HK1158205A

HK1158205A - Quinuclidine derivatives as muscarinic m3 receptor antagonists

Info

Publication number: HK1158205A
Application number: HK11112749.6A
Authority: HK
Inventors: Rhonan Lee Ford; Andrew Nigel Mather; Antonio Mete; Richard James Bull; Elizabeth Anne Skidmore
Original assignee: 阿斯利康(瑞典)有限公司; 帕尔梅根治疗(协同)有限公司
Filing date: 2008-05-13
Publication date: 2012-07-13

Description

Quinuclidine derivatives as M3 muscarinic receptor antagonists

Technical Field

The present invention relates to cycloalkyl-substituted alkyl esters of polycyclic amino alcohols, processes for their preparation, pharmaceutical compositions containing them, processes for preparing pharmaceutical compositions, their use in therapy and intermediates used in their preparation.

Background

The Muscarinic receptor (Muscarinic receptor) is a family of G-protein coupled receptors (GPCRs) with 5 family members M₁、M₂、M₃、M₄And M₅. Of the 5 muscarinic subtypes, three subtypes (M) are known₁、M₂And M₃) Has physiological effect on human lung tissue.

Parasympathetic nerves are the major route of reflex bronchoconstriction in the human airways, modulating airway tone (airway tone) by releasing acetylcholine into muscarinic receptors. Airway tone is increased in patients with respiratory disorders such as asthma and Chronic Obstructive Pulmonary Disease (COPD), and muscarinic receptor antagonists have been developed for the treatment of airway diseases. Muscarinic receptor antagonists, commonly referred to as anticholinergics in clinical practice, have gained wide acceptance as a first-line treatment for COPD individuals and their use has been extensively described in the literature (e.g., Lee et al, Current Opinion in Pharmacology 2001, 1, 223-.

When muscarinic receptor antagonists are used to treat respiratory disorders, they are typically administered by inhalation. However, when administered by inhalation, a significant proportion of muscarinic receptor antagonists are typically inhaled into the systemic circulation, resulting in reported side effects such as dry mouth. In addition, most muscarinic antagonists have a relatively short duration of action, requiring several administrations per day. Such a multiple daily dosing regimen not only presents inconvenience to the patient, but also presents a significant risk of inadequate treatment due to patient non-compliance with the frequently repeated dosing regimen.

Thus, there remains a need for new compounds that are capable of blocking muscarinic receptors. In particular, there remains a need for new muscarinic antagonists with high potency and low systemic side effects when administered by inhalation. Furthermore, there remains a need for new muscarinic antagonists which act for long durations when administered by inhalation and which allow administration 1 or 2 times per day.

WO98/04517 discloses arylcyclopropane, arylcyclobutane, arylcyclopentane and arylcyclohexane carboxylic acid esters which have antimuscarinic activity on bladder smooth muscle.

The applicant's co-pending application PCT/GB2007/004350 relates to compounds of formula (I):

wherein

R¹And R²Together with the carbon atoms to which they are both directly attached, form a 7-membered aliphatic carbocyclic ring, which 7-membered aliphatic carbocyclic ring may be optionally substituted with one or more substituents independently selected from: halogen, hydroxy, C_1-6Alkoxy, NH₂、NH(C_1-6Alkyl group), N (C)_1-6Alkyl radical)₂And C_1-6Alkyl radical, wherein said C_1-6Alkyl may be optionally substituted with one or more substituents independently selected from halogen and hydroxy;

R³represents phenyl or a 5-to 6-membered heteroaryl ring, each of which may be optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro, SH, S (O)_0-2R⁹、NR¹⁰R¹¹、S(O)₂NR¹²R¹³、C(O)NR¹⁴R¹⁵、C(O)₂R¹⁶、NR¹⁷S(O)₂R¹⁸、NR¹⁹C(O)R²⁰、NR²¹C(O)₂R²²、NR²³C(O)NR²⁴R²⁵、OR²⁶And C_1-6Alkyl radical, wherein C_1-6Alkyl groups may be optionally substituted with one or more substituents independently selected from: halogen, hydroxy, C_1-6Alkoxy, NH₂、NH(C_1-6Alkyl) and N (C)_1-6Alkyl radical)₂；

R⁴A group of formula (II) or (IIIa) or (IIIb),

wherein

Y is-CH₂-、-CH₂CH₂-or-CH₂CH₂CH₂-, and the substitution on the ring in the radical (II) may be in its 3-or 4-position；

a is 1 or 2;

b is 1 or 2;

z is-CH₂-；

R⁵A group of the formula (IV)

Wherein

w is 0 or 1;

R⁶is represented by C_1-4Alkylene optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, C_1-6Alkoxy, NH₂、NH(C_1-6Alkyl) and N (C)_1-6Alkyl radical)₂；

When w is 0, y is 0; when w is 1, y is 0 or 1;

q represents O, S (O)_0-2、NR⁸、-CONR⁸-、-SO₂NR⁸-、-NR⁸CO-、-NR⁸SO₂-, -oc (O) -, -c (O) O-, -HC ═ CH-, or ethynylene;

R⁷represents a cyclic group Cyc¹Or C_1-4Alkyl radical, said C_1-4Alkyl groups may be optionally substituted with one or more substituents independently selected from: halogen, hydroxy, C_1-4Alkoxy, NH₂、NH(C_1-4Alkyl group), N (C)_1-4Alkyl radical)₂Cyc, a cyclic group²and-OCyc²(ii) a And when Q represents O, NR⁸、-CONR⁸-、-SO₂NR⁸-, -C (O) O-, -HC ═ CH-, or ethynylene, R⁷May also represent hydrogen;

Cyc¹and Cyc²Each independently represents aryl, heteroaryl, 3-to 8-membered aliphatic carbocyclic group orA4 to 8 membered aliphatic heterocyclic group, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, nitro, SH, S (O)_0-2R⁹、NR¹⁰R¹¹、S(O)₂NR¹²R¹³、C(O)NR¹⁴R¹⁵、C(O)₂R¹⁶、NR¹⁷S(O)₂R¹⁸、NR¹⁹C(O)R²⁰、NR²¹C(O)₂R²²、NR²³C(O)NR²⁴R²⁵、OR²⁶Phenyl and C_1-6Alkyl, wherein said phenyl or C_1-6Alkyl groups may be optionally substituted with one or more substituents independently selected from: halogen, hydroxy, C_1-6Alkoxy, NH₂、NH(C_1-6Alkyl) and N (C)_1-6Alkyl radical)₂；

R⁸Represents hydrogen or C_1-6An alkyl group;

R⁹and R¹⁸Each independently represents C_1-6Alkyl radical, wherein said C_1-6Alkyl groups may be optionally substituted with one or more substituents independently selected from: halogen, hydroxy, C_1-6Alkoxy, NH₂、NH(C_1-6Alkyl) and N (C)_1-6Alkyl radical)₂(ii) a And is

R¹⁰、R¹¹、R¹²、R¹³、R¹⁴、R¹⁵、R¹⁶、R¹⁷、R¹⁹、R²⁰、R²¹、R²²、R²³、R²⁴、R²⁵And R²⁶Each independently represents hydrogen or C_1-6Alkyl radical, wherein said C_1-6Alkyl groups may be optionally substituted with one or more substituents independently selected from: halogen, hydroxy, C_1-6Alkoxy, NH₂、NH(C_1-6Alkyl) and N (C)_1-6Alkyl radical)₂(ii) a Or R¹⁰And R¹¹、R¹²And R¹³、R¹⁴And R¹⁵Or R²⁴And R²⁵To which two groups of any one group are attachedThe attached nitrogen atoms together may form a4 to 8 membered aliphatic heterocyclic group, wherein the aliphatic heterocyclic group may be optionally substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy and C_1-6Alkyl radical, wherein said C_1-6Alkyl groups may be optionally substituted with one or more substituents independently selected from: halogen and hydroxy;

and X represents a pharmaceutically acceptable anion of a mono-or poly-acid.

Disclosure of Invention

The present invention provides compounds within the scope of the applicant's co-pending application PCT/GB2007/004350 referred to above, but these compounds are not specifically disclosed in said application.

Accordingly, the present invention provides a quaternary ammonium compound selected from the group consisting of:

(R) -1- [ (6-methyl-pyridin-3-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (6-methyl-pyrazin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [ (6-trifluoromethyl-pyridazin-3-ylcarbamoyl) -methyl ] -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- (benzo [ d ] isoxazol-3-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- (pyridazin-3-ylcarbamoylmethyl) -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (5-methyl-isoxazol-3-ylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (3-methyl-isoxazol-5-ylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (3-fluoro-phenylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (5-methyl-pyrazin-2-ylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- (benzo [ d ] isoxazol-3-ylcarbamoylmethyl) -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- (pyrazin-2-ylcarbamoylmethyl) -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- [1- (3-fluoro-phenyl) -cycloheptanecarbonyloxy ] -1- (pyrazin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- [1- (3-fluoro-phenyl) -cycloheptanecarbonyloxy ] -1- (isoxazol-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (5-fluoro-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (5-methyl-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (2-methyl-pyridin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1-phenylcarbamoylmethyl-3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (2-fluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (2, 3-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [2- (2, 3-dihydro-benzofuran-5-yl) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [2- (4-fluoro-phenoxy) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridazin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (5-fluoro-pyridin-3-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [2- (pyridin-3-yloxy) -ethyl ] -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (6-methyl-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (o-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (2- (pyrazin-2-yl) -ethyl) -1-azonia-bicyclo [2.2.2] octane X;

(S) -1- (3-phenoxy-propyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- { [2- (3-fluoro-phenoxy) -ethylcarbamoyl ] -methyl } -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (3, 5-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [2- (4-methoxy-benzyloxy) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- (2-phenethyloxy-ethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (2, 6-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (methyl-phenyl-carbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [3- (4-cyano-phenoxy) -propyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (2, 5-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [2- (4-cyano-benzyloxy) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [ (6-trifluoromethyl-pyridin-2-ylcarbamoyl) -methyl ] -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (4-methyl-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (5-chloro-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (p-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (m-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- (oxazol-2-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (6-methyl-pyridazin-3-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (5-cyano-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (3-fluoro-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (3-fluoro-pyridin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {2- [ (pyrazin-2-ylcarbonyl) -amino ] -ethyl } -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- ([1, 2, 4] thiadiazol-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {3- [ (pyridin-2-ylcarbonyl) -amino ] -propyl } -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (2-methyl-pyrimidin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [ (6-methyl-pyrimidin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {2- [ (pyridin-2-ylcarbonyl) -amino ] -ethyl } -1-azonia-bicyclo [2.2.2] octane X; and

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (3- (pyridin-4-yl) -propyl) -1-azonia-bicyclo [2.2.2] octane X;

wherein X represents a pharmaceutically acceptable anion of a mono-or poly-acid.

The compounds of formula (I) as well as the compounds of the invention mentioned above comprise an anion X associated with the positive charge on the quaternary nitrogen atom. The anion X may be any pharmaceutically acceptable anion of a mono-or poly (e.g. di) acid. In one embodiment of the invention, X may be an anion of an inorganic acid, such as chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, for example an acetate ion, maleate ion, fumarate ion, citrate ion, oxalate ion, succinate ion, tartrate ion, methanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion or naphthalenedisulfonate ion (naphthalene-1, 5-disulfonate ion) (for example heminapadisylate ion (heminapadisylate ion)), 5-dichlorobenzenesulfonate ion, 1-hydroxynaphthalene-2-sulfonate ion or xinafoate ion (1-hydroxy-2-naphthoate ion).

The present invention also provides a compound selected from the group consisting of:

It will be understood that certain compounds of the present invention may exist in solvated, e.g., hydrated, as well as unsolvated forms. It is to be understood that the invention encompasses all such solvated forms. Certain compounds of the present invention may exist as tautomers. Tautomers and mixtures thereof likewise form an aspect of the invention.

The compounds of the present invention exhibit beneficial pharmaceutical properties. For example, the compounds of the invention are shown to act as muscarinic receptors, particularly muscarinic M₃Antagonist activity of the receptor. Furthermore, said compounds also exhibit desirable plasma protein binding properties (plasma protein binding properties). Plasma protein binding may be an advantageous property for compounds administered by inhalation, as this may reduce the effect of any systemic effects (system effects) the compounds may experience.

