consisting of one or more of age-associated memory impairment, mild cognitive impairment, early-onset dementia, early-onset Alzheimer's disease, senile dementia, Alzheimer's type dementia, mild to moderate Alzheimer's type dementia, Lewy body dementia, vascular dementia, Alzheimer's disease, stroke, AIDS dementia complex, attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, schizophrenia, schizophreniform disorder, schizoaffective disorder, cognitive impairment in schizophrenia, and cognitive dysfunction in schizophrenia.

[0072] The pharmaceutical composition may be for use in improving any of those conditions, diseases, and symptoms associated with the disorders.

[0073] Preferably, the treatment is for preventing and / or suppressing cough, preventing the progression of cough, improving the symptoms of cough, and improving the recurrence of cough. The treatment may be for treating the origin of cough. Hereinafter, "cough" is understood to be related to the expulsion of air from the lungs, for example, from the lungs of a subject, for example, from the lungs of a human subject. Advantageously, the compounds of the invention, for example, the compounds of general formulas (I) and (II) can be used as antitussives. Accordingly, there are also provided compounds described herein for use as antitussives, such as compounds of general formula (I) or (II) for use as antitussives. More specifically, an antitussive can inhibit cough through a central mechanism, or a peripheral mechanism, or a mixture of the two mechanisms.

[0074] The pharmaceutical compositions described herein can be used as selective α7 nAChR agonists. The pharmaceutical compositions described herein can also be used as cough suppressants. The pharmaceutical compositions described herein can also be used as anti-inflammatory agents, for example, as anti-inflammatory agents for acute lung injury, allergen exposure, and / or Gram-negative bacterial infection. As a result, the pharmaceutical compositions described herein can be for use in the treatment of inflammation, for example, the treatment of acute lung injury, the treatment of allergen exposure, and / or the treatment of Gram-negative bacterial infections.

[0075] The compounds described herein can also be used as adjuvant therapies in combination with existing therapies, for example, in the management of any of the aforementioned types of diseases and disorders. In such situations, it is preferred to administer the active ingredient in a manner that minimizes the effect on nAChR. Including subtypes such as those related to muscle and ganglia. This can be achieved by targeted drug delivery and / or by adjusting the dosage so that the desired effect is obtained without meeting the threshold dosage required to achieve significant side effects.

[0076] Optionally, the uses, uses or methods described herein may be such that the compound is administered orally. Preferably, the compound is 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucridin-3-yl]oxy-1,3,4-thiadiazole which is administered orally.

[0077] Optionally, the uses, uses or methods described herein may be such that the compound is administered by inhalation.

[0078] Optionally, the uses, uses or methods described herein may be such that the compound is administered in dry powder form. Preferably, the compound is the dry powder 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole, for example, dry powder insufflated 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole.

[0079] Optionally, the uses, uses or methods described herein may be such that the compound is administered in spray form. Preferably, the compound is atomized 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole.

[0080] Optionally, the uses, uses or methods described herein may be such that the compound is orally administered at a dose of 0.1 mg to 1 g / kg per day.

[0081] For example, the compound may be orally administered at a dose of at least about 0.00001 mg / kg per day, at least about 0.0001 mg / kg per day, at least about 0.001 mg / kg per day, at least about 0.01 mg / kg per day, at least about 0.1 mg / kg per day, at least about 0.2 mg / kg per day, at least about 0.3 mg / kg per day, at least about 0.4 mg / kg per day, at least about 0.5 mg / kg per day. The compound may include any range from a given endpoint.

[0082] For example, the compound may be orally administered at a dose of about 0.01 g / kg or less per day, about 0.1 g / kg or less per day, about 0.5 g / kg or less per day, about 0.9 g / kg or less per day, about 1 g / kg or less per day, about 1.1 g / kg or less per day, about 1.2 g / kg or less per day, about 1.5 g / kg or less per day, or about 2 g / kg or less per day. The compound may include any range from a given endpoint.

[0083] For example, the compound may be orally administered at a dose of at least about 0.00001 mg / kg per day to about 2 g / kg or less per day, at least about 0.0001 mg / kg / day to about 1.5 g / kg / day or less, at least about 0.001 mg / kg / day to about 1.2 g / kg / day or less, at least about 0.01 mg / kg per day to about 1.1 g / kg or less per day, at least about 0.1 mg / kg / day to about 1 g / kg or less, at least about 0.2 mg / kg / day to about 0.9 g / kg / day or less, at least about 0.3 mg / kg / day to about 0.5 g / kg / day or less, at least about 0.4 mg / kg per day to about 0.1 g / kg or less per day, or at least about 0.5 mg / kg per day to about 0.01 g / kg or less per day. The compound may include any range from a given endpoint.

[0084] For example, the compound for use, the use or method, may be such that the compound is orally administered at a dose of 0.1 mg / kg per day, or it may be 0.2 mg / kg per day, 0.3 mg / kg per day, 0.4 mg / kg per day, 0.5 mg / kg per day, 1 mg / kg / day, 2 mg / kg per day, 3 mg / kg / day, 4 mg / kg per day, 5 mg / kg per day, 10 mg / kg / day, 15 mg / kg / day, 20 mg / kg per day, 25 mg / kg per day, 30 mg / kg / day, 35 mg / kg / day, 40 mg / kg / day, 45 mg / kg per day, 50 mg / kg per day, 100 mg / kg per day, 150 mg / kg / day, 200 mg / kg / day, 250 mg / kg per day, 300 mg / kg / day, 350 mg / kg per day, 400 mg / kg per day, 450 mg / kg per day, 500 mg / kg per day, 550 mg / kg per day, 600 mg / kg per day, 650 mg / kg per day, 700 mg / kg per day, 750 mg / kg per day, 800 mg / kg per day, 850 mg / kg per day, 900 mg / kg per day, 950 mg / kg per day, 1000 mg / kg / day, 1100 mg / kg / day, 1200 mg / kg per day, 1300 mg / kg per day, 1400 mg / kg / day, 1500 mg / kg / day, 1600 mg / kg / day, 1700 mg / kg per day, 1800 mg / kg / day, 1900 mg / kg / day, 2000 mg / kg / day. The compound may include any range from a given endpoint.

[0085] Optionally, the use, use, or method described herein may be such that the compound is orally administered at 5 mg to 2 g per day.

[0086] For example, the compound may be orally administered at a dose of at least about 0.1 mg / day, at least about 1 mg / day, at least about 3 mg / day, at least about 4 mg / day, at least about 5 mg / day, at least about 5.1 mg / day, at least about 6 mg / day, at least about 10 mg / day, at least about 50 mg / day. The compound may include any range from a given endpoint.

[0087] For example, the compound may be orally administered at a dosage of about 0.2 g / day or less, about 0.5 g / day or less, about 1 g / day or less, about 1.5 g / day or less, about 2 g / day or less, about 2.5 g / day or less, about 3 g / day or less, about 5 g / day or less, about 10 g / day or less. The compound may include any range from a given endpoint.

[0088] For example, the compound may be orally administered at a dosage of at least about 0.1 mg / day to about 10 g / day or less, at least about 1 mg / day to about 5 g / day or less, at least about 3 mg / day to about 3 g / day or less, at least about 4 mg / day to about 2.5 g / day or less, at least about 5 mg / day to about 2 g / day or less, at least about 5.1 mg / day to about 1.5 g / day or less, at least about 6 mg / day to about 1 g / day or less, at least about 10 mg / day to about 0.5 g / day or less, at least about 50 mg / day to about 0.2 g / day or less. The compound may include any range from a given endpoint.

[0089] For example, the compound may be orally administered at a dosage of 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1100 mg / day, 1200 mg / day, 1300 mg / day, 1400 mg / day, 1500 mg / day, 1600 mg / day, 1700 mg / day, 1800 mg / day, 1900 mg / day, 2000 mg / day, 2100 mg / day, 2200 mg / day, 2300 mg / day, 2400 mg / day, 2500 mg / day. The compound may include any range from a given endpoint.

[0090] The expression "about" regarding a numerical value is understood to be average ±10%, preferably ±5%, for example ±10% w / w, preferably ±5% w / w.

[0091] Optionally, the compounds, uses, or methods for use described herein may be such that the composition is in the form of a tablet. The tablet may be a film-coated tablet. The uses, uses, or methods described herein may be such that the composition is in the form of a capsule, for example a gelatin capsule.

[0092] Optionally, the compounds, uses, or methods for use described herein may be such that the compound is administered parenterally, topically, rectally, transmucosally, or enterally.

[0093] According to the present invention, there is also provided a method for producing a compound of general formula (I) or (II) shown in Scheme (I). [Chemical formula]

[0094] Optionally, R 1 and R 2 are as defined above. For example, for a compound of general formula (I), R 1 and R 2 may each be the same or different, and one or both of the aryl groups contain a carbocyclic or heterocyclic aromatic ring, one or both of the aryl groups are monocyclic or polycyclic, and R 1 and R 2 are optionally fused. For a compound of general formula (II), R 1 is an optionally substituted aryl group containing a carbocyclic or heterocyclic aromatic ring, the aryl group is monocyclic or polycyclic, and X is halogen or triflate. Alternatively, for a compound of general formula (I), R 1is optionally substituted aryl or optionally substituted heteroaryl, and R 2 is halogen, triflate, optionally substituted aryl, optionally substituted heteroaryl, or absent. In Scheme (I), X may be halo or triflate. Halo may be fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts).

[0095] As will be apparent to those skilled in the art, the compounds of formulas (I) and (II) include ethers of 3-hydroxy-2-(3-pyridylmethyl)quinuclidine. The methods by which the compounds of the present invention can be prepared can vary, but the compounds can be advantageously prepared using intermediates (e.g., ketones and alcohols) generated during the synthesis of the target compounds shown in Scheme (I) above.

