NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS

Background

Nicotinic acetylcholine receptors (nAChRs) have been extensively characterized for their function in peripheral and central neurons where they play a role in modulating neurotransmission. nAChRs typically associated with the central nervous system (CNS) have been shown to occur in several subtypes. The most common nAChR subtypes are a4p2 and a7 subtypes. a7 nAChRs belong to the family of acetylcholine-gated cation channels and exhibit distinct biophysical and pharmacological profiles relative to other nAChR subtypes.

Although these receptors are predominantly expressed in neuronal tissues, several types of immune cells also express a7 nAChR mRNA. Examples for such immune cells expressing a7 nAChR mRNA are macrophages, T-cells, B-cells, microglia, monocytes and dendritic cells. Immunological responses to protect against excessive inflammation can be regulated by the CNS through the cholinergic antiinflammatory pathway, in which acetylcholine is released from vagus nerves. Consequently, acetylcholine activates the post-synaptic a7 nAChR of innervated tissues including splenic nerves following its stimulation and in turn inhibits inflammatory cytokines.

Various nicotinic compounds have been known to interact with a7 nAChR and thus have been proposed for therapy. However, a disadvantage of those known nicotinic compounds is that they are associated with various undesirable side effects, for example, by stimulating muscle and ganglionic receptors.

In turn, there is a need for compounds, compositions, and methods for preventing or treating various conditions or disorders, such as CNS disorders, including alleviating the symptoms of these disorders but without the associated side effects. More specifically, there is a need for compounds, compositions, and methods that affect CNS function without significantly affecting those nicotinic receptor subtypes which have the potential to induce undesirable side effects, such as appreciable activity at cardiovascular and skeletal muscle sites. of Invention

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

(I), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each an optionally substituted aryl group which may be the same or different, wherein one or both aryl groups comprises a carbocyclic or heterocyclic aromatic ring and wherein one or both aryl groups is monocyclic or polycyclic, and wherein R ¹ and R ² are optionally fused.

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

(I), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is an optionally substituted aryl or an optionally substituted heteroaryl; and

R ² is a halogen, a triflate, an optionally substituted aryl, an optionally substituted heteroaryl or is absent; or wherein R ¹ and R ² together form an optionally substituted aryl or an optionally substituted heteroaryl.

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

(II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is an optionally substituted aryl group which comprises a carbocyclic or heterocyclic aromatic ring and wherein the aryl group is monocyclic or polycyclic, and

X is a halogen or a triflate.

Also provided are a pharmaceutical composition comprising the compound of general formula (I) or (II), uses of the compound of general formulae (I) or (II), uses of the composition comprising the compound of general formula (I) or (II), and methods of manufacturing the compound of general formulae (I) and (II) as defined in the appended independent claims, to which reference should now be made. Preferred or advantageous features of the invention are set out in dependent claims and described further below.

The compounds of general formulae (I) and (II) of the invention advantageously affect the central nervous system without inducing potentially undesirable side effects of nicotinic receptor subtypes. These potentially undesirable side effects may include appreciable activity at cardiovascular and skeletal muscle sites.

More specifically, the compounds of general formulae (I) and (II) of the present invention are a7 nAChR agonists, which provide a novel, non-narcotic approach to therapy in patients with acute and chronic cough. As described below, potential application of selective a7 nAChR agonists as antitussive agents according to the invention was demonstrated in in vivo experiments by inhibiting cough responses in guinea pigs evoked by citric acid.

In addition, a7 nAChR agonists as described herein might be beneficial for the treatment of cough origins. In preclinical studies of pulmonary disease, a7 nAChR agonists demonstrated antiinflammatory effects in models of acute lung injury, allergen challenge and gram-negative bacterial infection. According to an aspect of the present invention, there is provided a compound of general formula (I): or a pharmaceutically acceptable salt thereof. R 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 comprise 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.

According to another aspect of the invention, there is provided a compound of general formula (I): or a pharmaceutically acceptable salt thereof. R ¹ may be an optionally substituted aryl or an optionally substituted heteroaryl. R ² may be a halogen, a triflate, an optionally substituted aryl, an optionally substituted heteroaryl or may be absent. R ¹ and R ² together may form an optionally substituted aryl or an optionally substituted heteroaryl.

According to a further aspect of the invention, there is provided a compound of general formula (II): (II), or a pharmaceutically acceptable salt thereof. R ¹ may be an optionally substituted aryl group which may comprise a carbocyclic or heterocyclic aromatic ring and wherein the aryl group may be monocyclic or polycyclic. X may be a halogen or a triflate.

As shown in Figure 1A, a7 nAChR pharmacophoric elements include adjacent to cationic center hydrogen bond acceptors and a hydrophobic part that are considered essential for ir-interaction. The quinuclidine basic nitrogen occupies a bridgehead position within an azabicyclic system and provides maximal electrostatic interaction combined with minimal steric demand. Due to the strong basicity of quinuclidine derivatives (pKa ~ 10-11 ), a7 nAChR ligands exist in physiological conditions in cationic form with a well-defined proton orientation. Small aliphatic groups (e.g. methyl) or larger groups (e.g. benzyl) in position 2 of the azabicyclic ring may reduce binding to the nAChR.

The compounds of invention incorporate a (pyridin-3-yl)methyl moiety which improves the pharmacological profile, resulting in better selectivity (especially over 5-HT3 receptor), increased a7 nAChR affinity and elimination of inhibition of the hERG (human ether-a-go-go-related gene) channel.

The term “halo” or “halogen” as used herein refers to any radical of fluorine, chlorine, bromine or iodine.

The term “aryl” as used herein refers to monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbon atoms in the ring. Common aryl groups include Ce-Cu aryl, for example, Ce-Cw aryl. Non-limiting examples of Ce-Cu aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups. An “optionally substituted aryl” group may include the substituents as described herein.

The term “heteroaryl” as used herein refers to aromatic groups having 5 to 14 ring atoms (for example, 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 (furanyl), benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4/7- quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, (3-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide. An “optionally substituted heteroaryl” group may include the substituents as described herein.

Optionally, the or each aromatic ring of the carbocyclic or heterocyclic aromatic ring of one or both 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) is a 3- to 10-membered ring, for example a 5- to 10-membered ring. For example, the or each aromatic ring of the carbocyclic or heterocyclic aromatic ring of one or both 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) may be a 3-membered ring, 4- membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9- membered ring, or 10-membered ring.

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

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

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

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

Optionally, the substituents are independently selected from the group consisting of: alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (for example, 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 individually hydrogen, lower alkyl. The lower alkyl may be methyl, ethyl, propyl, isopropyl, butyl, or t- butyl. For example, the substituents may be straight chain or branched alkyl including CrCs, preferably C1-C5, such as methyl, ethyl or isopropyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl).

Optionally, R' and R" combine to form a cyclic functionality.

Optionally, the substituents are independently selected from the group consisting of: cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy and alkylthio.

Optionally, R ¹ of general formulae (I) and (II) is selected from: 1 ,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

Optionally, R ² of general formula (I) is selected from indolyl, benzofuranyl, benzothiazolyl and phenyl. Optionally, R ¹ and R ² of general formula (I) may be fused. Therefore, R ¹ and R ² of general formula (I) may be bonded together to form an optionally substituted aryl group. R ¹ and R ² of general formula (I) may together form a carbocyclic or heterocyclic aromatic ring. R ¹ and R ² of general formula (I) may together form a monocyclic or polycyclic group. For example, R ¹ and R ² of general formula (I) may together form a 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9- membered ring, 10-membered ring, 11 -membered ring, 12-membered ring, 13-membered ring, 14- membered ring, 15-membered ring, 16-membered ring, or 17-membered ring.

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.

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

Optionally, the compound is selected from the group consisting of:

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

3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucli dine; 2-phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole; 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridyl]-1 H-indole; 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl] -1 H-indole;

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

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

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

3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidi ne; 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.

Advantageously, 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole significantly reduces the citric acid-induced cough counts when compared with saline control.

Advantageously, 2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine significantly reduces the citric acid-induced cough counts when compared with saline control.

Advantageously, 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl] -1 H-indole significantly reduces the citric acid-induced cough counts when compared with saline control.

Optionally, the compound is selected from the group consisting of: trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (2) trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinucli dine (4) trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridy l]-1 H-indole (5) c/s-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucl idine (6) c/s-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3 -yl]-1 H-indole (7) trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucl idine (8) trans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2 -yl]-1 H-indole (9) trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (10) trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole (11 ) (2S,3R)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridaz in-3-yl]-1 H-indole (2S,3R-11 ) (2R,3S)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridaz in-3-yl]-1 H-indole (2R,3S-11 ) trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 ,3-benzothiazol-2-amine (12) trans-tert-Butyl 2- [6- [2- (3-py ridy Im ethy l)qu in uclid in -3-y l]oxypy ridazi n-3-y l]py rro le- 1 -carboxylate (13) trans-2-(3-Pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14) trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (15) trans-2-(1 H-lndol-5-yl)-5-[2-(3-pyridylmethyl)quin uclidi n-3-yl]oxy-1 ,3,4-thiadiazole (16) trans-3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline (17) trans-2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline (18) trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (19) trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (20)

Advantageously, trans-2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole significantly reduces the citric acid-induced cough counts when compared with saline control. Advantageously, trans-2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxy quinuclidine significantly reduces the citric acid-induced cough counts when compared with saline control.

Advantageously, trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole significantly reduces the citric acid-induced cough counts when compared with saline control

Furthermore, 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy- 1 ,3,4-thiadiazole also showed significant improvement in cough incubation period at dosage approximately 20 to 30-fold lower than codeine which is considered as the “gold standard” narcotic cough suppressant.

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

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

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

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

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

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.

Optionally, the compounds of general formulae (I) and (II) may exist in unsolvated forms as well as solvated forms, including hydrated forms. “Hydrate” refers to a complex formed by combination of water molecules with molecules or ions of the solute. “Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrate. Some examples of solvents include, but are not limited to, methanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Optionally, the compounds of general formulae (I) and (II) may exist as solid material in e.g. multiple 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.

“Tautomer” means compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom (See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992)). The tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily 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.

“Isomers” mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. “Stereoisomer” and “stereoisomers” refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centres or a double bond with asymmetric substitution and, therefore, may be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer may be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or laevorotatory (/.e., as (+) or (-)-isomers respectively). A chiral compound may exist as either individual enantiomers or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of Advanced Organic Chemistry, 6th edition J. March, John Wiley and Sons, New York, 2007) differ in the chirality of one or more stereocentres.