The compounds of the invention have pharmaceutical activity, particularly as anticholinergic agents, including muscarinic receptor (M1, M2 and M3) antagonists, particularly M3 antagonists. Diseases and conditions that may be treated using the compounds of the present invention include:

1. respiratory tract: airway obstructive diseases include: asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced (including aspirin and NSAID-induced) asthma and dust-induced asthma, intermittent asthma and persistent asthma, and asthma of various severity, and airway hyperresponsiveness due to other causes; chronic Obstructive Pulmonary Disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicated by antineoplastic therapy and chronic infections (including tuberculosis and aspergillosis and other fungal infections); complications of lung transplantation; vasculitis and thrombotic disorders of the pulmonary vessels and pulmonary hypertension; antitussive activity, including treatment of chronic cough and iatrogenic cough associated with airway inflammation and secretion; acute and chronic rhinitis including rhinitis medicamentosa and vasomotor rhinitis; perennial (perennial) allergic rhinitis and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infections, including the common cold and infections caused by respiratory syncytial virus, influenza, coronaviruses (including SARS) and adenoviruses;

2. bone and joint: arthritis associated with or including osteoarthritis/osteoarthrosis, including primary and secondary arthritis, such as congenital hip dysplasia; cervical and lumbar spondylitis and low back and neck pain; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infection-related joint and bone diseases, such as tuberculosis, including Potts' disease and fluffy syndrome; crystal-induced acute and chronic synovitis including urate deposition disease, calcium pyrophosphate deposition disease and calcium apatite related tendon, bursal and synovial inflammation; behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies, including dermatomyositis and polymyositis; polymyalgia rheumatica; juvenile arthritis, including idiopathic inflammatory arthritis and associated syndromes distributed in any joint and rheumatic fever and its systemic complications; vasculitis (vasculitis), including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitis associated with viral infections, hypersensitivity, cryoglobulin, and foreign proteins; low back pain; familial mediterranean fever, Muckle-Wells syndrome (Muckle-Wells syndrome), and Familial Ireland fever (Familial hibern Fever), Kikuchi disease (Kikuchi disease); drug-induced joint pain, tendonitis, and myopathy;

3. pain and connective tissue remodeling musculoskeletal diseases caused by injury (e.g., sports injury) or disease: arthritis (e.g., rheumatoid arthritis, osteoarthritis, gout, or crystal arthropathy), other joint diseases (e.g., intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling diseases (e.g., osteoporosis, Paget's disease, or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease, spondyloarthropathy, or periodontal disease (e.g., periodontitis);

4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed type hypersensitivity; vegetative and solar dermatitis; seborrheic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus atrophicus, pyoderma gangrenosum, dermatosarcoidosis, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, swelt's syndrome, wir-gram syndrome, erythema multiforme; cellulitis, including infectious and non-infectious cellulitis; panniculitis; cutaneous lymphomas, non-melanoma skin cancers and other dysplastic lesions; drug-induced diseases including fixed drug eruptions;

5. eye: blepharitis; conjunctivitis, including perennial allergic conjunctivitis or vernal allergic conjunctivitis; iritis; anterior uveitis and posterior uveitis; choroiditis; autoimmunity; degenerative or inflammatory diseases affecting the retina; ophthalmia, including sympathetic ophthalmia; sarcoidosis; infections, including viral, fungal and bacterial infections;

6. gastrointestinal tract: glossitis, gingivitis, periodontitis; esophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritus ani; abdominal diseases, irritable bowel syndrome, and food-related allergies with off-bowel effects (e.g. migraine, rhinitis or eczema);

7. abdomen: hepatitis, including autoimmune, alcoholic and viral hepatitis; liver fibrosis and cirrhosis; cholecystitis (cholecystitis); pancreatitis, including acute and chronic pancreatitis;

8. genitourinary system: nephritis, including interstitial nephritis and glomerulonephritis; nephrotic syndrome; cystitis, including acute and chronic (interstitial) cystitis and Hanna's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vaginitis of vulva; peyronie's disease; erectile dysfunction (male and female);

9. allograft rejection: acute and chronic allograft rejection after, for example, kidney, heart, liver, lung, bone marrow, skin or cornea transplantation or after blood transfusion; or chronic graft versus host disease;

CNS: alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether central or peripheral) including visceral, headache, migraine, trigeminal neuralgia, atypical facial, joint and bone pain, pain due to cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic and HIV-associated neuropathies; neurogenic sarcoidosis; central and peripheral nervous system complications of malignant, infectious, or autoimmune processes;

11. other autoimmune and allergic diseases, including Hashimoto's thyroiditis, Graves ' disease, Addison's disease, diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, hyper IgE syndrome, antiphospholipid syndrome;

12. other diseases with an inflammatory or immune component, including acquired immunodeficiency syndrome (AIDS), leprosy, Sezary syndrome (Sezary syndrome), and extratumoral syndrome;

13. cardiovascular: atherosclerosis, which affects the coronary and peripheral circulation; pericarditis; myocarditis; inflammatory and autoimmune cardiomyopathies, including myocardial sarcoidosis; ischemic reperfusion injury; endocarditis, valvular inflammation and aortic inflammation, including infectious (e.g., syphilitic); vasculitis; diseases of the proximal and peripheral veins, including phlebitis and complications of thrombosis, including deep vein thrombosis and varicose veins;

14. tumor: treatment of cancers in general, including prostate, breast, lung, ovarian, pancreatic, intestinal and colon, gastric, skin and brain tumors and malignancies affecting the bone marrow (including leukemias) and lymphoproliferative systems (e.g., Hodgkin's and non-Hodgkin's lymphomas); including the prevention and treatment of metastatic disease and tumor recurrence and extratumoral syndromes; and

15. gastrointestinal tract: coeliac disease, proctitis, eosinophilic gastroenteritis, mast cell hyperplasia, crohn's disease, ulcerative colitis, microscopic colitis, indeterminate colitis, irritable bowel disease, irritable bowel syndrome, noninflammatory diarrhea, food-related allergies with off-bowel effects (e.g. migraine, rhinitis or eczema).

Accordingly, the present invention also provides a compound as defined hereinbefore for use in therapy.

In a further aspect, the present invention provides the use of a compound as defined hereinbefore in the manufacture of a medicament for use in therapy.

In the context of this specification, the term "treatment" also includes "prevention", unless there is a specific statement to the contrary. The terms "therapeutic" and "therapeutically" should also be construed accordingly.

Another aspect of the invention provides a method of treating a disease as described above in a mammal suffering from, or at risk of, said disease, said method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the invention as described above.

The present invention also provides a compound of the invention as defined above for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD), such as irreversible COPD.

The present invention also provides a compound of the invention as defined above for use in the treatment of asthma.

The invention also provides the use of a compound of the invention as defined above in the treatment of Chronic Obstructive Pulmonary Disease (COPD), such as irreversible COPD.

The invention also provides the use of a compound of the invention as defined above in the treatment of asthma.

The invention also provides the use of a compound of the invention as defined above in the manufacture of a medicament for the treatment of Chronic Obstructive Pulmonary Disease (COPD), such as irreversible COPD.

The invention also provides the use of a compound of the invention as defined above in the manufacture of a medicament for the treatment of asthma.

The present invention further provides a method of treatment of Chronic Obstructive Pulmonary Disease (COPD), such as irreversible COPD, in a warm-blooded animal such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention as defined above.

The present invention further provides a method of treatment of asthma in a warm-blooded animal such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention as defined above.

For the use of the compounds of the invention in the therapeutic treatment of a warm-blooded animal such as man, the ingredients are generally formulated in accordance with standard pharmaceutical practice in the form of pharmaceutical compositions.

Thus in a further aspect the present invention provides a pharmaceutical composition comprising a compound of the invention as defined above and a pharmaceutically acceptable adjuvant, diluent or carrier. In another aspect, the invention provides a process for preparing the composition, which process comprises mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition may comprise 0.05-99% w (weight percent), such as 0.05-80% w, for example 0.10-70% w, such as 0.10-50% w, of the active ingredient, all weight percentages being calculated on the basis of the entire composition.

The pharmaceutical compositions of the invention may be administered in standard manner for the condition which it is desired to treat, for example by topical (such as to the lungs and/or airways or the skin), oral, rectal or parenteral administration. To achieve the above objects, the compounds of the present invention can be formulated, for example, into aerosols, dry powder preparations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (liquid) emulsions, dispersible powders, suppositories, ointments, creams, drops, and sterile injectable aqueous or oily solutions or suspensions by means known in the art.

Suitable pharmaceutical compositions of the invention are suitable for oral administration in unit dosage form, e.g. in the form of tablets or capsules, containing 0.1mg to 1g of the active ingredient.

In another aspect, the pharmaceutical compositions of the invention are suitable for intravenous, subcutaneous or intramuscular useAnd (4) carrying out internal injection. An acceptable dose per patient, e.g. intravenous, subcutaneous or intramuscular, is 0.01mgkg^-1To 100mgkg^-1The amount of the compound (1) is, for example, 0.1mgkg^-1To 20mgkg^-1The composition of the present invention is administered 1 to 4 times per day. Intravenous, subcutaneous and intramuscular doses may be administered by bolus injection. Alternatively, intravenous doses may be administered by continuous infusion over a period of time. Alternatively, each patient may take an oral daily dose approximately equivalent to the parenteral daily dose, and the composition is administered 1-4 times per day.

Other suitable pharmaceutical compositions of the invention are suitable for administration by inhalation, which is a particularly useful method of administering the compounds of the invention in the treatment of respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD) or asthma. When administered by inhalation, the compounds of the invention are effective at a dose in the μ g range, e.g., 0.1-500 μ g, 0.1-50 μ g, 0.1-40 μ g, 0.1-30 μ g, 0.1-20 μ g, 0.1-10 μ g, 5-50 μ g, 5-40 μ g, 5-30 μ g, 5-20 μ g, 5-10 μ g, 10-50 μ g, 10-40 μ g, 10-30 μ g, or 10-20 μ g of the active ingredient.

In one embodiment of the invention there is provided a pharmaceutical composition comprising a compound of the invention as defined above in association with a pharmaceutically acceptable adjuvant, diluent or carrier, formulated for administration by inhalation.

When administered by inhalation, the active ingredient dispersed in a suitable propellant may be administered using a metered dose inhaler device, with or without the addition of other excipients such as alcohols, surfactants, lubricants or stabilizers. Suitable propellants include hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (e.g. sevoflurane) propellants or mixtures of any of the foregoing propellants. Preferred propellants are P134a and P227, which may be used alone or in combination with other propellants and/or surfactants and/or other excipients. The atomized aqueous suspensions or preferably solutions may be used in single or multiple dose formulations with or without appropriate adjustment of pH and/or tonicity.

Dry powder inhalers can be used to administer the active ingredients, either alone or in combination with a pharmaceutically acceptable carrier, which latter case can be in the form of a finely divided powder or ordered mixture. Dry powder inhalers can be single or multi-dose and can use dry powders or capsules containing dry powders.

Metered dose inhalers, nebulizers and dry powder inhalation devices are well known and a variety of such devices may be used.

The invention also relates to combination therapies in which a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered simultaneously or sequentially with another therapeutic agent or agents, or together with another therapeutic agent or agents as a combined preparation for the treatment of one or more of the listed conditions.

In particular, for the treatment of inflammatory diseases such as (but not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, Chronic Obstructive Pulmonary Disease (COPD), psoriasis and inflammatory bowel disease, the compounds of the invention may be combined with:

non-steroidal anti-inflammatory drugs (hereinafter NSAIDs) including non-selective cyclooxygenase COX-1/COX-2 inhibitors (such as piroxicam; diclofenac; propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen; fenamic acids such as mefenamic acid, indomethacin, sulindac, apazone (azapropazone), pyrazolones such as phenylbutazone; salicylates such as aspirin), whether applied topically or systemically; selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumiracoxib (lumaroxib), parecoxib, and etoricoxib); nitric Oxide Donors (CINODs) that inhibit cyclooxygenase; glucocorticoids (whether administered by topical, oral, intramuscular, intravenous or intra-articular routes); methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; an analgesic; diacerein (diacerein); intra-articular therapeutic agents such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The invention also relates to the combination of a compound of the invention with: agonists or antagonists of cytokines or cytokine function (including drugs acting on cytokine signaling pathways, such as modulators of the SOCS system), including alpha-, beta-and gamma-interferons; type I insulin-like growth factor (IGF-1); interleukins (IL), including IL1 to 17 and interleukin antagonists or inhibitors (such as anakinra); alpha tumor necrosis factor (TNF-alpha) inhibitors, such as anti-TNF monoclonal antibodies (e.g., infliximab, adalimumab, and CDP-870) and TNF receptor antagonists (including immunoglobulin molecules such as etanercept and low molecular weight drugs such as pentoxifylline (pentoxyfylline)).

In addition, the present invention relates to a combination of a compound of the invention with: monoclonal antibodies targeting B lymphocytes, such as CD20 (rituximab), MRA-aILl6R, and monoclonal antibodies targeting T lymphocytes (CTLA4-Ig, HuMax Il-15).

The invention also relates to the combination of a compound of the invention with: modulators of chemokine receptor function such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (family C-C); antagonists of CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5(C-X-C family); and CX₃CR1(C-X₃-antagonists of family C).