[0096] Although other synthetic strategies will be apparent to those skilled in the art, 2-(3-pyridylmethyl)quinuclidine derivatives can be synthesized by reduction of the aldol condensation product formed from 3-pyridinecarboxaldehyde and quinuclidin-3-one.

[0097] For example, 3-quinuclidinone hydrochloride may be reacted with pyridine-3-carboxaldehyde in the presence of potassium hydroxide in methanol. Then, 2-((3-pyridinyl)methylene)quinuclidin-3-one results from the reaction.

[0098] The multi-step reduction of the conjugated enone functional group can be achieved via several different procedures to provide 2-(3-pyridylmethyl)quinuclidin-3-ol. For example, catalytic hydrogenation (palladium catalyst) of the enone can produce the saturated ketone, 2-(3-pyridylmethyl)quinuclidin-3-one, which is an intermediate in the synthesis of the compounds of the present invention.

[0099] The reduction of a ketone to an alcohol can be achieved, for example, using sodium borohydride, aluminum isopropoxide, or other reagents known in the art of chemical synthesis for performing similar reductions.

[0100] The alcohol 2-(3-pyridylmethyl)quinuclidin-3-ol may be a mixture of cis and trans diastereomers (the former being predominant) and may also be an intermediate in the synthesis of the compounds of the present invention.

[0101] The choice of reducing agent can affect the cis / trans ratio. The enantioselective synthesis of cis-3-quinuclidinol can be carried out by Ru-catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution or by the Meerwein-Ponndorf-Verley reaction.

[0102] Successively, the inversion of the trans isomer of 2-substituted cis-3-quinuclidinol can be carried out using p-nitrobenzoic acid as a nucleophilic partner in the Mitsunobu reaction. The various combinations of aryl groups in general formula (I) can be achieved via the Suzuki cross-coupling reaction.

[0103] Compounds 1 to 20 can also be named as follows. cis-2-(3-pyridylmethyl)quinuclidin-3-ol (1) trans-[2-(3-pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (2) trans-2-(3-pyridylmethyl)quinuclidin-3-ol (3) trans-3-[(5-bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine (4) trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole (5) cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (6) cis-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole(7) trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine(8) trans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole(9) trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine(10) trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole(11) (2S,3R)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole(2S,3R-11) (2R,3S)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole(2R,3S-11) trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine(12) trans-tert-Butyl 2-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylate(13) trans-2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine(14) trans-2-Bromo-5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole(15) trans-2-(1H-Indol-5-yl)-5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole(16) trans-3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline(17) trans-2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline (18) trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (19) trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (20)

[0104] As will be apparent to those skilled in the art, the methods by which the compounds of the present invention can be prepared can be varied. For example, the compounds can be advantageously prepared using intermediates generated during the synthesis of the target compounds, as shown in Scheme (II). Since 2,3-disubstituted quinuclidine derivatives can form geometric isomers, both cis- and trans-2-(3-pyridylmethyl)quinuclidin-3-ol were explored as intermediates in the synthesis of the target molecule. Reduction of 2-(3-pyridylmethyl)quinuclidin-3-one with aluminum isopropoxide mainly gave one diastereomer, cis-alcohol 1, presumably brought about by selective hydride transfer to the face with the least steric hindrance of the carbonyl moiety. Inversion of the cis-alcohol 1 to the trans isomer 3 was achieved via Mitsunobu reaction with p-nitrobenzoic acid and subsequent hydrolysis of the resulting ester 2, as shown in Scheme (II). [Chemical Formula]

[0105] The reagents and conditions of Scheme (II) are as follows. (a) p-Nitrobenzoic acid, diisopropyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0-25°C, 12 h, (b) Lithium hydroxide, tetrahydrofuran / water, 12 h, (c) 5-Bromo-2-chloropyridine, potassium tert-butoxide, tetrahydrofuran, 25°C, 12 h, (d) Indole-5-boronic acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, cesium carbonate, dioxane / water, 90 °C, 12 h, (e) 3,6-Dichloropyridazine, potassium tert-butoxide, tetrahydrofuran, 25 °C, 2 h, (f) Indole-5-boronic acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90 °C, 12 h, (g) 2,5-Dichloropyrazine, potassium tert-butoxide, tetrahydrofuran, 25 °C, 2 h, (h) Indole-5-boronic acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate, dimethoxyethane / water, 90 °C, 12 h.

[0106] Reaction with cis alcohol or trans alcohol 1 or 3, and consecutive nucleophilic substitution of the halogen in the dihalogen derivative of the nitrogen-containing aromatic heterocycle after Suzuki coupling resulted in a series of ethers. As the electronegative nitrogen-containing aromatic heterocycles, pyridine, pyrazine, pyridazine, and thiadiazole were explored. Cross-coupling reactions of various arylboronic acids with intermediates 4, 6, 8, 10, and 15 gave a set of diverse biaryl ethers. To evaluate the effect of the benzene ring fused to pyridine, isoquinoline and quinoline ethers 17 and 18 were obtained as shown in Scheme (III).

Chemical formula

[0107] The reagents and conditions of Scheme (III) are as follows. (a) 3,6-Dichloropyridazine, potassium tert-butoxide, tetrahydrofuran, 25 °C, 2 h, (b) Indole-5-boronic acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90 °C, 12 h, (c) 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine, (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, cesium carbonate, dioxane / water, 90 °C, 12 h, (d) 1-(tert-Butoxycarbonyl)pyrrole-2-boronic acid, (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90 °C, 12 h, (e) Hydrogen chloride, dioxane, 25 °C, 12 h, (f) 2,5-Dibromo-1,3,4-thiadiazole, potassium tert-butoxide, tetrahydrofuran, 25 °C, 2 h, (g) Indole-5-boronic acid, (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, cesium carbonate, dioxane / water, 90 °C, 12 h, (h) 2-Chloroquinoline, potassium tert-butoxide, tetrahydrofuran, 25 °C, 2 h, (i) 3-Chloroisoquinoline, sodium hydride, N,N-dimethylformamide, 25 - 90 °C, 2 h, (j) Phenylboronic acid, (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90 °C, 7 h, (k) Phenylboronic acid, (1,1'-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90 °C, 12 h.

[0108] Specific Examples of Compounds Examples of representative compounds of the present invention include, but are not limited to, the following compounds.

[0109] 2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole

Chemical formula

[0110] 3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

Chem.

[0111] 2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole

Chem.

[0112] 5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole

Chem.

[0113] 5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole

Chem.

[0114] 5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole

Chem.

[0115] 6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine

Chem.

[0116] 2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine

Chemical Structure

[0117] 3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine

Chemical Structure

[0118] 6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline

Chemical Structure

[0119] 2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline

Chemical Structure

[0120] 3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline

Chemical Structure

[0121] 3-(6-Imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

Chemical Structure

[0122] 2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole [Chemistry]

[0123] cis-2-(3-Pyridylmethyl)quinuclidin-3-ol [Chemistry]

[0124] trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate [Chemistry]

[0125] trans-2-(3-Pyridylmethyl)quinuclidin-3-ol (3) [Chemistry]

[0126] trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine [Chemistry]

[0127] trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole [Chemistry]

[0128] cis-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine [Chemistry]

[0129] cis-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole

Chem.

[0130] trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine

Chem.

[0131] trans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole

Chem.

[0132] trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

Chem.

[0133] trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole

Chem.

[0134] trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine

Chem.

[0135] trans-tert-Butyl 2-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylate

Chem.

[0136] trans-2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinucidine

Chem.

[0137] trans-2-Bromo-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole

Chem.

[0138] trans-2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole

Chem.

[0139] trans-3-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxyisoquinoline

Chem.

[0140] trans-2-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxyquinoline

Chem.

[0141] trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

Chemical formula

[0142] trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole

Chemical formula

[0143] Numbered Paragraphs Aspects of the present invention are described in the following numbered paragraphs.

[0144] 1. A compound of general formula (I),

Chemical formula

[0145] 2. The compound according to numbered paragraph 1, wherein the aromatic ring or each aromatic ring of the carbocyclic or heterocyclic aromatic ring of one or both of the aryl groups is a 3- to 10-membered ring, such as a 5-membered ring or a 6-membered ring.

[0146] 3. The compound according to numbered paragraph 1 or numbered paragraph 2, wherein one or both of the aryl groups are monocyclic.

[0147] 4. The compound according to numbered paragraph 3, wherein one or both aryl groups are independently selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

[0148] 5. The compound according to either numbered paragraph 1 or numbered paragraph 2, wherein one or both aryl groups are polycyclic.

[0149] 6. The compound according to numbered paragraph 5, wherein one or both aryl groups are independently selected from the group consisting of naphthalenyl, anthracenyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzodioxolanyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, purinyl, thienopyrazinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8 - naphthyridinyl, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and azulenyl.

[0150] 7. The compound according to any of the preceding numbered paragraphs, wherein one or both aryl groups are substituted with, for example, 1, 2, or 3 substituents.

[0151] 8. The substituents are alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br, or I), --OR’, --NR’R’’, ‐‐CF3, --CN, --NO 2 , --SR’, --N 3 , --C(=O)NR’R’’, --NR’C(=O)R’’, --C(=O)R’, --C(=O)OR’, --OC(=O)R’, --O(CR’R’’), --C(=O)R’, --SO 2 R’, and --SO 2Independently selected from the group consisting of NR’R’’, wherein R’ and R’’ are each hydrogen, lower alkyl (e.g., C 1 ~C 8 linear or branched alkyl including, preferably C 1 ~C 5 , e.g., methyl, ethyl or isopropyl), cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl), wherein R’ and R’’ are optionally combined to form a cyclic functional group, the compound according to numbered paragraph 7.

