Nicotinic acetylcholine receptor ligands

Abstract

Compounds of general formula (I), pharmaceutical compositions comprising said compounds, uses of said compositions and methods of making said compounds are disclosed. The compounds are nicotinic acetylcholine receptor (nAChR) ligands and can be used to prevent and / or inhibit cough. # imgabs0 #

Description

Background Art

[0001] Nicotinic acetylcholine receptors (nAChRs) have been extensively studied for their functions in peripheral and central neurons, where they play a role in regulating neurotransmission. Several subtypes of nAChRs, commonly associated with the central nervous system (CNS), have been demonstrated to exist. The most common nAChR subtypes are the α4β2 and α7 subtypes. The α7 nAChR belongs to the family of acetylcholine-gated cation channels and exhibits different biophysical and pharmacological properties relative to other nAChR subtypes.

[0002] Although these receptors are mainly expressed in neuronal tissue, several types of immune cells also express α7nAChRmRNA. Examples of such immune cells expressing α7nAChR mRNA include macrophages, T-cells, B-cells, microglia, monocytes, and dendritic cells. The immune response to prevent excessive inflammation can be regulated by the CNS through the cholinergic anti-inflammatory pathway in which acetylcholine is released from the vagus nerve. Therefore, acetylcholine activates the postsynaptic α7nAChR of the innervated tissue (including the splenic nerve) after its stimulation and then inhibits inflammatory cytokines.

[0003] Various nicotinic compounds are known to interact with α7 nAChR and have therefore been proposed for therapeutic use. However, a disadvantage of these known nicotinic compounds is that they are associated with various adverse side effects, for example by stimulating muscle and ganglion receptors.

[0004] There is a need for compounds, compositions and methods for preventing or treating various illnesses or conditions, such as CNS conditions, including alleviating the symptoms of these conditions without associated side effects. More specifically, there is a need for compounds, compositions and methods that will affect CNS function without significantly affecting those nicotinic receptor subtypes that may induce adverse side effects, such as significant activity at cardiovascular and skeletal muscle sites. Summary of the invention

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

[0006]

[0007] or a pharmaceutically acceptable salt thereof,

[0008] Where R 1 and R 2 each is an optionally substituted aryl group which may be the same or different, wherein one or both aryl groups contain a carbocyclic or heterocyclic aromatic ring and wherein one or both aryl groups are monocyclic or polycyclic,

[0009] And where R 1 and R2 It is optionally fused.

[0010] According to another aspect of the present invention, there is provided a compound of general formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof,

[0013] in:

[0014] R 1 is optionally substituted aryl or optionally substituted heteroaryl; and

[0015] R 2 is halogen, triflate, optionally substituted aryl, optionally substituted heteroaryl or absent;

[0016] or where R 1 and R 2 Together they form an optionally substituted aryl or an optionally substituted heteroaryl.

[0017] According to another aspect of the present invention, there is provided a compound of general formula (II):

[0018]

[0019] or a pharmaceutically acceptable salt thereof,

[0020] Where R 1 is an optionally substituted aryl group containing a carbocyclic or heterocyclic aromatic ring and wherein the aryl group is monocyclic or polycyclic, and

[0021] X is halogen or triflate.

[0022] Also provided is a pharmaceutical composition comprising a compound of formula (I) or (II), the use of a compound of formula (I) or (II), the use of a composition comprising a compound of formula (I) or (II) and a process for making a compound of formula (I) and (II), as defined in the accompanying independent claims to which reference should now be made. Preferred or advantageous features of the invention are set out in the dependent claims and are further described below.

[0023] The compounds of formula (I) and (II) of the present invention advantageously affect the central nervous system without inducing potential adverse side effects of nicotinic receptor subtypes. These potential adverse side effects may include significant activity at cardiovascular and skeletal muscle sites.

[0024] More specifically, the compounds of general formula (I) and (II) of the present invention are α7nAChR agonists, which provide a novel non-anesthetic treatment method for patients with acute and chronic cough. As described below, the potential application of selective α7nAChR agonists as antitussives according to the present invention was confirmed in an in vivo experiment by inhibiting the cough response induced by citric acid in guinea pigs.

[0025] Additionally, α7nAChR agonists as described herein may be beneficial in the treatment of the source of cough. In preclinical studies of lung disease, α7nAChR agonists have demonstrated anti-inflammatory effects in models of acute lung injury, allergen challenge, and Gram-negative bacterial infection.

[0026] According to one aspect of the present invention, there is provided a compound of general formula (I):

[0027]

[0028] or a pharmaceutically acceptable salt thereof. 1 and R 2 may each be an optionally substituted aryl group which may be the same or different, wherein one or both aryl groups may contain a carbocyclic or heterocyclic aromatic ring and wherein one or both aryl groups may be monocyclic or polycyclic, and wherein R 1 and R 2 May be optionally fused.

[0029] According to another aspect of the present invention, there is provided a compound of general formula (I):

[0030]

[0031] or a pharmaceutically acceptable salt thereof. 1 R may be an optionally substituted aryl group or an optionally substituted heteroaryl group. 2 R may be halogen, triflate, optionally substituted aryl, optionally substituted heteroaryl, or may be absent. 1 and R 2 Together they may form an optionally substituted aryl or an optionally substituted heteroaryl.

[0032] According to another aspect of the present invention, there is provided a compound of general formula (II):

[0033]

[0034] or a pharmaceutically acceptable salt thereof. 1 X may be an optionally substituted aryl group which may contain a carbocyclic or heterocyclic aromatic ring and wherein the aryl group may be monocyclic or polycyclic. X may be a halogen or a triflate.

[0035] like Figure 1A As shown in , the pharmacophore elements of α7nAChR include hydrogen bond acceptors and hydrophobic moieties adjacent to the cationic center, which are believed to be essential for π-interactions. The quinuclidine basic nitrogen occupies the bridgehead position in the azabicyclic ring system and provides the greatest electrostatic interaction and the least steric demand. Due to the strong basicity of quinuclidine derivatives (pKa ~ 10-11), α7nAChR ligands exist as cationic forms under physiological conditions with a well-defined proton orientation. Small aliphatic groups (e.g., methyl) or larger groups (e.g., benzyl) in the 2-position of the azabicyclic ring may reduce binding to nAChR.

[0036] The compounds of the present invention incorporate a (pyridin-3-yl)methyl moiety which improves pharmacological properties, leading to better selectivity (especially for 5-HT3 receptors), increased α7nAChR affinity and abolished inhibition of hERG (human ether-a-go-go-related gene) channels.

[0037] As used herein, the term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

[0038] As used herein, the term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 carbon atoms in the ring. Common aryl groups include C 6 -C 14 Aryl, such as C 6 -C 10 Aryl. C 6 -C 14 Non-limiting examples of aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. An "optionally substituted aryl" group may include substituents as described herein.

[0039] As used herein, the term "heteroaryl" refers to an aromatic group having 5 to 14 ring atoms (e.g., 5 to 10 ring atoms) and 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 (furyl) , benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, dibenzothioxanthane, pyrrolyl (including but not limited to 2H-pyrrolyl), imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl (pyr idyl / pyridinyl) (including but not limited to 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, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, The term "optionally substituted heteroaryl" refers to an alkyl, aryl, pyridinyl, phenanthroline, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl. In the case where the heteroaryl group contains a nitrogen atom in the ring, such a nitrogen atom may be in the form of an N-oxide, for example, pyridinyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide. An "optionally substituted heteroaryl" group may include substituents as described herein.

[0040] Optionally, the or each aromatic ring of the carbocyclic or heterocyclic aromatic ring of one or two aryl groups of general formula (I) and general formula (II), the aryl of the optionally substituted aryl of general formula (I), and the heteroaryl of the optionally substituted heteroaryl of general formula (I) are 3- to 10-membered rings, such as 5- to 10-membered rings. For example, the or each aromatic ring of the carbocyclic or heterocyclic aromatic ring of one or two aryl groups of general formula (I) and general formula (II), the aryl of the optionally substituted aryl of general formula (I), and the heteroaryl of the optionally substituted heteroaryl of general formula (I) can be 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings or 10-membered rings.

[0041] Optionally, one or two aryl groups of formula (I) and formula (II) and each aryl or heteroaryl group of formula (I) are monocyclic. For example, one or two aryl groups of formula (I) and formula (II) and each aryl or heteroaryl group of formula (I) can be independently selected from: phenyl, furanyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and thiadiazolyl. In one embodiment, R 1 Phenyl is not included.

[0042] Optionally, one or two aryl groups of formula (I) and formula (II) and each aryl or heteroaryl group of formula (I) are polycyclic. For example, one or two aryl groups of formula (I) and formula (II) and each aryl or heteroaryl group of formula (I) can be independently selected from: naphthyl, anthracenyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzodioxolanyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, purinyl, thienopyrazinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and azulenyl.

[0043] Optionally, one or both aryl groups of formula (I) and formula (II) and each aryl or heteroaryl group of formula (I) are independently selected from the group consisting of acenaphthylene, acetylphenol anthracene, acridine, anthracene, anthracene, 9,10-anthracene dione, 9(10H)-anthraquinone, anthraquinone, anthraquinone, benzo[e]acetylphenol anthracene, benzo[c]acridine, benz[a]anthracene, 7H-benzo[de]anthracen-7-one, benzanthrone, benzo[b] Benzo[c] Benzo[g] 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 (quinolene), 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, diphenylene, 9H-carbazole, Coronet, 4H-cyclopenta[def]phenanthrene, cyclopenta[cd]pyrene, dibenzo[a,h]acridine, dibenzo[a,j]acridine, dibenzo[c,h]acridine, dibenzo[a,c]anthracene, dibenzo[a,h]anthracene, dibenzo[a,j]anthracene, 7H-dibenzo[a,g]carbazole, 13H-dibenzo[a,i]carbazole, 7H-dibenzo[c,g]carbazole, dibenzo[b,def] dibenzo[def,mno] Dibenzo[def,p] 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, tetracene, naphthalene, naphtho[1,2,3,4-def] naphtho[2,3-f]quinoline, pentaphene, perylene, 1H-phenalene, phenanthrenequinone, phenanthrene, 9,10-phenanthrenedione, phenanthridine, 1,10-phenanthroline, phenanthro[4,5-bcd]thiophene, phenazine, phenazone, phenanthroline, pyrene, quinoline, triphenylene, and 9H-xanthene.

[0044] Optionally, one or both aryl groups of formula (I) and formula (II) and each aryl or heteroaryl group of formula (I) is substituted, for example, by 1, 2 or 3 substituents.

[0045] Optionally, the substituents are independently selected from: alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halogen (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. The lower alkyl group may be methyl, ethyl, propyl, isopropyl, butyl or tert-butyl. For example, the substituent may be a straight chain or branched chain alkyl group, including C 1 -C 8 , preferably C 1 -C 5 , such as methyl, ethyl or isopropyl, cycloalkyl, heterocyclyl, aryl or arylalkyl (such as benzyl).

[0046] Optionally, R' and R" combine to form a cyclic functional group.

[0047] Optionally, substituents are independently selected from the group consisting of cyano, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

[0048] Optionally, R of the general formula (I) and (II) 1 Selected from: 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

[0049] Optionally, R of the general formula (I)2 Selected from indolyl, benzofuranyl, benzothiazolyl and phenyl.