The invention also relates to the combination of a compound of the invention with: inhibitors of Matrix Metalloproteinases (MMPs), i.e., stromelysin, collagenase and gelatinase, and of proteolytic enzymes (aggrecanase), particularly collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), and MMP-9 and MMP-12, including drugs such as doxycycline.

The invention also relates to the combination of a compound of the invention with: leukotriene biosynthesis inhibitors, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists such as zileuton; ABT-761; fenton; teposalin; abbott-79175; abbott-85761; n- (5-substituted) -thiophen-2-alkylsulfonamide; 2, 6-di-tert-butylphenol hydrazone; methoxytetrahydropyrans, such as Zeneca ZD-2138; compound SB-210661; pyridyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,530; or indole or quinoline compounds such as MK-591, MK-886 and BAY x 1005.

The invention also relates to the combination of a compound of the invention with: receptor antagonists for Leukotriene (LT) B4, LTC4, LTD4 and LTE4, selected from phenothiazin-3-yl compounds, such as L-651, 392; amidino compounds such as CGS-25019 c; benzo (b) isAmines (benzoxamine), such as ondansetron; benzamidine (benzaximid amide), such as BIIL 284/260; and compounds such as zafirlukast, montelukast, pranlukast, vilukast (MK-679), RG-12525, Ro-245913, ilakast (CGP 45715A), and BAY × 7195.

The invention also relates to the combination of a compound of the invention with: phosphodiesterase (PDE) inhibitors such as methylxanthine (methylxanthine), including theophylline and aminophylline; a selective PDE isozyme inhibitor, comprising a PDE4 inhibitor, an isoform PDE4D inhibitor or a PDE5 inhibitor.

The invention also relates to the combination of a compound of the invention with: histamine type 1 receptor antagonists, such as cetirizine, loratadine, desloratadine, fexofenadine, avastin, terfenadine, astemizole, nitrogenStatin, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; oral, topical or parenteral administration.

The invention also relates to the combination of a compound of the invention with: proton pump inhibitors (such as omeprazole) or gastroprotective histamine type 2 receptor antagonists.

The invention also relates to the combination of a compound of the invention with: a histamine type 4 receptor antagonist.

The invention also relates to the combination of a compound of the invention with: alpha 1/alpha 2 adrenoceptor agonists, vasoconstrictors, sympathomimetics such as propylhexedrine (propylhexedrine), phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride, or ethylnorepinephrine hydrochloride.

The invention also relates to the combination of a compound of the invention with: beta-adrenoceptor agonists (including beta receptor subtypes 1-4) such as isoproterenol (isoprenaline), salbutamol (salbutamol), formoterol (formoterol), salmeterol (salmeterol), terbutaline (terbutaline), orciprenaline (orciprenaline), bitolterol mesylate (bitolterol mesylate), pirbuterol (pirbuterol) or indacaterol or their chiral enantiomers.

The invention also relates to the combination of a compound of the invention with: chromones, such as cromolyn sodium or nedocromil sodium.

The invention also relates to the combination of a compound of the invention with: glucocorticoids such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The invention also relates to the combination of a compound of the invention with: drugs that modulate nuclear hormone receptors (e.g., PPARs).

The invention also relates to a combination of a compound of the invention together with: immunoglobulin (Ig) or Ig preparations; or antagonists or antibodies that modulate Ig function, such as anti-IgE (e.g., omalizumab).

The invention also relates to the combination of a compound of the invention with: another antiinflammatory agent for systemic or topical application, such as thalidomide (thalidomide) or its derivatives, retinoids, dithranol (dithranol) or calcipotriol (calcipotriol).

The invention also relates to the combination of a compound of the invention with: a combination of aminosalicylate and sulfapyridine (such as sulfasalazine, mesalamine, balsalazide, and olsalazine); and immunomodulatory drugs such as thiopurines and corticosteroids (such as budesonide).

The invention also relates to a combination of a compound of the invention together with: antibacterial agents such as penicillin derivatives, tetracycline, macrolides, beta-lactams, fluoroquinolones, metronidazole, inhaled aminoglycosides; antiviral agents including acyclovir, famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir (zanamavir) and oseltamavir (oseltamavir); protease inhibitors such as indinavir, nelfinavir, ritonavir, and saquinavir; nucleoside reverse transcriptase inhibitors such as didanosine, lamivudine, stavudine (stavudine), zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine (nevirapine) or efavirenz (efavirenz).

The invention also relates to the combination of a compound of the invention with: cardiovascular agents such as calcium channel blockers, beta-adrenoceptor blockers, Angiotensin Converting Enzyme (ACE) inhibitors, angiotensin 2 receptor antagonists; lipid lowering drugs such as statins or fibrates; blood cell morphology modulators, such as decimphine (pentoxyfylline); thrombolytic or anticoagulant drugs, such as platelet aggregation inhibitors.

The invention also relates to the combination of a compound of the invention with: CNS drugs such as antidepressants (such as sertraline), anti-parkinson drugs (such as propiophenone, L-dopa, ropinirole, pramipexole, MAOB inhibitors (such as selegiline and rasagiline), comp inhibitors (such as tolcapone (tasmar)), a-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists or neuronal nitric oxide synthase inhibitors) or anti-alzheimer drugs (such as donepezil (donepezil), rivastigmine, tacrine, COX-2 inhibitors, propentofylline or metrexate).

The invention also relates to the combination of a compound of the invention with: drugs for the treatment of acute or chronic pain, such as centrally or peripherally acting analgesics (e.g. opioids or derivatives thereof), carbamazepine, phenytoin, sodium valproate, amitriptyline or other antidepressants, acetaminophen or non-steroidal anti-inflammatory drugs.

The invention also relates to a combination of a compound of the invention together with: a parenterally or topically applied (including inhaled) local anaesthetic, such as lignocaine or a derivative thereof.

The compounds of the invention may also be used in combination with: anti-osteoporosis agents, including hormonal agents such as raloxifene (raloxifene) or bisphosphonates such as alendronate (alendronate).

The invention also relates to the combination of a compound of the invention with: (i) tryptase (tryptase) inhibitors; (ii) platelet Activating Factor (PAF) antagonists; (iii) interleukin Converting Enzyme (ICE) inhibitors; (iv) an IMPDH inhibitor; (v) adhesion molecule inhibitors, including VLA-4 antagonists; (vi) (ii) a cathepsin; (vii) kinase inhibitors, such as tyrosine kinase (such as Btk, Itk, Jak3 or MAP) inhibitors (e.g. gefitinib or imatinib mesylate), serine/threonine kinase inhibitors (such as MAP kinase (e.g. p38, JNK, protein kinase A, B or C, or IKK) inhibitors) or kinases involved in cell cycle regulation (such as cyclin dependent kinases); (viii) glucose-6 phosphate dehydrogenase inhibitors; (ix) kinins B₁Receptors or kinins B₂A receptor antagonist; (x) Anti-gout agents, such as colchicine; (xi) Xanthine oxidase inhibitors, such as allopurinol; (xii) Uricosuric agents, such as probenecid, sulindac, or benzbromarone; (xiii) Growth hormone secretagogues; (xiv) Transforming growth factor (TGF β); (xv) Platelet Derived Growth Factor (PDGF); (xvi) Fibroblast growth factors, such as basic fibroblast growth factor (bFGF); (xvii) Granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) Capsaicin oil (capsaicin tear); (xix) Tachykinin NK₁Receptor or tachykinin NK₃Receptor antagonists, such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) Elastase inhibitors such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitors (TACE); (xxii) An Induced Nitric Oxide Synthase (iNOS) inhibitor; (xxiii) Chemoattractant receptor-homologous molecules expressed on TH2 cells (e.g., CRTH2 antagonists); (xxiv) Inhibitors of P38; (xxv) Agents that modulate Toll-like receptor (TLR) function; (xxvi) Agents that modulate the activity of purinergic receptors, such as P2X 7; or (xxvii) inhibitors of transcription factor activation, such as NFkB, API or STATS.

The compounds of the invention may also be used in combination with existing therapeutic agents for the treatment of cancer, suitable agents including, for example:

(i) an anti-proliferative/antineoplastic agent or combination thereof for use in medical oncology, such as an alkylating agent (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, or nitrosourea); an antimetabolite (e.g., an antifolate such as fluoropyrimidine-like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, gemcitabine, or paclitaxel); an anti-tumor antibiotic (e.g., an anthracycline, such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C, dactinomycin, or mithramycin); antimitotic agents (e.g. vinca alkaloids such as vincristine, vinblastine, vindesine or vinorelbine; or taxanes such as taxol or taxotere); or a topoisomerase inhibitor (e.g., an epipodophyllotoxin, such as etoposide, teniposide, ansacholine, topotecan, or camptothecin);

(ii) cell growth inhibitory drugs, such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, or iodoxyfene); estrogen receptor downregulators (e.g., fulvestrant); anti-androgens (e.g., bicalutamide, flutamide, nilutamide, or cyproterone acetate); LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, or buserelin); progestins (e.g., megestrol acetate); an aromatase (aromatase) inhibitor (e.g. anastrozole, letrozole, vorazole (vorazole) or exemestane); or 5 alpha-reductase inhibitors (e.g., finasteride);

(iii) drugs that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors (e.g., marimastat) or inhibitors of urokinase plasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example: growth factor antibodies (e.g., anti-erb b2 antibody trastuzumab or anti-erb b1 antibody cetuximab [ C225 ]); farnesyl transferase inhibitors; tyrosine kinase inhibitors or serine/threonine kinase inhibitors; an epidermal growth factor family inhibitor (e.g. an EGFR family tyrosine kinase inhibitor such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)); platelet derived growth factor family inhibitors; or a hepatocyte growth factor family inhibitor;

(v) anti-angiogenic agents, such as anti-angiogenic agents that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856, or WO 98/13354); or a compound that acts by another mechanism (e.g., linoxamine, an inhibitor of integrin α v β 3 function, or angiostatin);

(vi) vascular damaging agents, such as combretastatin a4 or compounds disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(vii) drugs used in antisense therapy, such as antisense therapeutic drugs directed to one of the above-listed targets, e.g., ISIS 2503, anti-ras antisense;

(viii) drugs used in, for example, the following gene therapy methods: methods of replacing an aberrant gene (e.g., aberrant p53 or aberrant BRCA1 or BRCA 2); GDEPT (gene-mediated enzyme prodrug therapy) methods, such as GDEPT methods using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and methods of increasing the tolerance of a patient to chemotherapy or radiation therapy, such as multiple drug resistant gene therapy; or

(ix) Drugs used in, for example, the following immunotherapeutic methods: ex vivo and in vivo methods of enhancing the immunogenicity of tumor cells in a patient, such as transfection with cytokines (e.g., interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor); methods of reducing T cell anergy; methods using transfected immune cells (e.g., cytokine-transfected dendritic cells); methods of using cytokine-transfected tumor cell lines; and methods of using anti-idiotypic antibodies.

In another aspect, the present invention provides a pharmaceutical product (pharmaceutical product) comprising a first active ingredient which is a compound of the invention as described above in combination with at least one further active ingredient selected from:

● A phosphodiesterase inhibitor for the treatment of chronic hepatitis,

● beta 2-adrenoceptor agonists,

● modulators of chemokine receptor function,

● an inhibitor of the function of a kinase,

● protease inhibitors

● a steroidal glucocorticoid receptor agonist, and

● non-steroidal glucocorticoid receptor agonists.

The pharmaceutical product of this embodiment may be, for example, a pharmaceutical composition comprising a mixture of a first active ingredient and another active ingredient. Alternatively, the pharmaceutical product may for example comprise the first active ingredient and the further active ingredient in separate pharmaceutical formulations, suitable for simultaneous, sequential or separate administration to a patient in need of such treatment.

The pharmaceutical product of this embodiment is particularly useful for treating respiratory diseases such as asthma, COPD or rhinitis.