The present invention also embraces isotopically-labelled compounds which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into 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 CI, and ¹²⁵ L Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition or its isotopes, such as deuterium (D) or tritium ( ³ H). Certain isotopically-labelled compounds of the present invention (e.g., those labelled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (/.e., ³ H) and carbon- 14 (/.e., ¹⁴ C) and fluorine-18 (/.e., ¹⁸ F) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (/.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of the present invention may generally be prepared by following procedures analogous to those described herein, by substituting an isotopically labelled reagent for a non-isotopically labelled reagent.

According to the present invention, there is also provided a pharmaceutical composition comprising a compound described herein and a pharmaceutically or therapeutically acceptable excipient or carrier, for example a pharmaceutical composition comprising a compound of general formula (I) or (II) and a pharmaceutically or therapeutically acceptable excipient or carrier. For example, a pharmaceutical composition may comprise 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy- 1 ,3,4-thiadiazole or a pharmaceutically acceptable salt thereof. For example, a pharmaceutical composition may comprise 2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2- yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof. For example, a pharmaceutical composition may comprise 5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3- yl]-1 H-indole.

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

Pharmaceutically acceptable excipients or carriers may include fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which may be chosen 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, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank’s solution, Ringer’s solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like. Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethyl cellulose, cross-linked sodium carboxymethylcellulose, 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 cotton seed oil, castor seed oil mineral oil, polyethylene glycol (e.g. PEG 400 or PEG 4000-8000), polyoxyethylene glycol, poloxamers, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylic acid divinylbenzene copolymer, sodium docusate, cyclodextrins (e.g. 2-hydroxypropyl-. delta. -cyclodextrin), polysorbates (e.g. polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid ester of polyethylene glycols, or a polyoxyalkylene sorbitan fatty acid ester (e.g., polyoxyethylene sorbitan ester Tween®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid ester, e.g. a sorbitan fatty acid ester from a fatty acid such as oleic, stearic or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methyl celluloses), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, and the like.

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

For example, trans-2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder. For example, trans-2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)15yridazine-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder. For example, trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder.

According to the present invention, there is also provided a compound described herein for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR), for example a compound of general formula (I) or (II) for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR). For example, 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy- 1 ,3,4-thiadiazole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR). For example, 2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl) 15yridazine-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR). For example, 5-[6-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1 H-indole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR).

For example, trans-2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR). For example, trans-2-(3-pyridylmethyl)- 3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR). For example, trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole or a pharmaceutically acceptable salt thereof may be for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR).

Advantageously, the compounds described herein, for example compounds of general formulae (I) and (II), competitively inhibit the binding of radiolabeled MLA to human a7 nAChR subtype with equilibrium constant (Ki) values of 1 -1000 nM. It follows that the compounds described herein, for example compounds of general formulae (I) and (II), are suitable for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR).

The expression “mediated”, for example “mediated by nAChR”, is understood to mean linked to the activity of nAChR. For example, the expression “mediated” may be understood to mean “controlled by”, for example “transcriptionally or translationally controlled”, or “transcriptionally or translationally regulated”, for example, up-regulated or down-regulated. Preferably, the expression “mediated by nAChR” may be understood to relate to activation (i.e. opening) of the nAChR ion channel. More specifically, the conformational changes of the nAChR ion channel may occur upon binding a compound leading to a quaternary symmetrical twist of M1 -M4 domains that opens the hydrophobic gate and in turn allows the passage of ions. For example, this process may involve permeable to monovalent Na ⁺ and K ⁺ ions, and Ca ²⁺ ions. Advantageously, the ability of nAChRs to alter intracellular calcium levels may lead to activation of different downstream intracellular pathways such as neuronal signalling and plasticity.

Moreover, the expression “mediated” may be understood to include to the promotion of intracellular signalling, for example, through a G protein binding cluster contained in the intracellular loop of the a7 subunit.

Optionally, the compounds described herein, for example compounds of general formulae (I) and (II), may desensitize nAChR. It follows that the compounds described herein, for example compounds of general formulae (I) and (II), may be suitable for desensitizing nAChR. Accordingly, there is also provided a compound described herein, for example a compound of general formula (I) or (II), for use as a nAChR desensitizer.

More specifically, nAChR may rapidly transform to a closed state and followed by a desensitized state following activation. Desensitization is a loss of the biological response due to agonist stimulation. Upon washout of a ligand, the receptor may return to the basal or resting allosteric state. According to the present invention, there is also provided the use of a compound described herein in the manufacture of a medicament for the treatment of a disease or disorder, for example the use of a compound of general formula (I) or (II) in the manufacture of a medicament for the treatment of a disease or disorder.

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

Optionally, the disease or disorder is a disease or disorder mediated by an a7 nAChR.

Optionally, the disease or disorder is selected from: a cognitive and neurodegenerative disease; a psychotic disorder, such as schizophrenia; acute nociceptive, neuropathic or inflammatory pain; and an affective disorder, such as depression and inflammation.

For example, the disease or disorder may be selected from the group consisting of: i) pain, including one or more of acute, neurologic, inflammatory, neuropathic, chronic pain, severe chronic pain, post-operative pain, pain associated with cancer, angina, renal or biliary colic, menstruation, migraine, gout, arthritis, rheumatoid disease, teno-synovitis, vasculitis, trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, low back pain, deafferentation syndromes, and brachial plexus avulsion; ii) metabolic syndrome, weight gain, type I diabetes mellitus, type II diabetes mellitus, or diabetic neuropathy; ill) 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, aphteous stomatitis, pouchitis, glomerulonephritis, lupus nephritis, thrombosis, and graft vs. host reaction; and/or iv) cognition, including one or more of age-associated memory impairment, mild cognitive impairment, pre-senile dementia, early onset Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, mild to moderate dementia of the Alzheimer's type, 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, and cognitive dysfunction in schizophrenia.

The pharmaceutical compositions may be for use in ameliorating any of the symptoms associated with those conditions, diseases and disorders.

Preferably, the treatment is for preventing and/or suppressing cough, the progression of cough, ameliorate symptoms of cough, and ameliorate to the recurrence of cough. The treatment may be for the treatment of cough origins. Hereafter, a “cough” is understood to relate to the expelling of air from the lungs, for example, from the lungs of a subject, for example a human subject. Advantageously, compounds of the present invention, for example compounds of general formulae (I) and (II), may be used as antitussive agents. Accordingly, there is also provided a compound described herein for use as an antitussive agent, for example a compound of general formula (I) or (II) for use as an antitussive agent. More specifically, the antitussive agent may inhibit a cough through a central mechanism, or a peripheral mechanism, or a mixture of the two mechanisms.

The pharmaceutical composition described herein may be used as a selective a7 nAChR agonist. The pharmaceutical composition described herein may also be used as a antitussive agent. The pharmaceutical composition described herein may also be used as an anti-inflammatory agent, for example as an anti-inflammatory agent for acute lung injury, allergen challenge and/or gram-negative bacterial infection. Consequently, pharmaceutical composition described herein may for use in the treatment of inflammation, e.g. in the treatment of an acute lung injury, in the treatment of an allergen challenge and/or in the treatment of gram-negative bacterial infection.

The compounds described herein may also be used in as adjunct therapy in combination with existing therapies, for example, in the management of any the aforementioned types of diseases and disorders. In such situations, it is preferably to administer the active ingredients in a manner that minimizes effects upon nAChR subtypes such as those that are associated with muscle and ganglia. This may be accomplished by targeted drug delivery and/or by adjusting the dosage such that a desired effect is obtained without meeting the threshold dosage required to achieve significant side effects.

Optionally, the compound for use, use or method according described here, may be such that the compound is administered orally. Preferably, the compound is orally-administered 2-(1 H-indol-5-yl)-5- [2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole.

Optionally, the compound for use, use or method according described here, may be such that the compound is administered by inhalation.

Optionally, the compound for use, use or method according described here, may be such that the compound is administered in a dry powder form. Preferably, the compound is dry powder 2-(1 H-indol- 5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole, for example, dry powder insufflated 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole.

Optionally, the compound for use, use or method according described here, may be such that the compound is administered in a nebulised form. Preferably, the compound is nebulised 2-(1 H-indol-5- yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole.

Optionally, the compound for use, use or method according described here, may be such that the compound is orally administered at a dose of from 0.1 mg to 1 g/kg per day.

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

For example, the compound may be the compound is orally administered at a dose of no more than about 0.01 g/kg per day, no more than about 0.1 g/kg per day, no more than about 0.5 g/kg per day, no more than about 0.9 g/kg per day, no more than about 1 g/kg per day, no more than about 1 .1 g/kg per day, no more than about 1 .2 g/kg per day, no more than about 1 .5 g/kg per day, no more than about 2 g/kg per day. The compound may comprise any range from the given endpoints.

For example, the compound may be orally administered at a dose of at least about 0.00001 mg/kg per day to no more than about 2 g/kg per day, at least about 0.0001 mg/kg per day to no more than about 1 .5 g/kg per day, at least about 0.001 mg/kg per day to no more than about 1 .2 g/kg per day, at least about 0.01 mg/kg per day to no more than about 1 .1 g/kg per day, at least about 0.1 mg/kg per day to no more than about 1 g/kg per day, at least about 0.2 mg/kg per day to no more than about 0.9 g/kg per day, at least about 0.3 mg/kg per day to no more than about 0.5 g/kg per day, at least about 0.4 mg/kg per day to no more than about 0.1 g/kg per day, at least about 0.5 mg/kg per day to no more than about 0.01 g/kg per day. The compound may comprise any range from the given endpoints. For example, the compound for use, use or method according described here, may be such that the compound is orally administered at 0.1 mg/kg per day, 0.2 mg/kg per day, 0.3 mg/kg per day, 0.4 mg/kg per day, 0.5 mg/kg per day, 1 mg/kg per day, 2 mg/kg per day, 3 mg/kg per day, 4 mg/kg per day, 5 mg/kg per day, 10 mg/kg per day, 15 mg/kg per day, 20 mg/kg per day, 25 mg/kg per day, 30 mg/kg per day, 35 mg/kg per day, 40 mg/kg per day, 45 mg/kg per day, 50 mg/kg per day, 100 mg/kg per day, 150 mg/kg per day, 200 mg/kg per day, 250 mg/kg per day, 300 mg/kg per day, 350 mg/kg per day, 400 mg/kg per day, 450 mg/kg per day, 500 mg/kg per day, 550 mg/kg per day, 600 mg/kg per day, 650 mg/kg per day, 700 mg/kg per day, 750 mg/kg per day, 800 mg/kg per day, 850 mg/kg per day, 900 mg/kg per day, 950 mg/kg per day, 1000 mg/kg per day, 1100 mg/kg per day, 1200 mg/kg per day, 1300 mg/kg per day, 1400 mg/kg per day, 1500 mg/kg per day, 1600 mg/kg per day, 1700 mg/kg per day, 1800 mg/kg per day, 1900 mg/kg per day, 2000 mg/kg per day. The compound may comprise any range from the given endpoints.