[0050] Optionally, R of the general formula (I) 1 and R 2 Therefore, R of the general formula (I) 1 and R 2 may be bonded together to form an optionally substituted aryl group. 1 and R 2 They may be taken together to form a carbocyclic or heterocyclic aromatic ring. 1 and R 2 They can form a monocyclic or polycyclic group together. 1 and R 2 They may be taken together to form a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, a 12-membered ring, a 13-membered ring, a 14-membered ring, a 15-membered ring, a 16-membered ring, or a 17-membered ring.

[0051] Optionally, one or both aryl groups of general formula (I) may comprise a carbocyclic or heterocyclic aromatic ring. Optionally, one or both aryl groups of general formula (I) may be an optionally substituted carbocyclic or heterocyclic aromatic ring.

[0052] Optionally, R of the general formula (I) 1 and R 2 can together form an optionally substituted aryl group or an optionally substituted heteroaryl group. In this case, R 1 and R 2 may be independently an optionally substituted aryl group or an optionally substituted heteroaryl group. 1 and R 2 may be bonded together to form an optionally substituted aryl group or an optionally substituted heteroaryl group. 1 and R 2 They can form a monocyclic or polycyclic group together. 1 and R 2 They may be taken together to form a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, a 12-membered ring, a 13-membered ring, a 14-membered ring, a 15-membered ring, a 16-membered ring, or a 17-membered ring.

[0053] Optionally, the compound is selected from:

[0054] 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole;

[0055] 3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine;

[0056] 2-phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole;

[0057] 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxy-3-pyridinyl]-1H-indole;

[0058] 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole;

[0059] 5-[5-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole;

[0060] 6-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine;

[0061] 2-(3-pyridinylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine;

[0062] 3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine;

[0063] 6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline;

[0064] 2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline;

[0065] 3-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline;

[0066] 3-(6-imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine; and

[0067] 2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0068] Advantageously, 2-(1H-indol-5-yl)-5-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole significantly reduced citric acid-induced cough counts when compared to saline controls.

[0069] Advantageously, 2-(3-pyridinylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine significantly reduced citric acid-induced cough counts when compared to saline controls.

[0070] Advantageously, 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole significantly reduced citric acid-induced cough counts when compared to saline controls.

[0071] Optionally, the compound is selected from:

[0072] trans-4-nitrobenzoic acid [2-(3-pyridylmethyl)quinuclidin-3-yl] ester (2)

[0073] trans-3-[(5-bromo-2-pyridinyl)oxy]-2-(3-pyridinylmethyl)quinuclidine (4)

[0074] trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole (5)

[0075] cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (6)

[0076] cis-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole (7)

[0077] trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine (8)

[0078] trans-5-[5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyrazin-2-yl]-1H-indole (9)

[0079] trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (10)

[0080] trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole (11)

[0081] (2S,3R)-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole(2S,3R-11)

[0082] (2R,3S)-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole(2R,3S-11)

[0083] trans-6-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine (12)

[0084] Trans-2-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylic acid tert-butyl ester (13)

[0085] trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14)

[0086] trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole (15)

[0087] trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole (16)

[0088] trans-3-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyisoquinoline (17)

[0089] trans-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline (18)

[0090] trans-3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (19)

[0091] trans-2-phenyl-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole (20)

[0092] Advantageously, trans-2-(1H-indol-5-yl)-5-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole significantly reduced citric acid-induced cough counts when compared to saline controls.

[0093] Advantageously, trans-2-(3-pyridinylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine significantly reduced citric acid-induced cough counts when compared to saline controls.

[0094] Advantageously, trans-5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole significantly reduced citric acid-induced cough counts when compared to saline controls.

[0095] In addition, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole also showed significant improvement in cough latency at doses approximately 20 to 30 times lower than codeine, which is considered the "gold standard" narcotic cough suppressant.

[0096] Therefore, in a preferred embodiment of the present invention, there is provided: 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof. Therefore, in another preferred embodiment of the present invention, there is provided: 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof. Therefore, in another preferred embodiment of the present invention, there is provided: 5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole.

[0097] In a preferred embodiment of the present invention, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0098]

[0099] In a preferred embodiment of the present invention, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0100]

[0101] In a preferred embodiment of the present invention, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0102]

[0103] In a preferred embodiment of the present invention, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0104]

[0105] In a preferred embodiment of the present invention, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0106]

[0107] In a preferred embodiment of the present invention, there is provided a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0108]

[0109] Optionally, the pharmaceutically acceptable salt is selected from one or more of the following: 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 with acidic amino acids, for example aspartate or glutamate, or hydrates or ethanol solvates.

[0110] Optionally, the compounds of general formula (I) and (II) can exist in unsolvated form and solvated form, including hydrated form. "Hydrate" refers to a complex formed by the combination of water molecules with molecules or ions of a solute. "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent can be an organic compound, an inorganic compound, or a mixture of the two. Solvates are intended to include hydrates. Some examples of solvents include, but are not limited to, methanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Optionally, the compounds of general formula (I) and (II) can exist as solid materials, for example, in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[0111] "Tautomer" means a compound resulting from a phenomenon in which a proton of one atom of a molecule is transferred to another atom (see Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992)). Tautomer also refers to one of two or more structural isomers that are in equilibrium and are easily converted from one isomeric form to another. The compounds described herein may have one or more tautomers and therefore include various isomers. All such isomeric forms of these compounds are expressly included in the present invention.

[0112] "Isomer" means a compound with the same molecular formula but different bonding properties or order of its atoms or the arrangement of its atoms in space. Isomers whose atoms are arranged differently in space are called "stereoisomers". "Stereoisomers (stereoisomer and stereoisomers)" refer to compounds that exist in different stereoisomeric forms when they have one or more asymmetric centers or have asymmetrically substituted double bonds, and can therefore be produced as individual stereoisomers or as a mixture. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R- and S- ordering rules of Cahn and Prelog, or described by the way in which the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture". Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see Advanced Organic Chemistry, 6th edition, J. March, John Wiley and Sons, New York, 2007, Chapter 4, discussion), differing in the chirality of one or more stereocenters.

[0113] The present invention also encompasses isotopically-labeled compounds which are identical to the compounds described herein except 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 isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen or its isotope, such as deuterium (D) or tritium (3 H). Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) and fluorine-18 (i.e., 18 F) isotopes are useful because of their ease of preparation and their detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) may offer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those described herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0114] According to the present invention, also provided are pharmaceutical compositions comprising a compound described herein and a pharmaceutically or therapeutically acceptable excipient or carrier, such as a pharmaceutical composition comprising a compound of formula (I) or (II) and a pharmaceutically or therapeutically acceptable excipient or carrier.

[0115] For example, the pharmaceutical composition may include 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may include 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may include 5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole.

[0116] For example, the pharmaceutical composition may include trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may include trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical composition may include trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole.

[0117] Pharmaceutically acceptable excipients or carriers may include fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers and surfactants, which may be selected to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, starch types, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solutions, dextrose solutions, Hank's solutions, Ringer's solutions, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, etc. Excipients can also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, croscarmellose sodium, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor seed oil, mineral oil, polyethylene glycol (e.g., PEG 400 or PEG 4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, crosslinked sodium carboxymethylcellulose, alginic acid, casein, divinylbenzene methacrylate copolymer, docusate sodium, cyclodextrin (e.g., 2-hydroxypropyl-.delta.-cyclodextrin), polysorbate (e.g., polysorbate 80), cetyltrimethylammonium bromide, TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid esters of polyethylene glycol or polyoxyalkylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan esters ), 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 spray-dried lactose, sucrose, fructose, calcium phosphate, calcium hydrogen phosphate, tricalcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, polydimethylsiloxane, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, etc.

[0118] According to the present invention, there is also provided a compound described herein for use in treating a disease or condition, for example, a compound of formula (I) or (II) for use in treating a disease or condition. For example, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition. For example, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition. For example, 5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition.

[0119] For example, trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition. For example, trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)13-pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition. For example, trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition.

[0120] According to the present invention, there is also provided a compound described herein for treating a disease or condition mediated by an α7 nicotinic acetylcholine receptor (nAChR), for example, a compound of formula (I) or (II) for treating a disease or condition mediated by an α7 nicotinic acetylcholine receptor (nAChR). For example, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition mediated by an α7 nicotinic acetylcholine receptor (nAChR). For example, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)13 pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition mediated by an α7 nicotinic acetylcholine receptor (nAChR). For example, 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0121] For example, trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition mediated by the α7 nicotinic acetylcholine receptor (nAChR). For example, trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition mediated by the α7 nicotinic acetylcholine receptor (nAChR).

[0122] Advantageously, the compounds described herein, such as compounds of formula (I) and (II), competitively inhibit the binding of radiolabeled MLA to the human α7 nAChR subtype with an equilibrium constant (Ki) value of 1-1000 nM. Therefore, the compounds described herein, such as compounds of formula (I) and (II), are suitable for treating diseases or conditions mediated by α7 nicotinic acetylcholine receptor (nAChR).

[0123] The expression "mediated", such as "mediated by nAChR", should be understood to mean related to the activity of nAChR. For example, the expression "mediated" can be understood to mean "controlled by", such as "transcriptional or translational control", or "transcriptional or translational regulation", such as up-regulation or down-regulation. 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, conformational changes in the nAChR ion channel can occur upon binding of the compound, resulting in a distortion of the quaternary symmetry of the M1-M4 domains, thereby opening the hydrophobic gate and thereby allowing ions to pass. For example, the process can involve the activation of monovalent Na + and K + Ions and Ca 2+ Ion Permeability. Advantageously, the ability of nAChRs to alter intracellular calcium levels can lead to the activation of various downstream intracellular pathways such as neuronal signaling and plasticity.

[0124] Furthermore, the expression "mediate" may be understood to include promoting intracellular signaling, for example via a G protein binding cluster contained in the intracellular loop of the α7 subunit.

[0125] Optionally, the compounds described herein, such as compounds of formula (I) and (II), can desensitize nAChR. Thus, the compounds described herein, such as compounds of formula (I) and (II), can be suitable for desensitizing nAChR. Thus, also provided is a compound described herein, such as a compound of formula (I) or (II), for use as a nAChR desensitizer.

[0126] More specifically, nAChRs can rapidly transition to a closed state upon activation, followed by a desensitized state. Desensitization is the loss of a biological response due to agonist stimulation. Upon washout of the ligand, the receptor can return to the basal or resting allosteric state.

[0127] According to the present invention, there is also provided use of the compounds described herein in the manufacture of a medicament for treating a disease or condition, such as use of a compound of formula (I) or (II) in the manufacture of a medicament for treating a disease or condition.

[0128] According to the present invention, there is also provided a method for treating a disease or condition, comprising the step of administering a compound described herein or a pharmaceutical composition described herein to a patient in need thereof. For example, there is provided a method for treating a disease or condition, comprising the step of administering a compound of formula (I) or (II) or a pharmaceutical composition comprising a compound of formula (I) or (II) to a patient in need thereof. For example, the method for treating a disease or condition may include the step of administering 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole or a pharmaceutical composition described herein to a patient in need thereof.

[0129] Optionally, the disease or condition is a disease or condition mediated by α7 nAChR.

[0130] Optionally, the disease or disorder is selected from: cognitive and neurodegenerative diseases; psychiatric disorders, such as schizophrenia; acute nociceptive, neuropathic or inflammatory pain; and affective disorders, such as depression and agitation.