Examples of phosphodiesterase inhibitors that may be used in the pharmaceutical product of this embodiment include PDE4 inhibitors, such as PDE4D inhibitors, PDE3 inhibitors, and PDE5 inhibitors. Examples include the following compounds:

(Z) -3- (3, 5-dichloro-4-pyridinyl) -2- [4- (2-indanyloxy-5-methoxy-2-pyridinyl ] acrylonitrile,

n- [ 9-amino-4-oxo-1-phenyl-3, 4, 6, 7-tetrahydropyrrolo [3, 2, 1-jk][1，4]Benzodiazepine-3(R) -radical]Pyridine-3-carboxamide (CI-1044),

3- (benzyloxy) -1- (4-fluorobenzyl) -N- [3- (methylsulfonyl) phenyl ] -1H-indole-2-carboxamide,

(1S-exo) -5- [3- (bicyclo [2.2.1] hept-2-yloxy) -4-methoxyphenyl ] tetrahydro-2 (1H) -pyrimidinone (Atizoram),

n- (3, 5-dichloro-4-pyridinyl) -2- [1- (4-fluorobenzyl) -5-hydroxy-1H-indol-3-yl ] -2-oxoacetamide (AWD-12-281),

beta- [3- (cycloalkyloxy) -4-methoxyphenyl ] -1, 3-dihydro-1, 3-dioxo-2H-isoindole-2-propionamide (CDC-801),

n- [ 9-methyl-4-oxo-1-phenyl-3, 4, 6, 7-tetrahydropyrrolo [3, 2, 1-jk][1，4]Benzodiazepine-3(R) -radical]Pyridine-4-carboxamide (CI-1018),

cis- [ 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid (cilomilast),

8-amino-1, 3-bis (cyclopropylmethyl) xanthine (sipamphetamine),

n- (2, 5-dichloro-3-pyridinyl) -8-methoxy-5-quinolinecarboxamide (D-4418),

5- (3, 5-di-tert-butyl-4-hydroxybenzylidene) -2-iminothiazolidin-4-one (dabufenone),

2-methyl-1- [2- (1-methylethyl) pyrazolo [1, 5-a ] pyridin-3-yl ] -1-propanone (Ibudilast),

methanesulfonic acid 2- (2, 4-dichlorophenylcarbonyl) -3-ureidobenzofuran-6-yl ester (limemilast),

(-) - (R) -5- (4-methoxy-3-propoxyphenyl) -5-methylOxazolidin-2-one (Mesopram),

(-) -cis-9-ethoxy-8-methoxy-2-methyl-1, 2, 3, 4, 4a, 10 b-hexahydro-6- (4-diisopropylaminocarbonylphenyl) -benzo [ c ] [1, 6] naphthyridine (Primafenil),

3- (cyclopropylmethoxy) -N- (3, 5-dichloro-4-pyridinyl) -4- (difluoromethoxy) benzamide (roflumilast),

the N-oxide of roflumilast,

5, 6-diethoxybenzo [ b ] thiophene-2-carboxylic acid (sulfanilast),

2, 3, 6, 7-tetrahydro-2- (mesitylimino) -9, 10-dimethoxy-3-methyl-4H-pyrimido [6, 1-a ] isoquinolin-4-one (ququicin), and

3- [ [3- (cyclopentyloxy) -4-methoxyphenyl ] -methyl ] -N-ethyl-8- (1-methylethyl) -3H-purin-6-amine (V-11294A).

Beta useful in the pharmaceutical product of this embodiment₂Examples of adrenergic receptor agonists include metaproterenol, isoproterenol (isoproterenol), isoproterenol (isoprenaline), salbutamol (albuterol), albuterol (e.g. as the sulfate salt), formoterol (e.g. as the fumarate salt), salmeterol (e.g. as the xinafoate salt), terbutaline, metaproterenol, bitolterol (e.g. as the mesylate salt), pirbuterol or indacaterol (indacaterol). Beta in this embodiment₂The adrenergic receptor agonist can be a long-acting beta₂Agonists, such as salmeterol (e.g. as xinafoate), formoterol (e.g. as fumarate), bambuterol (e.g. as hydrochloride), carmoterol (carmoterol, TA 2005, identified by the chemical method as [ R- (R —)^*，R^*)]-8-hydroxy-5- [ 1-hydroxy-2- [ [2- (4-methoxy-phenyl) -1-methylethyl]-amino group]Ethyl radical]-2(1H) -quinolone monohydrochloride is also identified by Chemical Abstract Service Registry Number (Chemical Abstract Service Registry Number)137888-11-0 and disclosed in U.S. patent No. 4,579,854), indacaterol (CAS Number 312753-06-3; QAB-149), carboxamidobenzene derivatives such as 3- (4- { [6- ({ (2R) -2- [3- (formylamino) -4-hydroxyphenyl) disclosed in WO 2002/76933]-2-hydroxyethyl } amino) hexyl radical]Oxy } -butyl) -benzenesulfonamide, benzenesulfonamide derivatives such as 3- (4- { [6- ({ (2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxy-methyl) phenyl ] disclosed in WO 2002/88167]Ethyl } amino) -hexyl radical]Oxy } butyl) benzenesulfonamide, arylaniline receptor agonists as disclosed in WO 2003/042164 and WO 2005/025555, indole derivatives as disclosed in WO 2004/032921 and US2005/222144, and the compounds GSK 159797, GSK 159802, GSK 597901, GSK 642444 and GSK 678007。

Examples of chemokine receptor function modulators useful in the pharmaceutical product of this embodiment include CCR1 receptor antagonists.

Examples of kinase function inhibitors that may be used in the pharmaceutical products of the above embodiments include p38 kinase inhibitors and IKK inhibitors.

Examples of protease inhibitors that may be used in the pharmaceutical product of this embodiment include neutrophil elastase (MMP 12) inhibitors or MMP12 inhibitors.

Examples of steroidal glucocorticoid receptor agonists that may be used in the pharmaceutical product of this embodiment include budesonide, fluticasone (e.g., fluticasone propionate), mometasone (e.g., mometasone furoate), beclomethasone (e.g., beclomethasone 17-propionate or beclomethasone 17, 21-dipropionate), ciclesonide, loteprednol (e.g., loteprednol etabonate), etabon (e.g., etabonate dichloroacetate), triamcinolone (e.g., acetonide), flunisolide, zoticasone, flumonanide, rofleponide, butocort (e.g., propionate), prednisolone, prednisone, tiprednisone, steroid esters such as 6 α, 9 α -difluoro-17 α - [ (2-furylcarbonyl) oxy ] -11 β -hydroxy-16 α -methyl-3-oxo-androst-1, 4-diene-17 beta-thiocarboxylic acid S-fluoromethyl ester, 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha-propionyloxy-androsta-1, 4-diene-17 beta-thiocarboxylic acid S- (2-oxo-tetrahydrofuran-3S-yl) ester and 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-17 alpha- [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy ] -3-oxo-androsta-1, 4-diene-17 beta-thiocarboxylic acid S-fluoromethyl ester, the steroid esters disclosed in DE 4129535, the process for preparing them, the use thereof, and the use thereof, Steroids disclosed in WO2002/00679, WO 2005/041980, or the steroids GSK 870086, GSK685698 and GSK 799943.

Examples of non-steroidal glucocorticoid receptor agonists that may be used in the pharmaceutical product of the present embodiment include the drugs disclosed in WO 2006/046916.

The invention is illustrated by the following examples. The following figures are presented in the examples:

FIG. 1: an X-ray powder diffraction pattern of form a of example 14.

FIG. 2: an X-ray powder diffraction pattern of form a of example 15.

In an embodiment, the NMR spectra are measured on a Varian Unity Inova spectrometer at a proton frequency of 300 or 400 or 500MHz, or on a Bruker DRX spectrometer at a proton frequency of 400 or 500MHz, or on a Bruker Avance spectrometer at a proton frequency of 600MHz, or on a Bruker Avance DPX 300 spectrometer at a proton frequency of 300 MHz. MS spectra were measured on an Agilent 1100MSD G1946D spectrometer or a Hewlett packard HP1100 MSD G1946A spectrometer or a Waters Micromass ZQ2000 spectrometer. The name was generated using Autonom 2000 (version 4.01.305) software provided by MDL.

XRPD data were collected using a PANALYtic CubiX PRO instrument or a PANALYtic X-Pert instrument.

XRPD-PANalytical CubiX PRO

Data were collected using a PANalytical CubiX PRO instrument scanning in the range of 2 ° to 40 ° 2 θ in a θ - θ configuration, 100 seconds exposure time/0.02 ° increment. The X-rays were generated from a long, fine focal tube made of copper, which was operated at 45kV and 40 mA. The copper X-ray has a wavelength ofData were collected on a zero background container, onto which-2 mg of compound was placed. The container is made of single crystal silicon that is cut along a non-diffractive plane and then polished on an optical flat refiner. The incidence of X-rays on this plane is counteracted by Bragg extinction.

PANalytical X-Pert

Data were collected using a PANalytical X-Pert instrument scanning in the range of 2 ° to 40 ° 2 θ, 100 seconds exposure time/0.02 ° increment in a2 θ - θ configuration. The X-rays were generated from a long small focal tube made of copper, which was operated at 45kV and 40 mA. The copper X-ray has a wavelength ofData were collected on a zero background container, onto which-2 mg of compound was placed. The container is made of single crystal silicon that is cut along a non-diffractive plane and then polished on an optical flat refiner. The incidence of X-rays on this plane is counteracted by Bragg extinction.

Differential Scanning Calorimetry (DSC) thermograms were measured using a TAQ1000 Differential Scanning Calorimeter with an aluminum pan and a perforated lid. The sample weight varied between 0.5 and 5 mg. The operation was carried out under the following conditions: the nitrogen flow rate was 50mL/min and the temperature studied was between 25 and 300 ℃ at a constant rate of 10 ℃ per minute.

Thermogravimetric analysis (TGA) thermograms were measured using a TA Q500 thermovirimetricanalyser with a platinum disk. Sample weights varied between 1 and 5 mg. The operation was carried out under the following conditions: the nitrogen flow rate was 60mL/min and the temperatures studied were from 25 ℃ to 300 ℃ with a constant ramp rate of 10 ℃/min.

GVS curves were measured using a Dynamic vapor transduction DVS-1 instruments. Approximately 1-5mg of the solid sample is placed in a glass tube or wire screen and the sample weight is recorded in a two cycle step process (40 to 90 or 0% Relative Humidity (RH), in a step of 10% RH).

Abbreviations used in the experimental section:

aq is aqueous or aqueous solution

DCE ═ 1, 2-dichloroethane

DCM ═ dichloromethane

DMF ═ dimethylformamide

DMSO ═ dimethyl sulfoxide

EtOAc ═ ethyl acetate

EtOH ═ ethanol

GVS vapor sorption

HATU ═ O- (7-azabenzotriazol-1-yl) -N, N' -tetramethylHexafluorophosphates

MeCN ═ acetonitrile

MeOH ═ methanol

RT ═ room temperature

Rt retention time

THF ═ tetrahydrofuran

Satd ═ saturated

DSC (differential scanning calorimeter)

TGA-thermogravimetric analysis

XRPD ═ X-ray powder diffraction

Detailed description of the preferred embodiments

Example 1: (R) -1- [ (6-methyl-pyridin-3-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 1-phenyl-cycloheptanol

To a solution of magnesium (1.2g) in anhydrous tetrahydrofuran (60mL) under a nitrogen atmosphere at a rate that maintains the reaction at a steady refluxTo this was added crystals of iodine followed by bromobenzene (7.85 g). The reaction mixture was stirred for 20 minutes, then cycloheptanone (4.48g) was added carefully. After stirring for 10 min, saturated aqueous ammonium chloride (10mL) was added and the reaction mixture was partitioned between water (100mL) and isohexane (100 mL). The organic layer was dried (MgSO₄) And evaporated to give the sub-title compound (7.6g) as an oil.

¹H NMR(300MHz，CDCl₃)δ7.53-7.47(m，2H)，7.36-7.29(m，2H)，7.26-7.19(m，1H)，2.07(ddd，2H)，1.97-1.50(m，11H).

b) 1-methoxy-1-phenyl-cycloheptane

1-phenyl-cycloheptanol (example 1a) (7.6g) was dissolved in tetrahydrofuran (100mL) and sodium hydride (60% in oil, 2.0g) was added. The reaction mixture was stirred at 60 ℃ for 5 minutes and iodomethane (7.1g) was added. The mixture was kept at 60 ℃ overnight, then an additional amount of sodium hydride (60% in oil, 2.0g) and methyl iodide (7.1g) were added and the reaction mixture was refluxed for 70 hours. The reaction mixture was partitioned between water (100mL) and isohexane (100mL) and the organic layer was separated and dried (MgSO)₄) And evaporated to give the sub-title compound (11.31 g).

¹H NMR(300MHz，CDCl₃)δ7.43-7.37(m，2H)，7.37-7.30(m，2H)，7.24-7.19(m，1H)，2.98(s，3H)，2.12-1.88(m，4H)，1.88-1.45(m，8H).

c) 1-phenyl-cycloheptane carboxylic acids

Potassium (2.62g) and sodium were added under nitrogen(0.52g) were heated together in mineral oil at 120 ℃ for 30 minutes and then cooled to room temperature. The oil was removed and replaced with diethyl ether (100mL) and 1-methoxy-1-phenyl-cycloheptane (example 1b) (4.9g) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was cooled to-78 ℃ and solid carbon dioxide (. about.20 g) was added with stirring. The reaction mixture was warmed to room temperature and water (150mL) was carefully added under nitrogen. The aqueous layer was separated, neutralized with concentrated hydrochloric acid and extracted with ether (150 mL). The organic layer was dried (MgSO₄) And evaporated to give the sub-title compound (4.15g) as an oil.