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

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

For example, the compound may be orally administered 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. The compound may comprise any range from the given endpoints.

For example, the compound may be orally administered at a dose 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 may comprise any range from the given endpoints.

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

The expression “about” in relation to numerical values is understood to mean ±10%, preferably ±5%, e.g. ±10% w/w, preferably ±5% w/w.

Optionally, the compound for use, use or method described herein may be such that the composition is in the form of a tablet. The tablet may be a film-coated tablet. The compound for use, use or method described herein may be such that the composition is in the form of a capsule, for example a gelatin capsule.

Optionally, the compound for use, use or method described herein may be such that the compound is administered parenterally, topically, rectally, transmucosally, or intestinally.

According to the present invention, there is also provided a method of manufacturing a compound of general formula (I) or (II) as shown in Scheme (I):

Scheme (I).

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

As will be apparent to the skilled person, compounds of formulae (I) and (II) include ethers of 3-hydroxy-2-(3-pyridylmethyl)quinuclidines. While the methods by which compounds of the present invention can be prepared may vary, the compounds may be advantageously prepared using intermediates (e.g. ketones and alcohols) generated during the synthesis of target compounds, which is shown in Scheme (I) above.

While other synthetic strategies will be apparent to those of skilled in the art, 2-(3- pyridylmethyl)quinuclidine derivatives can be synthesised by reduction of aldol condensation products formed from 3-pyridinecarboxaldehyde and quinuclidin-3-one.

For example, 3-quinuclidinone hydrochloride may be reacted with pyridine-3-carboxaldehyde in the presence of methanolic potassium hydroxide. In turn 2-((3-pyridinyl)methylene)quinuclidin-3-one results from the reaction.

Stepwise reduction of the conjugated enone functionality may be accomplished through several different sequences to provide 2-(3-pyridylmethyl)quinuclidin-3-ol. For example, catalytic hydrogenation (palladium catalyst) of the enone may produce the saturated ketone, 2-(3- pyridylmethyl)quinuclidin-3-one, i.e. an intermediate in the synthesis of compounds of the present invention.

Reduction of the ketone to the alcohol may be accomplished, for example, using sodium borohydride, aluminium isopropoxide, or other reagents known in the art of chemical synthesis for carrying out similar reductions.

The alcohol, 2-(3-pyridylmethyl)quinuclidin-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 compounds of the present invention. The choice of reducing agent may affect the cis/trans ratio. The enantio-selective synthesis of cis-3- quinuclidinols may be implemented by Ru-catalysed asymmetric transfer hydrogenation via dynamic kinetic resolution or by the Meerwein-Ponndorf-Verley reaction.

Consecutively, inversion of 2-substituted cis-3-quinuclidinols into trans-isomers may be performed using p-nitrobenzoic acid as the nucleophilic partner in the Mitsunobu reaction. Diverse combination of aryl groups in general formula (I) may be achieved via the Suzuki cross-coupling reaction.

Compounds 1 to 20 may also be referred to as follows: c/s-2-(3-Pyridylmethyl)quinuclidin-3-ol (1 ) trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (2) trans-2-(3-Pyridylmethyl)quinuclidin-3-ol (3) trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinucli dine (4) trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridy l]-1 H-indole (5) c/s-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucl idine (6) c/s-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3 -yl]-1 H-indole (7) trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucl idine (8) trans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2 -yl]-1 H-indole (9) trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (10) trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole (11 ) (2S,3R)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridaz in-3-yl]-1 H-indole (2S,3R-11 ) (2R,3S)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridaz in-3-yl]-1 H-indole (2R,3S-11 ) trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 ,3-benzothiazol-2-amine (12) trans-tert-Butyl 2- [6- [2- (3-py ridy Im ethy l)qu in uclid in -3-y l]oxypy ridazi n-3-y l]py rro le- 1 -carboxylate (13) trans-2-(3-Pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14) trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (15) trans-2-(1 H-lndol-5-yl)-5-[2-(3-pyridylmethyl)quin uclidi n-3-yl]oxy-1 ,3,4-thiadiazole (16) trans-3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline (17) trans-2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline (18) trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (19) trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (20)

As will be apparent to the skilled person, the methods by which compounds of the present invention can be prepared may vary. For example, the compounds may be advantageously prepared using intermediates generated during the synthesis of target compounds as shown in Scheme (II). Since 2,3-disubstituted quinuclidine derivatives may form geometric isomers, both cis- and trans-2-(3- pyridylmethyl)quinuclidin-3-ols were explored, as intermediates for target molecule synthesis. Reduction of 2-(3-pyridylmethyl)quinuclidin-3-one with aluminum isopropoxide resulted in predominantly one diastereomer, cis-alcohol 1 , presumably by selective hydride transfer to the least hindered face of the carbonyl moiety. Inversion of cis-alcohol 1 into trans-isomer 3 was accomplished via the Mitsunobu reaction with p-nitrobenzoic acid and subsequent hydrolysis of resulting ester 2 as shown in Scheme (II):

Scheme (II).

Reagents and conditions for scheme (II) are as follows:

(a) p-nitrobenzoic acid, diisopropyl azodicarboxylate, triphenylphosphine, tetrahydrofuran, 0-25°C, 12 h;

(b) lithium hydroxide, tetrahydrofuran/water, 12 h;

(c) 5-bromo-2-chloropyridine, potassium tert-butoxide, tetrahydrofuran, 25°C, 12 h;

(d) indole-5-boronic acid, (1 ,1 '-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, cesium carbonate, dioxane/water, 90°C, 12 h;

(e) 3,6-dichloropyridazine, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 h;

(f) indole-5-boronic acid, (1 ,1 '-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, potassium carbonate, dioxane/water, 90°C, 12 h;

(g) 2,5-dichloropyrazine, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 h;

(h) indole-5-boronic acid, tetrakis(triphenylphosphine)palladium(0), sodium carbonate, dimethoxyethane/water, 90°C, 12 h. Consecutive nucleophilic substitution of halogen in dihalogen derivatives of nitrogen-containing aromatic heterocycles by reaction with cis- or trans-alcohols 1 or 3 and following the Suzuki coupling resulted in the series of ethers. As electronegative nitrogen-containing aromatic heterocycles, pyridine, pyrazine, pyridazine and thiadiazole were explored. Cross-coupling reaction of intermediates 4, 6, 8, 10 and 15 with various arylboronic acids provided diverse set of biaryl ethers. To evaluate effect of a benzene ring fused to pyridine, isoquinoline and quinoline ethers 17 and 18 were obtained, as shown in Scheme (III):

Scheme (III).

Reagents and conditions for scheme (III) are as follows:

(a) 3,6-dichloropyridazine, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 h; (b) indole-5-boronic acid, (1 ,1 '- bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, potassium carbonate, dioxane/water, 90°C, 12 h;

(c) 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-benzothiazol-2-amine, (1 ,1 '- bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, cesium carbonate, dioxane/water, 90°C, 12 h;

(d) 1 -(tert-butoxycarbonyl)pyrrole-2-boronic acid, (1 ,1 '- bis(diphenylphosphino) ferrocene)palladium(ll) dichloride, potassium carbonate, dioxane/water, 90°C, 12 h;

(e) hydrogen chloride, dioxane, 25°C, 12 h;

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

(g) indole-5-boronic acid, (1 ,1 '- bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, cesium carbonate, dioxane/water, 90°C, 12 h;

(h) 2-chloroquinoline, potassium tert-butoxide, tetrahydrofuran, 25°C, 2 h;

(i) 3- chloroisoquinoline, sodium hydride, N,N-dimethylformamide, 25-90°C, 2 h; (j) phenylboronic acid, (1 ,1 '-bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, potassium carbonate, dioxane/water, 90°C, 7 h;

(k) phenylboronic acid, (1 ,1 '- bis(diphenylphosphino)ferrocene)palladium(ll) dichloride, potassium carbonate, dioxane/water, 90°C, 12 h.

Specific examples of compounds

Examples of representative compounds of the present invention include (but are not limited to) the following compounds:

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

3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucli dine

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

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

5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3- yl]-1 H-indole 5-[5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2-yl]- 1 H-indole

-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]- 1 ,3-benzothiazol-2-amine -(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine -(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidine

-fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline -[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinoline -[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline

3-(6-imidazol-1 -ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine

2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole c/s-2-(3-Pyridylmethyl)quinuclidin-3-ol

frans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate 2 frans-2-(3-Pyridylmethyl)quinuclidin-3-ol (3)

3

frans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinucli dine frans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridy l]-1 H-indole c/s-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucl idine c/s-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3 -yl]-1 H-indole

frans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucl idine frans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2 -yl]-1 H-indole 9 trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine frans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole frans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 ,3-benzothiazol-2-amine trans-tert-Butyl 2-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl] pyrrole-1 -carboxylate frans-2-(3-Pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine frans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidiri-3-yl]oxy-1 ,3,4-thiadiazole trans-2-(1 H-lndol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole frans-3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquiriolir ie frans-2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline

18 frans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidirie frans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole

Numbered Paragraphs

Aspects of the invention are described in the following numbered paragraphs:

1. A compound of general formula (I):

(I), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each an optionally substituted aryl group which may be the same or different, wherein one or both aryl groups comprises a carbocyclic or heterocyclic aromatic ring and wherein one or both aryl groups is monocyclic or polycyclic, and wherein R ¹ and R ² are optionally fused.

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

3. The compound according to numbered paragraph 1 or numbered paragraph 2, wherein one or both aryl groups are monocyclic.

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

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

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

7. The compound according to any preceding numbered paragraph, wherein one or both aryl groups are substituted, for example with 1 , 2 or 3 substituents.

8. The compound according to numbered paragraph 7, wherein the substituents are independently selected from the group consisting of: alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo (for example, 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', -SO2R', and -SO2NR'R", wherein R' and R" are individually hydrogen, lower alkyl (for example, straight chain or branched alkyl including CrCs, preferably C1-C5, such as methyl, ethyl or isopropyl), cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl), and wherein R' and R" optionally combine to form a cyclic functionality.

9. The compound according to numbered paragraph 8, wherein the substituents are independently selected from the group consisting of: cyano, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy and alkylthio.

10. The compound according to any preceding numbered paragraph, wherein R ¹ is selected from: 1 ,3,4-thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

11 . The compound according to any preceding numbered paragraph, wherein R ² is selected from indolyl, benzofuranyl, benzothiazolyl and phenyl.