[0131] For example, the disease or condition may be selected from:

[0132] i) pain, including one or more of acute pain, neuropathic pain, inflammatory pain, neuropathic pain, chronic pain, severe chronic pain, postoperative pain, cancer-related pain, angina, renal or biliary colic, menstrual pain, migraine, gout, arthritis, rheumatoid arthritis, tenosynovitis, vasculitis, trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, low back pain, deafferentation syndrome, and brachial plexus avulsion;

[0133] ii) metabolic syndrome, weight gain, type I diabetes, type II diabetes, or diabetic neuropathy;

[0134] iii) inflammation, including 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 transplant 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, pouchitis, glomerulonephritis, lupus nephritis, thrombosis, and graft-versus-host reaction; and / or

[0135] iv) cognition, including one or more of age-related memory impairment, mild cognitive impairment, precocious 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 deficits in schizophrenia patients, and cognitive dysfunction in schizophrenia patients.

[0136] The pharmaceutical compositions may be used to ameliorate any symptoms associated with these conditions, diseases and disorders.

[0137] Preferably, the treatment is used to prevent and / or suppress cough, cough progression, improve cough symptoms and improve cough recurrence. Treatment can be used to treat the source of cough. Hereinafter, "cough" is understood to refer to the discharge of air from the lungs, for example, the discharge of air from the lungs of a subject (e.g., a human subject). Advantageously, the compounds of the present invention, such as compounds of formula (I) and (II), can be used as antitussives. Therefore, there is also provided a compound described herein for use as an antitussive, such as a compound of formula (I) or (II) for use as an antitussive. More specifically, antitussives can suppress coughs by a central mechanism or a peripheral mechanism or a mixture of the two mechanisms.

[0138] The pharmaceutical compositions described herein can be used as selective α7nAChR agonists. The pharmaceutical compositions described herein can also be used as antitussives. The pharmaceutical compositions described herein can also be used as anti-inflammatory agents, for example, for acute lung injury, allergen attack and / or Gram-negative bacterial infection. Therefore, the pharmaceutical compositions described herein can be used to treat inflammation, for example, for the treatment of acute lung injury, the treatment of allergen attack and / or the treatment of Gram-negative bacterial infection.

[0139] The compounds described herein may also be used as adjunctive therapy in conjunction with existing therapies, for example, for the management of any of the aforementioned types of diseases and conditions. In such cases, it is preferred to minimize the effects on nAChRs.

[0140] The active ingredient can be administered in a manner that affects only certain subtypes of the nervous system, such as those associated with muscles and ganglia. This can be achieved by targeted drug delivery and / or by adjusting the dose so that the desired effect is achieved without reaching a threshold dose required to achieve significant side effects.

[0141] Optionally, the compound for use, use or method according to the present invention may be an orally administered compound. Preferably, the compound is an orally administered 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0142] Optionally, the compound for use, use or method according to the present description may be administration of the compound by inhalation.

[0143] Optionally, the compound, use or method for use according to the present invention may be administered in the form of a dry powder. Preferably, the compound is a dry powder 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole, such as dry powder insufflated 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole.

[0144] Optionally, the compound for use, use or method according to the present invention may be administered in aerosolized form. Preferably, the compound is aerosolized 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0145] Optionally, the compound for use, use or method according to the present description may be to administer the compound orally at a dose of 0.1 mg to 1 g / kg / day.

[0146] For example, the compound can be orally administered at a dosage of at least about 0.00001 mg / kg / day, at least about 0.0001 mg / kg / day, at least about 0.001 mg / kg / day, at least about 0.01 mg / kg / day, at least about 0.1 mg / kg / day, at least about 0.2 mg / kg / day, at least about 0.3 mg / kg / day, at least about 0.4 mg / kg / day, at least about 0.5 mg / kg / day. The compound can include any range of given endpoints.

[0147] For example, the compound can be administered orally at a dosage of no more than about 0.01 g / kg / day, no more than about 0.1 g / kg / day, no more than about 0.5 g / kg / day, no more than about 0.9 g / kg / day, no more than about 1 g / kg / day, no more than about 1.1 g / kg / day, no more than about 1.2 g / kg / day, no more than about 1.5 g / kg / day, no more than about 2 g / kg / kg / day. The compound can include any range of given endpoints.

[0148] For example, the compound can be orally administered at a dosage of at least about 0.00001 mg / kg / day to no more than about 2 g / kg / day, at least about 0.0001 mg / kg / day to no more than about 1.5 g / kg / day, at least about 0.001 mg / kg / day to no more than about 1.2 g / kg / day, at least about 0.01 mg / kg / day to no more than about 1.1 g / kg / day, at least about 0.1 mg / kg / day to no more than about 1 g / kg / day, at least about 0.2 mg / kg / day to no more than about 0.9 g / kg / day, at least about 0.3 mg / kg / day to no more than about 0.5 g / kg / day, at least about 0.4 mg / kg / day to no more than about 0.1 g / kg / day, at least about 0.5 mg / kg / day to no more than about 0.01 g / kg / day. The compound can include any range of given endpoints.

[0149] For example, the compounds for use, uses or methods described herein can be administered at 0.1 mg / kg / day, 0.2 mg / kg / day, 0.3 mg / kg / day, 0.4 mg / kg / day, 0.5 mg / kg / day, 1 mg / kg / day, 2 mg / kg / day, 3 mg / kg / day, 4 mg / kg / day, 5 mg / kg / day, 10 mg / kg / day, 15 mg / kg / day, 20 mg / kg / day, 25 mg / kg / day, 30 mg / kg / day, 35 mg / kg / day, 40 mg / kg / day, 45 mg / kg / day, 50 mg / kg / day, 100 mg / kg / day, 150 mg / kg / day, 200 mg / kg / day, 250 mg / kg / day, 300 mg / kg / day, 350 mg / kg / day In some embodiments, the compound may be administered orally at 400 mg / kg / day, 500 mg / kg / day, 550 mg / kg / day, 600 mg / kg / day, 650 mg / kg / day, 700 mg / kg / day, 750 mg / kg / day, 800 mg / kg / day, 850 mg / kg / day, 900 mg / kg / day, 950 mg / kg / day, 1000 mg / kg / day, 1100 mg / kg / day, 1200 mg / kg / day, 1300 mg / kg / day, 1400 mg / kg / day, 1500 mg / kg / day, 1600 mg / kg / day, 1700 mg / kg / day, 1800 mg / kg / day, 1900 mg / kg / day, 2000 mg / kg / day. The compound may include any range of given endpoints.

[0150] Optionally, the compound for use, use or method described herein may be for oral administration of the compound at 5 mg to 2 g / day.

[0151] For example, the compound can be administered orally at a dosage 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 can include any range of given endpoints.

[0152] For example, the compound can be administered orally at a dosage of no more than about 0.2 g / day, no more than about 0.5 g / day, no more than about 1 g / day, no more than about 1.5 g / day, no more than about 2 g / day, no more than about 2.5 g / day, no more than about 3 g / day, no more than about 5 g / day, no more than about 10 g / day. The compound can include any range of given endpoints.

[0153] For example, the compound can be orally administered at a dosage of at least about 0.1 mg / day to no more than about 10 g / day, at least about 1 mg / day to no more than about 5 g / day, at least about 3 mg / day to no more than about 3 g / day, at least about 4 mg / day to no more than about 2.5 g / day, at least about 5 mg / day to no more than about 2 g / day, at least about 5.1 mg / day to no more than about 1.5 g / day, at least about 6 mg / day to no more than about 1 g / day, at least about 10 mg / day to no more than about 0.5 g / day, at least about 50 mg / day to no more than about 0.2 g / day. The compound can include any range of given endpoints.

[0154] For example, the compound can be administered at 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 The compound can be administered orally at a dosage of 500 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 can include any range of given endpoints.

[0155] The expression "about" with respect to numerical values ​​is to be understood as meaning ±10%, preferably ±5%, for example ±10% w / w, preferably ±5% w / w.

[0156] Optionally, the compounds, uses or methods described herein for use may be a composition in the form of a tablet. The tablet may be a film-coated tablet. The compounds, uses or methods described herein for use may be a composition in the form of a capsule, such as a gelatin capsule.

[0157] Optionally, the compound for use, use or method described herein may be for parenteral, topical, rectal, transmucosal or enteral administration of the compound.

[0158] According to the present invention, there is also provided a method for preparing a compound of general formula (I) or (II), as shown in scheme (I):

[0159]

[0160] Optionally, R 1 and R 2 As defined above, for example, for compounds of formula (I), R 1 and R 2 each is an optionally substituted aryl group which may be the same or different, wherein one or both aryl groups contain a carbocyclic or heterocyclic aromatic ring and one or both aryl groups are monocyclic or polycyclic, and wherein R 1 and R 2 For compounds of general formula (II), R 1 is an optionally substituted aryl group containing a carbocyclic or heterocyclic aromatic ring and wherein the aryl group is monocyclic or polycyclic, and X is halogen or triflate. Alternatively, for compounds of formula (I), R 1 is 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 can be halogen or triflate. Halogen can be fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At) and (Ts).

[0161] As will be apparent to the skilled person, compounds of formula (I) and (II) include ethers of 3-hydroxy-2-(3-pyridylmethyl)quinuclidine. Although the methods by which the compounds of the invention may be prepared may vary, it may be advantageous to use intermediates (e.g., ketones and alcohols) generated during the synthesis of the target compound to prepare the compounds, as shown in Scheme (I) above.

[0162] Although other synthetic strategies will be apparent to those skilled in the art, 2-(3-pyridylmethyl)quinuclidine derivatives can be synthesized by reducing the aldol condensation product formed from 3-pyridinecarboxaldehyde and quinuclidine-3-one.

[0163] For example, 3-quinuclidinone hydrochloride can be reacted with pyridine-3-carboxaldehyde in the presence of methanolic potassium hydroxide. 2-((3-pyridyl)methylene)quinuclidin-3-one is produced from the reaction.

[0164] The stepwise reduction of the conjugated enone functional group to provide 2-(3-pyridylmethyl)quinuclidine-3-ol can be achieved by several different sequences. For example, catalytic hydrogenation of enone (palladium catalyst) can produce the saturated ketone 2-(3-pyridylmethyl)quinuclidine-3-one, an intermediate in the synthesis of the compounds of the present invention.

[0165] Reduction of the ketone to the alcohol can be accomplished, for example, using sodium borohydride, aluminum isopropoxide, or other reagents known in the art of chemical synthesis to perform similar reductions.

[0166] The alcohol 2-(3-pyridylmethyl)quinuclidine-3-ol may be a mixture of cis- and trans-diastereomers, with the former predominating, and may also be an intermediate in the synthesis of the compounds of the present invention.

[0167] The choice of reducing agent may 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.

[0168] Subsequently, the inversion of the 2-substituted cis-3-quinuclidinol to the trans isomer can be carried out using p-nitrobenzoic acid as the nucleophilic partner in the Mitsunobu reaction. Various combinations of aryl groups in general formula (I) can be achieved via Suzuki cross-coupling reactions.