[0152] 9. The compound according to numbered paragraph 8, wherein the substituent is independently selected from the group consisting of cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

[0153] 10. R 1 is selected from 1,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, the compound according to any of the preceding numbered paragraphs.

[0154] 11. R 2 is selected from indolyl, benzofuranyl, benzothiazolyl, and phenyl, the compound according to any of the preceding numbered paragraphs.

[0155] 12. The compound is 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, 3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine, 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole, 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole, 5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole, 6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine, 2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine, 3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine, 6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline, 2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline, 3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline, 3-(6-Imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine, and A compound according to any of the preceding numbered paragraphs selected from the group consisting of 2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0156] 13. The compound according to numbered paragraph 12, wherein the compound is 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0157] 14. The compound according to numbered paragraph 12, wherein the compound is 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine.

[0158] 15. The compound according to numbered paragraph 12, wherein the compound is 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole.

[0159] 16. The compound is trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (2); trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine (4); trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole (5); cis-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (6); cis-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (7); trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine (8); trans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole (9); trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (10); trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (11); (2S,3R)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (2S,3R-11); (2R,3S)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (2R,3S-11); trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine (12); trans-tert-Butyl 2-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylate (13); trans-2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14); trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (15); trans-2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (16); trans-3-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline (17); trans-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline (18); trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (19), and trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (20), a compound as described in any of the preceding numbered paragraphs, selected from the group consisting of.

[0160] 17. The compound according to numbered paragraph 16, wherein the compound is trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0161] 18. The compound according to numbered paragraph 16, wherein the compound is trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine.

[0162] 19. The compound according to numbered paragraph 16, wherein the compound is trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole.

[0163] 20. A pharmaceutically acceptable salt is selected from one or more of the following: chlorides, bromides, sulfates, phosphates, and nitrates; organic acid addition salts such as acetates, galactarates, propionates, succinates, lactates, glycolates, malates, tartrates, citrates, maleates, fumarates, methanesulfonates, p-toluenesulfonates, ascorbates; salts containing acidic amino acids such as aspartates or glutamates, or hydrates or ethanol solvates of the compounds described in any of the preceding numbered paragraphs.

[0164] 21. A compound of general formula (II),

Chemical formula

[0165] 22. A compound of general formula (I),

Chemical formula

[0166] 23. A pharmaceutical composition comprising a compound according to any one of numbered paragraphs 1 to 22 and a pharmaceutically or therapeutically acceptable excipient or carrier.

[0167] 24. A compound according to any one of numbered paragraphs 1 to 22 for use in the treatment of a disease or disorder.

[0168] 25. A compound according to any one of numbered paragraphs 1 to 22 for use in the treatment of a disease or disorder mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0169] 26. Use of a compound according to any one of numbered paragraphs 1 to 22 in the manufacture of a medicament for the treatment of a disease or disorder.

[0170] 27. A method of treating a disease or disorder comprising administering to a patient in need thereof a compound according to any one of numbered paragraphs 1 to 22 or a pharmaceutical composition according to numbered paragraph 23.

[0171] 28. The treatment is for preventing and / or suppressing cough, for the progression of cough, for improving the symptoms of cough, and for improving the recurrence of cough. A compound for use according to numbered paragraph 24 or numbered paragraph 25, the use according to numbered paragraph 26, or the method according to numbered paragraph 27.

[0172] 29. The disease or disorder is selected from cognitive and neurodegenerative diseases, mental disorders such as schizophrenia, acute nociceptive, neuropathic, or inflammatory pain, and mood disorders such as depression and inflammation. A compound for use according to numbered paragraph 24 or paragraph 25, the use according to numbered paragraph 26, or the method according to paragraph 27.

[0173] 30. The use, use, or method according to numbered paragraph 28 or numbered paragraph 29, wherein the compound is administered orally.

[0174] 31. The use, use, or method according to numbered paragraph 30, wherein the compound is orally administered at a dose of 0.1 mg to 1 g / kg per day.

[0175] 32. A compound, use, or method for use according to numbered paragraph 30, wherein the compound is orally administered at a dose of at least about 0.00001 mg / kg per day, at least about 0.0001 mg / kg per day, at least about 0.001 mg / kg per day, at least about 0.01 mg / kg per day, at least about 0.1 mg / kg per day, at least about 0.2 mg / kg per day, at least about 0.3 mg / kg per day, at least about 0.4 mg / kg per day, or at least about 0.5 mg / kg per day.

[0176] 33. A compound, use, or method for use according to numbered paragraph 30, wherein the compound is orally administered at a dose of about 0.01 g / kg or less per day, about 0.1 g / kg or less per day, about 0.5 g / kg or less per day, about 0.9 g / kg or less per day, about 1 g / kg or less per day, about 1.1 g / kg or less per day, about 1.2 g / kg or less per day, about 1.5 g / kg or less per day, or about 2 g / kg or less per day.

[0177] 34. A compound, use, or method for use according to numbered paragraph 30, wherein the compound is orally administered at a dose of at least about 0.00001 mg / kg to about 2 g / kg or less per day, at least about 0.0001 mg / kg / day to about 1.5 g / kg / day or less, at least about 0.001 mg / kg / day to about 1.2 g / kg / day or less, at least about 0.01 mg / kg per day to about 1.1 g / kg per day or less, at least about 0.1 mg / kg per day to about 1 g / kg per day or less, at least about 0.2 mg / kg / day to about 0.9 g / kg / day or less, at least about 0.3 mg / kg / day to about 0.5 g / kg / day or less, at least about 0.4 mg / kg per day to about 0.1 g / kg per day or less, or at least about 0.5 mg / kg per day to about 0.01 g / kg per day or less.

[0178] A compound, use or method for use as described in numbered paragraph 30, wherein the compound is administered orally at a dose of 5 mg to 2 g per day.

[0179] 36. A compound, use or method for use as described in numbered paragraph 30, wherein the compound is administered orally at a dose of at least about 0.1 mg per day, at least about 1 mg per day, at least about 3 mg per day, at least about 4 mg per day, at least about 5 mg per day, at least about 5.1 mg per day, at least about 6 mg per day, at least about 10 mg per day, at least about 50 mg per day.

[0180] 37. A compound, use or method for use as described in numbered paragraph 30, wherein the compound is administered orally at a dose of about 0.2 g per day or less, about 0.5 g per day or less, about 1 g per day or less, about 1.5 g per day or less, about 2 g per day or less, about 2.5 g per day or less, about 3 g per day or less, about 5 g per day or less, about 10 g per day or less.

[0181] 38. A compound, use or method for use as described in numbered paragraph 30, wherein the compound is administered orally at a dose of at least about 0.1 mg per day to about 10 g per day or less, at least about 1 mg per day to about 5 g per day or less, at least about 3 mg per day to about 3 g per day or less, at least about 4 mg per day to about 2.5 g per day or less, at least about 5 mg per day to about 2 g per day or less, at least about 5.1 mg per day to about 1.5 g per day or less, at least about 6 mg per day to about 1 g per day or less, at least about 10 mg per day to about 0.5 g per day or less, at least about 50 mg per day to about 0.2 g per day or less.

[0182] 39. A compound, use or method for use as described in any of numbered paragraphs 30 to 38, wherein the composition is in the form of a tablet.

[0183] 40. A compound, use or method for use as described in numbered paragraph 28 or paragraph 29, wherein the compound is administered parenterally, topically, rectally, transmucosally, intraperitoneally, or enterally.

[0184] 41. A method for producing a compound of general formula (I) or (II) shown in Scheme (I),

Chemical formula

[0185] 42. A method for producing a compound of general formula (I) or (II) shown in Scheme (II).

Chemical formula

[0186] 43. A method for producing a compound of general formula (I) or (II) shown in Scheme (III).

Chemical formula

Brief Description of the Drawings

[0187]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

[0188] Experiment Examples of the synthesis of the compounds are described in Examples 1 to 25, the biological activity examples of Examples 26 and 27, and the in vivo evaluation of antipsychotic efficacy in Example 28, which are provided to illustrate the present invention and should not be construed as limiting its scope. In these examples, all parts and percentages are by weight unless otherwise specified. The reaction yields are reported as mole percentages.

[0189] Example 1 (Reference): 2-[(3-Pyridinyl)methylene]quinuclidin-3-one To a solution of quinuclidin-3-one hydrochloride (45.0 g, 278 mmol) in methanol (450 mL) was added KOH (31.2 g, 556 mmol, 2.00 equivalents). The mixture was stirred at 50 °C for 2 hours. Pyridine-3-carboxaldehyde (29.8 g, 278 mmol, 26.2 mL, 1.00 equivalent) was added at 25 °C, and the mixture was stirred at 50 °C for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was triturated with water (150 mL) for 10 hours. 2-[(3-Pyridinyl)methylene]quinuclidin-3-one (57.0 g, 266 mmol, yield 95.6%) was obtained as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.98 (d, J = 1.9 Hz, 1H), 8.47 - 8.41 (m, 2H), 7.24 (dd, J = 4.8, 7.9 Hz, 1H), 6.92 (s, 1H), 3.15 - 2.90 (m, 4H), 2.60 - 2.59 (m, 1H), 2.00 - 1.72 (m, 4H). LCMS: m / z = 215.2 (M + 1)+.