12. The compound according to any preceding numbered paragraph, wherein the compound is selected from the group consisting of:

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

3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucli dine;

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

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

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

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

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

3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinuclidi ne;

6-fluoro-2-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxyquinol ine; 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.

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

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

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

16. The compound according to any preceding numbered paragraph, wherein the compound is selected from the group consisting of: trans-[2-(3-Pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (2); trans-3-[(5-Bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinucli dine (4); trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxy-3-pyridy l]-1 H-indole (5); c/s-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinucl idine (6); c/s-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3 -yl]-1 H-indole (7); trans-3-(5-Chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucl idine (8); trans-5-[5-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2 -yl]-1 H-indole (9); trans-3-(6-Chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (10); trans-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole (11 );

(2S,3R)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyri dazin-3-yl]-1 H-indole (2S,3R-11 );

(2R,3S)-5-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyri dazin-3-yl]-1 H-indole (2R,3S-11 ); trans-6-[6-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 ,3-benzothiazol-2-amine (12); trans-tert-Butyl 2-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl] pyrrole-1 -carboxylate (13); trans-2-(3-Pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (14); trans-2-Bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (15); trans-2-(1 H-lndol-5-yl)-5-[2-(3-pyridylmethyl)quin uclidi n-3-yl]oxy-1 ,3,4-thiadiazole (16); trans-3-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyisoquinoline (17); trans-2-[2-(3-Pyridylmethyl)quinuclidin-3-yl]oxyquinoline (18); trans-3-(6-Phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (19); and trans-2-Phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (20). 17. The compound according to numbered paragraph 16, wherein the compound is trans-2-(1 H- indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole.

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

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

20. The compound according to any preceding numbered paragraph, wherein 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.

21 . A compound of general formula (II):

(II), or a pharmaceutically acceptable salt thereof, wherein R ¹ is an optionally substituted aryl group which comprises a carbocyclic or heterocyclic aromatic ring and wherein the aryl group is monocyclic or polycyclic, and

X is a halogen or a triflate.

22. A compound of general formula (I):

(I), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is an optionally substituted aryl or an optionally substituted heteroaryl; and

R ² is a halogen, a triflate, an optionally substituted aryl, an optionally substituted heteroaryl or is absent; or wherein R ¹ and R ² together form an optionally substituted aryl or an optionally substituted heteroaryl.

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

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

25. A compound according to any of numbered paragraphs 1 to 22 for use in the treatment for use in the treatment of a disease or disorder mediated by an a7 nicotinic acetylcholine receptor (nAChR).

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

27. A method of treating a disease or disorder, comprising the step of administering a compound according to any of numbered paragraphs 1 to 22, or a pharmaceutical composition according to numbered paragraph 23, to a patient in need of same.

28. The compound for use according to numbered paragraph 24 or numbered paragraph 25, the use according to numbered paragraph 26, or the method according to numbered paragraph 27, wherein the treatment is for preventing and/or suppressing cough, the progression of cough, ameliorate symptoms of cough, and ameliorate to the recurrence of cough. 29. The compound for use according to numbered paragraph 24 or numbered paragraph 25, the use according to numbered paragraph 26, or the method according to numbered paragraph 27, wherein the disease or disorder is selected from: a cognitive and neurodegenerative disease; a psychotic disorder, such as schizophrenia; acute nociceptive, neuropathic or inflammatory pain; and an affective disorder, such as depression and inflammation.

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

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

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

33. The compound for use, use or method according to numbered paragraph 30, wherein the compound is orally administered at a dose of no more than about 0.01 g/kg per day, no more than about 0.1 g/kg per day, no more than about 0.5 g/kg per day, no more than about 0.9 g/kg per day, no more than about 1 g/kg per day, no more than about 1 .1 g/kg per day, no more than about 1 .2 g/kg per day, no more than about 1 .5 g/kg per day, no more than about 2 g/kg per day.

34. The compound for use, use or method according to numbered paragraph 30, wherein the compound is orally administered at a dose of at least about 0.00001 mg/kg per day to no more than about 2 g/kg per day, at least about 0.0001 mg/kg per day to no more than about 1 .5 g/kg per day, at least about 0.001 mg/kg per day to no more than about 1 .2 g/kg per day, at least about 0.01 mg/kg per day to no more than about 1 .1 g/kg per day, at least about 0.1 mg/kg per day to no more than about 1 g/kg per day, at least about 0.2 mg/kg per day to no more than about 0.9 g/kg per day, at least about 0.3 mg/kg per day to no more than about 0.5 g/kg per day, at least about 0.4 mg/kg per day to no more than about 0.1 g/kg per day, at least about 0.5 mg/kg per day to no more than about 0.01 g/kg per day.

35. The compound for use, use or method according to numbered paragraph 30, wherein the compound is orally administered at 5 mg to 2 g/day. 36. The compound for use, use or method according to numbered paragraph 30, wherein the compound is orally administered at a dose of at least about 0.1 mg/day, at least about 1 mg/day, at least about 3 mg/day, at least about 4 mg/day, at least about 5 mg/day, at least about 5.1 mg/day, at least about 6 mg/day, at least about 10 mg/day, at least about 50 mg/day.

37. The compound for use, use or method according to numbered paragraph 30, wherein the compound is orally administered 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.

38. The compound for use, use or method according to numbered paragraph 30, wherein the compound is orally administered at a dose 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.

39. The compound for use, use or method according to any of numbered paragraphs 30 to 38, wherein the composition is in the form of a tablet.

40. The compound for use, use or method according to numbered paragraph 28 or numbered paragraph 29, wherein the compound is administered parenterally, topically, rectally, transmucosally, intraperitoneally or intestinally.

41 . A method of manufacturing a compound of general formula (I) or (II) as shown in Scheme (I): Scheme (I), wherein R ¹ and R ² are as defined in any of numbered paragraphs 1 to 11 , 21 or 22 and X is halo (for example, F, Cl, Br or I) or triflate.

of general formula (I) or (II) as shown in Scheme (II):

of general formula (I) or (II) as shown in Scheme (III):

List of Figures

Figure 1 is a structural overview of a7 nAChR pharmacophoric elements and a flow chart showing the evaluation of cough responses in a cough model.

Figure 2 is an arrangement of bar charts showing the effect of 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole on cumulative number of coughs induced by citric acid.

Figure 3 is an arrangement of bar charts showing the effect of 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole on cough incubation period of coughs induced by citric acid.

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

Figure 5 is an arrangement of bar charts showing the effect of dry powder insufflated 2-(1 H-indol-5- yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole on cumulative number of coughs induced by citric acid.

Figure 6 is an arrangement of bar charts showing the effect of nebulised 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole on cumulative number of coughs induced by citric acid.

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

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

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

Synthetic examples of compounds are set out in Examples 1 -25, the biological activity examples in Example 26 and 27, and the in vivo assessment of the antitussive efficacy 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 noted. Reaction yields are reported in mole percentage.

Example 1 (Reference): 2-[(3-Pyridinyl)methylenelauinuclidin-3-one

To a solution of quinuclidin-3-one hydrochloride (45.0 g, 278 mmol) in methanol (450 mL) was added KOH (31.2 g, 556 mmol, 2.00 eq). The mixture was stirred at 50 °C for 2 hrs. Pyridine-3- carboxaldehyde (29.8 g, 278 mmol, 26.2 mL, 1 .00 eq) was added at 25 °C, the mixture was stirred at 50 °C for 5 hrs. The reaction mixture was concentrated under reduced pressure. The residue was triturated with water (150 mL) for 10 hrs. 2-[(3-pyridinyl)methylene]quinuclidin-3-one (57.0 g, 266 mmol, 95.6% yield) was obtained as light yellow solid. 1 H NMR (400 MHz, CDCI3): 5 8.98 (d, J = 1 .9 Hz, 1 H), 8.47-8.41 (m, 2H), 7.24 (dd, J = 4.8, 7.9 Hz, 1 H), 6.92 (s,1 H), 3.15-2.90 (m, 4H), 2.60-2.59 (m, 1 H), 2.00-1 .72 (m, 4H). LCMS: m/z = 215.2 (M+1 )+.

Example 2 (Reference): 2-(3-Pyridylmethyl)quinuclidin-3-one

A mixture of 2-[(3-pyridinyl)methylene]quinuclidin-3-one (57.0 g, 266 mmol, 1.00 eq), Pd/C (5.70 g, 26.6 mmol, 10% purity, 0.100 eq), H2 (536 mg, 266 mmol, 1.00 eq) in methanol (600 mL) was degassed and purged with H ₂ for 3 times, and then the mixture was stirred at 25° C for 12 hrs under H ₂ atmosphere (15 psi). The reaction mixture was filtered and concentrated under reduced pressure. 2-(3-Pyridylmethyl)quinuclidin-3-one (56.0 g, 258 mmol, 97.3% yield) was obtained as a white solid. 1 H NMR (400 MHz, CDCI3): 5 8.50-8.44 (m, 2H), 7.59 (dd, J = 2.5, 4.5 Hz, 1 H), 7.27-7.19 (m, 1 H), 3.32-2.47 (m, 7H), 2.46 (d, J = 2.1 Hz, 1 H), 2.02-1 .96 (m, 4H). LCMS: m/z = 217.2 (M+1 )+.

Example 3 (Reference): Cis-2-(3-pyridylmethyl)quinuclidin-3-ol

To a solution of 2-(3-pyridylmethyl)quinuclidin-3-one (20.0 g, 92.4 mmol, 1 .00 eq) in isopropanol (500 mL) was added aluminum isopropoxide (56.6 g, 277 mmol, 55.0 mL, 3.00 eq). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was diluted with saturated NaCI 300 mL and 50% NaOH (aq), extracted with dichloromethane 200 mL (100 mL * 2). The combined organic layers were washed with brine 200 mL (100 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane/methanol = 50/0 to 10/1 ). Cis-2-(3-pyridylmethyl)quinuclidin-3-ol (16.0 g, 73.3 mmol, 79.2% yield) was obtained as yellow solid. 1 H NMR (400 MHz, CDCI3): 5 8.52 (s, 1 H), 8.34 (dd, J = 1 .5, 4.8 Hz, 1 H), 7.64-7.61 (m, 1 H), 7.21 -7.16 (m, 1 H), 3.89-3.86 (m, 1 H), 3.23-3.07 (m, 3H), 2.87-2.79 (m, 4H), 1.97-1.91 (m, 2H), 1 .66-1 .65 (m, 1 H), 1 .64-1 .63 (m, 1 H), 1 .48-1 .32 (m, 1 H). LCMS: m/z = 219.2 (M+1 )+. Example 4: Trans-[2-(3-pyridylmethyl)auinuclidin-3-yll 4-nitrobenzoate

To a solution of cis-2-(3-pyridylmethyl)quinuclidin-3-ol (16.0 g, 73.3 mmol, 1 .00 eq) and 4-nitrobenzoic acid (36.7 g, 219 mmol, 3.00 eq) in tetrahydrofuran (160 mL) was added triphenylphosphine (57.6 g, 219 mmol, 3.00 eq) and diisopropyl azodicarboxylate (44.4 g, 219 mmol, 42.7 mL, 3.00 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane/methanol=1/0 to 10/1 ). Trans-[2-(3-pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (26.0 g, crude) was obtained as brown oil. LCMS: m/z = 368.2 (M+1 )+.