[0169] Compounds 1 to 20 may also be referred to as follows:

[0170] cis-2-(3-pyridylmethyl)quinuclidine-3-ol (1)

[0171] trans-4-nitrobenzoic acid [2-(3-pyridylmethyl)quinuclidin-3-yl] ester (2)

[0172] trans-2-(3-pyridylmethyl)quinuclidine-3-ol (3)

[0173] trans-3-[(5-bromo-2-pyridinyl)oxy]-2-(3-pyridinylmethyl)quinuclidine (4)

[0174] trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole (5)

[0175] cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (6)

[0176] cis-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole (7)

[0177] trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine (8)

[0178] trans-5-[5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyrazin-2-yl]-1H-indole (9)

[0179] trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (10)

[0180] trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole (11)

[0181] (2S,3R)-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole(2S,3R-11)

[0182] (2R,3S)-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole(2R,3S-11)

[0183] trans-6-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine (12)

[0184] Trans-2-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylic acid tert-butyl ester (13)

[0185] trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14)

[0186] trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole (15)

[0187] trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole (16)

[0188] trans-3-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyisoquinoline (17)

[0189] trans-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline (18)

[0190] trans-3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (19)

[0191] trans-2-phenyl-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole (20)

[0192] As will be apparent to the skilled artisan, the methods by which the compounds of the invention may be prepared may vary. For example, intermediates generated during the synthesis of the target compound may be advantageously used to prepare the compound, as shown in Scheme (II). Since 2,3-disubstituted quinuclidine derivatives can form geometric isomers, both cis- and trans-2-(3-pyridylmethyl)quinuclidine-3-ols were explored as intermediates in the synthesis of the target molecule. Reduction of 2-(3-pyridylmethyl)quinuclidine-3-one with aluminum isopropoxide produces primarily one diastereomer: cis-alcohol 1, which may be due to selective hydride transfer to the least hindered face of the carbonyl moiety. Flipping of cis-alcohol 1 to trans-isomer 3 is achieved via a Mitsunobu reaction with p-nitrobenzoic acid and subsequent hydrolysis of the resulting ester 2, as shown in Scheme (II):

[0193]

[0194] The reagents and conditions of scheme (II) are as follows:

[0195] (a) p-nitrobenzoic acid, diisopropyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0-25°C, 12 hours;

[0196] (b) lithium hydroxide, tetrahydrofuran / water, 12 hours;

[0197] (c) 5-bromo-2-chloropyridine, potassium tert-butoxide, tetrahydrofuran, 25°C, 12 hours;

[0198] (d) indole-5-boronic acid, (1,1'-bis(diphenylphosphino)ferrocene) dichloropalladium(II), cesium carbonate, dioxane / water, 90°C, 12 hours;

[0199] (e) 3,6-dichloropyridazine, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 hours;

[0200] (f) indole-5-boric acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90°C, 12 hours;

[0201] (g) 2,5-dichloropyrazine, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 hours;

[0202] (h) Indole-5-boric acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate, dimethoxyethane / water, 90°C, 12 hours.

[0203] Successive nucleophilic substitution of the halogen in dihalogen derivatives of nitrogen-containing aromatic heterocycles by reaction with cis- or trans-alcohols 1 or 3 and subsequent Suzuki coupling yielded a series of ethers. As electronegative nitrogen-containing aromatic heterocycles, pyridine, pyrazine, pyridazine, and thiadiazole were explored. Cross-coupling reactions of intermediates 4, 6, 8, 10, and 15 with various arylboronic acids afforded a variety of biaryl ethers. To evaluate the effect of benzene rings fused to pyridine, isoquinoline, and quinoline, ethers 17 and 18 were obtained, as shown in Scheme (III):

[0204]

[0205] The reagents and conditions of scheme (III) are as follows:

[0206] (a) 3,6-dichloropyridazine, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 hours; (b) indole-5-boric acid, (1,1'-bis(diphenylphosphino)ferrocene) dichloropalladium(II), potassium carbonate, dioxane / water, 90°C, 12 hours;

[0207] (c) 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine, (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II), cesium carbonate, dioxane / water, 90°C, 12 hours;

[0208] (d) 1-(tert-Butoxycarbonyl)pyrrole-2-boronic acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90°C, 12 hours;

[0209] (e) Hydrogen chloride, dioxane, 25°C, 12 hours;

[0210] (f) 2,5-dibromo-1,3,4-thiadiazole, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 hours;

[0211] (g) indole-5-boric acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, cesium carbonate, dioxane / water, 90°C, 12 hours;

[0212] (h) 2-Chloroquinoline, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 hours;

[0213] (i) 3-chloroisoquinoline, sodium hydride, N,N-dimethylformamide, 25-90°C, 2 hours;

[0214] (j) phenylboronic acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90°C, 7 hours;

[0215] (k) Phenylboronic acid, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, potassium carbonate, dioxane / water, 90°C, 12 hours.

[0216] Specific examples of compounds

[0217] Examples of representative compounds of the present invention include, but are not limited to, the following compounds:

[0218] 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0219]

[0220] 3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0221] 2-phenyl-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0222] 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxy-3-pyridinyl]-1H-indole

[0223] 5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole

[0224] 5-[5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyrazin-2-yl]-1H-indole

[0225] 6-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine

[0226] 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine

[0227] 3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0228] 6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline

[0229] 2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline

[0230] 3-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyisoquinoline

[0231] 3-(6-Imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0232] 2-Bromo-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0233] cis-2-(3-pyridylmethyl)quinuclidine-3-ol

[0234]

[0235] trans-4-nitrobenzoic acid [2-(3-pyridylmethyl)quinuclidin-3-yl] ester trans-2-(3-pyridylmethyl)quinuclidine-3-ol (3)

[0236]

[0237] trans-3-[(5-bromo-2-pyridinyl)oxy]-2-(3-pyridinylmethyl)quinuclidine

[0238] trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1H-indole

[0239] cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0240]

[0241] cis-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole

[0242] trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine trans-5-[5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyrazin-2-yl]-1H-indole

[0243] trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0244] trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole

[0245] trans-6-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine

[0246]

[0247] trans-2-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylic acid tert-butyl ester

[0248]

[0249] trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine

[0250] trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0251] trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0252]

[0253] trans-3-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyisoquinoline

[0254]

[0255] trans-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline

[0256]

[0257] trans-3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0258] trans-2-phenyl-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0259]

[0260] Numbered paragraphs

[0261] Various aspects of the invention are described in the following numbered paragraphs:

[0262] 1. A compound of general formula (I):

[0263]

[0264] or a pharmaceutically acceptable salt thereof,

[0265] Where R 1 and R 2 each is an optionally substituted aryl group which may be the same or different, wherein one or both aryl groups contain a carbocyclic or heterocyclic aromatic ring and wherein one or both aryl groups are monocyclic or polycyclic,

[0266] And where R 1 and R 2 It is optionally fused.

[0267] 2. A compound according to numbered paragraph 1, wherein the or each of the carbocyclic or heterocyclic aromatic rings of one or both aryl groups is a 3- to 10-membered ring, such as a 5-membered ring or a 6-membered ring.

[0268] 3. A compound according to numbered paragraph 1 or numbered paragraph 2, wherein one or both aryl groups are monocyclic.

[0269] 4. A compound according to numbered paragraph 3, wherein one or two 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.

[0270] 5. A compound according to any one of numbered paragraphs 1 or 2, wherein one or both aryl groups are polycyclic.

[0271] 6. A compound according to numbered paragraph 5, wherein one or two aryl groups are independently selected from the group consisting of naphthyl, anthracenyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzodioxolanyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, purinyl, thienopyrazinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and azulenyl.

[0272] 7. A compound according to any preceding numbered paragraph, wherein one or both aryl groups are substituted, for example, by 1, 2 or 3 substituents.

[0273] 8. A compound according to numbered paragraph 7, wherein the substituents are independently selected from: alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halogen (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 (eg, straight or branched chain alkyl, including C 1 -C 8 , preferably C 1 -C 5 , such as methyl, ethyl or isopropyl), cycloalkyl, heterocyclyl, aryl or arylalkyl (such as benzyl), and wherein R' and R" are optionally combined to form a cyclic functional group.

[0274] 9. A compound according to numbered paragraph 8, wherein the substituents are independently selected from the group consisting of cyano, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

[0275] 10. A compound according to any preceding numbered paragraph, wherein R 1 Selected from: 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl.

[0276] 11. A compound according to any preceding numbered paragraph, wherein R 2 Selected from indolyl, benzofuranyl, benzothiazolyl and phenyl.

[0277] 12. A compound according to any preceding numbered paragraph, wherein the compound is selected from:

[0278] 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole;

[0279] 3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine;

[0280] 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxy-3-pyridinyl]-1H-indole;

[0281] 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole;

[0282] 5-[5-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole;

[0283] 6-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine;

[0284] 2-(3-pyridinylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine;

[0285] 3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine;

[0286] 6-Fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline;

[0287] 2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline;

[0288] 3-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline;

[0289] 3-(6-imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine; and

[0290] 2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0291] 13. A 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.

[0292] 14. A compound according to numbered paragraph 12, wherein the compound is 2-(3-pyridinylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine.

[0293] 15. A compound according to numbered paragraph 12, wherein the compound is 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole.

[0294] 16. A compound according to any preceding numbered paragraph, wherein the compound is selected from:

[0295] trans-4-nitrobenzoic acid [2-(3-pyridylmethyl)quinuclidin-3-yl] ester (2);

[0296] trans-3-[(5-bromo-2-pyridinyl)oxy]-2-(3-pyridinylmethyl)quinuclidine (4);

[0297] trans-5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxy-3-pyridinyl]-1H-indole (5);

[0298] cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (6);

[0299] cis-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (7);

[0300] trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine (8);

[0301] trans-5-[5-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole (9);

[0302] trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (10);

[0303] trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole (11);

[0304] (2S,3R)-5-[6-[2-(3-pyridinylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole (2S,3R-11);

[0305] (2R,3S)-5-[6-[2-(3-pyridinylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole (2R,3S-11);

[0306] trans-6-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine (12);

[0307] trans-tert-butyl 2-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylate (13);

[0308] trans-2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14);

[0309] trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (15);

[0310] trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (16);

[0311] trans-3-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline (17);

[0312] trans-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline (18);

[0313] trans-3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (19); and

[0314] trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (20).

[0315] 17. A 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.

[0316] 18. A compound according to numbered paragraph 16, wherein the compound is trans-2-(3-pyridinylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine.

[0317] 19. A compound according to numbered paragraph 16, wherein the compound is trans-5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole.

[0318] 20. A compound according to any preceding numbered paragraph, wherein the 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 with acidic amino acids, for example aspartates or glutamates, or hydrates or ethanol solvates.

[0319] 21. A compound of general formula (II):

[0320]

[0321] or a pharmaceutically acceptable salt thereof,

[0322] Where R 1is an optionally substituted aryl group containing a carbocyclic or heterocyclic aromatic ring and wherein the aryl group is monocyclic or polycyclic, and

[0323] X is halogen or triflate.

[0324] 22. A compound of general formula (I):

[0325]

[0326] or a pharmaceutically acceptable salt thereof,

[0327] in:

[0328] R 1 is optionally substituted aryl or optionally substituted heteroaryl; and

[0329] R 2 is halogen, triflate, optionally substituted aryl, optionally substituted heteroaryl or absent;

[0330] or where R 1 and R 2 Together they form an optionally substituted aryl or an optionally substituted heteroaryl.

[0331] 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.