¹H NMR(300MHz，CDCl₃)δ7.40-7.20(m，5H)，2.49-2.35(m，2H)，2.16-2.03(m，2H)，1.76-1.47(m，8H).

d) 1-phenyl-cycloheptanecarboxylic acid methyl ester

1-phenyl-cycloheptanecarboxylic acid (example 1c) (4.15g) was refluxed in methanol (150mL) and concentrated hydrochloric acid (5mL) for 24 h. The solvent was evaporated and the residue was dissolved in ether (100mL), washed with water (100mL), saturated sodium bicarbonate (50mL) and water (100mL), dried (MgSO₄) And evaporated to give the sub-title compound (3.5g) as an oil.

¹H NMR(300MHz，CDCl₃)δ7.37-7.18(m，5H)，3.63(s，3H)，2.47-2.35(m，2H)，2.08-1.97(m，2H)，1.70-1.48(m，8H).

e) 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester

Methyl 1-phenyl-cycloheptanecarboxylate (example 1d) (1.0g) and (R) -quinuclidin-3-ol (0.39g) were refluxed in heptane (50mL) containing sodium (. about.5 mg) in a Dean and Stark apparatus for 24 hours. Heptane (20mL) was replaced with toluene (20mL) and refluxing continued for 3 days. The reaction mixture was partitioned between water (50mL) and diethyl ether (50mL) and the diethyl ether layer was separated and dried (MgSO)₄) And evaporated. The crude product was purified by silica gel column chromatography eluting with ethyl acetate/triethylamine (99/1) to give the title compound as an oil (0.83 g).

m/e 328[M+H]⁺

¹H NMR(300MHz，CDCl₃)δ7.35-7.27(m，4H)，7.23-7.16(m，1H)，4.78-4.71(m，1H)，3.12(ddd，1H)，2.79-2.32(m，7H)，2.16-1.98(m，2H)，1.91-1.80(m，1H)，1.70-1.34(m，12H).

f) 2-chloro-N- (6-methyl-pyridin-3-yl) -acetamide

A mixture of 6-methylpyridin-3-amine (1g) and triethylamine (2.2mL) in dry THF (20mL) was stirred and cooled to-60 ℃. 2-Chloroachlorochloride (1.567g) was added to the stirred mixture via syringe to form a yellow suspension. The mixture was stirred at-60 ℃ until analysis showed complete disappearance of the starting material. The reaction slurry was poured into water and the product was extracted with ethyl acetate (2 × 150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to dryness. The crude brown solid was recrystallized from diethyl ether to give the sub-title compound (700 mg).

¹H NMR(400MHz，DMSO-D₆)δ10.40(1H，s)，8.60(1H，d)，7.91(1H，dd)，7.22(1H，d)，4.27(2H，s)，2.42(3H，s).

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 1e) (52mg) was dissolved in acetonitrile (2mL) and 2-chloro-N- (6-methylpyridin-3-yl) acetamide (example 1f) (29mg) was added. The reaction mixture was stirred for 10 days and diluted with ethyl acetate (4mL) and isohexane (14 mL). The mixture was allowed to stand for 5 days, followed by separation of the resulting crystals and washing with diethyl ether (0.5mL) to give the title compound as a solid (36 mg).

m/e 476[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.33(s，1H)，8.70(d，1H)，7.91(dd，1H)，7.38-7.30(m，4H)，7.27(d，1H)，7.28-7.20(m，1H)，5.16-5.07(m，1H)，4.36(d，1H)，4.31(d，1H)，4.16-4.07(m，1H)，3.72-3.54(m，4H)，3.44-3.34(m，2H)，2.44(s，3H)，2.42-2.28(m，2H)，2.22-2.10(m，2H)，2.01-1.86(m，3H)，1.83-1.71(m，1H)，1.69-1.41(m，8H).

Example 2: (R) -1- [ (6-methyl-pyrazin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (6-methyl-pyrazin-2-yl) -acetamide

6-methyl-pyrazin-2-ylamine (150mg) and potassium carbonate (571mg) were added to dichloromethane (25 mL). 2-Bromoacetyl bromide (0.120mL) was added to the suspension with stirring. The reaction mixture was stirred overnight, then water (0.1mL) was added with additional stirring. An additional amount of potassium carbonate (571mg), 2-bromoacetyl bromide (0.120mL), and water (0.1mL) was added over 2 hours until the reaction was complete. The reaction mixture was diluted with water (100mL), acidified carefully with hydrochloric acid and extracted with dichloromethane (2 × 50mL), dried and evaporated to give the sub-title compound, which was used as such (365 mg).

¹H NMR(400MHz，CDCl₃)δ9.45(s，1H)，9.37(s，1H)，8.33(s，1H)，4.05(s，2H)，2.51(s，3H).

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 1e) (70mg) and 2-bromo-N- (6-methylpyrazin-2-yl) acetamide (example 2a) (49.2mg) were dissolved in acetonitrile (1mL) and left to stand overnight. The crystals were isolated by standing and filtered and washed with acetonitrile (2x 1mL), ethyl acetate (2x3mL) and diethyl ether (2x3mL) and dried to give the title compound (24 mg).

m/e 477[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.33(s，1H)，9.09(s，1H)，8.37(s，1H)，7.38-7.31(m，4H)，7.27-7.22(m，1H)，5.15-5.09(m，1H)，4.36-4.25(m，2H)，4.16-4.07(m，1H)，3.68-3.56(m，4H)，3.46-3.33(m，1H)，2.47(s，3H)，2.42-2.29(m，2H)，2.24-2.11(m，2H)，2.04-1.87(m，3H)，1.83-1.73(m，1H)，1.68-1.45(m，9H).

Example 3: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [ (6-trifluoromethyl-pyridazin-3-ylcarbamoyl) -methyl ] -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (6-trifluoromethyl-pyridazin-3-yl) -acetamide

6-trifluoromethyl-pyridazin-3-ylamine (0.042g) (prepared by a similar procedure as described in WO 2007048779) was dissolved in dichloromethane (40mL) and stirred with potassium carbonate (0.214 g). 2-Bromoacetyl bromide (0.12mL) was added and stirring was continued for 1.5 h. Water (0.24mL) was added and the reaction mixture was stirred for 1.5 hours, after which water (40mL) was added and the reaction mixture was stirred for an additional 1.5 hours. The dichloromethane was separated and dried (MgSO₄) And evaporated to give the sub-title compound as a white solid (0.053 g).

m/e 284/286[M+H]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.04(s，1H)，8.79(d，1H)，7.91(d，1H)，4.31(s，2H).

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 1e) (61.1mg) and 2-bromo-N- (6-trifluoromethyl-pyridazin-3-yl) -acetamide (example 3a) (53.0mg) were dissolved in acetonitrile (2mL) and left to stand overnight. The solvent was evaporated and the product was purified by silica gel column chromatography (eluting with 10% methanol in dichloromethane) to give the title compound (107 mg).

m/e 531[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ12.17(s，1H)，8.50(d，1H)，8.36(d，1H)，7.40-7.32(m，4H)，7.28-7.23(m，1H)，5.17-5.10(m，1H)，4.57-4.42(m，2H)，4.22-4.14(m，1H)，3.76-3.61(m，4H)，3.47(dd，1H)，2.43-2.30(m，2H)，2.25-2.12(m，2H)，2.07-1.88(m，3H)，1.86-1.73(m，1H)，1.72-1.44(m，9H).

Example 4: (R) -1- (benzo [ d ] isoxazol-3-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) N-benzo [ d ]]Different from each otherAzol-3-yl-2-chloro-acetamide

To a stirred mixture of benzo [ d ] isoxazol-3-ylamine (1g) and cesium carbonate (2.42g) in anhydrous DMF (20mL) at room temperature was added dropwise bromoacetyl chloride (0.62 mL). After stirring the mixture for 8 hours, the reaction mixture was poured into water (100mL) and the product was extracted into ether (2 × 200 mL). The combined extracts were dried over magnesium sulfate and concentrated to dryness. The crude product was purified on silica gel (eluting with diethyl ether/isohexane (4/6)) to give the sub-title compound as a colourless solid (0.5 g).

m/e 210[M+H]⁺

Example 4: (R) -1- (benzo [ d ] isoxazol-3-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 1e) (114mg) and N-benzo [ d ] isoxazol-3-yl-2-chloro-acetamide (example 4a) (89mg) were dissolved in acetonitrile (10mL) and left to stand for one week. The resulting crystals were filtered off and washed with diethyl ether (3 × 10mL) to give the title compound as a solid (120 mg).

m/e 502[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ12.15(s，1H)，8.16(d，1H)，7.74(d，1H)，7.72-7.67(m，1H)，7.44-7.39(m，1H)，7.38-7.30(m，4H)，7.27-7.19(m，1H)，5.18-5.11(m，1H)，4.63-4.46(m，2H)，4.17(ddd，1H)，3.76-3.61(m，4H)，3.49(dd，1H)，2.43-2.29(m，2H)，2.24-2.12(m，2H)，2.03-1.89(m，3H)，1.86-1.74(m，1H)，1.70-1.44(m，9H).

Example 5: (R) -1- (pyridazin-3-ylcarbamoylmethyl) -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-but-3-enyl-2- (thiophen-2-yl) -hex-5-enoic acid ethyl ester

Ethyl 2- (thien-2-yl) acetate (2.35g) was dissolved in tetrahydrofuran (30mL) and cooled to-78 ℃. A solution of lithium bis (trimethylsilyl) amide (2.31g) in THF (1M solution, 13.8mL) was added and the solution was stirred for 30 minutes. 4-bromo-but-1-ene (1.4mL) was added and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was again cooled to-78 ℃ and a solution of lithium bis (trimethylsilyl) amide (2.31g) in THF (1M solution, 13.8mL) was added and the solution was stirred for 30 min. 4-bromo-but-1-ene (1.4mL) was added and the reaction mixture was warmed to room temperature and allowed to stand overnight. HPLC-MS analysis showed incomplete reaction, so the reaction mixture was again cooled to-78 deg.C and a further amount of lithium bis (trimethylsilyl) amide (1M solution, 10mL) and 4-bromo-but-1-ene (1.0mL) were added, followed by the above procedure. In thatAfter stirring for an additional 2 hours, water (30mL) was added and the reaction mixture was extracted with diethyl ether (2 × 60 mL). The combined organic extracts were dried (MgSO)₄) And evaporated. The resulting oil was purified by silica gel column chromatography (eluting with ethyl acetate/isohexane (1/99)) to give the sub-title compound (3.18 g).

¹H NMR(400MHz，DMSO-D₆)δ7.21(dd，1H)，6.97-6.94(m，2H)，5.79(ddt，2H)，5.01(dq，2H)，4.95(dq，2H)，4.17(q，2H)，2.22-2.08(m，4H)，2.00-1.85(m，4H)，1.24(t，3H).

b)1- (Thien-2-yl) -cyclohept-4-enecarboxylic acid ethyl ester

To a solution of ethyl 2-but-3-enyl-2- (thiophen-2-yl) -hex-5-enoate (example 5a) (3.18g) in dichloromethane (100mL) was added Grubbs' catalyst (2nd Generation, Sigma-Aldrich company Ltd) (0.100 g). The mixture was warmed to reflux under nitrogen. After 20 hours, the mixture was cooled to room temperature and evaporated to an oil. This was purified by silica gel column chromatography (eluting with ethyl acetate/isohexane (10: 90)) to give the sub-title compound (2.60g) as a coloured oil.

¹H NMR(400MHz，DMSO-D₆)δ7.19(dd，1H)，6.98-6.92(m，2H)，5.72(t，2H)，4.15(q，2H)，2.66-2.59(m，2H)，2.25-2.14(m，6H)，1.21(t，3H).

c)1- (Thien-2-yl) -cycloheptanecarboxylic acid ethyl ester

Ethyl 1- (thien-2-yl) -cyclohept-4-enecarboxylate (example 5b) (2.86g) was dissolved in ethanol (30mL) and tris (triphenylphosphine) rhodium (I) chloride (0.100g) was added. The reaction mixture was stirred rapidly under 5 hydrogen atmosphere overnight. Tritriphenylphosphine rhodium (I) chloride (0.050g) was added thereto and the reaction mixture was stirred under a 5 hydrogen atmosphere for 3 days. Tris (triphenylphosphine) rhodium (I) chloride (0.050g) was added a third time and the reaction mixture was stirred overnight under a 3 hydrogen atmosphere. The contents were evaporated to dryness and purified on silica gel (eluting with ethyl acetate/isohexane (5/95)) to give the sub-title compound (2.500g) as a clear, almost colourless oil.

m/e 253[M+H⁺]

¹H NMR(400MHz，DMSO-D₆)δ7.17(dd，1H)，6.95-6.91(m，2H)，4.13(q，2H)，2.53(dd，2H)，2.14-2.03(m，2H)，1.70-1.50(m，8H)，1.20(t，3H).

d)1- (Thien-2-yl) -cycloheptane carboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester

1- (Thien-2-yl) -cycloheptanecarboxylic acid ethyl ester (example 5c) (2.5g) and (R) -quinuclidin-3-ol (2.08g) were dissolved in toluene (350mL) and sodium hydride (0.1g) was added under nitrogen. The mixture was heated to reflux and held for 20 hours after which the toluene was carefully distilled off to leave-100 mL, cooled and washed with water (100mL), dried (MgSO)₄) And evaporated. The crude product was purified by silica gel column chromatography eluting with ethyl acetate/triethylamine (99/1) to give the sub-title compound (2.84 g).

m/e 334[M+H⁺]

¹H NMR(400MHz，CDCl₃)δ7.18(t，1H)，6.95-6.92(m，2H)，4.77-4.72(m，1H)，3.14(ddd，1H)，2.83-2.64(m，4H)，2.59-2.50(m，3H)，2.18-2.08(m，2H)，1.95-1.90(m，1H)，1.71-1.44(m，11H)，1.34-1.23(m，1H).

e) 2-bromo-N- (pyridazin-3-yl) -acetamides

To a suspension of pyridazin-3-ylamine (2.7g) and diisopropylethylamine (6.3mL) in dichloromethane (100mL) at 0 deg.C was added dropwise a solution of bromoacetic anhydride (9.0g) in dichloromethane (10 mL). The mixture was stirred at 0 ℃ for 0.5 h and then warmed to room temperature. The resulting suspension was filtered, washed with dichloromethane and dried to give the sub-title compound as a solid (2.0 g).