Example 5 (Reference): Trans-2-(3-pyridylmethyl)quinuclidin-3-ol

To a solution of trans-[2-(3-pyridylmethyl)quinuclidin-3-yl] 4-nitrobenzoate (26.0 g, 70.7 mmol, 1.00 eq) in tetrahydrofuran (160 mL) was added LiOH*H2O (4.45 g, 106 mmol, 1 .50 eq) in H2O (40 mL). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (300 mL and 100 mL * 5). The combined organic layers were washed with brine 100 mL (100 mL * 2), dried over 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)quinuclidin-3-ol (6.00 g, 27.4 mmol, 38.8% yield) was obtained as black brown gum. LCMS: m/z = 219.2 (M+1)+.

Example 6: Trans-3-[(5-bromo-2-pyridyl)oxyl-2-(3-pyridylmethyl)auinucli dine

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.300 g, 1.37 mmol, 1.00 eq) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (308 mg, 2.75 mmol, 2.00 eq). The mixture was stirred at 25 °C for 1 hr. 5-Bromo-2-chloro-pyridine (290 mg, 1 .51 mmol, 1 .10 eq) was added, the mixture was stirred at 25 °C for 11 hrs. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane 150 mL (50 mL * 3). The combined organic layers were washed with brine 60 mL (30 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Trans- 3-[(5-bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinuclidine (0.280 g, 748 pmol, 54.4% yield) was obtained as yellow oil. LCMS: m/z = 374.1 (M+1 )+.

Example 7: Trans-5-[6-[2-(3-pyridylmethyl)auinuclidin-3-yl]oxy-3-pyridy ll-1 H-indole

A mixture of trans-3-[(5-bromo-2-pyridyl)oxy]-2-(3-pyridylmethyl)quinucli dine (0.280 g, 748 pmol, 1 .00 eq), indole-5-boronic acid (180 mg, 1 .12 mmol, 1 .50 eq), Cs2CO3 (731 mg, 2.24 mmol, 3.00 eq) and Pd(dppf)CI2 (54.7 mg, 74.8 pmol, 0.100 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ). TLC (dichloromethane/methanol = 10/1 ) showed one major spot (Rf = 0.25) was detected. Trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy- 3-pyridyl]-1 H-indole (131 mg, 311 pmol, 41 .6% yield, 97.4% purity) was obtained as light yellow solid. 1 H NMR (400 MHz, CD3OD): 58.45 (s, 1 H), 8.26-8.21 (m, 2H), 7.82-7.71 (m, 3H), 7.45 (d, J = 8.4 Hz, 1 H), 7.30-7.26 (m, 3H), 6.60 (d, J = 8.6 Hz, 1 H), 6.49 (dd, J = 0.7, 3.1 Hz, 1 H), 4.93 (s, 1 H), 3.31 -2.97 (m, 6H), 2.77-2.76 (m, 1 H), 2.21 (d, J = 1 .6 Hz, 1 H), 1 .92-1 .80 (m, 3H), 1 .47-1 .45 (m, 1 H). LCMS: m/z = 411.3 (M+1 )+.

Example 8: Trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucl idine

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.150 g, 687 pmol, 1.00 eq) in tetrahydrofuran (5 mL) were added potassium tert-butoxide (154 mg, 1 .37 mmol, 2.00 eq) at 25 °C for 1 hr and 2,5-dichloropyrazine (123 mg, 825 pmol, 1 .20 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water 20 mL and extracted with dichloromethane 200 mL (50 mL * 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1%NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1% NH3*H2O) showed one major spot (Rf = 0.55) was detected. Trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucl idine (74.6 mg, 222 pmol, 32.3% yield, 98.5% purity) was obtained as off-white solid. 1 H NMR (400 MHz, CDCI3): 5 8.46- 8.35 (m, 2H), 8.01 (d, J = 1 .2 Hz, 1 H), 7.83 (d, J = 1 .2 Hz, 1 H), 7.53 (dd, J = 1 .6, 7.8 Hz, 1 H), 7.13- 7.10 (m, 1 H), 4.80-4.79 (m, 1 H), 3.09-2.96 (m, 6H), 2.94-2.91 (m, 1 H), 2.15-2.14 (m, 1 H), 1.79-1.70 (m, 3H), 1 .38-1 .37 (m, 1 H). LCMS: m/z = 331 .0 (M+1 )+. Example 9: Trans-5-[5-[2-(3-pyridylmethyl)auinuclidin-3-ylloxypyrazin-2 -yll-1 H-indole

A mixture of trans-3-(5-chloropyrazin-2-yl)oxy-2-(3-pyridylmethyl)quinucl idine (0.100 g, 302 pmol, 1.00 eq), indole-5-boronic acid (60.0 mg, 372 pmol, 1.23 eq), Na2CO3 (100 mg, 943 pmol, 3.12 eq), tetrakis(triphenylphosphine)palladium(0) (40.0 mg, 34.6 pmol, 0.115 eq) in dimethoxyethane (5 mL)and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1% NH3*H2O). Trans-5-[5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyrazin-2 -yl]-1 H-indole (45.2 mg, 107 pmol, 35.7% yield, 98.1% purity) was obtained as off-white solid. 1 H NMR (400 MHz, CDCI3): 5 9.26 (s, 1 H), 8.51 -8.45 (m, 2H), 8.34 (dd, J = 1.4, 4.8 Hz, 1 H), 8.16-8.13 (m, 2H), 7.73-7.70 (m, 1 H), 7.63-7.52 (m, 1 H), 7.43-7.41 (m, 1 H), 7.207.19 (m, 1 H), 7.11 (dd, J = 4.9, 7.8 Hz, 1 H), 6.60 (s, 1 H), 4.89 (t, J = 3.2 Hz, 1 H), 3.17-2.98 (m, 6H), 2.97-2.76 (m, 1 H), 2.23-2.22 (m, 1 H), 1.76-1.75 (m, 1 H), 1 .74-1 .72 (m, 2H), 1 .40-1 .39 (m, 1 H). LCMS: m/z = 412.1 (M+1 )+.

Example 10: Trans-2-bromo-5-[2-(3-pyridylmethyl)guinuclidin-3-yl]oxy-1 ,3,4-thiadiazole

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.200 g, 916 pmol, 1.00 eq) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (154 mg, 1 .37 mmol, 1 .50 eq). The mixture was stirred at 25 °C for 1 hr. And then 2,5-dibromo-1 ,3,4-thiadiazole (223 mg, 916 pmol, 1 .00 eq) was added, the mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water 20 mL and extracted with dichloromethane 150 mL (50 mL * 3). The combined organic layers were washed with brine 60 mL (30 mL * 2), 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 yellow solid. LCMS: m/z = 383.1 (M+1 )+.

Example 11 : Trans-2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)guinuclidin-3-yl1oxy-1 ,3,4-thiadiazole

A mixture of trans-2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (0.350 g, 917 pmol, 1.00 eq), indole-5-boronic acid (221 mg, 1.38 mmol, 1.50 eq), Cs2CO3 (897 mg, 2.75 mmol, 3.00 eq), Pd(dppf)CI2 (67.1 mg, 91 .7 pmol, 0.100 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; NH3*H2O) showed one major spot (Rf = 0.35) was detected. Trans-2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (44.3 mg, 106 pmol, 11.5% yield, 100% purity) was obtained as light yellow solid. 1 H NMR (400 MHz, CDCI3): 5 8.55-8.42 (m, 2H), 8.41 (dd, J = 1.5, 4.8 Hz, 1 H), 8.04 (d, J = 0.7 Hz, 1 H), 7.75-7.72 (m, 1 H), 7.46- 7.44 (m, 1 H), 7.29-7.28 (m, 1 H), 7.28-7.27 (m, 1 H), 7.18-7.17 (m, 1 H), 6.63 (t, J = 2.1 Hz, 1 H), 4.95 (t, J = 3.1 Hz, 1 H), 3.16-3.05 (m, 5H), 3.00-2.96 (m, 1 H), 2.51 -2.50 (m, 1 H), 1.79-1.73 (m, 4H), 1.46- 1 .44 (m, 1 H). LCMS: m/z = 418.2 (M+1 )+.

Example 12: 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-benzothiazol-2-amine A mixture of 6-bromo-1 ,3-benzothiazol-2-amine (1 .00 g, 4.36 mmol, 1 .00 eq), bis(pinacolato)diboron (1 .66 g, 6.54 mmol, 1 .50 eq), potassium acetate (1 .28 g, 13.0 mmol, 3.00 eq), Pd(dppf)CI2 (319 mg, 436 pmol, 0.100 eq) in dioxane (10 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3- benzothiazol-2-amine (1 .60 g, crude) was obtained as black brown solid. LCMS: m/z = 277.1 (M-55)+.

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.150 g, 687 pmol, 1.00 eq) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (1 M, 1 .34 mL, 1 .95 eq). The mixture was stirred at 25 °C for 1 hr. And then 3,6-dichloropyridazine (120 mg, 805 pmol, 1 .17 eq) was added, the mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water 20 mL and extracted with dichloromethane 150 mL (50 mL * 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ). TLC (dichloromethane/methanol = 10/1 ) showed one major spot (Rf = 0.45) was detected. Trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (120 mg, 362 umol, 52.7% yield) was obtained as yellow oil.