[0190] Example 2 (Reference): 2-(3-Pyridylmethyl)quinuclidin-3-one A mixture of 2-[(3-pyridinyl)methylene]quinuclidin-3-one (57.0 g, 266 mmol, 1.00 equivalent), Pd / C (5.70 g, 26.6 mmol, purity 10%, 0.100 equivalent), and H2 (536 mg, 266 mmol, 1.00 equivalent) in methanol (600 mL) was degassed and purged with H 2 three times, and then the mixture was purged with H 2It was stirred at 25 °C for 12 hours under an atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure. 2-(3-Pyridylmethyl)quinuclidin-3-one (56.0 g, 258 mmol, yield 97.3%) was obtained as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.50 - 8.44 (m, 2H), 7.59 (dd, J = 2.5, 4.5 Hz, 1H), 7.27 - 7.19 (m, 1H), 3.32 - 2.47 (m, 7H), 2.46 (d, J = 2.1 Hz, 1H), 2.02 - 1.96 (m, 4H). LCMS: m / z = 217.2 (M+1)+.

[0191] Example 3 (Reference): cis-2-(3-Pyridylmethyl)quinuclidin-3-ol To a solution of 2-(3-pyridylmethyl)quinuclidin-3-one (20.0 g, 92.4 mmol, 1.00 equiv) in isopropanol (500 mL) was added aluminum isopropoxide (56.6 g, 277 mmol, 55.0 mL, 3.00 equiv). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with 300 mL of saturated NaCl and 50% NaOH (aqueous solution), and extracted with dichloromethane (200 mL, 100 mL × 2). The combined organic layers were washed with 200 mL of brine (100 mL × 2), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , dichloromethane / methanol = 50 / 0 - 10 / 1). cis-2-(3-Pyridylmethyl)quinuclidin-3-ol (16.0 g, 73.3 mmol, yield 79.2%) was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.34 (dd, J = 1.5, 4.8 Hz, 1H), 7.64 - 7.61 (m, 1H), 7.21 - 7.16 (m, 1H), 3.89 - 3.86 (m, 1H), 3.23 - 3.07 (m, 3H), 2.87 - 2.79 (m, 4H), 1.97 - 1.91 (m, 2H), 1.66 - 1.65 (m, 1H), 1.64 - 1.63 (m, 1H), 1.48 - 1.32 (m, 1H). LCMS: m / z = 219.2 (M+1)+.

[0192] Example 4: trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-Nitrobenzoate To a solution of cis-2-(3-pyridylmethyl)quinuclidin-3-ol (16.0 g, 73.3 mmol, 1.00 equiv) and 4-nitrobenzoic acid (36.7 g, 219 mmol, 3.00 equiv) in tetrahydrofuran (160 mL) were added triphenylphosphine (57.6 g, 219 mmol, 3.00 equiv) and diisopropyl azodicarboxylate (44.4 g, 219 mmol, 42.7 mL, 3.00 equiv) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , dichloromethane / methanol = 1 / 0 to 10 / 1). trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (26.0 g, crude) was obtained as a brown oil. LCMS: m / z = 368.2 (M+1)+.

[0193] Example 5 (Reference): trans-2-(3-Pyridylmethyl)quinuclidin-3-ol To a solution of trans-[2-(3-pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (26.0 g, 70.7 mmol, 1.00 equiv) in tetrahydrofuran (160 mL) was added LiOH·H 2 O (4.45 g, 106 mmol, 1.50 equiv) in H 2 O (40 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (300 mL and 100 mL × 5). The combined organic layers were washed with brine 100 mL (100 mL × 2), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , dichloromethane / methanol = 100 / 1 to 0 / 1). trans-2-(3-Pyridylmethyl)quinuclidin-3-ol (6.00 g, 27.4 mmol, yield 38.8%) was obtained as a black-brown gum. LCMS: m / z = 219.2 (M+1)+.

[0194] Example 6: trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.300 g, 1.37 mmol, 1.00 eq) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (308 mg, 2.75 mmol, 2.00 eq). The mixture was stirred at 25 °C for 1 h. 5-Bromo-2-chloro-pyridine (290 mg, 1.51 mmol, 1.10 eq) was added and the mixture was stirred at 25 °C for 11 h. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane 150 mL (50 mL×3). The combined organic layers were washed with brine 60 mL (30 mL×2) and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine (0.280 g, 748 μmol, 54.4% yield) was obtained as a yellow oil. LCMS: m / z = 374.1 (M+1)+.

[0195] Example 7: trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole A mixture of trans-3-[(5-bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine (0.280 g, 748 μmol, 1.00 eq), indole-5-boronic acid (180 mg, 1.12 mmol, 1.50 eq), Cs 2 CO 3 (731 mg, 2.24 mmol, 3.00 eq) and Pd(dppf)Cl 2 (54.7 mg, 74.8 μmol, 0.100 eq) in dioxane (5 mL) and H 2 O (1 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 90 °C for 12 h under a N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2, purified by dichloromethane / methanol = 10 / 1). By TLC (dichloromethane / methanol = 10 / 1), it was found that one major spot (Rf = 0.25) was detected. trans-5-[6-[2-(3-Pyridylmethyl)quinucridin-3-yl]oxy-3-pyridyl]-1H-indole (131 mg, 311 μmol, yield 41.6%, purity 97.4%) was obtained as a pale yellow solid. 1H NMR (400 MHz, CD3OD): δ8.45 (s, 1H), 8.26 - 8.21 (m, 2H), 7.82 - 7.71 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H), 7.30 - 7.26 (m, 3H), 6.60 (d, J = 8.6 Hz, 1H), 6.49 (dd, J = 0.7, 3.1 Hz, 1H), 4.93 (s, 1H), 3.31 - 2.97 (m, 6H), 2.77 - 2.76 (m, 1H), 2.21 (d, J = 1.6 Hz, 1H), 1.92 - 1.80 (m, 3H), 1.47 - 1.45 (m, 1H). LCMS: m / z = 411.3 (M+1)+.

[0196] Example 8: trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucridine To a solution of trans-2-(3-pyridylmethyl)quinucridin-3-ol (0.150 g, 687 μmol, 1.00 equivalent) in tetrahydrofuran (5 mL), potassium tert-butoxide (154 mg, 1.37 mmol, 2.00 equivalents) was added at 25 °C for 1 hour, and 2,5-dichloropyrazine (123 mg, 825 μmol, 1.20 equivalents) was added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 200 mL (50 mL × 4) of dichloromethane. The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O). By TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H 2It was shown that one major spot (Rf = 0.55) was detected by (O). trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucridine (74.6 mg, 222 μmol, yield 32.3%, purity 98.5%) was obtained as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.46 - 8.35 (m, 2H), 8.01 (d, J = 1.2 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.53 (dd, J = 1.6, 7.8 Hz, 1H), 7.13 - 7.10 (m, 1H), 4.80 - 4.79 (m, 1H), 3.09 - 2.96 (m, 6H), 2.94 - 2.91 (m, 1H), 2.15 - 2.14 (m, 1H), 1.79 - 1.70 (m, 3H), 1.38 - 1.37 (m, 1H). LCMS: m / z = 331.0 (M + 1)+.

[0197] Example 9: trans-5-[5-[2-(3-Pyridylmethyl)quinucridin-3-yl]oxypyrazin-2-yl]-1H-indole A mixture of trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucridine (0.100 g, 302 μmol, 1.00 equivalent), indole-5-boronic acid (60.0 mg, 372 μmol, 1.23 equivalents), Na 2 CO 3 (100 mg, 943 μmol, 3.12 equivalents), and tetrakis(triphenylphosphine)palladium(0) (40.0 mg, 34.6 μmol, 0.115 equivalent) in dimethoxyethane (5 mL) and H 2 O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 85 °C for 12 hours under a N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was separated by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2It was purified by (O). trans-5-[5-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxypyrazin-2-yl]-1H-indole (45.2 mg, 107 μmol, yield 35.7%, purity 98.1%) was obtained as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 9.26 (s, 1H), 8.51 - 8.45 (m, 2H), 8.34 (dd, J = 1.4, 4.8 Hz, 1H), 8.16 - 8.13 (m, 2H), 7.73 - 7.70 (m, 1H), 7.63 - 7.52 (m, 1H), 7.43 - 7.41 (m, 1H), 7.20 - 7.19 (m, 1H), 7.11 (dd, J = 4.9, 7.8 Hz, 1H), 6.60 (s, 1H), 4.89 (t, J = 3.2 Hz, 1H), 3.17 - 2.98 (m, 6H), 2.97 - 2.76 (m, 1H), 2.23 - 2.22 (m, 1H), 1.76 - 1.75 (m, 1H), 1.74 - 1.72 (m, 2H), 1.40 - 1.39 (m, 1H). LCMS: m / z = 412.1 (M+1)+.

[0198] Example 10: trans-2-Bromo-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole To a solution of trans-2-(3-pyridylmethyl)quinucidin-3-ol (0.200 g, 916 μmol, 1.00 equivalent) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (154 mg, 1.37 mmol, 1.50 equivalents). The mixture was stirred at 25 °C for 1 hour. Then, 2,5-dibromo-1,3,4-thiadiazole (223 mg, 916 μmol, 1.00 equivalent) was added and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 150 mL (50 mL × 3) of dichloromethane. The combined organic layers were washed with 60 mL (30 mL × 2) of brine and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. trans-2-Bromo-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole (0.350 g, crude) was obtained as a yellow solid. LCMS: m / z = 383.1 (M+1)+.