[0332] 24. A compound according to any one of numbered paragraphs 1 to 22 for use in treating a disease or condition.

[0333] 25. A compound according to any one of numbered paragraphs 1 to 22 for use in treating a disease or condition mediated by the alpha 7 nicotinic acetylcholine receptor (nAChR).

[0334] 26. Use of a compound according to any one of numbered paragraphs 1 to 22 in the manufacture of a medicament for treating a disease or condition.

[0335] 27. A method of treating a disease or condition comprising the step of 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.

[0336] 28. A compound for use in treating a disease or condition according to numbered paragraph 24 or numbered paragraph 25, a use according to numbered paragraph 26, or a method according to numbered paragraph 27, wherein the treatment is for preventing and / or inhibiting cough, cough progression, improving cough symptoms, and improving cough recurrence.

[0337] 29. A compound for use in treating a disease or condition according to numbered paragraph 24 or numbered paragraph 25, a use according to numbered paragraph 26, or a method according to numbered paragraph 27, wherein the disease or condition is selected from: cognitive and neurodegenerative diseases; psychiatric disorders such as schizophrenia; acute nociceptive, neuropathic or inflammatory pain; and affective disorders such as depression and agitation.

[0338] 30. A compound, use or method for treating a disease or condition according to numbered paragraph 28 or numbered paragraph 29, wherein the compound is administered orally.

[0339] 31. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally at a dose of 0.1 mg to 1 g / kg / day.

[0340] 32. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally at a dose of at least about 0.00001 mg / kg / day, at least about 0.0001 mg / kg / day, at least about 0.001 mg / kg / day, at least about 0.01 mg / kg / day, at least about 0.1 mg / kg / day, at least about 0.2 mg / kg / day, at least about 0.3 mg / kg / day, at least about 0.4 mg / kg / day, at least about 0.5 mg / kg / day.

[0341] 33. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally at a dose of no more than about 0.01 g / kg / day, no more than about 0.1 g / kg / day, no more than about 0.5 g / kg / day, no more than about 0.9 g / kg / day, no more than about 1 g / kg / day, no more than about 1.1 g / kg / day, no more than about 1.2 g / kg / day, no more than about 1.5 g / kg / day, no more than about 2 g / kg / kg / day.

[0342] 34. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally at a dosage of at least about 0.00001 mg / kg / day to no more than about 2 g / kg / day, at least about 0.0001 mg / kg / day to no more than about 1.5 g / kg / day, at least about 0.001 mg / kg / day to no more than about 1.2 g / kg / day, at least about 0.01 mg / kg / day to no more than about 1.1 g / kg / day, at least about 0.1 mg / kg / day to no more than about 1 g / kg / day, at least about 0.2 mg / kg / day to no more than about 0.9 g / kg / day, at least about 0.3 mg / kg / day to no more than about 0.5 g / kg / day, at least about 0.4 mg / kg / day to no more than about 0.1 g / kg / day, at least about 0.5 mg / kg / day to no more than about 0.01 g / kg / day.

[0343] 35. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally at 5 mg to 2 g / day.

[0344] 36. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally 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.

[0345] 37. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally at a dose of no more than about 0.2 g / day, no more than about 0.5 g / day, no more than about 1 g / day, no more than about 1.5 g / day, no more than about 2 g / day, no more than about 2.5 g / day, no more than about 3 g / day, no more than about 5 g / day, no more than about 10 g / day.

[0346] 38. A compound, use or method for treating a disease or condition according to numbered paragraph 30, wherein the compound is administered orally at a dosage of at least about 0.1 mg / day to no more than about 10 g / day, at least about 1 mg / day to no more than about 5 g / day, at least about 3 mg / day to no more than about 3 g / day, at least about 4 mg / day to no more than about 2.5 g / day, at least about 5 mg / day to no more than about 2 g / day, at least about 5.1 mg / day to no more than about 1.5 g / day, at least about 6 mg / day to no more than about 1 g / day, at least about 10 mg / day to no more than about 0.5 g / day, at least about 50 mg / day to no more than about 0.2 g / day.

[0347] 39. A compound, use or method for treating a disease or condition according to any one of numbered paragraphs 30 to 38, wherein the composition is in the form of a tablet.

[0348] 40. A compound, use or method for treating a disease or condition according to numbered paragraph 28 or numbered paragraph 29, wherein the compound is administered parenterally, topically, rectally, transmucosally, intraperitoneally or enterally.

[0349] 41. A method for making a compound of formula (I) or (II), as shown in Scheme (I):

[0350]

[0351] Where R 1 and R 2 is as defined in any one of numbered paragraphs 1 to 11, 21 or 22 and X is halogen (eg, F, Cl, Br or I) or triflate.

[0352] 42. A method for making a compound of formula (I) or (II), as shown in Scheme (II):

[0353]

[0354] 43. A method for making a compound of formula (I) or (II), as shown in Scheme (III):

[0355] BRIEF DESCRIPTION OF THE DRAWINGS

[0356] FIG. 1 is a structural overview of the pharmacophore elements of the α7 nAChR and a flow chart showing the evaluation of cough responses in the cough model.

[0357] Figure 2 The arrangement of the bar graphs shows the effect of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole on the cumulative number of citric acid-induced coughs.

[0358] Figure 3 Arrangement of bar graphs showing the effect of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole on the cough latency of citric acid-induced cough.

[0359] Figure 4 is a flow chart showing the experimental setup for the evaluation of the antitussive efficacy of inhaled 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

[0360] Figure 5 The bar graph arrangement shows the effect of dry powder insufflation of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole on the cumulative number of citric acid-induced coughs.

[0361] Figure 6 Arrangement of bar graphs showing the effect of aerosolized 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole on the cumulative number of citric acid-induced coughs.

[0362] Figure 7 Arrangement of bar graphs showing the effect of orally administered 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole on the cumulative number of citric acid-induced coughs.

[0363] Figure 8 is a bar graph showing the effect of intraperitoneally administered 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole on the cumulative number of citric acid-induced coughs.

[0364] Fig. 9 is a bar graph showing the effect of intraperitoneally administered 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine on the cumulative number of citric acid-induced coughs.

[0365] experiment

[0366] The synthesis examples of the compounds are described in Examples 1-25, the biological activity examples are described in Examples 26 and 27, and the antitussive efficacy in vivo is described in Example 28, which are provided to illustrate the present invention and should not be construed as limiting the scope thereof. In these examples, all parts and percentages are by weight unless otherwise stated. The reaction yields are reported in molar percentages.

[0367] Example 1 (reference): 2-[(3-pyridyl)methylene]quinuclidine-3-one

[0368] To a solution of quinuclidine-3-one hydrochloride (45.0 g, 278 mmol) in methanol (450 mL) was added KOH (31.2 g, 556 mmol, 2.00 equiv). The mixture was stirred at 50 °C for 2 hours. Pyridine-3-carboxaldehyde (29.8 g, 278 mmol, 26.2 mL, 1.00 equiv) 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-pyridyl)methylene]quinuclidine-3-one (57.0 g, 266 mmol, yield 95.6%) was obtained as a light yellow solid. 1H NMR (400MHz, CDCl3): δ8.98 (d, J=1.9Hz, 1H), 8.47-8.41 (m, 2H), 7.24 (dd, J=4.8, 7.9Hz,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)+.

[0369] Example 2 (reference): 2-(3-pyridylmethyl)quinuclidine-3-one

[0370] A mixture of 2-[(3-pyridyl)methylene]quinuclidine-3-one (57.0 g, 266 mmol, 1.00 equiv), Pd / C (5.70 g, 26.6 mmol, 10% purity, 0.100 equiv), and H2 (536 mg, 266 mmol, 1.00 equiv) in methanol (600 mL) was degassed and heated with H 2 Purged 3 times, and then the mixture was stirred under H 2 The mixture was stirred at 25 °C for 12 hours under a 15 psi atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. 2-(3-pyridylmethyl)quinuclidine-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)+.

[0371] Example 3 (reference): cis-2-(3-pyridylmethyl)quinuclidine-3-ol

[0372] To a solution of 2-(3-pyridylmethyl)quinuclidine-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 saturated NaCl 300 mL and 50% NaOH (aqueous solution) and extracted with dichloromethane 200 mL (100 mL*2). The organic layers were combined, washed with brine 200 mL (100 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, dichloromethane / methanol=50 / 0 to 10 / 1). Cis-2-(3-pyridylmethyl)quinuclidine-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)+.

[0373] Example 4: trans-4-nitrobenzoic acid [2-(3-pyridylmethyl)quinuclidine-3-yl] ester

[0374] To a solution of cis-2-(3-pyridylmethyl)quinuclidine-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) was 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol=1 / 0 to 10 / 1). Trans-4-nitrobenzoic acid [2-(3-pyridylmethyl)quinuclidine-3-yl] ester (26.0 g, crude product) was obtained as a brown oil. LCMS: m / z=368.2 (M+1)+.

[0375] Example 5 (reference): trans-2-(3-pyridylmethyl)quinuclidine-3-ol

[0376] To a solution of trans-4-nitrobenzoic acid [2-(3-pyridylmethyl)quinuclidine-3-yl] ester (26.0 g, 70.7 mmol, 1.00 equiv) in tetrahydrofuran (160 mL) was added LiOH·H2O (4.45 g, 106 mmol, 1.50 equiv) in H2O (40 mL). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (300 mL and 100 mL*5). The organic layers were combined, washed with brine 100 mL (100 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol=100 / 1 to 0 / 1). Trans-2-(3-pyridylmethyl)quinuclidine-3-ol (6.00 g, 27.4 mmol, yield 38.8%) was obtained as a dark brown gum. LCMS: m / z=219.2 (M+1)+.

[0377] Example 6: trans-3-[(5-bromo-2-pyridinyl)oxy]-2-(3-pyridinylmethyl)quinuclidine

[0378] To a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (0.300 g, 1.37 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (308 mg, 2.75 mmol, 2.00 equiv). The mixture was stirred at 25°C for 1 hour. 5-Bromo-2-chloro-pyridine (290 mg, 1.51 mmol, 1.10 equiv) was added and the mixture was stirred at 25°C for 11 hours. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane 150 mL (50 mL*3). The organic layers were combined, washed with brine 60 mL (30 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure. Trans-3-[(5-bromo-2-pyridinyl)oxy]-2-(3-pyridinylmethyl)quinuclidine (0.280 g, 748 μmol, yield 54.4%) was obtained as a yellow oil. LCMS: m / z=374.1 (M+1)+.

[0379] Example 7: trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-3-pyridyl]-1H-indole

[0380] A mixture of trans-3-[(5-bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine (0.280 g, 748 μmol, 1.00 equiv), indole-5-boronic acid (180 mg, 1.12 mmol, 1.50 equiv), Cs2CO3 (731 mg, 2.24 mmol, 3.00 equiv) and Pd(dppf)Cl2 (54.7 mg, 74.8 μmol, 0.100 equiv) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90°C under N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1). TLC (dichloromethane / methanol=10 / 1) showed that one major spot was detected (Rf=0.25). Trans-5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxy-3-pyridinyl]-1H-indole (131 mg, 311 μmol, yield 41.6%, purity 97.4%) was obtained as a light yellow solid. 1HNMR (400MHz, CD3OD): δ8.45(s,1H),8.26-8.21(m,2H),7.82-7.71(m,3H),7.45(d,J=8.4Hz,1H),7.30-7.26(m,3H),6.60(d,J=8.6Hz,1H), 6.49(dd,J=0.7,3.1Hz,1H),4.93(s,1H),3.31-2.97(m,6H),2.77-2.76(m,1H),2.21(d,J=1.6Hz,1H),1.92-1.80(m,3H),1.47-1.45(m,1H). LCMS: m / z=411.3(M+1)+.