Example 14: Trans-6-[6-[2-(3-pvridvlmethvl)auinuclidin-3-vlloxvPvridazin -3-vll-1 ,3-benzothiazol-2- amine

A mixture of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (0.100 g, 302 pmol, 1.00 eq), 6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 ,3-benzothiazol-2-amine (166 mg, 604 pmol, 2.00 eq), Cs2CO3 (295 mg, 906 pmol, 3.00 eq), Pd(dppf)CI2 (22.1 mg, 30.2 pmol, 0.100 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1 % NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1 % NH3*H2O) showed one major spot (Rf = 0.35) was detected. Trans-6-[6-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1 ,3-benzothiazol-2-amine (27.5 mg, 60.8 pmol, 20.1% yield, 98.2% purity) was obtained as yellow solid. 1 H NMR (400 MHz, CD3OD): 5 8.46 (d, J = 1 .8 Hz, 1 H), 8.21 -8.20 (m, 2H), 7.96-7.93 (m, 3H), 7.48 (d, J = 8.4 Hz, 1 H), 7.23 (dd, J = 5.0, 7.8 Hz, 1 H), 6.94 (dd, J = 1 .5, 9.2 Hz, 1 H), 5.15 (s, 1 H), 3.25-3.02 (m, 6H), 2.99-2.76 (m, 1 H), 2.32 (d, J = 2.3 Hz, 1 H), 1 .94-1 .84 (m, 3H), 1 .51 -1 .50 (m, 1 H). LCMS: m/z = 445.3 (M+1 )+.

:in-3-vllDvrrole-1 -

A mixture of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (0.120 g, 362 pmol, 1.00 eq), (1 -tert-butoxycarbonylpyrrol-2-yl)boronic acid (92.0 mg, 435 pmol, 1.20 eq), Pd(dppf)CI2 (30.0 mg, 41 .0 pmol, 0.113 eq), K2CO3 (150 mg, 1 .09 mmol, 2.99 eq) in dioxane (5 mL) and H2O (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1% NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1 % NH3*H2O) showed one major spot (Rf = 0.45) was detected. tert-Butyl trans-2-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]pyrrole-1 - carboxylate (80.0 mg, 173 pmol, 47.7% yield) was obtained as yellow oil. LCMS: m/z = 462.3 (M+1 )+.

Example 16: Trans-2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-ylloxy-guinuclidine

To a solution of tert-butyl trans-2-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]pyrrole-1 - carboxylate (80.0 mg, 173 pmol, 1 .00 eq) in dioxane (3 mL) was added HCI/dioxane (4 M, 3 mL, 69.2 eq). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1% NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1 % NH3*H2O) showed one major spot (Rf = 0.55) was detected. Trans-2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxy-quinuclidine (58.1 mg, 160 pmol, 92.8% yield, 100% purity) was obtained as light yellow solid. 1 H NMR (400 MHz, CDCI3): 5 9.93 (s, 1 H), 8.50 (d, J = 1 .8 Hz, 1 H), 8.32 (dd, J = 1.6, 4.9 Hz, 1 H), 7.57-7.53 (m, 2H), 7.27-7.06 (m, 1 H), 6.97-6.96 (m, 1 H), 6.77-6.75 (m, 1 H), 6.64-6.63 (m, 1 H), 6.30-6.29 (m, 1 H), 5.11 -5.10 (m, 1 H), 3.14-2.98 (m, 6H), 2.97-2.94 (m, 1 H), 2.37-2.36 (m, 1 H), 1.76-1.73 (m, 3H), 1.39-1.25 (m, 1 H). LCMS: m/z = 362.3 (M+1 )+.

Example 17: T rans-6-fluoro-2-[2-(3-pyridylmethyl)auinuclidin-3-yl]oxyauin oline

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.100 g, 458 pmol, 1.00 eq) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (1 M, 916 pL, 2.00 eq). The mixture was stirred at 25 °C for 1 hr. 2-Chloro-6-fluoro-quinoline (99.8 mg, 549 pmol, 1.20 eq) was added, the mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water 30 mL and extracted with dichloromethane 240 mL (60 mL * 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1 % NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1 % NH3*H2O) showed one major spot (Rf = 0.55) was detected. Trans-6-fluoro-2-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxyquinoline (124 mg, 332 pmol, 72.6% yield, 96.9% purity) was obtained as colorless oil. 1 H NMR (400 MHz, CD3OD): 5 8.42 (d, J = 1 .8 Hz, 1 H), 8.12 (dd, J = 1 .6, 4.9 Hz, 1 H), 8.00 (d, J = 8.9 Hz, 1 H), 7.74-7.72 (m, 2H), 7.46-7.42 (m, 2H), 7.14 (dd, J = 4.9, 7.8 Hz, 1 H), 6.74 (d, J = 8.9 Hz, 1 H), 5.16 (t, J = 3.0 Hz, 1 H), 3.24-3.22 (m, 3H), 3.04-3.01 (m, 3H), 3.00-2.99 (m, 1 H), 2.28-2.26 (m, 1 H), 1 .87-1 .84 (m, 3H), 1 .49-1 .47 (m, 1 H). LCMS: m/z = 364.2 (M+1 )+.

Example 18: Trans-2-[2-(3-pyridylmethyl)guinuclidin-3-ylloxyauinoline

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.170 g, 778 pmol, 1.00 eq) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (1 M, 1 .56 mL, 2.00 eq). The mixture was stirred at 25 °C for 1 hr. 2-Chloroquinoline (152 mg, 934 pmol, 124 pL, 1 .20 eq) was added, the mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water 30 mL and extracted with dichloromethane 240 mL (60 mL * 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1% NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1% NH3*H2O) showed one major spot (Rf = 0.49) was detected. Trans-2-[2-(3-pyridylmethyl)quinuclidin- 3-yl]oxyquinoline (163 mg, 469 umol, 60.3% yield, 99.1% purity) was obtained as colorless oil. 1 H NMR (400 MHz, CD3OD): 58.42 (d, J = 1 .7 Hz, 1 H), 8.13-8.12 (m, 1 H), 8.02 (d, J = 8.8 Hz, 1 H), 7.76- 7.72 (m, 3H), 7.61 (ddd, J = 1 .5, 7.0, 8.4 Hz, 1 H), 7.38-7.37 (m, 1 H), 7.14-7.13 (m, 1 H), 6.71 (d, J = 8.9 Hz, 1 H), 5.18-5.16 (m, 1 H), 3.28-3.18 (m, 3H), 3.05-3.01 (m, 3H), 2.99-2.98 (m, 1 H), 2.30-2.27 (m, 1 H), 1 .86-1 .83 (m, 3H), 1 .49-1 .47 (m, 1 H). LCMS: m/z = 346.2 (M+1 )+.

Example 19: Trans-3-[2-(3-Dyridylmethyl)auinuclidin-3-ylloxyisoauinoline

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (0.0500 g, 229 pmol, 1.00 eq) in N,Ndimethylformamide (3 mL) was added sodium hydride (18.3 mg, 458 pmol, 60% purity, 2.00 eq). The mixture was stirred at 25 °C for 1 hrs. 3-chloroisoquinoline (56.2 mg, 343 pmol, 1.50 eq) was added, the mixture was stirred at 90 °C for 11 hrs. The reaction mixture was quenched by addition of saturated aqueous NH4CI 2 mL at 0 °C, and then diluted with water 20 mL and extracted with dichloromethane 160 mL (40 mL * 4). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1 % NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1 % NH3*H2O) showed one major spot (Rf = 0.6) was detected. Trans-3-[2-(3-pyridylmethyl)quinuclidin- 3-yl]oxyisoquinoline (14.8 mg, 42.5 pmol, 18.5% yield, 98.8% purity) was obtained as brown solid. 1 H NMR (400 MHz, CD3OD): 5 8.84 (s, 1 H), 8.43 (s, 1 H), 8.10 (dd, J = 1 .1 , 4.8 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 7.76-7.58 (m, 3H), 7.62-7.60 (m, 1 H), 7.15 (dd, J = 4.9, 7.8 Hz, 1 H), 6.88 (s, 1 H), 4.92-4.88 (m, 1 H), 3.17-3.06 (m, 6H), 3.04-3.01 (m, 1 H), 2.25-2.22 (m, 1 H), 1.86-1.83 (m, 4H). LCMS: m/z = 346.2 (M+1 )+.

Example 20: Trans-3-(6-imidazol-1 -ylDyridazin-3-yl)oxy-2-(3-pyridylmethyl) guinuclidine

To a solution of trans-2-(3-pyridylmethyl)quinuclidin-3-ol (200 mg, 916 pmol, 1.00 eq) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (102 mg, 916 pmol, 1 .00 eq). The mixture was stirred at 25 °C for 1 hr. 3-Chloro-6-imidazol-1 -yl-pyridazine (165 mg, 916 pmol, 1.00 eq) was added, the mixture was stirred at 50 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% NH3*H2O). Trans-3-(6-imidazol-1 -ylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinuclidine (43.2 mg, 119 pmol, 13.0% yield, 100% purity) was obtained as offwhite solid. 1 H NMR (400 MHz, CDCI3): 5 8.47 (d, J = 1 .6 Hz, 1 H), 8.32-8.27 (m, 2H), 7.64 (s, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.47 (d, J = 9.4 Hz, 1 H), 7.22 (s, 1 H), 7.09 (dd, J = 4.9, 7.6 Hz, 1 H), 6.95 (d, J = 9.4 Hz, 1 H), 5.12 (s, 1 H), 3.15-3.14 (m, 1 H), 3.03-2.97 (m, 5H), 2.96-2.94 (m, 1 H), 2.37-2.34 (m, 1 H), 1 .77-1 .73 (m, 3H), 1 .42-1 .40 (m, 1 H). LCMS: m/z = 363.2 (M+1 )+. Example 21 : Trans-5-[6-[2-(3-pyridylmethyl)auinuclidin-3-yl]oxyPyridazin -3-yll-1 H-indole

To a solution of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (800 mg, 2.42 mmol, 1 .00 eq) and indole-5-boronic acid (976.00 mg, 6.06 mmol, 2.51 eq) in dioxane (5.00 mL) and ethanol (5.00 mL) was added Pd(dppf)CI2 (176.00 mg, 250.75 pmol) and dicyclohexyl-(2- phenylphenyl)phosphine (48.00 mg, 136.96 umol) , Na2CO3 (1 M, 8.00 mL, 3.31 eq). The mixture was stirred at 150 °C for 0.5 hr under N2 with microwave (3 batches). The mixture was filtered and the filtrate was extracted with ethyl acetate (200 mL), dried over Na2SO4, concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC (0.1 % NH3*H2O). Trans-5-[6-[2- (3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1 Hindole (2.20 g, 5.13 mmol, 70.7% yield, 96% purity) was obtained as an yellow solid. 1 H NMR (400 MHz, CD3OD): 5 8.44 (s, 1 H), 8.26-8.22 (m, 1 H), 7.77-7.75 (m, 1 H), 7.56-7.53 (m, 1 H), 7.26-7.23 (m, 1 H), 6.26-6.23 (m, 1 H), 5.08-5.07 (m, 1 H),