[0199] Example 11: trans-2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole A mixture of trans-2-bromo-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole (0.350 g, 917 μmol, 1.00 equivalent), indole-5-boronic acid (221 mg, 1.38 mmol, 1.50 equivalents), Cs 2 CO 3 (897 mg, 2.75 mmol, 3.00 equivalents), and Pd(dppf)Cl 2 (67.1 mg, 91.7 μmol, 0.100 equivalent) in dioxane (5 mL) and H2O (1 mL) was degassed and purged three times with N 2 and then the mixture was stirred at 90 °C for 12 h under a N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; NH 3 ·H 2 O). TLC (dichloromethane / methanol = 10 / 1, NH 3 ·H 2By [O], it was found that one major spot (Rf = 0.35) was detected. trans-2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinucridin-3-yl]oxy-1,3,4-thiadiazole (44.3 mg, 106 μmol, yield 11.5%, purity 100%) was obtained as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.55 - 8.42 (m, 2H), 8.41 (dd, J = 1.5, 4.8 Hz, 1H), 8.04 (d, J = 0.7 Hz, 1H), 7.75 - 7.72 (m, 1H), 7.46 - 7.44 (m, 1H), 7.29 - 7.28 (m, 1H), 7.28 - 7.27 (m, 1H), 7.18 - 7.17 (m, 1H), 6.63 (t, J = 2.1 Hz, 1H), 4.95 (t, J = 3.1 Hz, 1H), 3.16 - 3.05 (m, 5H), 3.00 - 2.96 (m, 1H), 2.51 - 2.50 (m, 1H), 1.79 - 1.73 (m, 4H), 1.46 - 1.44 (m, 1H). LCMS: m / z = 418.2 (M + 1)+.

[0200] Example 12: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine 6-Bromo-1,3-benzothiazol-2-amine (1.00 g, 4.36 mmol, 1.00 equivalent), bis(pinacolato)diboron (1.66 g, 6.54 mmol, 1.50 equivalents), potassium acetate (1.28 g, 13.0 mmol, 3.00 equivalents), Pd(dppf)Cl 2 (319 mg, 436 μmol, 0.100 equivalent) in dioxane (10 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 100 °C for 12 h under an N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine (1.60 g, crude) was obtained as a black-brown solid. LCMS: m / z = 277.1 (M - 55)+.

[0201] Example 13: trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucridine To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.150 g, 687 μmol, 1.00 eq) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (1 M, 1.34 mL, 1.95 eq). The mixture was stirred at 25 °C for 1 h. Then 3,6-dichloropyridazine (120 mg, 805 μmol, 1.17 eq) was added and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with 20 mL of water and extracted with dichloromethane (150 mL, 50 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1). It was found by TLC (dichloromethane / methanol = 10 / 1) that one major spot (Rf = 0.45) was detected. trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (120 mg, 362 μmol, 52.7% yield) was obtained as a yellow oil.

[0202] Example 14: trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine A mixture of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (0.100 g, 302 μmol, 1.00 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine (166 mg, 604 μmol, 2.00 eq), Cs 2 CO 3 (295 mg, 906 μmol, 3.00 eq), and Pd(dppf)Cl 2 (22.1 mg, 30.2 μmol, 0.100 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N 2 three times, and then the mixture was heated at 90 °C for 12 h under a N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2 、 Purified by dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O). TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H 2 O) showed that one major spot (Rf = 0.35) was detected. trans-6-[6-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine (27.5 mg, 60.8 μmol, yield 20.1%, purity 98.2%) was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.46 (d, J = 1.8 Hz, 1H), 8.21 - 8.20 (m, 2H), 7.96 - 7.93 (m, 3H), 7.48 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 5.0, 7.8 Hz, 1H), 6.94 (dd, J = 1.5, 9.2 Hz, 1H), 5.15 (s, 1H), 3.25 - 3.02 (m, 6H), 2.99 - 2.76 (m, 1H), 2.32 (d, J = 2.3 Hz, 1H), 1.94 - 1.84 (m, 3H), 1.51 - 1.50 (m, 1H). LCMS: m / z = 445.3 (M + 1)+.

[0203] Example 15: trans-2-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylic acid tert-butyl trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucidine (0.120 g, 362 μmol, 1.00 equiv), (1-tert-Butoxycarbonylpyrrol-2-yl)boronic acid (92.0 mg, 435 μmol, 1.20 equiv), Pd(dppf)Cl 2 (30.0 mg, 41.0 μmol, 0.113 equiv), K 2 CO 3 (150 mg, 1.09 mmol, 2.99 equiv) in a mixture of dioxane (5 mL) and H 2 O (1 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 90 °C under N 2 atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was separated by preparative TLC (SiO 2, dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O) was purified. TLC (dichloromethane / methanol = 10 / 1, 1% NH3·H2O) showed that one major spot (Rf = 0.45) was detected. tert-Butyl trans-2-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylate (80.0 mg, 173 μmol, yield 47.7%) was obtained as a yellow oil. LCMS: m / z = 462.3 (M+1)+.

[0204] Example 16: trans-2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine To a solution of tert-butyl trans-2-[6-[2-(3-pyridylmethyl)quinucidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylate (80.0 mg, 173 μmol, 1.00 equiv) in dioxane (3 mL) was added HCl / dioxane (4 M, 3 mL, 69.2 equiv). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O). TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H 2It was shown that one major spot (Rf = 0.55) was detected by (O). trans-2-(3-Pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (58.1 mg, 160 μmol, yield 92.8%, purity 100%) was obtained as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.93 (s, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.32 (dd, J = 1.6, 4.9 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.27 - 7.06 (m, 1H), 6.97 - 6.96 (m, 1H), 6.77 - 6.75 (m, 1H), 6.64 - 6.63 (m, 1H), 6.30 - 6.29 (m, 1H), 5.11 - 5.10 (m, 1H), 3.14 - 2.98 (m, 6H), 2.97 - 2.94 (m, 1H), 2.37 - 2.36 (m, 1H), 1.76 - 1.73 (m, 3H), 1.39 - 1.25 (m, 1H). LCMS: m / z = 362.3 (M + 1)+.

[0205] Example 17: trans-6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.100 g, 458 μmol, 1.00 equivalent) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (1 M, 916 μL, 2.00 equivalents). The mixture was stirred at 25 °C for 1 hour. 2-Chloro-6-fluoro-quinoline (99.8 mg, 549 μmol, 1.20 equivalents) was added and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with 30 mL of water and extracted with 240 mL (60 mL × 4) of dichloromethane. The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O). TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H 2By (O), it was shown that one major spot (Rf = 0.55) was detected. trans-6-Fluoro-2-[2-(3-pyridylmethyl)quinucidin-3-yl]oxyquinoline (124 mg, 332 μmol, yield 72.6%, purity 96.9%) was obtained as a colorless oil. 1H NMR (400 MHz, CD3OD): δ 8.42 (d, J = 1.8 Hz, 1H), 8.12 (dd, J = 1.6, 4.9 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.74 - 7.72 (m, 2H), 7.46 - 7.42 (m, 2H), 7.14 (dd, J = 4.9, 7.8 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 5.16 (t, J = 3.0 Hz, 1H), 3.24 - 3.22 (m, 3H), 3.04 - 3.01 (m, 3H), 3.00 - 2.99 (m, 1H), 2.28 - 2.26 (m, 1H), 1.87 - 1.84 (m, 3H), 1.49 - 1.47 (m, 1H). LCMS: m / z = 364.2 (M + 1)+.

[0206] Example 18: trans-2-[2-(3-Pyridylmethyl)quinucidin-3-yl]oxyquinoline To a solution of trans-2-(3-pyridylmethyl)quinucidin-3-ol (0.170 g, 778 μmol, 1.00 equiv) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (1 M, 1.56 mL, 2.00 equiv). The mixture was stirred at 25 °C for 1 hour. 2-Chloroquinoline (152 mg, 934 μmol, 124 μL, 1.20 equiv) was added and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with 30 mL of water and extracted with 240 mL (60 mL × 4) of dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O). TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H 2It was shown that one major spot (Rf = 0.49) was detected by (O). trans-2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline (163 mg, 469 μmol, yield 60.3%, purity 99.1%) was obtained as a colorless oil. 1H NMR (400 MHz, CD3OD): δ 8.42 (d, J = 1.7 Hz, 1H), 8.13 - 8.12 (m, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.76 - 7.72 (m, 3H), 7.61 (ddd, J = 1.5, 7.0, 8.4 Hz, 1H), 7.38 - 7.37 (m, 1H), 7.14 - 7.13 (m, 1H), 6.71 (d, J = 8.9 Hz, 1H), 5.18 - 5.16 (m, 1H), 3.28 - 3.18 (m, 3H), 3.05 - 3.01 (m, 3H), 2.99 - 2.98 (m, 1H), 2.30 - 2.27 (m, 1H), 1.86 - 1.83 (m, 3H), 1.49 - 1.47 (m, 1H). LCMS: m / z = 346.2 (M + 1)+.

[0207] Example 19: trans-3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline To a solution of trans-2-(3-pyridylmethyl)quinuclin-3-ol (0.0500 g, 229 μmol, 1.00 equivalent) in N,N-dimethylformamide (3 mL) was added sodium hydride (18.3 mg, 458 μmol, purity 60%, 2.00 equivalents). The mixture was stirred at 25 °C for 1 hour. 3-Chloroisoquinoline (56.2 mg, 343 μmol, 1.50 equivalents) was added and the mixture was stirred at 90 °C for 11 hours. The reaction mixture was quenched by adding 2 mL of saturated NH 4 Cl solution at 0 °C, then diluted with 20 mL of water and extracted with dichloromethane (160 mL, 40 mL × 4). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O). TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H2 By (O), it was shown that one major spot (Rf = 0.6) was detected. trans-3-[2-(3-Pyridylmethyl)quinucridin-3-yl]oxyisoquinoline (14.8 mg, 42.5 μmol, yield 18.5%, purity 98.8%) was obtained as a brown solid. 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 8.43 (s, 1H), 8.10 (dd, J = 1.1, 4.8 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.76 - 7.58 (m, 3H), 7.62 - 7.60 (m, 1H), 7.15 (dd, J = 4.9, 7.8 Hz, 1H), 6.88 (s, 1H), 4.92 - 4.88 (m, 1H), 3.17 - 3.06 (m, 6H), 3.04 - 3.01 (m, 1H), 2.25 - 2.22 (m, 1H), 1.86 - 1.83 (m, 4H). LCMS: m / z = 346.2 (M+1)+.