[0381] Example 8: trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0382] Potassium tert-butoxide (154 mg, 1.37 mmol, 2.00 equiv) was added to a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (0.150 g, 687 μmol, 1.00 equiv) in tetrahydrofuran (5 mL) at 25°C, reacted for 1 hour, and then 2,5-dichloropyrazine (123 mg, 825 μmol, 1.20 equiv) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water 20 mL and extracted with dichloromethane 200 mL (50 mL*4). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol = 10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol = 10 / 1; 1% NH3·H2O) showed that one major spot was detected (Rf = 0.55). Trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine (74.6 mg, 222 μmol, yield 32.3%, purity 98.5%) was obtained as an off-white solid. 1H NMR (400MHz, CDCl3): δ8.46-8.35(m,2H),8.01(d,J=1.2Hz,1H),7.83(d,J=1.2Hz,1H),7.53(dd,J=1.6,7.8Hz,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)+.

[0383] Example 9: trans-5-[5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyrazin-2-yl]-1H-indole

[0384] A mixture of trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine (0.100 g, 302 μmol, 1.00 equiv), indole-5-boric acid (60.0 mg, 372 μmol, 1.23 equiv), Na2CO3 (100 mg, 943 μmol, 3.12 equiv), tetrakis(triphenylphosphine)palladium(0) (40.0 mg, 34.6 μmol, 0.115 equiv) in dimethoxyethane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 85°C under N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). Trans-5-[5-[2-(3-pyridylmethyl)quinuclidine-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): δ9.26 (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), 7.207.19 (m, 1H), 7.11(dd,J=4.9,7.8Hz,1H),6.60(s,1H),4.89(t,J=3.2Hz,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)+.

[0385] Example 10: trans-2-bromo-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0386] Potassium tert-butoxide (154 mg, 1.37 mmol, 1.50 equiv) was added to a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (0.200 g, 916 μmol, 1.00 equiv) in tetrahydrofuran (5 mL). The mixture was stirred at 25°C for 1 hour. Then 2,5-dibromo-1,3,4-thiadiazole (223 mg, 916 μmol, 1.00 equiv) was added and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water 20 mL and extracted with dichloromethane 150 mL (50 mL*3). The organic layers were combined, washed with brine 60 mL (30 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure. Trans-2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (0.350 g, crude) was obtained as a yellow solid. LCMS: m / z=383.1 (M+1)+.

[0387] Example 11: trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1, 3,4-Thiadiazole

[0388] A mixture of trans-2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (0.350 g, 917 μmol, 1.00 equiv), indole-5-boronic acid (221 mg, 1.38 mmol, 1.50 equiv), Cs2CO3 (897 mg, 2.75 mmol, 3.00 equiv), Pd(dppf)Cl2 (67.1 mg, 91.7 μmol, 0.100 equiv) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90°C under N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; NH3·H2O). TLC (dichloromethane / methanol=10 / 1; NH3·H2O) showed that a main spot was detected (Rf=0.35). Trans-2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole (44.3 mg, 106 μmol, yield 11.5%, purity 100%) was obtained as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ8.55-8.42 (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=2.1Hz,1H),4.95(t,J=3.1Hz,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)+.

[0389] Example 12: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine

[0390] A mixture of 6-bromo-1,3-benzothiazol-2-amine (1.00 g, 4.36 mmol, 1.00 equiv), bis(pinacol)diboron (1.66 g, 6.54 mmol, 1.50 equiv), potassium acetate (1.28 g, 13.0 mmol, 3.00 equiv), Pd(dppf)Cl2 (319 mg, 436 μmol, 0.100 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 ° C under N2 atmosphere for 12 hours. 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 product) was obtained as a dark brown solid. LCMS: m / z=277.1 (M-55)+.

[0391] Example 13: trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0392] Potassium tert-butoxide (1M, 1.34 mL, 1.95 equiv) was added to a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (0.150 g, 687 μmol, 1.00 equiv) in tetrahydrofuran (5 mL). The mixture was stirred at 25°C for 1 hour. 3,6-dichloropyridazine (120 mg, 805 μmol, 1.17 equiv) was then added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water 20 mL and extracted with dichloromethane 150 mL (50 mL*3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1). TLC (dichloromethane / methanol=10 / 1) showed that one major spot (Rf=0.45) was detected. Trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (120 mg, 362 umol, yield 52.7%) was obtained as a yellow oil.

[0393] Example 14: trans-6-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1,3-benzene Thiazol-2-amine

[0394] A mixture of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (0.100 g, 302 μmol, 1.00 equiv), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine (166 mg, 604 μmol, 2.00 equiv), Cs2CO3 (295 mg, 906 μmol, 3.00 equiv), Pd(dppf)Cl2 (22.1 mg, 30.2 μmol, 0.100 equiv) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90°C under N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol=10 / 1; 1% NH3·H2O) showed that one major spot was detected (Rf=0.35). Trans-6-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1,3-benzothiazole-2-amine (27.5 mg, 60.8 μmol, yield 20.1%, purity 98.2%) was obtained as a yellow solid. 1H NMR (400MHz, CD3OD): δ8.46(d,J=1.8Hz,1H),8.21-8.20(m,2H),7.96-7.93(m,3H),7.48(d,J=8.4Hz,1H),7.23(dd,J=5.0,7.8Hz,1H),6. 94(dd,J=1.5,9.2Hz,1H),5.15(s,1H),3.25-3.02(m,6H),2.99-2.76(m,1H),2.32(d,J=2.3Hz,1H),1.94-1.84(m,3H),1.51-1.50(m,1H). LCMS: m / z=445.3(M+1)+.

[0395] Example 15: trans-2-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]pyrrole-1- Tert-Butyl Formate

[0396] A mixture of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (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)Cl2 (30.0 mg, 41.0 μmol, 0.113 equiv), K2CO3 (150 mg, 1.09 mmol, 2.99 equiv) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90°C under N2 atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol=10 / 1; 1% NH3·H2O) showed that one main spot was detected (Rf=0.45). Trans-2-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylic acid tert-butyl ester (80.0 mg, 173 μmol, yield 47.7%) was obtained as a yellow oil. LCMS: m / z=462.3 (M+1)+.

[0397] Example 16: trans-2-(3-pyridinylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinine ring

[0398] To a solution of trans-2-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]pyrrole-1-carboxylic acid tert-butyl ester (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 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol=10 / 1; 1% NH3·H2O) showed that one major spot was detected (Rf=0.55). 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 light yellow solid. 1HNMR (400MHz, CDCl3): δ9.93 (s, 1H), 8.50 (d, J = 1.8Hz, 1H), 8.32 (dd, J = 1.6, 4 .9Hz,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,6 H),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)+.

[0399] Example 17: trans-6-fluoro-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline

[0400] To a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (0.100 g, 458 μmol, 1.00 equiv.) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (1 M, 916 μL, 2.00 equiv.). The mixture was stirred at 25°C for 1 hour. 2-Chloro-6-fluoro-quinoline (99.8 mg, 549 μmol, 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 of dichloromethane (60 mL*4). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol=10 / 1; 1% NH3·H2O) showed that one major spot was detected (Rf=0.55). Trans-6-fluoro-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline (124 mg, 332 μmol, yield 72.6%, purity 96.9%) was obtained as a colorless oil. 1HNMR (400MHz, CD3OD): δ8.42(d,J=1.8Hz,1H),8.12(dd,J=1.6,4.9Hz,1H),8.00 (d,J=8.9Hz,1H),7.74-7.72(m,2H),7.46-7.42(m,2H),7.14(dd,J=4.9,7.8Hz,1 H),6.74(d,J=8.9Hz,1H),5.16(t,J=3.0Hz,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)+.

[0401] Example 18: trans-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline

[0402] Potassium tert-butoxide (1M, 1.56mL, 2.00equiv) was added to a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (0.170g, 778μmol, 1.00equiv) in tetrahydrofuran (3mL). The mixture was stirred at 25°C for 1 hour. 2-Chloroquinoline (152mg, 934μmol, 124μL, 1.20equiv) was added and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with 30mL of water and extracted with 240mL of dichloromethane (60mL*4). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol=10 / 1; 1% NH3·H2O) showed that a major spot was detected (Rf=0.49). Trans-2-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyquinoline (163 mg, 469 umol, yield 60.3%, purity 99.1%) was obtained as a colorless oil. 1H NMR (400 MHz, CD3OD): δ8.42 (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=8.9Hz,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)+.

[0403] Example 19: trans-3-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyisoquinoline

[0404] To a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (0.0500 g, 229 μmol, 1.00 equiv.) in N,N-dimethylformamide (3 mL) was added sodium hydride (18.3 mg, 458 μmol, purity 60%, 2.00 equiv.). The mixture was stirred at 25°C for 1 hour. 3-Chloroisoquinoline (56.2 mg, 343 μmol, 1.50 equiv.) was added, and the mixture was stirred at 90°C for 11 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution 2 mL at 0°C, then diluted with water 20 mL and extracted with dichloromethane 160 mL (40 mL*4). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol=10 / 1; 1% NH3·H2O) showed that a major spot was detected (Rf=0.6). Trans-3-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxyisoquinoline (14.8 mg, 42.5 μmol, yield 18.5%, purity 98.8%) was obtained as a brown solid. 1HNMR (400MHz, CD3OD): δ8.84(s,1H),8.43(s,1H),8.10(dd,J=1.1,4.8Hz,1H),7.93(d,J=8.3Hz,1H),7.76-7.58(m,3H),7.62-7.60(m,1H ),7.15(dd,J=4.9,7.8Hz,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)+.

[0405] Example 20: trans-3-(6-imidazol-1-ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0406] To a solution of trans-2-(3-pyridylmethyl)quinuclidine-3-ol (200 mg, 916 μmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (102 mg, 916 μmol, 1.00 equiv). The mixture was stirred at 25 ° C for 1 hour. 3-Chloro-6-imidazol-1-yl-pyridazine (165 mg, 916 μmol, 1.00 equiv) was added and the mixture was stirred at 50 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% NH3·H2O). Trans-3-(6-imidazol-1-ylpyridazine-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 (400MHz, CDCl3): δ8.47(d,J=1.6Hz,1H),8.32-8.27(m,2H),7.64(s,1H),7 .54(d,J=7.9Hz,1H),7.47(d,J=9.4Hz,1H),7.22(s,1H),7.09(dd,J=4.9,7.6H z,1H),6.95(d,J=9.4Hz,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)+.