¹H NMR(400MHz，DMSO-D₆)δ11.51(s，1H)，9.00(dd，1H)，8.28(dd，1H)，7.74-7.68(m，1H)，4.15(s，2H).

1- (Thien-2-yl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 5d) (80mg) and 2-bromo-N- (pyridazin-3-yl) -acetamide (example 5e) (52mg) were dissolved in acetonitrile (3mL) and stirred overnight. Ethyl acetate (9mL) and isohexane (4mL) were added and stirred overnight. The resulting crystals were filtered off and then triturated with ethyl acetate to give the title compound (14 mg).

m/e 469[M⁺]

¹H NMR(400MHz，DMSO-D₆)δ11.68(s，1H)，9.05(dd，1H)，8.25(d，1H)，7.79(dd，1H)，7.44(dd，1H)，7.03(dd，1H)，6.99(dd，1H)，5.14-5.09(m，1H)，4.37(s，2H)，4.17-4.08(m，1H)，3.76-3.57(m，4H)，3.57-3.46(m，1H)，2.48-2.42(m，1H)，2.29-2.22(m，1H)，2.21-2.11(m，1H)，2.07-1.90(m，4H)，1.90-1.80(m，1H)，1.78-1.68(m，1H)，1.66-1.46(m，8H).

Example 6: (R) -1- [ (5-methyl-isoxazol-3-ylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (5-methyl-isoxazol-3-yl) -acetamide

To a stirred suspension of sodium bicarbonate (1.242g) and 5-methyl-isoxazol-3-ylamine (1.45g) in dichloromethane (50mL) was added 2-bromoacetyl bromide (1.28mL) dropwise. The reaction mixture was stirred overnight and then washed with water (2 × 50 mL). The organic fraction was separated, dried over magnesium sulfate and evaporated to give the sub-title compound (279 mg).

¹H NMR(400MHz，DMSO-D₆)δ11.32(s，1H)，6.62(s，1H)，4.06(s，2H)，2.38(s，3H).

1- (thiophen-2-yl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 5d) (68mg) and 2-bromo-N- (5-methyl-isoxazol-3-yl) -acetamide (example 6a) (45mg) were dissolved in acetonitrile (2mL) and stirred overnight. Ethyl acetate (10mL) and isohexane (9mL) were added and stirred overnight. The resulting crystals were filtered off and washed with ethyl acetate to give the title compound (82 mg).

m/e 472[M⁺]

¹H NMR(400MHz，DMSO-D₆)δ11.55(s，1H)，7.44(dd，1H)，7.03(dd，1H)，6.99(dd，1H)，6.61(s，1H)，5.13-5.08(m，1H)，4.31(d，1H)，4.26(d，1H)，4.14-4.05(m，1H)，3.72-3.55(m，4H)，3.53-3.43(m，1H)，2.54-2.42(m，1H)，2.41(d，3H)，2.27-2.22(m，1H)，2.19-2.13(m，1H)，2.07-1.90(m，4H)，1.89-1.77(m，1H)，1.77-1.65(m，1H)，1.63-1.48(m，8H).

Example 7: (R) -1- [ (3-methyl-isoxazol-5-ylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (3-methyl-isoxazol-5-yl) -acetamide

Reacting 3-methyl-isoAzol-5-ylamine (2.9g) and potassium carbonate (9.8g) were suspended in dichloromethane (100mL) at room temperature and 2-bromoacetyl bromide (6g) was added dropwise. The mixture was stirred overnight. Water (0.3mL) was added with an additional amount of potassium carbonate (3g) and the reaction mixture was stirred for an additional 30 minutes. The reaction mixture was poured into water (100mL) and extracted with dichloromethane (2 × 50 mL). The combined organic extracts were dried over magnesium sulfate and then evaporated in vacuo. The crude product was purified by silica gel column chromatography (eluting with ethyl acetate/isohexane (50: 50)) to give the sub-title compound (4.8 g).

¹H NMR(300MHz，CDCl₃)δ11.97(s，1H)，6.16(s，1H)，4.09(s，2H)，2.19(s，3H).

1- (thien-2-yl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 5d) (50mg) and 2-bromo-N- (3-methylisoxazol-5-yl) acetamide (example 7a) (32mg) were dissolved in acetonitrile (2mL) and left to stand overnight. Ethyl acetate (10mL) and isohexane (10mL) were added and the crystals were filtered off, washed with ethyl acetate and dried to give the title compound (37 mg).

m/e 472[M⁺]

¹H NMR(400MHz，DMSO-D₆)δ12.21(s，1H)，7.44(dd，1H)，7.03(dd，1H)，6.99(dd，1H)，6.18(s，1H)，5.15-5.07(m，1H)，4.35(d，1H)，4.30(d，1H)，4.14-4.05(m，1H)，3.73-3.54(m，4H)，3.54-3.43(m，1H)，3.17(d，1H)，2.47-2.42(m，1H)，2.27-2.20(m，1H)，2.21(s，3H)，2.19-2.12(m，1H)，2.08-1.77(m，4H)，1.77-1.65(m，1H)，1.65-1.46(m，8H).

Example 8: (R) -1- [ (3-fluoro-phenylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (3-fluoro-phenyl) -acetamide

To a suspension of sodium bicarbonate (1g) and 3-fluoroaniline (0.46g) in dichloromethane (100mL) was added 2-bromoacetyl bromide (0.36mL) dropwise. After stirring overnight, the reaction mixture was washed with water, dried over magnesium sulfate and evaporated to give the sub-title compound (1.07 g).

m/e 232[M+H⁺]

¹H NMR(300MHz，CDCl₃)δ8.14(s，1H)，7.50(dt，1H)，7.31(td，1H)，7.18(ddd，1H)，6.87(tdd，1H)，4.03(s，2H).

1- (thien-2-yl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 5d) (96mg) and 2-bromo-N- (3-fluoro-phenyl) -acetamide (example 8a) (67mg) were dissolved in acetonitrile (2mL) and left to stand overnight. Ether (10mL) and isohexane (8mL) were added and the mixture was allowed to stand overnight. The resulting crystals were filtered off and washed with diethyl ether to give the title compound (90 mg).

m/e 485[M⁺]

¹H NMR(400MHz，DMSO-D₆)δ10.84(s，1H)，7.58(dt，1H)，7.46-7.39(m，2H)，7.33-7.29(m，1H)，7.04(dd，1H)，7.02-6.96(m，2H)，5.15-5.10(m，1H)，4.33-4.24(m，2H)，4.17-4.07(m，1H)，3.77-3.58(m，4H)，3.51(dd，1H)，2.56-2.44(m，1H)，2.28-2.22(m，1H)，2.21-2.12(m，1H)，2.08-1.70(m，6H)，1.66-1.47(m，8H).

Example 9: (R) -1- [ (5-methyl-pyrazin-2-ylcarbamoyl) -methyl ] -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (5-methyl-pyrazin-2-yl) -acetamide

To a mixture of 5-methyl-pyrazin-2-ylamine and cesium carbonate (11.2g) in anhydrous DMF (30mL) was added bromoacetyl bromide (2.89g) dropwise and the mixture was stirred at room temperature for 2 hours. Water (200mL) was added and the mixture was extracted with ethyl acetate (2 × 100mL) and dried over magnesium sulfate. The extract was concentrated to 50mL and isohexane (100mL) was added to give the sub-title compound as a solid (1.64 g).

¹H NMR(400MHz，DMSO-D₆)δ11.06(1H，s)，9.17(1H，s)，8.31(1H，d)，4.16(2H，s)，2.46(3H，s).

1- (thiophen-2-yl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 5d) (48mg) was dissolved in acetonitrile (2mL) and 2-bromo-N- (5-methyl-pyrazin-2-yl) -acetamide (example 9a) (33mg) was added. After stirring for 1 week, diethyl ether (8mL) and isohexane (5mL) were added. The crystals were collected by filtration, washed with ethyl acetate (2 × 4mL) and dried to give the title compound (26 mg).

m/e 483[M⁺]

¹H NMR(400MHz，DMSO-D₆)δ11.26(s，1H)，9.15(s，1H)，8.36(s，1H)，7.44(dd，1H)，7.04(dd，1H)，6.99(dd，1H)，5.15-5.08(m，1H)，4.33(s，2H)，4.13(ddd，1H)，3.75-3.57(m，4H)，3.56-3.46(m，1H)，2.48(s，3H)，2.50-2.44(m，1H)，2.28-2.22(m，1H)，2.20-2.11(m，1H)，2.08-1.90(m，4H)，1.90-1.80(m，1H)，1.79-1.69(m，1H)，1.64-1.48(m，8H).

Example 10: (R) -1- (benzo [ d ] isoxazol-3-ylcarbamoylmethyl) -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

1- (thiophen-2-yl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 5d) (71mg) and N-benzo [ d ] isoxazol-3-yl-2-chloro-acetamide (example 4a) (54mg) were dissolved in acetonitrile (10mL) and left to stand for 6 days. The resulting crystals were filtered off and washed with diethyl ether (3 × 10mL) to give the title compound (82 mg).

m/e 509[M⁺]

¹H NMR(400MHz，DMSO-D₆)δ12.16(s，1H)，8.17(d，1H)，7.74(d，1H)，7.72-7.67(m，1H)，7.44-7.39(m，2H)，7.04(dd，1H)，6.98(dd，1H)，5.16-5.11(m，1H)，4.64-4.50(m，2H)，4.21-4.13(m，1H)，3.82-3.64(m，4H)，3.59(dd，1H)，2.56-2.44(m，2H)，2.29-2.22(m，1H)，2.22-2.13(m，1H)，2.08-1.89(m，3H)，1.89-1.81(m，1H)，1.80-1.69(m，1H)，1.64-1.47(m，8H).

Example 11: (R) -1- (pyrazin-2-ylcarbamoylmethyl) -3- (1- (thiophen-2-yl) -cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (pyrazin-2-yl) -acetamide

To a suspension of pyrazin-2-ylamine (1.87g) and potassium carbonate (8.19g) in dichloromethane (25mL) was added 2-bromoacetyl bromide (1.72mL) dropwise. The reaction mixture was stirred overnight and then washed with water (2 × 50 mL). The organic phase was separated, dried over magnesium sulfate and evaporated to give the sub-title compound (0.70 g).

¹H NMR(400MHz，CDCl₃)δ9.51(d，1H)，8.63(s，1H)，8.42(d，1H)，8.30(dd，1H)，4.06(s，2H).

1- (thiophen-2-yl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 5d) (116mg) and 2-bromo-N- (pyrazin-2-yl) -acetamide (example 11a) (75mg) were dissolved in acetonitrile (2mL) and left to stand overnight. Ether (10mL) and isohexane (8mL) were added and the mixture was allowed to stand overnight. The resulting crystals were filtered off and washed with diethyl ether to give the title compound (117 mg).

m/e 469[M⁺]

¹H NMR(400MHz，DMSO-D₆)δ11.38(s，1H)，9.28(s，1H)，8.50-8.45(m，2H)，7.44(dd，1H)，7.04(dd，1H)，6.99(dd，1H)，5.15-5.09(m，1H)，4.36(s，2H)，4.18-4.08(m，1H)，3.76-3.58(m，4H)，3.58-3.46(m，1H)，3.33-3.29(m，1H)，2.55-2.43(m，1H)，2.29-2.22(m，1H)，2.21-2.12(m，1H)，2.08-1.88(m，3H)，1.88-1.79(m，1H)，1.79-1.72(m，1H)，1.64-1.48(m，8H).