[0208] Example 20: trans-3-(6-Imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucridine To a solution of trans-2-(3-pyridylmethyl)quinucridin-3-ol (200 mg, 916 μmol, 1.00 equivalent) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (102 mg, 916 μmol, 1.00 equivalent). The mixture was stirred at 25 °C for 1 hour. 3-Chloro-6-imidazol-1-yl-pyridazine (165 mg, 916 μmol, 1.00 equivalent) was added and the mixture was stirred at 50 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The crude product was purified by reverse-phase HPLC (0.1% NH 3 ·H 2It was purified by (O). trans-3-(6-Imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (43.2 mg, 119 μmol, yield 13.0%, purity 100%) was obtained as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.47 (d, J = 1.6 Hz, 1H), 8.32 - 8.27 (m, 2H), 7.64 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 9.4 Hz, 1H), 7.22 (s, 1H), 7.09 (dd, J = 4.9, 7.6 Hz, 1H), 6.95 (d, J = 9.4 Hz, 1H), 5.12 (s, 1H), 3.15 - 3.14 (m, 1H), 3.03 - 2.97 (m, 5H), 2.96 - 2.94 (m, 1H), 2.37 - 2.34 (m, 1H), 1.77 - 1.73 (m, 3H), 1.42 - 1.40 (m, 1H). LCMS: m / z = 363.2 (M + 1)+.

[0209] Example 21: trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole To a solution of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (800 mg, 2.42 mmol, 1.00 equivalent) and indole-5-boronic acid (976.00 mg, 6.06 mmol, 2.51 equivalents) in dioxane (5.00 mL) and ethanol (5.00 mL), Pd(dppf)Cl 2 (176.00 mg, 250.75 μmol) and dicyclohexyl-(2-phenylphenyl)phosphine (48.00 mg, 136.96 μmol), Na 2 CO 3 (1 M, 8.00 mL, 3.31 equivalents) were added. The mixture was stirred at 150 °C for 0.5 h under N 2 using microwave (3 batches). Then, the reaction mixture was extracted with ethyl acetate (200 mL), dried over Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (0.1% NH 3 ·H 2It was purified by (O). Trans-5-[6-[2-(3-pyridylmethyl)quinucridin-3-yl]oxypyridazin-3-yl]-1H-indole (2.20 g, 5.13 mmol, yield 70.7%, purity 96%) was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 8.44 (s, 1H), 8.26 - 8.22 (m, 1H), 7.77 - 7.75 (m, 1H), 7.56 - 7.53 (m, 1H), 7.26 - 7.23 (m, 1H), 6.26 - 6.23 (m, 1H), 5.08 - 5.07 (m, 1H), 3.25 - 2.92 (m, 6H), 2.80 - 2.73 (m, 1H), 2.27 - 2.24 (m, 1H), 1.87 - 1.79 (m, 3H), 1.52 - 1.46 (m, 1H). The separation of racemic trans-5-[6-[2-(3-pyridylmethyl)quinucridin-3-yl]oxypyridazin-3-yl]-1-H-indole was carried out by chiral supercritical fluid chromatography (SFC) using a column Chiralpak AD-3 50×4.6 mm I.D., 3 μm; mobile phase: Phase A was CO 2, Phase B was gradient eluted with isopropanol (0.05% diethylamine): 0 - 40% B, flow rate: 3 mL / min, detector: PDA; column temperature: 35 °C, backpressure: 100 Bar 2S,3R-5-[6-[2-(3-pyridylmethyl)quinucridin-3-yl]oxypyridazin-3-yl]-1H-indole, off-white solid; RT = 2.000 min, ee 100%; 1H NMR (400 MHz, CD3OD): δ8.48 (s, 1H), 8.23 - 8.22 (m, 1H), 8.12 - 8.11 (m, 1H), 7.98 - 7.96 (m, 1H), 7.80 - 7.76 (m, 1H), 7.73 - 7.70 (m, 1H), 7.52 - 7.49 (m, 1H), 7.31 - 7.30 (m, 1H), 7.26 - 7.22 (m, 1H), 6.96 - 6.94 (m, 1H), 6.56 (m, 1H), 5.17 (m, 1H), 3.25 - 2.97 (m, 6H), 2.85 - 2.78 (m, 1H), 2.37 - 2.34 (m, 1H), 1.96 - 1.84 (m, 3H), 1.57 - 1.39 (m, 1H). 2R,3S-5-[6-[2-(3-pyridylmethyl)quinucridin-3-yl]oxypyridazin-3-yl]-1H-indole, off-white solid; RT = 2.110 min, ee 100%; 1H NMR (400 MHz, CD3OD): δ8.47 (s, 1H), 8.23 - 8.21 (m, 1H), 8.11 (s, 1H), 7.98 - 7.96 (m, 1H), 7.80 - 7.70 (m, 2H), 7.51 - 7.49 (m, 1H), 7.31 - 7.22 (m, 2H), 6.96 - 6.94 (m, 1H), 6.56 (m, 1H), 5.17 (m, 1H), 3.25 - 2.97 (m, 6H), 2.85 - 2.78 (m, 1H), 2.37 - 2.34 (m, 1H), 1.96 - 1.83 (m, 3H), 1.57 - 1.50 (m, 1H).

[0210] Example 22: cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucridine A solution of cis-2-(3-pyridylmethyl)quinuclidin-3-ol (0.100 g, 458 μmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added with potassium tert-butoxide (51.4 mg, 458 μmol, 1.00 equiv). The mixture was stirred at 25 °C for 1 h. 3,6-Dichloropyridazine (85.3 mg, 572 μmol, 1.25 equiv) was added and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with 20 mL of water and extracted with 90 mL (30 mL × 3) of ethyl acetate. The combined organic layers were washed with 20 mL (10 mL × 2) of brine and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. Cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (150 mg, 453 μmol, 98.9% yield) was obtained as a yellow gum.

[0211] Example 23: Cis-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole To a solution of cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (0.150 g, 453 μmol, 1.00 equiv) and indole-5-boronic acid (87.5 mg, 544 μmol, 1.20 equiv) in dioxane (5 mL) and H 2 O (1 mL) were added K 2 CO 3 (188 mg, 1.36 mmol, 3.00 equiv) and Pd(dppf)Cl 2 (33.1 mg, 45.3 μmol, 0.100 equiv). The mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2 O). TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H 2By [O], it was shown that one major spot (Rf = 0.35) was detected. cis-5-[6-[2-(3-Pyridylmethyl)quinucridin-3-yl]oxypyridazin-3-yl]-1H-indole (45.8 mg, 108 μmol, yield 23.8%, purity 97.1%) was obtained as a brown solid. 1H NMR (400 MHz, CDCl3): δ 9.65 (s, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.34 (dd, J = 1.5, 4.8 Hz, 1H), 8.20 (s, 1H), 7.85 - 7.77 (m, 2H), 7.43 - 7.41 (m, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.20 (t, J = 2.8 Hz, 1H), 7.04 - 7.02 (m, 1H), 7.01 (d, J = 9.3 Hz, 1H), 6.59 (s, 1H), 5.66 - 5.56 (m, 1H), 3.47 - 3.44 (m, 1H), 3.13 (m, 1H), 3.06 - 2.90 (m, 2H), 2.91 - 2.83 (m, 3H), 2.54 (s, 1H), 1.83 - 1.70 (m, 1H), 1.69 - 1.65 (m, 2H), 1.39 - 1.37 (m, 1H). LCMS: m / z = 412 (M + 1)+.

[0212] Example 24: trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucridine To a solution of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucridine (0.150 g, 453 μmol, 1.00 equivalent) and phenylboronic acid (66.3 mg, 544 μmol, 1.20 equivalents) in dioxane (5 mL) and H 2 O (1 mL), K 2 CO 3 (188 mg, 1.36 mmol, 3.00 equivalents) and Pd(dppf)Cl 2 (33.1 mg, 45.3 μmol, 0.100 equivalent) were added. The mixture was stirred at 90 °C for 7 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , dichloromethane / methanol = 10 / 1; 1% NH 3 ·H 2It was purified by (O). TLC (dichloromethane / methanol = 10 / 1, 1% NH 3 ·H 2 O) showed that one major spot (Rf = 0.35) was detected. trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (70.3 mg, 175 μmol, yield 38.8%, purity 93.2%) was obtained as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.37 (s, 1H), 8.01 - 7.99 (m, 2H), 7.74 (d, J = 9.2 Hz, 1H), 7.52 - 7.51 (m, 1H), 7.50 - 7.49 (m, 3H), 7.13 - 7.11 (dd, J = 4.8, 7.6 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 5.31 - 5.10 (m, 1H), 3.19 - 3.01 (m, 6H), 2.99 - 2.98 (m, 1H), 2.44 - 2.41 (m, 1H), 1.83 - 1.75 (m, 3H), 1.43 - 1.42 (m, 1H). LCMS: m / z = 373 (M + 1)+.