[0407] Example 21: trans-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole Indole

[0408] To a solution of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (800 mg, 2.42 mmol, 1.00 equiv) and indole-5-boronic acid (976.00 mg, 6.06 mmol, 2.51 equiv) in dioxane (5.00 mL) and ethanol (5.00 mL) was added Pd(dppf)Cl2 (176.00 mg, 250.75 μmol) and dicyclohexyl-(2-phenylphenyl)phosphine (48.00 mg, 136.96 umol), Na2CO3 (1 M, 8.00 mL, 3.31 equiv). The mixture was stirred at 150°C under N2 and microwave for 0.5 h (in 3 batches). The mixture was filtered and the filtrate was extracted with ethyl acetate (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (0.1% NH 3 ·H 2 O) to give trans -5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H indole (2.20 g, 5.13 mmol, yield 70.7%, purity 96%) as a yellow solid. 1H NMR (400MHz, CD3OD): δ8.44(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)quinuclidine-3-yl]oxypyridazin-3-yl]-1H indole was carried out by chiral supercritical fluid chromatography (SFC), using a Chiralpak AD-350×4.6mm ID, 3μm column; mobile phase: phase A is CO2, phase B is isopropanol (0.05% diethylamine), gradient elution: 0-40% B; flow rate: 3mL / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar.2S,3R-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole, off-white solid; RT = 2.000min, ee 100%; 1H NMR (400MHz, 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)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole, off-white solid; RT = 2.110min, ee 100%; 1H NMR (400MHz, 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).

[0409] Example 22: cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0410] To a solution of cis-2-(3-pyridylmethyl)quinuclidine-3-ol (0.100 g, 458 μmol, 1.00 equiv.) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (51.4 mg, 458 μmol, 1.00 equiv.). The mixture was stirred at 25 °C for 1 hour. 3,6-dichloropyridazine (85.3 mg, 572 μmol, 1.25 equiv.) 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 ethyl acetate 90 mL (30 mL*3). The organic layers were combined, washed with 20 mL of brine (10 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure. Cis-3-(6-chloropyridazine-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (150 mg, 453 μmol, yield 98.9%) was obtained as a yellow gum.

[0411] Example 23: cis-5-[6-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxypyridazin-3-yl]-1H-indole Indole

[0412] To a solution of cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (0.150 g, 453 umol, 1.00 equiv) and indole-5-boronic acid (87.5 mg, 544 μmol, 1.20 equiv) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (188 mg, 1.36 mmol, 3.00 equiv) and Pd(dppf)Cl2 (33.1 mg, 45.3 μmol, 0.100 equiv). The mixture was stirred at 90°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol=10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol=10 / 1; 1% NH3·H2O) showed that a major spot was detected (Rf=0.35). cis-5-[6-[2-(3-pyridylmethyl)quinuclidine-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 (400MHz, CDCl3): δ9.65(s,1H),8.50(d,J=1.8Hz,1H),8.34(dd,J=1.5,4.8Hz,1H),8.20(s,1H) ,7.85-7.77(m,2H),7.43-7.41(m,1H),7.21(d,J=8.6Hz,1H),7.20(t,J=2.8Hz,1H),7.04-7.02(m,1 H),7.01(d,J=9.3Hz,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)+.

[0413] Example 24: trans-3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

[0414] To a solution of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (0.150 g, 453 μmol, 1.00 equiv) and phenylboronic acid (66.3 mg, 544 μmol, 1.20 equiv) in dioxane (5 mL) and H2O (1 mL) were added K2CO3 (188 mg, 1.36 mmol, 3.00 equiv) and Pd(dppf)Cl2 (33.1 mg, 45.3 μmol, 0.100 equiv). The mixture was stirred at 90°C for 7 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol = 10 / 1; 1% NH3·H2O). TLC (dichloromethane / methanol = 10 / 1; 1% NH3·H2O) showed that one major spot was detected (Rf = 0.35). 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 light yellow solid. 1H NMR (400MHz, CDCl3): δ8.55(s,1H),8.37(s,1H),8.01-7.99(m,2H),7.74(d ,J=9.2Hz,1H),7.52-7.51(m,1H),7.50-7.49(m,3H),7.13-7.11(dd,J=4.8 ,7.6Hz,1H),6.88(d,J=9.2Hz,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)+.

[0415] Example 25: trans-2-phenyl-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole

[0416] To a solution of trans-2-bromo-5-[2-(3-pyridylmethyl)quinuclidine-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) was added K2CO3 (326 mg, 2.36 mmol, 3.00 equiv) and Pd(dppf)Cl2 (57.5 mg, 78.6 μmol, 0.100 equiv). The mixture was stirred at 90°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give trans-2-phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole (76.0 mg, 200 μmol, yield 25.5%, purity 100%) as a light yellow solid. 1H NMR (400MHz, CDCl3): δ8.51-8.50(m,1H),8.38(dd,J=1.6,4.8Hz,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)+.

[0417] Example 26: Biological Activity

[0418] The compounds described in Examples 1-25 competitively inhibit the binding of radiolabeled α-bungarotoxin to the human α7 nAChR subtype with equilibrium constant (Ki) values ​​ranging from 1 to 1000 nM.

[0419] Human recombinant nicotinic acetylcholine α7 receptors were expressed in SH-SY5Y cells. 20 μg portions of the membrane were incubated with 0.4 nM [125I]α-bungarotoxin in modified phosphate buffer pH 7.4 at 37°C for 120 minutes. Nonspecific binding was estimated in the presence of 1 μM α-bungarotoxin. The membrane was filtered and washed, and the filter was counted to determine the specifically bound [125I]α-bungarotoxin. IC was determined by nonlinear least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK) 50 value.

[0420] Observed IC using test compounds 50The Ki values ​​were calculated using the Cheng and Prusoff equation, based on the concentration of radioligand used in the assay and the historical value of the KD of the ligand (0.40 nM [125I]α-bungarotoxin).

[0421] The Ki values ​​in nM for each compound tested are summarized in Table 1 below, and the binding affinity to nAChR is shown in more detail in Table 2.

[0422] Table 1

[0423]

[0424] Table 2

[0425]

[0426] The configuration of the quinuclidine ether significantly affects the interaction mode with different nAChR subtypes. Thus, the cis-isomer 7 preferentially binds to the α4β2 nAChR, whereas the trans-isomer 11 is a very selective α7 nAChR ligand. While most of the resulting compounds were tested as racemates in the initial screening, a pair of enantiomers, 2S,3R-11 and 2R,3S-11, were also evaluated. The spatial arrangement of the pharmacophore elements within the enantiomer 2S,3R-11 favors its optimal and selective interaction with the α7 nAChR. Among the screened hydrogen bond acceptors (pyridine, pyrazine, pyridazine, and 1,3,4-thiadiazole) linked to the quinuclidine ring via an ether bond in position 3, compounds containing pyridazine and 1,3,4-thiadiazole fragments in combination with the indole rings 11 and 16 showed the best pharmacological properties in terms of affinity and selectivity. Fusion of nitrogen-containing aromatic rings to benzene rings (compounds 17 and 18) in an attempt to combine hydrogen bond receptors with hydrophobic π-interactions weakened the interaction of the compounds with nAChRs.

[0427] With reference to Table 2, α7 nAChR ligands 11, 14 and 16 were evaluated in the in vivo guinea pig model of chemically induced cough.

[0428] Example 27: In vivo cough induction experiment

[0429] Materials and methods

[0430] like Figure 1B and Figure 1CAs shown in the figure, coughing was induced by placing guinea pigs in a whole body plethysmograph (WBP) equipped with an AeronebTM vibrating mesh nebulizer and including a pressure sensor and a detection device (EMKA technologies). A main microphone (EMKA Technologies) was provided to acoustically confirm the cough frequency in the form of a digital trace using EMKA software. Data acquisition software (iOX2, version 2.10.5.28, EMKA Technologies, France) displays the pressure signal detected from the pressure sensor and calculates the cough frequency and intensity measured during the test.

[0431] An auxiliary microphone (T1 True Wireless Earphone, ) and connected to a smartphone via Bluetooth to enable the observer to hear audible sounds during the test. A bias flow rate of 2 L / min was used to continuously draw atmospheric air (during the fresh air period) or aerosolized citric acid from the nebulizer into the WBP and expel it through the exhaust tube. The chamber pressure in the WBP was set between -10 and -30 Pa relative to ambient pressure.

[0432] Prior to citric acid challenge, guinea pigs were administered (ip) different doses of vehicle control, positive control or test compound (as applicable) (Table 3) and placed in WBP for at least 5 minutes for acclimatization.

[0433] Table 3

[0434]

[0435] The procedure was as follows: injection → place guinea pig in box with citric acid for 10 minutes (count coughs) → fill box with air for 5 minutes (count coughs) → move guinea pig to recovery cage.

[0436] Use appropriate concentration of citric acid to generate aerosol and deliver to WBP, continue 10 minutes, while constantly recording pressure measurements. The average concentration of citric acid is 1283.1 ± 137.2 μg / L. After completing the citric acid challenge, allow guinea pigs to recover and continue to record cough counts for another 5 minutes. Subsequently, closely monitor whether guinea pigs are fully recovered from the attack in the recovery cage and there are no adverse events before the animals are returned to their home cages. Starting from citric acid stimulation, record cough counts (CCnt) in a time period of at least 10 minutes, and cough latency (CIP) is defined as the time spent for the first cough after citric acid stimulation.

[0437] Carefully monitor cough response during citric acid challenge and post-treatment recovery using the following methods:

[0438] -Continuous pressure monitoring (plethysmography monitoring software)

[0439] - Acoustic confirmation of cough using microphones (primary and secondary)

[0440] -Visual confirmation of coughing by postural change.

[0441] Statistical analysis and data presentation

[0442] Data were analyzed using one-way ANOVA when compared to saline controls (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001), and each column represents the mean±SEM.

[0443] Figure 2 and Figure 3 Involves evaluating the antitussive efficacy of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole using an in vivo model of chemically induced cough in guinea pigs.

[0444] Respectively, Figure 2 A and 3A show mean ± SEM, while Figure 2 B and 3B show the results for each replicate.

[0445] result

[0446] like Figure 2 As shown in the cough counts, 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 citric acid-induced cough counts when compared to saline controls.

[0447] More specifically, compared with the saline control (0.9% sodium chloride, cough count = 17), 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole significantly reduced citric acid-induced cough counts at low concentrations (1 mg / kg, cough count = 5, p<0.0001), medium concentrations (3 mg / kg, cough count = 5, p<0.001), and high concentrations (9.5 mg / kg, cough count = 7, p<0.01).

[0448] The reduction of citric acid-induced cough counts by 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole was similar to that of 30 mg / kg codeine. However, at 1 mg / kg to 9.5 mg / kg, the dose of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole was approximately 20 to 30 times lower than the 30 mg / kg dose of codeine.

[0449] In addition, if Figure 3 As shown in the data regarding latency, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole showed a significant improvement in cough latency.

[0450] More specifically, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole significantly increased cough latency at low (1 mg / kg, 548 sec, p<0.001), medium (3 mg / kg, 455 sec, p<0.01), and high (9.5 mg / kg, 489 sec, p<0.05) concentrations compared to saline controls (0.9% sodium chloride, 206 sec).

[0451] The increase in cough latency with 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole was similar to that with 30 mg / kg of codeine. However, at 1 mg / kg to 9.5 mg / kg, the doses of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole were approximately 20 to 30 times lower than the 30 mg / kg dose of codeine.

[0452] in conclusion

[0453] 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 citric acid-induced cough counts when compared to saline controls (see Figure 2 ).

[0454] In addition, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole also showed significant improvement in cough latency at doses approximately 20 to 30 times lower than codeine, which is considered the "gold standard" narcotic cough suppressant (see Figure 3 ).

[0455] Example 28: In vivo evaluation of the antitussive efficacy of inhaled compounds

[0456] A set of proof-of-concept experiments was designed to evaluate the antitussive effect of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole via inhalation in vivo.