3.25-2.92 (m, 6H), 2.80-2.73 (m, 1 H), 2.27-2.24 (m, 1 H), 1.87-1.79 (m, 3H), 1.52-1.46 (m, 1 H). Separation of racemic trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin -3-yl]-1 Hindole was performed by chiral supercritical fluid chromatography (SFC) using column Chiralpak AD-350x4.6mm I.D., 3pm; mobile phase: Phase A for CO2, and Phase B for isopropanol (0.05% diethylamine) with 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)quinuclidin-3-yl]oxypyridazin -3-yl]-1 H-indole, off- white solid; RT = 2.000 min, ee 100%; 1 H NMR (400 MHz, CD3OD): 58.48 (s, 1 H), 8.23-8.22 (m, 1 H), 8.12-8.11 (m, 1 H), 7.98-7.96 (m, 1 H), 7.80-7.76 (m, 1 H), 7.73-7.70 (m, 1 H), 7.52-7.49 (m, 1 H), 7.31 - 7.30 (m, 1 H), 7.26-7.22 (m, 1 H), 6.96-6.94 (m, 1 H), 6.56 (m, 1 H), 5.17 (m, 1 H), 3.25-2.97 (m, 6H), 2.85-2.78 (m, 1 H), 2.37-2.34 (m, 1 H), 1.96-1.84 (m, 3H), 1.57-1.39 (m, 1 H). 2R,3S-5-[6-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1 H-indole, off-white solid; RT = 2.110 min, ee 100%; 1 H NMR (400 MHz, CD3OD): 58.47 (s, 1 H), 8.23-8.21 (m, 1 H), 8.11 (s, 1 H), 7.98-7.96 (m, 1 H), 7.80- 7.70 (m, 2H), 7.51 -7.49 (m, 1 H), 7.31 -7.22 (m, 2H), 6.96-6.94 (m, 1 H), 6.56 (m, 1 H), 5.17 (m, 1 H),

3.25-2.97 (m, 6H), 2.85-2.78 (m, 1 H), 2.37-2.34 (m, 1 H), 1 .96-1 .83 (m, 3H), 1 .57-1 .50 (m, 1 H).

To a solution of cis-2-(3-pyridylmethyl)quinuclidin-3-ol (0.100 g, 458 pmol, 1 .00 eq) in tetrahydrofuran (5 mL) was added potassium tert-butoxide (51.4 mg, 458 pmol, 1.00 eq). The mixture was stirred at 25 °C for 1 hr. 3,6-Dichloropyridazine (85.3 mg, 572 pmol, 1 .25 eq) was added, the mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with water 20 mL and extracted with ethyl acetate 90 mL (30 mL * 3). The combined organic layers were washed with brine 20 mL (10 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure. Cis-3-(6-chloropyridazin-3-yl)oxy-2- (3-pyridylmethyl)quinuclidine (150 mg, 453 pmol, 98.9% yield) was obtained as a yellow gum. in-3-yll-1 H-indole To a solution of cis-3-(6-chloropyridazin-3-yl)oxy-2-(3-yridylmethyl)quinucli dine (0.150 g, 453 umol, 1.00 eq) and indole-5-boronic acid (87.5 mg, 544 pmol, 1.20 eq) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (188 mg, 1.36 mmol, 3.00 eq) and Pd (dppf)CI2 (33.1 mg, 45.3 pmol, 0.100 eq). The mixture was stirred at 90 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1% NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1% NH3*H2O) showed one major spot (Rf = 0.35) was detected. Cis-5-[6-[2-(3pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3- yl]-1 H-indole (45.8 mg, 108 pmol, 23.8% yield, 97.1 % purity) was obtained as a brown solid. 1 H NMR (400 MHz, CDCI3): 5 9.65 (s, 1 H), 8.50 (d, J=1 .8 Hz, 1 H), 8.34 (dd, J=1 .5, 4.8 Hz, 1 H), 8.20 (s, 1 H), 7.85-7.77 (m, 2H), 7.43-7.41 (m, 1 H), 7.21 (d, J=8.6 Hz, 1 H), 7.20 (t, J=2.8 Hz, 1 H), 7.04-7.02 (m, 1 H), 7.01 (d, J=9.3 Hz, 1 H), 6.59 (s, 1 H), 5.66-5.56 (m, 1 H), 3.47-3.44 (m, 1 H), 3.13 (m, 1 H), 3.06-2.90 (m, 2H), 2.91 - 2.83 (m, 3H), 2.54 (s, 1 H), 1 .83-1 .70 (m, 1 H), 1 .69-1 .65 (m, 2H), 1 .39-1 .37 (m, 1 H). LCMS: m/z = 412 (M+1)+.

Example 24: Trans-3-(6-DhenylDyridazin-3-yl)oxy-2-(3-Dyridylmethyl)guinu clidine

To a solution of trans-3-(6-chloropyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (0.150 g, 453 pmol, 1.00 eq) and phenylboronic acid (66.3 mg, 544 pmol, 1.20 eq) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (188 mg, 1.36 mmol, 3.00 eq) and Pd(dppf)CI2 (33.1 mg, 45.3 pmol, 0.100 eq). The mixture was stirred at 90 °C for 7 hrs. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, dichloromethane/methanol = 10/1 ; 1% NH3*H2O). TLC (dichloromethane/methanol = 10/1 ; 1 % NH3*H2O) showed one major spot (Rf = 0.35) was detected. Trans-3-(6-phenylpyridazin-3-yl)oxy-2-(3-pyridylmethyl)quinu clidine (70.3 mg, 175 pmol, 38.8% yield, 93.2% purity) was obtained as a light yellow solid. 1 H NMR (400 MHz, CDCI3): 5 8.55 (s, 1 H), 8.37 (s, 1 H), 8.01 -7.99 (m, 2H), 7.74 (d, J=9.2 Hz, 1 H), 7.52-7.51 (m, 1 H), 7.50-7.49 (m, 3H), 7.13-7.11 (dd, J=4.8, 7.6 Hz, 1 H), 6.88 (d, J=9.2 Hz, 1 H), 5.31 -5.10 (m, 1 H), 3.19- 3.01 (m, 6H), 2.99-2.98 (m, 1 H), 2.44-2.41 (m, 1 H), 1 .83-1 .75 (m, 3H), 1 .43-1 .42 (m, 1 H). LCMS: m/z = 373 (M+1 )+.

Example 25: Trans-2-Dhenyl-5-[2-(3-pyridylmethyl)guinuclidin-3-yl1oxy-1 ,3,4-thiadiazole

To a solution of trans-2-bromo-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole (0.300 g, 786 pmol, 1.00 eq) and phenylboronic acid (105 mg, 865 pmol, 1.10 eq) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (326 mg, 2.36 mmol, 3.00 eq) and Pd(dppf)CI2 (57.5 mg, 78.6 pmol, 0.100 eq). The mixture was stirred at 90 °C for 12 hrs. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain (76.0 mg, 200 pmol, 25.5% yield, 100% purity) of trans-2-phenyl-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole as a light yellow solid. 1 H NMR (400 MHz, CDCI3): 58.51 -8.50 (m, 1 H), 8.38 (dd, J=1 .6, 4.8 Hz, 1 H), 7.80- 7.78 (m, 2H), 7.58-7.56 (m, 1 H), 7.44-7.30 (m, 3H), 7.17-7.15 (m, 1 H), 5.05-4.80 (m, 1 H), 3.72-3.68 (m, 1 H), 3.11 -3.02 (m, 5H), 2.96-2.72 (m, 1 H), 1.79-1.72 (m, 3H), 1.43-1.24 (m, 1 H), 1.22-1.20 (m, 1 H). LCMS: m/z = 379 (M+1)+.

Example 26: Biological Activity Compounds described in Examples 1 -25 competitively inhibited the binding of radiolabelled a- Bungarotoxin to human a7 nAChR subtype with equilibrium constant (Ki) values of 1 -1000 nM.

Human recombinant nicotinic acetylcholine a7 receptor were expressed in SH-SY5Y cells. A 20 pg aliquot of membranes are incubated in modified phosphate buffer pH 7.4 with 0.4 nM [125l]a- Bungarotoxin for 120 minutes at 37 ^s C. Non-specific binding is estimated in the presence of 1 pM a-

Bungarotoxin. Membranes are filtered and washed, and the filters are then counted to determine specifically-bound [125l]a-Bungarotoxin. IC50 values were determined by a non-linear, least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK). The Ki values were calculated using the equation of Cheng and Prusoff using the observed IC50 of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the KD of the ligand (0.40 nM [1251] a-Bungarotoxin).

The Ki values were summarised in nM for each compound tested in Table 1 below and the binding affinity to nAChRs is shown in more detail in Table 2.

Table 1

The configuration of quinuclidine ethers notably affects the mode of interaction with different nAChR subtypes. Thus, cis-isomer 7 preferably binds to the a4p2 nAChR, while trans-isomer 11 is a quite selective a7 nAChR ligand. While most obtained compounds were tested as racemates in the primary screening, a pair of enantiomers 2S,3R-11 and 2R,3S-11 was also evaluated. The spatial arrangement of pharmacophoric elements within enantiomer 2S,3R-11 facilitated its optimal and selective interaction with a7 nAChR. Among the screened hydrogen bond acceptors (pyridine, pyrazine, pyridazine and 1 ,3,4-thiadiazole) attached to the quinuclidine ring via an ether link in position 3, compounds containing pyridazine and 1 ,3,4-thiadiazole fragments in combination with the indole ring 11 and 16 demonstrated the best pharmacological profiles in terms of affinity and selectivity. Fusion of the nitrogen-containing aromatic ring with the benzene ring (compounds 17 and 18) in an attempt to combine a hydrogen bond acceptor and hydrophobic ir-interaction deteriorated compound interactions with nAChRs.

For Table 2, the a7 nAChR ligands 11 , 14 and 16 were evaluated in an in vivo guinea pig model of chemically induced cough.

Materials and Methods

As depicted in Figure 1 B and Figure 1C, cough induction is conducted by placing guinea pigs into a whole body plethysmograph (WBP) equipped with a Aeroneb™ vibrating mesh nebulizer, and including pressure transducers and detection equipment (EMKA technologies). A primary microphone is supplied (EMKA Technologies) for acoustic confirmation of cough frequency in the form of a digital trace using the EMKA software. The data acquisition software (iOX2, version 2.10.5.28, EMKA Technologies, France) displays the pressure signal detected from the pressure transducer and calculates both frequency and intensity of coughs measured during the testing period.

A secondary microphone (T1 True Wireless Earphone, QCY®) also is placed in the chamber and connected to a smartphone via Bluetooth to enable the observers to hear the audible sounds during the test. A bias flow rate of 2 L/min is used to continuously draw either atmospheric air (during the fresh air period) or aerosolized citric acid from the nebulizer into the WBP and expel it out through an exhaust pipe. Chamber pressure in the WBP is set to be between -10 to -30 Pa relative to ambient pressure.