[0213] Example 25: trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole To a solution of trans-2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (0.300 g, 786 μmol, 1.00 equiv) and phenylboronic acid (105 mg, 865 μmol, 1.10 equiv) in dioxane (5 mL) and H2O (1 mL), K 2 CO 3 (326 mg, 2.36 mmol, 3.00 equiv) and Pd(dppf)Cl 2(57.5 mg, 78.6 μmol, 0.100 eq) was added. The mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give trans-2-phenyl-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole (76.0 mg, 200 μmol, 25.5% yield, 100% purity) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.51 - 8.50 (m, 1H), 8.38 (dd, J = 1.6, 4.8 Hz, 1H), 7.80 - 7.78 (m, 2H), 7.58 - 7.56 (m, 1H), 7.44 - 7.30 (m, 3H), 7.17 - 7.15 (m, 1H), 5.05 - 4.80 (m, 1H), 3.72 - 3.68 (m, 1H), 3.11 - 3.02 (m, 5H), 2.96 - 2.72 (m, 1H), 1.79 - 1.72 (m, 3H), 1.43 - 1.24 (m, 1H), 1.22 - 1.20 (m, 1H). LCMS: m / z = 379 (M + 1)+.

[0214] Example 26: Biological Activity The compounds described in Examples 1 - 25 competitively inhibited the binding of radiolabeled α-bungarotoxin to the human α7 nAChR subtype with equilibrium constant (Ki) values of 1 - 1000 nM.

[0215] Human recombinant nicotinic acetylcholine α7 receptor was expressed in SH-SY5Y cells. A 20 μg aliquot of the membrane was incubated with 0.4 nM [125I]α-bungarotoxin in modified phosphate buffer pH 7.4 at 37 °C for 120 min. Nonspecific binding was estimated in the presence of 1 μM α-bungarotoxin. The membrane was filtered, washed, and then the filter was counted to determine specifically bound [125I]α-bungarotoxin. IC 50 values were determined by non-linear least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK).

[0216] The Ki value was the observed IC of the tested compound 50, using the concentration of the radioligand used in the assay and the historical value of the KD of the ligand (0.40 nM [125I]α-bungarotoxin), was calculated using the Cheng and Prusoff equation.

[0217] The Ki values are summarized in nM for each of the compounds tested in Table 1 below, and the binding affinities for nAChR are shown in more detail in Table 2.

Table 1

Table 2

[0218] The constitution of quinuclidine ethers particularly affects the mode of interaction with different nAChR subtypes. Thus, cis isomer 7 preferably binds to α4β2 nAChR, while trans isomer 11 is a fairly selective α7 nAChR ligand. Most of the compounds obtained were tested as racemates in the primary screening, but a pair of enantiomers 2S,3R-11 and 2R,3S-11 were also evaluated. The spatial arrangement of the pharmacologically active elements within enantiomer 2S,3R-11 facilitated its optimal and selective interaction with α7 nAChR. Among the screened hydrogen bond acceptors (pyridine, pyrazine, pyridazine, and 1,3,4-thiadiazole) attached to the quinuclidine ring via an ether bond at the 3-position, compounds containing a 1,3,4-thiadiazole fragment combined with pyridazine and indole rings 11 and 16 showed the best pharmacological profiles with respect to affinity and selectivity. Fusion of the benzene ring of the nitrogen-containing aromatic ring (compounds 17 and 18) in an attempt to combine hydrophobic π-interaction degradation compound interaction between the hydrogen bond acceptor and nAChR.

[0219] For Table 2, α7 nAChR ligands 11, 14, and 16 were evaluated in a chemically induced cough in vivo guinea pig model.

[0220] Example 27: In Vivo Cough Induction Experiment Materials and Methods As shown in FIGS. 1B and 1C, cough induction is performed by placing the guinea pigs in a whole body plethysmograph (WBP) equipped with an Aeroneb™ vibrating mesh nebulizer and including a pressure transducer and a detection device (EMKA Technologies). A primary microphone (EMKA Technologies) is provided for acoustic confirmation of cough frequency in the form of a digital trace using EMKA software. The data acquisition software (iOX2, version 2.10.5.28, EMKA Technologies, France) displays the pressure signal detected from the pressure transducer and calculates both the cough frequency and intensity measured during the test period.

[0221] A secondary microphone (T1 True Wireless Earphone, QCY®) is also placed inside the chamber and connected to a smartphone via Bluetooth, enabling the observer to hear audible sounds during the test. A bias flow rate of 2 L / min is used to continuously draw either air or aerosolized citric acid from the nebulizer into the WBP and discharge it through the exhaust pipe during the fresh air period. The chamber pressure inside the WBP is set to -10 to -30 Pa relative to the ambient pressure.

[0222] Prior to citric acid challenge, the guinea pigs are individually placed in the WBP for at least 5 minutes to acclimatize after being administered (intraperitoneally injected) with vehicle control, positive control, or test compound (if applicable) at different doses. [Table 3]

[0223] The procedure was as follows. Injection → Guinea pigs in a box with citric acid for 10 minutes (counting coughs) → Then, the box was filled with air for 5 minutes (counting coughs) → The guinea pigs were moved to the recovery cage.

[0224] An aerosol is generated using an appropriate concentration of citric acid and delivered to the WBP for 10 minutes while recording the pressure measurement values constantly. The average concentration of citric acid was 1283.1 ± 137.2 μg / L. When the citric acid challenge is completed, the guinea pigs are recovered and the recording of the number of coughs is continued for an additional 5 minutes. Thereafter, the guinea pigs are carefully monitored in a recovery cage for complete recovery from the challenge, and there are no adverse events before returning the animals to the home cage. The number of coughs (CCnt) is recorded for at least 10 minutes starting from the citric acid stimulation, and the cough incubation period (CIP) is defined as the time it takes to cough for the first time after the citric acid stimulation.

[0225] The cough response during citric acid loading and recovery after treatment is carefully monitored using the following: - Continuous pressure monitoring (Plethysmography monitoring software) - Acoustic confirmation of cough using a microphone (primary and secondary) - Visual confirmation of cough due to changes in posture.

[0226] Statistical analysis and data presentation Data are analyzed using one-way ANOVA (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001) when compared to the saline control, and each column represents the mean ± SEM.

[0227] Figures 2 and 3 relate to the evaluation of the antitussive efficacy of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucridin-3-yl]oxy-1,3,4-thiadiazole using a chemically induced cough in vivo model in guinea pigs.

[0228] Figures 2A and 3A show the mean ± SEM, and Figures 2B and 3B show the results of each replicate, respectively.

[0229] Results As shown in Figure 2 regarding the number of coughs, the exemplary compound of the present invention, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole, significantly reduced the number of citric acid-induced coughs compared to the physiological saline control.

[0230] More specifically, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole significantly reduced the number of citric acid-induced coughs at low concentration (1 mg / kg, number of coughs = 5, p < 0.0001), medium concentration (3 mg / kg, number of coughs = 5, p < 0.001), and high concentration (9.5 mg / kg, number of coughs = 7, p < 0.01) compared to the physiological saline control (0.9% sodium chloride, number of coughs = 17).

[0231] The decrease in the number of citric acid-induced coughs by 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole was similar compared to 30 mg / kg of codeine. However, at 1 mg / kg to 9.5 mg / kg, the dose of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole was approximately 20 to 30 times lower compared to the dose of 30 mg / kg of codeine.

[0232] Furthermore, as shown in Figure 3 regarding the incubation period, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole showed a significant improvement in the cough latency period.

[0233] More specifically, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole significantly increased the cough latency at low concentration (1 mg / kg, 548 seconds, p < 0.001), medium concentration (3 mg / kg, 455 seconds, p < 0.01), and high concentration (9.5 mg / kg, 489 seconds, p < 0.05) compared to the physiological saline control (0.9% sodium chloride, 206 seconds).

[0234] The increase in cough latency by 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole was similar compared to 30 mg / kg of codeine. However, at 1 mg / kg to 9.5 mg / kg, the dose of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole was approximately 20 - 30 times lower compared to the dose of 30 mg / kg of codeine.

[0235] Conclusion 2-(1H-Indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole, an exemplary compound of the present invention, significantly reduced the number of citric acid-induced coughs compared to the physiological saline control (see Figure 2).

[0236] Furthermore, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole also showed a significant improvement in cough latency at a dose approximately 20 - 30 times lower than that of codeine, which is considered a "representative" narcotic antitussive (see Figure 3).

[0237] Example 28: In Vivo Evaluation of the Antitussive Efficacy of Inhaled Compounds A set of proof-of-concept experiments was designed to evaluate the in vivo antitussive effect of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole via the inhalation route.

[0238] The experiments were conducted using the following methods: (i) Dry powder inhaler (DPI) (ii) Whole body plethysmograph (WBP) (iii) Oral administration. (iv) Intraperitoneal administration

[0239] Materials and methods The experimental setup for the in vivo evaluation of the antitussive efficacy of the inhaled compounds is summarized in Figure 4. More specifically, cough induction is performed by placing the guinea pig in a whole body plethysmograph (WBP) equipped with an Aeroneb™ vibrating mesh nebulizer and including a pressure transducer and a detection device (EMKA Technologies).

[0240] A primary microphone (EMKA Technologies) is provided for the acoustic confirmation of the cough frequency in the form of a digital trace using EMKA software (see Figure 1). The data acquisition software (iOX2, version 2.10.5.28, EMKA Technologies, France) displays the pressure signal detected from the pressure transducer and calculates both the cough frequency and intensity measured during the test period.

[0241] A secondary microphone (T1 True Wireless Earphone, QCY®) is also placed inside the chamber and connected to the smartphone via Bluetooth, enabling the observer to listen to the audible sound during the test. A bias flow rate of 2 L / min is used to continuously draw either air (during the fresh air period) or aerosolized citric acid from the nebulizer into the WBP and discharge it through the exhaust pipe. The chamber pressure inside the WBP is set to -10 to -30 Pa relative to the ambient pressure.