[0457] Experiment using the following methods:

[0458] (i) Dry Powder Insufflator (DPI)

[0459] (ii) Whole body plethysmograph (WBP)

[0460] (iii) Oral administration.

[0461] (iv) Intraperitoneal administration

[0462] Materials and methods

[0463] Figure 4 The experimental setup for the in vivo evaluation of the antitussive efficacy of inhaled compounds is summarized in . More specifically, guinea pigs were placed in an aerosol-equipped TM Cough induction was performed with a vibrating mesh nebulizer and a whole body plethysmograph (WBP) including a pressure sensor and detection equipment (EMKA technologies).

[0464] A primary microphone (EMKA Technologies) was provided for acoustic confirmation of cough frequency in the form of a digital trace using the EMKA software (see Figure 1). The data acquisition software (iOX2, version 2.10.5.28, EMKA Technologies, France) displayed the pressure signal detected from the pressure sensor and calculated the cough frequency and intensity measured during the test.

[0465] An auxiliary microphone (T1 True Wireless Earphone, ) and connected to a smartphone via Bluetooth to enable the observer to hear audible sounds during the test. A bias flow rate of 2 L / min was used to continuously draw atmospheric air (during the fresh air period) or aerosolized citric acid from the nebulizer into the WBP and expel it through the exhaust tube. The chamber pressure in the WBP was set between -10 and -30 Pa relative to ambient pressure.

[0466] Prior to citric acid challenge, guinea pigs were administered vehicle control, positive control or test compound (as applicable) by various routes and doses (for dry powder insufflator, see Table 4; for WBP nebulization, see Table 5; for oral administration, see Table 6; for intraperitoneal administration, see Table 7).

[0467] Table 4: Dry powder insufflator

[0468]

[0469] Table 5: Whole body plethysmograph (WBP)

[0470]

[0471] Table 6: Oral administration

[0472]

[0473] Table 7: Intraperitoneal administration

[0474]

[0475] For dry powder administration, the procedure was as follows: dry powder insufflation → place guinea pig in box with citric acid for 10 minutes (count coughs) → fill box with air for 5 minutes (count coughs) → move guinea pig to recovery cage.

[0476] For nebulization, the procedure was as follows: Nebulization via WBP → Keep guinea pig in box with citric acid for 10 minutes (count coughs) → Fill box with air for 5 minutes (count coughs) → Move guinea pig to recovery cage.

[0477] The aerosol was generated and delivered to the WBP using citric acid at an appropriate concentration for 10 minutes while continuously recording pressure measurements. For both approaches, the average concentration of citric acid was 1156.0 ± 111.8 μg / L. After completing the citric acid attack, the guinea pigs were allowed to recover and continue to record cough counts for another 5 minutes. Subsequently, the guinea pigs were closely monitored in the recovery cage to see if they had fully recovered from the attack and that there were no adverse events before the animals were returned to their home cages. Starting from the citric acid stimulation, the cough counts (CCnt) in the time period of at least 10 minutes were recorded, and the cough latency (CIP) was defined as the time spent for the first cough after the citric acid stimulation.

[0478] For oral administration, the duration between compound administration and the start of the citric acid challenge was 30 minutes. Data were compared to atmospheric air (control).

[0479] For intraperitoneal administration, the compound was administered approximately 10-15 minutes prior to the cough challenge (citric acid inhalation challenge). The test compound was administered at a dose between 1-30 mg / kg (as described herein for each experiment), while the positive control (codeine) was administered at a dose of 30 mg / kg, in each case using a dosing volume of 10 ml / kg, administered by a single intraperitoneal injection.

[0480] Carefully monitor cough response during citric acid challenge and post-treatment recovery using the following methods:

[0481] -Continuous pressure monitoring (plethysmography monitoring software)

[0482] - Acoustic confirmation of cough using microphones (primary and secondary)

[0483] -Visual confirmation of coughing by postural change.

[0484] Statistical analysis and data presentation

[0485] Data were analyzed using one-way ANOVA when compared to control (atmosphere) (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001), and each column represents the mean±SEM.

[0486] Correlation with cough count Figures 5 to 7 Data evaluating 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 are shown. Figure 5 Involving dry powder insufflation application, Figure 6 Involving aerosol application, Figure 7 Oral administration is contemplated.

[0487] More specifically, respectively, Figure 5 A, 6A, and 7A show mean ± SEM, while Figure 5 A, 6B and 7B show the results for each replicate.

[0488] result

[0489] like Figure 5 As shown in , the dry powder insufflation exemplary compound of the present invention, i.e., dry powder insufflation of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole, significantly reduced citric acid-induced cough counts when compared to air controls. More specifically, Figure 5 It was demonstrated that dry powder insufflation of 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole significantly reduced citric acid-induced cough counts when compared to air controls at doses of 1 mg / kg (p=0.0004) and 2 mg / kg (p=0.0042).

[0490] like Figure 6As shown, when compared to the air control, the nebulized exemplary compound of the present invention, namely nebulized 2-(1H-indol-5-yl)-5-[2-(pyridin-3-ylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, significantly reduced the citric acid-induced cough count. More specifically, Figure 6 It was confirmed that when compared to the air control, nebulized 2-(1H-indol-5-yl)-5-[2-(pyridin-3-ylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole significantly reduced the citric acid-induced cough count at 0.4 mg / kg (p = 0.0023 at 58 minutes of exposure).

[0491] As Figure 7 shown, when compared to the air control, the orally administered exemplary compound of the present invention, namely orally administered 2-(1H-indol-5-yl)-5-[2-(pyridin-3-ylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, significantly reduced the citric acid-induced cough count (p < 0.05 at 9.5 mg / kg).

[0492] As Figure 8 shown, when compared to the negative control, guinea pigs showed inhibition of cough frequency after prophylactic intraperitoneal treatment with 2-(1H-indol-5-yl)-5-[2-(pyridin-3-ylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole. More specifically, Figure 8 Cough counts were compared in animals treated intraperitoneally with the α7nAChR ligand 2-(1H-indol-5-yl)-5-[2-(pyridin-3-ylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole administered at 1, 3, and 9.5 mg / kg with negative control (saline) and positive control (codeine, 30 mg / kg). ****p < p < 0.0001, Dunnett's multiple comparison versus negative control (saline). Data are presented as mean ± SEM, and the group sizes (n) are indicated in the figure.

[0493] As Fig. 9 shown, when compared to the negative control, guinea pigs showed inhibition of cough frequency after prophylactic intraperitoneal treatment with 2-(pyridin-3-ylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine. More specifically, Fig. 9Cough counts in animals treated intraperitoneally with the α7 nAChR ligand 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine administered at 3.0, 9.5 and 30 mg / kg were compared with negative control (saline) and positive control (codeine, 30 mg / kg). **p<0.01, Dunnett's multiple comparisons compared to negative control (saline). Data are presented as mean ± SEM, with group size (n) indicated in the figure.

[0494] in conclusion

[0495] In an in vivo evaluation of the antitussive efficacy of inhaled compounds, an 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 citric acid-induced cough counts when administered by three administration methods.

[0496] More specifically, in the form of dry powder insufflation (at 1 mg / kg and 2 mg / kg; see Figure 5 ), in aerosol form (at 0.4 mg / kg; see Figure 6 ) and in oral form (at 9.5 mg / kg; see Figure 7 ), the exemplary compound of the present invention, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidine-3-yl]oxy-1,3,4-thiadiazole, all significantly reduced the cough counts induced by citric acid.

[0497] In an in vivo evaluation of the antitussive efficacy of inhaled compounds, an exemplary compound of the invention, 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole, significantly reduced citric acid-induced cough counts when administered intraperitoneally (see Figure 8 ).

[0498] In an in vivo evaluation of the antitussive efficacy of inhaled compounds, an exemplary compound of the invention, 2-(3-pyridylmethyl)-3-[6-(1H-pyrrol-2-yl)-5-pyridazin-3-yl]oxyquinuclidine, significantly reduced citric acid-induced cough counts when administered intraperitoneally (see Fig. 9 ).

Claims

1. A compound of general formula (I): or a pharmaceutically acceptable salt thereof, in R 1 is optionally substituted aryl or optionally substituted heteroaryl; and R 2 is halogen, triflate, optionally substituted aryl, optionally substituted heteroaryl or absent; or where R 1 and R 2 Together they form an optionally substituted aryl or an optionally substituted heteroaryl.

2. A compound according to claim 1, wherein the or each aryl or heteroaryl group is a 5- to 10-membered ring, such as a 5-membered ring or a 6-membered ring.

3. A compound according to claim 1 or claim 2, wherein one or both aryl or heteroaryl groups are monocyclic.

4. The compound of claim 3, wherein one or two aryl or heteroaryl groups are independently selected from the group consisting of phenyl, furanyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and thiadiazolyl.

5. A compound according to claim 1 or claim 2, wherein one or both aryl or heteroaryl groups are polycyclic.

6. The compound of claim 5, wherein one or two aryl or heteroaryl groups are independently selected from the group consisting of naphthyl, anthracenyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzodioxolanyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, purinyl, thienopyrazinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, naphthyridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and azulenyl.

7. A compound according to any preceding claim, wherein one or two aryl or heteroaryl groups are substituted, for example, by 1, 2 or 3 substituents, wherein optionally the substituents are independently selected from: alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halogen (e.g., F, Cl, Br or I), --OR', --NR'R", --CF3, -CN, --NO2, --SR', --N3, --C(=O)NR'R", --NR' C(=O)R", --C(=O)R', --C(=O)OR', --OC(=O)R', --O(CR'R"), --C(=O)R', --SO2R' and --SO2NR'R", wherein R' and R" are each hydrogen, lower alkyl (e.g., straight or branched alkyl, including C1-C8, preferably C1-C5, such as methyl, ethyl or isopropyl), cycloalkyl, heterocyclyl, aryl or arylalkyl (such as benzyl), and wherein R' and R" are optionally combined to form a cyclic functional group.

8. The compound of claim 7, wherein the substituents are independently selected from the group consisting of cyano, halogen, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, and alkylthio.

9. A compound according to any preceding claim, wherein R 1 is selected from 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and / or wherein R 2 Selected from indolyl, benzofuranyl, benzothiazolyl and phenyl.

10. A compound according to any preceding claim, wherein the compound is selected from: 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-pyridinylmethyl)quinuclidin-3-yl]oxy-3-pyridinyl]-1H-indole; 5-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole; 5-[5-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]-1H-indole; 6-[6-[2-(3-pyridinylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1,3-benzothiazol-2-amine; 2-(3-pyridinylmethyl)-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, For example, the compound is 2-(1H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1,3,4-thiadiazole.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically or therapeutically acceptable excipient or carrier.

12. A compound according to any one of claims 1 to 10 for use in treating a disease or disorder.

13. A compound according to any one of claims 1 to 10 for use in the treatment of a disease or condition mediated by the alpha 7 nicotinic acetylcholine receptor (nAChR).

14. A compound for use in treating a disease or condition according to claim 12 or claim 13, wherein the treatment is for preventing and / or inhibiting cough, cough progression, improving cough symptoms and improving cough recurrence.

15. A method for preparing a compound of general formula (I), as shown in Scheme (I): Where R 1 and R 2 is as defined in any one of claims 1 to 14 and X is halogen (eg, F, Cl, Br or I) or triflate.

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