Example 12: (R) -3- [1- (3-fluoro-phenyl) -cycloheptanecarbonyloxy ] -1- (pyrazin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-but-3-enyl-2- (3-fluoro-phenyl) -hex-5-enoic acid methyl ester

(3-fluoro-phenyl) -acetic acid methyl ester (4.30g) was dissolved in tetrahydrofuran (20mL) and cooled to-78 ℃. Lithium bis (trimethylsilyl) amide (25.6mL, 1M in THF) was added and the solution was stirred for 30 minutes. 4-bromo-but-1-ene (2.60mL) was added and the reaction contents warmed to room temperature and stirred for 1 hour. The reaction mixture was again cooled to-78 ℃. Lithium bis (trimethylsilyl) amide (25.6mL, 1M in THF) was added and the solution was stirred for 30 minutes. 4-bromo-1-butene (2.60mL) was added and the reaction mixture was warmed to room temperature and stirred for 1 hour. The contents were again cooled to-78 ℃ and additional aliquots of lithium bis (trimethylsilyl) amide (25.6mL of 1M THF solution) and 4-bromo-1-butene (2.60mL) were added, followed by the above procedure. After stirring overnight, water (20mL) was added and the reaction mixture was extracted with ether (2 × 60 mL). The combined organic extracts were dried over magnesium sulfate and evaporated. The resulting liquid was purified by silica gel column chromatography (eluting with ethyl acetate/isohexane (1/99)) to give the sub-title compound (5.0 g).

m/e 277[M+H]⁺

b)1- (3-fluoro-phenyl) -cyclohept-4-enecarboxylic acid methyl ester

To a solution of methyl 2-but-3-enyl-2- (3-fluoro-phenyl) -hex-5-enoate (example 12a) (5.0g) in dichloromethane (100mL) was added Grubbs' catalyst (2nd Generation, Sigma-Aldrich company Ltd) (0.05 g). The mixture was warmed to reflux under nitrogen. After 20 hours, the reaction mixture was cooled to room temperature, evaporated to an oil and purified by silica gel column chromatography eluting with ethyl acetate/isohexane (5/95) to give an oil. Analysis of the product showed that there was a significant amount of starting material in the mixture, so the mixture was subjected to repeated reaction conditions and purification as above to give the sub-title compound as a coloured oil (3.60 g).

m/e 249[M+H]⁺

c)1- (3-fluoro-phenyl) -cycloheptanecarboxylic acid methyl ester

Methyl 1- (3-fluoro-phenyl) -cyclohept-4-enecarboxylate (example 12b) (1.09g) was dissolved in methanol (20mL), palladium on charcoal (50mg) was added and the mixture was stirred under 4atm hydrogen overnight. The solution was filtered and evaporated to give the sub-title compound (1.09 g).

m/e 251[M+H]⁺

d)1- (3-fluoro-phenyl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester

Methyl 1- (3-fluoro-phenyl) -cycloheptanecarboxylate (example 12c) (0.280g) was dissolved in toluene (100mL) and (R) -quinuclidin-3-ol (0.320g) was added. Toluene (10mL) was distilled off on a Dean and Stark apparatus, and after cooling, sodium hydride (10mg) was added. The reaction mixture was refluxed in a Dean and Stark apparatus for 4 hours, after which an additional amount of sodium hydride (10mg) was added and the reaction mixture was heated to reflux and held for an additional 4 hours. After cooling to room temperature, the toluene was washed with water and dried (MgSO)₄) And evaporated. The residue was purified by column chromatography (eluting with ethyl acetate/isohexane/triethylamine (50/50/1), then ethyl acetate/triethylamine (99/1)) to give the sub-title compound (0.200 g).

m/e 346[M+H]⁺

¹H NMR(399.824MHz，CDCl₃)δ7.26(td，1H)，7.10-7.07(m，1H)，7.04(dd，1H)，6.90(ddd，1H)，4.78-4.73(m，1H)，3.14(ddd，1H)，2.79-2.66(m，3H)，2.66-2.56(m，1H)，2.53-2.46(m，1H)，2.46-2.36(m，2H)，2.13-1.99(m，2H)，1.90-1.85(m，1H)，1.73-1.40(m，11H)，1.29-1.18(m，1H).

1- (3-fluoro-phenyl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 12d) (0.100g) was dissolved in acetonitrile (8mL) and 2-bromo-N- (pyrazin-2-yl) -acetamide (example 11a) (0.05g) was added. The reaction mixture was stirred for 3 days, diluted with ether (8mL), stirred for a further 10 minutes, the resulting solid filtered and washed with ether (3 × 8mL) to give a solid which was recrystallised from hot butanone (8mL) to give the title compound as a solid (0.081 g).

m/e 481[M⁺]

¹H NMR(399.826MHz，DMSO-D₆)δ11.42(s，1H)，9.28(s，1H)，8.49-8.45(m，2H)，7.40(td，1H)，7.19-7.12(m，2H)，7.09(td，1H)，5.17-5.10(m，1H)，4.40-4.30(m，2H)，4.16-4.07(m，1H)，3.71-3.57(m，4H)，3.52-3.41(m，1H)，2.43-2.27(m，2H)，2.26-2.19(m，1H)，2.19-2.09(m，1H)，2.05-1.87(m，3H)，1.86-1.76(m，1H)，1.71-1.46(m，9H).

Example 13: (R) -3- [1- (3-fluoro-phenyl) -cycloheptanecarbonyloxy ] -1- (isoxazol-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N-isoAzol-3-yl-acetamides

Will be different fromAzol-3-ylamine (1.14g) was dissolved in dichloromethane (50mL) and potassium carbonate (3.74g) was added. Bromoacetyl chloride (1.12mL) was added slowly with stirring and the suspension was stirred overnight. The reaction mixture was washed with water (2 × 50mL), dried and evaporated. The product was recrystallized from dichloromethane/isohexane to give the sub-title compound (2.3 g).

¹H NMR(299.946MHz，CDCl₃)δ8.94(s，1H)，8.34(s，1H)，7.06(s，1H)，4.03(s，2H).

1- (3-fluoro-phenyl) -cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 12d) (50mg) and 2-bromo-N-isoxazol-3-yl-acetamide (example 13a) (30mg) were dissolved in acetonitrile (4mL) and stirred overnight. The solution was diluted with ether (12mL) and stirred overnight. The resulting crystals were filtered off, washed with diethyl ether (3 × 10mL) and dried to give the title compound as a solid (48 mg).

m/e 470[M⁺]

¹H NMR(399.826MHz，DMSO-D₆)δ11.69(s，1H)，8.90(d，1H)，7.40(td，1H)，7.18-7.07(m，3H)，6.91(d，1H)，5.16-5.10(m，1H)，4.31(d，1H)，4.25(d，1H)，4.09(ddd，1H)，3.68-3.53(m，4H)，3.43(dd，1H)，2.42-2.27(m，2H)，2.25-2.19(m，1H)，2.18-2.09(m，1H)，2.04-1.88(m，3H)，1.85-1.75(m，1H)，1.69-1.51(m，9H).

Example 14: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

a) Cycloheptyl-phenyl-methanones

Phenylmagnesium bromide (3.0M in ether) (271mL) was added dropwise to a stirred (overhead stirrer) solution of cycloheptanecarbonitrile (50g) in 229mL of ether under nitrogen at a rate which maintained a slight reflux. The reaction mixture was then heated at reflux for 3 hours. TLC showed no starting material present in the reaction mixture. The reaction mixture was cooled to room temperature and allowed to stand overnight under nitrogen. The reaction mixture was cooled to 0 ℃ and treated dropwise with 102mL of 4N HCl (aq) while keeping the temperature below 20 ℃. 4N sulfuric acid (203mL) was added dropwise quickly at the beginning and then more slowly to the end. The ice bath was removed and the ether was distilled. The reaction mixture was heated at 80-90 ℃ for 3.5 hours then cooled to room temperature and left to stand overnight. The mixture was diluted with ether (about 450mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ether (2 × 400 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate (600mL) and brine (600mL), dried over magnesium sulfate, filtered and evaporated to give the sub-title compound as an orange liquid (86.5 g).

¹H NMR(300MHz，CDCl₃)δ7.96-7.91(d，2H)，7.54-7.49(m，1H)，7.48-7.40(t，2H)，3.48-3.37(m，1H)，1.98-1.88(m，2H)，1.85-1.44(m，10H).

b) (1-chloro-cycloheptyl) -phenyl-methanones

Sulfonyl chloride (210mL) was added dropwise to pure cycloheptyl-phenyl-methanone (example 14a) (86.5g) at 0 ℃ over about 1 hour. Gas evolution and an exotherm were observed. During the addition the internal temperature was kept below 15 ℃ and the released gas was washed with 10.2M aqueous NaOH solution. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to 0 ℃ and carefully poured into ice (1L) with stirring. The layers were separated and the aqueous layer was extracted with ether (2 × 400 mL). The combined organic layers were washed with water (600mL), saturated aqueous sodium bicarbonate (600mL) and brine (600mL), dried over magnesium sulfate, filtered and evaporated to give the sub-title compound as a brown oil (100 g).

¹H NMR(400MHz，CDCl₃)δ8.10-8.06(d，2H)，7.52-7.46(t，1H)，7.44-7.36(t，2H)，2.50(ddd，2H)，2.29(ddd，2H)，1.84-1.73(m，2H)，1.68-1.58(m，2H)，1.58-1.43(m，4H).

c) 1-phenyl-cycloheptane carboxylic acids

(1-chloro-cycloheptyl) -phenyl-methanone (example 14b) (100g) in 750mL of bisThe solution in the alkane was treated dropwise rapidly with a turbid solution of silver nitrate (137g) in water (85mL), which caused the formation of a precipitate. The reaction mixture was heated to 75 ℃ and held for 4.5 hours. The reaction mixture was cooled to room temperature and then filtered and concentrated to about 200 mL. Adding water(200mL) and diethyl ether (300mL) and the layers were separated. The aqueous layer was extracted with ether (2X 250 mL). The combined organic layers were extracted with 10% aqueous sodium carbonate (3 × 250 mL). The combined alkaline extracts were heated to 90 ℃ over 40 minutes and then cooled to room temperature and acidified with concentrated hydrochloric acid (aq). The resulting brown solid was filtered off, washed with water (x2) and dried in vacuo at 50 ℃. It was crystallized from hot ethanol (40mL) to give the sub-title compound as light brown crystals (9.83 g).

¹H NMR(400MHz，CD₃OD)δ7.36-7.26(m，4H)，7.21-7.15(m，1H)，2.43-2.35(m，2H)，2.07-1.98(m，2H)，1.70-1.53(m，8H).

d) 1-phenyl-cycloheptanecarboxylic acid methyl ester

A solution of 2.0M trimethylsilyldiazomethane (29.2mL) was added dropwise under a nitrogen atmosphere to a solution of 1-phenyl-cycloheptanecarboxylic acid (example 14c) (9.8g) in methanol (85mL) and toluene (300 mL).

After 45 min, the reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (eluting with 0-10% ethyl acetate/cyclohexane) to give the product as a light yellow oil (9.25 g).

¹H NMR(300MHz，CD₃OD)δ7.32-7.24(m，4H)，7.21-7.12(m，1H)，3.60(s，3H)，2.43-2.32(m，2H)，2.07-1.96(m，2H)，1.65-1.58(m，8H).

A solution of (R) - (3) -quinuclidinol (10.13g) and methyl 1-phenyl-cycloheptanecarboxylate (example 14d) (9.25g) in toluene (90mL) was heated to reflux with a Dean-Stark trap and held for 30 min. The reaction mixture was cooled to room temperature and the trap was removed. Sodium hydride (60% dispersed in mineral oil) (3.19g) was added in portions under nitrogen and the reaction mixture was heated to reflux under nitrogen overnight. The reaction mixture was cooled in an ice bath and diluted with ethyl acetate (200mL) and water (200 mL). The mixture was filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 250mL) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give the crude product which was purified by silica gel chromatography (eluting with EtOAc containing 1% triethylamine) to give the sub-title compound as a colourless oil (7.63 g).

¹H NMR(400MHz，CD₃OD)δ7.34-7.28(m，4H)，7.23-7.17(m，1H)，4.80-4.75(m，1H)，3.12(ddd，1H)，2.75-2.65(m，3H)，2.53-2.37(m，4H)，2.14-2.06(m，2H)，1.88-1.85(m，1H)，1.69-1.54(m，10H)，1.54-1.42(m，1H)，1.35-1.24(m，1H).

f) 2-chloro-N-pyridin-2-yl-acetamide

A solution of 2-amino-pyridine (1.0g) in dry dichloromethane (10.6mL) was treated with triethylamine (1.63mL) under nitrogen at 0 deg.C, followed by the slow addition of chloroacetyl chloride (0.93 mL). The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product which was purified by silica gel chromatography (eluting with 0-30% ethyl acetate/cyclohexane) to give the title compound (1.43g) as a pink solid. Further purification was accomplished by trituration with 40-60 petroleum ether to give 1.15g of the expected product. Crystallization of a 0.94g portion of material from refluxing acetonitrile (2.4mL) gave the sub-title compound as a pink solid (0.73 g).