[0242] Before the citric acid challenge, administer vehicle control, positive control, or test compound (if applicable) to the guinea pigs via different routes and doses (see Table 4 for dry powder insufflation device, Table 5 for WBP spray, Table 6 for oral administration, and Table 7 for intraperitoneal administration). [Table 4] [Table 5] [Table 6] [Table 7]

[0243] For dry powder administration, the procedure was as follows. Guinea pigs in a box with dry powder insufflation citric acid for 10 minutes (counting coughs) → then the box was filled with air for 5 minutes (counting coughs) → the guinea pigs were moved to a recovery cage.

[0244] For atomization, the procedure was as follows. Spray via WBP → guinea pigs in a box with citric acid for 10 minutes (counting coughs) → then the box was filled with air for 5 minutes (counting coughs) → the guinea pigs were moved to a recovery cage.

[0245] Generate an aerosol using an appropriate concentration of citric acid and deliver it to the WBP for 10 minutes while continuously recording the pressure measurement values. The average concentration of citric acid was 1156.0 ± 111.8 μg / L for both routes. When the citric acid challenge was completed, the guinea pigs were recovered and the recording of the cough count was continued for an additional 5 minutes. Thereafter, the guinea pigs were carefully monitored in a recovery cage for complete recovery from the challenge, and there were no adverse events before returning the animals to the home cage. The cough count (CCnt) was recorded for at least 10 minutes starting from the citric acid stimulation, and the cough incubation period (CIP) was defined as the time it took to cough for the first time after the citric acid stimulation.

[0246] For oral administration, the duration between compound administration and the start of citrate loading was 30 minutes. The data were compared with air (control).

[0247] For intraperitoneal administration, the compound was administered approximately 10 - 15 minutes before the cough challenge (citrate inhalation challenge). The test compound was administered at 1 - 30 mg / kg (as described herein for each experiment), while the positive control (codeine) was administered at 30 mg / kg, and in both cases, a dosing volume of 10 ml / kg was used and administered by single intraperitoneal injection.

[0248] During citrate loading and recovery after treatment, the cough response is carefully monitored using the following: - Continuous pressure monitoring (Plethysmography monitoring software) - Acoustic confirmation of cough using a microphone (primary and secondary) - Visual confirmation of cough by changes in posture.

[0249] Statistical analysis and data presentation The data were analyzed using one - way ANOVA (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001) when compared to the control (air), and each column represents the mean ± SEM.

[0250] Figures 5 - 7 regarding the number of coughs show data for the evaluation of the antitussive efficacy of 2 - (1H - indol - 5 - yl) - 5 - [2 - (3 - pyridylmethyl) quinuclidin - 3 - yl] oxy - 1,3,4 - thiadiazole via the inhalation route. Figure 5 is regarding dry powder insufflation administration, Figure 6 is regarding nebulization administration, and Figure 7 is regarding oral administration.

[0251] More specifically, Figures 5A, 6A, and 7A show the mean ± SEM, and Figures 5A, 6B, and 7B show the results of each replicate, respectively.

[0252] Results As shown in Figure 5, the exemplified compound of the present invention with dry powder insufflation, namely 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole with dry powder insufflation, significantly reduced the number of citric acid-induced coughs compared to the air control. More specifically, Figure 5 shows that 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole with dry powder insufflation significantly decreased the number of citric acid-induced coughs compared to the air control at doses of 1 mg / kg (p = 0.0004) and 2 mg / kg (p = 0.0042).

[0253] As shown in Figure 6, the exemplified compound of the present invention with spraying, namely 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole with spraying, significantly reduced the number of citric acid-induced coughs compared to the air control. More specifically, Figure 6 shows that 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole with spraying at 0.4 mg / kg significantly reduced the number of citric acid-induced coughs compared to the air control (p = 0.0023 at 58 minutes of exposure).

[0254] As shown in Figure 7, the exemplified compound of the present invention with oral administration, namely 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole with oral administration, significantly reduced the number of citric acid-induced coughs compared to the air control (p < 0.05 at 9.5 mg / kg).

[0255] As shown in Figure 8, guinea pigs showed suppression of cough frequency after prophylactic intraperitoneal treatment with 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole compared to the negative control. More specifically, Figure 8 compares the number of coughs in animals intraperitoneally treated with the α7 nAChR ligand 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole administered at 1, 3, and 9.5 mg / kg with the negative control (physiological saline) and the positive control (30 mg / kg of codeine). Compared to the negative control (physiological saline), ****p < p<0.0001, Dunnett's multiple comparison. Data are represented as mean ± SEM with the group size (n) shown in the graph.

[0256] As shown in Figure 9, guinea pigs showed suppression of cough frequency after prophylactic intraperitoneal treatment with 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinucidine compared to the negative control. More specifically, Figure 9 compares the number of coughs in animals intraperitoneally treated with the α7 nAChR ligand 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinucidine administered at 3.0, 9.5, and 30 mg / kg with the negative control (physiological saline) and the positive control (30 mg / kg of codeine). Compared to the negative control (physiological saline), **p < 0.01, Dunnett's multiple comparison. Data are represented as mean ± SEM with the group size (n) shown in the graph.

[0257] Conclusion In the in vivo evaluation of the antitussive efficacy of inhaled compounds, the exemplary compounds of the present invention, namely 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinucidin-3-yl]oxy-1,3,4-thiadiazole, significantly reduced the number of citric acid-induced coughs when administered by three administration methods.

[0258] More specifically, the exemplary compound of the present invention, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, significantly reduced the number of citric acid-induced coughs in the dry powder insufflation form (1 mg / kg and 2 mg / kg, see Figure 5), the aerosol form (0.4 mg / kg, see Figure 6), and the oral administration form (9.5 mg / kg, see Figure 7).

[0259] In the in vivo evaluation of the antitussive efficacy of the inhaled compounds, an example of the compound of the present invention, namely, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, significantly reduced the number of citric acid-induced coughs when administered intraperitoneally (see Figure 8).

[0260] In the in vivo evaluation of the antitussive efficacy of the inhaled compounds, the exemplary compound of the present invention, namely, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine, significantly reduced the number of citric acid-induced coughs when administered intraperitoneally (see Figure 9).

Claims

1. Compounds of general formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof R 1 However, it is an arbitrarily substituted aryl or an arbitrarily substituted heteroaryl, R 2 However, it is either a halogen, a triflate, an optionally substituted aryl, an optionally substituted heteroaryl, or none at all. Or in the formula, R 1 and R 2 A compound in which both elements form an optionally substituted aryl or optionally substituted heteroaryl.

2. The compound according to claim 1, wherein the aforementioned or each aryl or heteroaryl is a 5- to 10-membered ring, for example, a 5-membered ring or a 6-membered ring.

3. The compound according to claim 1 or claim 2, wherein one or both of the aryl group and / or heteroaryl group are monocyclic.

4. The compound according to claim 3, wherein one or both of the aryl group or heteroaryl group are independently selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

5. The compound according to claim 1 or claim 2, wherein one or both of the aryl group and / or heteroaryl group are polycyclic.

6. The compound according to claim 5, wherein one or both of the aryl group and / or heteroaryl group are independently selected from the group consisting of naphthalenyl, anthracenyl, indolidinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzodioxolanil, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, purinyl, thienopyrazinyl, quinolinyl, isoquinolinyl, sinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridine, pteridinyl, carbazolyl, acridinyl, naphthilidinyl, phenazinyl, phenothiazinyl, phenoxazinyl and azurenyl.

7. One or both of the aryl or heteroaryl groups are optionally substituted with one, two or three substituents independently selected from the group consisting of, for example, alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (e.g., F, Cl, Br or I), --OR', --NR'R'', --CF3, --CN, --NO 2 , --SR', --N 3 , --C(=O)NR'R'', --NR'C(=O)R'', --C(=O)R', --C(=O)OR', --OC(=O)R', --O(CR'R''), --C(=O)R', --SO 2 R', and --SO 2 NR'R'', wherein R' and R'' are each hydrogen, lower alkyl (e.g., C 1 ~C 8 including linear or branched alkyl, preferably C 1 ~C 5 , such as methyl, ethyl or isopropyl), cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl), wherein R' and R'' are optionally combined to form a cyclic functional group, the compound according to claim 1 or claim 2.

8. The compound according to claim 7, wherein the substituent is independently selected from the group consisting of cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

9. R 1 However, selected from 1,3,4-thiadiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, and pyrazinyl, and / or R 2 The compound according to claim 1 or claim 2, selected from indolyl, benzofuranyl, benzothiazolyl, and phenyl.

10. The aforementioned compound, 2-(1H-indole-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, 3-(6-phenylpyridazine-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine, 5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-3-pyridyl]-1H-indole, 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazine-3-yl]-1H-indole, 5-[5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyrazine-2-yl]-1H-indole, 6-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazine-3-yl]-1,3-benzothiazole-2-amine, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrole-2-yl)pyridazine-3-yl]oxyquinuclidine, 3-(5-chloropyrazine-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine, 6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline, 2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline, 3-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline, 3-(6-imidazole-1-ylpyridazine-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine, and Selected from the group consisting of 2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, For example, the compound according to claim 1 or claim 2, wherein the compound is 2-(1H-indole-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

11. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically or therapeutically acceptable excipient or carrier.

12. A pharmaceutical composition according to claim 11, for use in the treatment of a disease or disorder.

13. The pharmaceutical composition according to claim 11, for use in the treatment of diseases or disorders mediated by α7 nicotinic acetylcholine receptors (nAChRs).

14. The pharmaceutical composition according to claim 12 or 13, wherein the treatment is for the prevention and / or suppression of cough, progression of cough, improvement of cough symptoms, and improvement of cough recurrence.

15. A method for producing a compound of general formula (I) shown in scheme (I), 【Chemistry 2】 In the formula, R 1 and R 2 A method as defined in claim 1, wherein X is a halo (e.g., F, Cl, Br, or I) or a triflate.

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