Prior to the citric acid challenge, the guinea pigs are administered (intraperitoneal injection) with vehicle control, positive control or test compound (where applicable) with different dosage (Table 3) and placed individually into the WBP for at least 5 minutes in order to habituate. Table 3

The procedure was as follows: Injection -> guinea pig in box having citric acid for 10 mins (counting the cough) -> box then fill with air for 5 mins (counting the cough) -> guinea pig moved to recovery cage.

Appropriate concentration of citric acid is used to generate aerosol and deliver to WBP for 10 minutes with constant recording of pressure measurements. The mean concentration of citric acid was 1283.1 ± 137.2 pg/L. Upon completion of citric acid challenge, the guinea pig is allowed to recover and continue recording of cough counts for another 5 minutes. Subsequently, the guinea pigs are closely monitored in recovery cage for full recovery from the challenge and that no adverse events were present before returning the animals to its home cage. Cough counts (CCnt) are recorded over a period of at least 10 mins, starting from citric acid stimulation and cough incubation period (CIP) are defined as the time it takes to cough for the first time after citric acid stimulation.

The cough response during citric acid challenge and post-treatment recovery is carefully monitored using:

- continuous pressure monitoring (plethysmography monitoring software)

- acoustic confirmation of cough using microphones (primary and secondary)

- visual confirmation of cough through posture change.

Statistical Analysis and Data Representation

The data were analysed using Oneway ANOVA (* p < 0.05, “ p < 0.01 , *** p < 0.001 , **** p < 0.0001 ) when compared to saline control, and each column represents Mean ± SEM.

Figures 2 and 3 relate to the assessment of the antitussive efficacy of 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole using an in vivo model of chemically induced coughs in guinea pigs. Figures 2A and 3A show the mean ± SEM, whereas Figure 2B and 3B show the results for each replicate, respectively.

Results

As shown in Figure 2 relating to cough counts, an example compound of the invention, 2-(1 H-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 with saline control.

More specifically, 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole significantly reduced citric acid-induced cough counts in low concentration (1 mg/kg, number of coughs = 5, p < 0.0001 ), medium concentration (3 mg/kg, number of coughs = 5, p < 0.001 ), high concentration (9.5 mg/kg, number of coughs = 7, p < 0.01 ) compared with saline control (0.9% Sodium Chloride, number of coughs = 17).

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

Further, as shown in Figure 3 relating to incubation period, 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole showed a significant improvement in cough incubation period.

More specifically, 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole significantly increased the cough incubation period in low concentration (1 mg/kg, 548 sec, p < 0.001 ), medium concentration (3 mg/kg, 455 sec, p < 0.01 ), high concentration (9.5 mg/kg, 489 sec, p < 0.05) compared with saline control (0.9% Sodium Chloride, 206 sec).

The increase of cough incubation period by 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3- yl]oxy-1 ,3,4-thiadiazole had a similar compared with 30 mg/kg codeine. However, at 1 mg/kg to 9.5 mg/kg, the dose of 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole was approximately 20 to 30-fold lower compared with the 30 mg/kg dose of codeine.

Conclusions 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-th iadiazole, an example compound of the invention, significantly reduced the citric acid-induced cough counts when compared with saline control (see Figure 2).

Further, 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole also showed a significant improvement in cough incubation period at dosage approximately 20 to 30-fold lower than codeine which is considered to be the “gold standard” narcotic cough suppressant (see Figure 3).

Example 28: In vivo assessment of the antitussive efficacy of inhaled compounds

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

The experiments were conducted using the following methods:

(i) Dry powder insufflator (DPI)

(ii) Whole body plethysmograph (WBP)

(iii) Oral administration.

(iv) Intraperitoneal administration

Materials and Methods

The experimental setup of the in vivo assessment of the antitussive efficacy of inhaled compounds is summarised in Figure 4. More specifically, cough induction is conducted by placing guinea pigs into a whole body plethysmograph (WBP) equipped with a Aeroneb™ vibrating mesh nebulizer, and including pressure transducers and detection equipment (EMKA technologies).

A primary microphone is supplied (EMKA Technologies) 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) displays the pressure signal detected from the pressure transducer and calculates both frequency and intensity of coughs measured during the testing period.

A secondary microphone (T1 True Wireless Earphone, QCY®) also is placed in the chamber and connected to a smartphone via Bluetooth to enable the observers to hear the audible sounds during the test. A bias flow rate of 2 L/min is used to continuously draw either atmospheric air (during the fresh air period) or aerosolized citric acid from the nebulizer into the WBP and expel it out through an exhaust pipe. Chamber pressure in the WBP is set to be between -10 to -30 Pa relative to ambient pressure. Prior to the citric acid challenge, the guinea pigs are administered with vehicle control, positive control or test compound (where applicable) with different route and dosage (see Table 4 for dry powder insufflator, Table 5 for WBP nebulization, Table 6 for oral administration, and Table ? for intraperitoneal administration).

Table 4: Dry powder insufflator

Table 5: Whole body plethysmograph (WBP) Table 6: Oral administration

Table 7: Intraperitoneal administration Regarding dry powder administration, the procedure was as follows: Dry powder insufflation -> guinea pig in box having citric acid for 10 mins (counting the cough) -> box then fill with air for 5 mins (counting the cough) -» guinea pig moved to recovery cage.

Regarding nebulization, the procedure was as follows: Nebulization via WBP -> guinea pig in box having citric acid for 10 mins (counting the cough) -> box then fill with air for 5 mins (counting the cough) -» guinea pig moved to recovery cage.

Appropriate concentration of citric acid is used to generate aerosol and deliver to WBP for 10 minutes with constant recording of pressure measurements. The mean concentration of citric acid was 1156.0 ± 111 .8 pg/L for both routes. Upon completion of citric acid challenge, the guinea pig is allowed to recover and continue recording of cough counts for another 5 minutes. Subsequently, the guinea pigs are closely monitored in recovery cage for full recovery from the challenge and that no adverse events were present before returning the animals to its home cage. Cough counts (CCnt) are recorded over a period of at least 10 mins, starting from citric acid stimulation and cough incubation period (CIP) are defined as the time it takes to cough for the first time after citric acid stimulation.

Regarding oral administration, the duration between compound administration and start of citric acid challenge was 30 minutes. The data was compared to atmospheric air (control).

Regarding intraperitoneal administration, compounds were administered approximately 10-15 mins before the cough challenge (citric acid inhalation challenge). Test compounds were dosed at between 1 -30 mg/kg (as described herein for each experiment) while the positive control (codeine) was dosed at 30 mg/kg, in each case using a dosing volume of 10 ml/kg, by a single intraperitoneal injection.

The cough response during citric acid challenge and post-treatment recovery is carefully monitored using:

- continuous pressure monitoring (plethysmography monitoring software)

- acoustic confirmation of cough using microphones (primary and secondary)

- visual confirmation of cough through posture change.

Statistical Analysis and Data Representation

The data were analysed using One-way ANOVA (* p<0.05, ** p<0.01 , *** p<0.001 , **** p<0.0001 ) when compared to control (atmospheric air), and each column represents Mean ± SEM. Figures 5 to 7 relating to cough counts show the data for the assessment of the antitussive efficacy of

2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole via the inhalation route. Figure 5 relates to dry powder sufflation administration, Figure 6 relates to nebulised administration, and Figure 7 relates to oral administration.

More specifically, Figures 5A, 6A, and 7A show the mean ± SEM, whereas Figures 5A, 6B, and 7B show the results for each replicate, respectively.

Results

As shown in Figure 5, a dry powder insufflated example compound of the invention, i.e. dry powder insufflated 2-(1 H-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 with air control. More specifically, Figure 5 demonstrates that dry powder insufflated 2-(1 H-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 with air control at doses 1 mg/kg (p=0.0004) and 2 mg/kg (p = 0.0042).

As shown in Figure 6, a nebulised example compound of the invention, i.e. nebulised 2-(1 H-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 with air control. More specifically, Figure 6 demonstrates that nebulised 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole at 0.4 mg/kg significantly reduced the citric acid-induced cough counts when compared with air control (p = 0.0023 at 58 min exposure).

As shown in Figure 7, an orally-administered example compound of the invention, i.e. orally- administered 2-(1 H-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 with air control (p < 0.05 at 9.5 mg/kg).

As shown in Figure 8, guinea pigs showed suppression of cough frequency following prophylactic intraperitoneal treatment with 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)qu in uclidin-3-yl]oxy- 1 ,3,4- thiadiazole when compared to negative control. More specifically, Figure 8 compares cough counts in animals treated intraperitoneally with a7 nAChR ligand 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole administered at 1 , 3 and 9.5 mg/kg versus negative control (saline) and positive control (codeine at 30 mg/kg). ****p < p<0.0001 compared to negative control (saline), Dunnett’s multiple comparison. Data are presented as mean ± SEM with group size (n) indicated in the graph.

As shown in Figure 9, guinea pigs showed suppression of cough frequency following prophylactic intraperitoneal treatment with 2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3-yl]oxyquinuclidine when compared to negative control. More specifically, Figure 9 compares cough counts in animals treated intraperitoneally with a7 nAChR ligand 2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)pyridazin-3- yl]oxyquinuclidine administered at 3.0, 9.5 and 30 mg/kg versus negative control (saline) and positive control (codeine at 30 mg/kg). **p < 0.01 compared to negative control (saline), Dunnett’s multiple comparison. Data are presented as mean ± SEM with group size (n) indicated in the graph.

Conclusions

In the in vivo assessment of the antitussive efficacy of inhaled compounds, an example compound of the invention, i.e. 2-(1 H-indol-5-yl)-5-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole significantly reduced the citric acid-induced cough counts when administered by three methods of administration.

More specifically, the example compound of the invention, 2-(1 H-indol-5-yl)-5-[2-(3- pyridylmethyl)quinuclidin-3-yl]oxy-1 ,3,4-thiadiazole significantly reduced the citric acid-induced cough counts in dry powder insufflated form (at 1 mg/kg and 2 mg/kg; see Figure 5), in nebulised form (at 0.4 mg/kg; see Figure 6), and in orally-administered form (at 9.5 mg/kg; see Figure 7).

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

In the in vivo assessment of the antitussive efficacy of inhaled compounds, an example compound of the invention, i.e. 2-(3-pyridylmethyl)-3-[6-(1 H-pyrrol-2-yl)70yridazine-3-yl]oxyquinuclidine significantly reduced the citric acid-induced cough counts when administered intraperitoneally (see Figure 9).