¹H NMR(400MHz，CDCl₃)：δ8.96(s，1H)，8.32(ddd，1H)，8.21(d，1H)，7.76(ddd，1H)，7.12(ddd，1H)，4.20(s，2H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (254mg) in acetonitrile (5mL) was treated with 2-chloro-N-pyridin-2-yl-acetamide (example 14f) (146mg) and the resulting yellow solution was stirred at room temperature overnight during which time a solid precipitated. The reaction mixture was treated with-2 mL of diethyl ether and the solid was filtered off, washed with diethyl ether and dried in vacuo to give the title compound as an off-white solid (217 mg). It was crystallized from refluxing acetonitrile (20mL) to give 98mg of the title compound as a white crystalline solid.

m/e 462[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.09(s，1H)，8.34-8.32(d，1H)，7.97(d，1H)，7.85-7.79(t，1H)，7.33-7.25(m，4H)，7.21-7.13(m，2H)，5.07(m，1H)，4.29(s，2H)，4.07(ddd，1H)，3.65-3.51(m，4H)，3.41-3.29(m，1H)，2.36-2.23(m，2H)，2.17-2.04(m，2H)，1.99-1.81(m，3H)，1.78-1.66(m，1H)，1.77-1.19(m，9H).

Example 14: preparation of (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride crystalline form A

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (254mg, 0.78mmol) in acetonitrile (5mL) was treated with 2-chloro-N-pyridin-2-yl-acetamide (example 14f) (146mg) and the resulting yellow solution was stirred at room temperature overnight during which time a solid precipitated. The reaction mixture was treated with 2mL of diethyl ether and the solid was filtered off, washed with diethyl ether and dried in vacuo to give the title compound (217mg) as an off-white solid. It was crystallized from refluxing acetonitrile (20mL) to give 98mg of the title compound as a white crystalline solid.

m/e 462[M]⁺

For example 14: analysis of (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride crystalline form A

A sample of crystalline example 14 form a obtained by the above procedure was analyzed by XRPD (panalytical x' Pert system), DSC and TGA.

The melting temperature of example 14 chloride form a as determined by DSC was found to be 239 ℃ (initial) (± 2 ℃). The weight loss observed via TGA prior to melting was negligible. GVS determined a negligible weight gain (% w/w) (+ -0.2%) at 80% RH.

The XRPD spectrum of example 14 chloride form a is shown in figure 1.

Example 15: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N-pyridin-2-yl-acetamide

To a solution of 2-aminopyridine (48.8mmol) in anhydrous THF (98mL) at room temperature were added Et3N (58.6mmol) and bromoacetyl bromide (58.6mmol) dropwise. The mixture was stirred overnight and saturated NaHCO₃(aq) quenching. EtOAc was added to the mixture and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organics were dried (MgSO)₄) And concentrated in vacuo to afford a brown solid. Purification by flash chromatography on silica gel (eluting with 1-2% MeOH in dichloromethane) afforded the sub-title compound as a yellow solid (1.14 g).

¹H NMR(400MHz，CDCl₃)：δ8.75(s，1H)，8.26(ddd，1H)，8.10(d，1H)，7.67(ddd，1H)，7.03(ddd，1H)，3.94(s，2H).

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.79mmol) and 2-bromo-N-pyridin-2-yl-acetamide (example 15a) (0.87mmol) were stirred together in anhydrous MeCN at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the yellow solid was purified by flash silica gel column chromatography (eluting with 2-8% MeOH in dichloromethane) to give a brown solid which was crystallized from boiling MeCN to give the title compound as a white solid (211 mg).

m/e 462[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.02(s，1H)，8.33(ddd，1H)，7.97(d，1H)，7.86-7.80(m，1H)，7.32-7.25(m，4H)，7.23-7.12(m，2H)，5.09-5.04(m，1H)，4.23(s，2H)，4.06(ddd，1H)，3.63-3.49(m，4H)，3.41-3.29(m，1H)，2.37-2.22(m，2H)，2.17-2.04(m，2H)，1.98-1.83(m，3H)，1.78-1.66(m，1H)，1.65-1.39(m，9H).

Example 15: preparation of (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide crystalline form A

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.79mmol) and 2-bromo-N-pyridin-2-yl-acetamide (example 15a) (0.87mmol) were stirred together in anhydrous MeCN at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the yellow solid was purified by flash silica gel column chromatography (eluting with 2-8% MeOH in dichloromethane) to afford a brown solid. The solid was dissolved in refluxing MeCN and the solution was cooled to room temperature. The resulting crystals were filtered off and washed with a small amount of cold MeCN to give the title compound (211mg) as a white crystalline solid.

m/e 462[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.02(s，1H)，8.33(ddd，1H)，7.97(d，1H)，7.86-7.80(m，1H)，7.32-7.25(m，4H)，7.23-7.12(m，2H)，5.09-5.04(m，1H)，4.23(s，2H)，4.06(ddd，1H)，3.63-3.49(m，4H)，3.41-3.29(m，1H)，2.37-2.22(m，2H)，2.17-2.04(m，2H)，1.98-1.83(m，3H)，1.78-1.66(m，1H)，1.65-1.39(m，9H).

For example 15: analysis of (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide crystalline form A

A sample of crystalline example 15 form a obtained by the above procedure was analyzed by XRPD (panalytical x' Pert system), DSC and TGA.

The melting temperature of form A bromide of example 15, as determined by DSC, was found to be 230 ℃ (initial) (± 2 ℃). The weight loss observed via TGA prior to melting was negligible. GVS determined a negligible weight gain (% w/w) (+ -0.2%) at 80% RH.

The XRPD spectrum of example 15 bromide form a is shown in figure 2.

Example 16: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (pyridin-4-yl) -acetamide

A suspension of 4-aminopyridine (0.96g) in dry dichloromethane (10mL) was cooled to 0 ℃ in an ice bath under nitrogen. Triethylamine (1.56mL) was added followed by the slow addition of chloroacetyl chloride (0.89 mL). The ice bath was removed and the reaction mixture was allowed to reach room temperature. The reaction mixture was diluted with water (20mL) and dichloromethane (25 mL). The solid was filtered off, washed with pentane and dried to give the title compound as a brown solid (0.87 g). The respective filtrate layers were separated and the organic layer was washed with water, dried and the solvent was evaporated to give a dark brown glass. Trituration with pentane gave another crop of the title compound (0.91 g).

¹H NMR(400MHz，DMSO-D₆)δ10.79(s，1H)，8.47(d，2H)，7.59(d，2H)，4.33(s，2H).

2-chloro-N- (pyridin-4-yl) -acetamide (example 16a) (30mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (53mg) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 24 hours. Diethyl ether (2mL) was added and the reaction mixture was filtered to give a light brown solid. The solid was washed several times with diethyl ether and dried under vacuum at 40 ℃. Purification by column chromatography (eluting with 0-10% MeOH in dichloromethane) afforded the title compound as a white solid (20 mg).

m/e 462[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.34(s，1H)，8.46(d，2H)，7.55(d，2H)，7.34-7.26(m，4H)，7.22-7.17(m，1H)，5.08(m，1H)，4.30(s，2H)，4.11-4.02(m，1H)，3.65-3.51(m，4H)，3.42-3.30(m，1H)，2.38-2.24(m，2H)，2.17-2.06(m，2H)，1.99-1.84(m，3H)，1.79-1.67(m，1H)，1.69-1.26(m，9H).

Example 17: (R) -1- [ (5-fluoro-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (5-fluoro-pyridin-2-yl) -acetamide

The title compound (0.99g, 73%, white solid) was prepared according to the method used in example 14f but using 2-amino-5-fluoro-pyridine.

¹H NMR(400MHz，DMSO-D₆)δ10.91(s，1H)，8.35(d，1H)，8.10(dd，1H)，7.80-7.74(m，1H)，4.34(s，2H).

2-chloro-N- (5-fluoro-pyridin-2-yl) -acetamide (example 17a) (31mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (49mg) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature overnight. Ether (2mL) was added to the reaction mixture and the white solid was filtered off, washed several times with ether and dried under vacuum at 40 ℃ to give the title compound (49 mg).

m/e 480[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.19(s，1H)，8.36(d，1H)，8.02(m，1H)，7.81(ddd，1H)，7.33-7.26(m，4H)，7.22-7.17(m，1H)，5.07(m，1H)，4.26(s，2H)，4.11-4.03(m，1H)，3.64-3.50(m，4H)，3.41-3.29(m，1H)，2.36-2.23(m，2H)，2.17-2.05(m，2H)，1.99-1.82(m，3H)，1.78-1.65(m，1H)，1.70-1.41(m，9H).

Example 18: (R) -1- [ (5-methyl-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (5-methyl-pyridin-2-yl) -acetamide

The title compound (0.50g) was prepared according to the method used in example 14f but using 2-amino-5-methylpyridine.

¹H NMR(400MHz，DMSO-D₆)δ10.69(s，1H)，8.17(dt，1H)，7.95(d，1H)，7.63(dd，1H)，4.32(s，2H)，2.25(s，3H).

The title compound (36mg) was prepared according to the procedure used to prepare example 17 using 2-chloro-N- (5-methyl-pyridin-2-yl) -acetamide (example 18a) instead of 2-chloro-N- (5-fluoro-pyridin-2-yl) -acetamide.

m/e 476[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ10.98(s，1H)，8.17(d，1H)，7.88(d，1H)，7.65(dd，1H)，7.33-7.25(m，4H)，7.23-7.17(m，1H)，5.07(m，1H)，4.24(s，2H)，4.10-4.02(m，1H)，3.64-3.50(m，4H)，3.40-3.27(m，1H)，2.37-2.22(m，2H)，2.23(s，3H)，2.17-2.04(m，2H)，1.97-1.84(m，3H)，1.78-1.66(m，1H)，1.66-1.35(m，9H).

Example 19: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (pyridin-3-yl) -acetamide

A mixture of 3-aminopyridine (350mg) and sodium hydroxide (0.6g) was dissolved in water (8mL) and the reaction mixture was cooled in an ice bath. Chloroacetyl chloride (1.19mL) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane and the organic layer was concentrated and purified by column chromatography (eluting with 0-60% ethyl acetate/cyclohexane) to give the title compound (0.10g) as a white solid.

¹H NMR(400MHz，DMSO-D₆)δ10.51(s，1H)，8.73(d，1H)，8.30(dd，1H)，8.03(ddd，1H)，7.40-7.35(m，1H)，4.30(s，2H).

The title compound (78mg) was prepared via a similar method to that used in example 15 using 2-chloro-N- (pyridin-3-yl) -acetamide instead of 2-bromo-N-pyridin-2-yl-acetamide.

m/e 462[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.27(s，1H)，8.76(d，1H)，8.30(dd，1H)，7.98(ddd，1H)，7.37(ddd，1H)，7.33-7.25(m，4H)，7.22-7.15(m，1H)，5.07(d，1H)，4.28(dd，2H)，4.11-4.03(m，1H)，3.65-3.50(m，4H)，3.41-3.29(m，1H)，2.37-2.21(m，2H)，2.19-2.05(m，2H)，1.97-1.83(m，3H)，1.78-1.66(m，1H)，1.71-1.27(m，9H).

Example 20: (R) -1- [ (2-methyl-pyridin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (2-methyl-pyridin-4-yl) -acetamide

The title compound (1.0g) was prepared according to the method used in example 14f but using 4-amino-2-methylpyridine.

¹H NMR(400MHz，DMSO-D₆)δ10.64(s，1H)，8.32(d，1H)，7.44(d，1H)，7.38-7.35(m，1H)，4.30(s，2H)，2.42(s，3H).

The title compound was prepared using procedures analogous to those used to prepare example 17. Further purification was accomplished by chromatography on silica gel (eluting with 0-20% MeOH in dichloromethane) to afford the title compound as a white solid (57 mg).

m/e 476[M]⁺

¹H NMR(400MHz，DMSO-D₆)δ11.32(s，1H)，8.31(d，1H)，7.43(d，1H)，7.35-7.26(m，5H)，7.22-7.16(m，1H)，5.09-5.04(m，1H)，4.30(dd，2H)，4.09-4.01(m，1H)，3.64-3.49(m，4H)，3.41-3.29(m，1H)，2.38(s，3H)，2.39-2.23(m，2H)，2.17-2.05(m，2H)，1.97-1.82(m，3H)，1.78-1.65(m，1H)，1.65-1.41(m，9H).

Example 21: (R) -1-Phenylcarbamoylmethyl-3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N-phenyl-acetamides

Aniline (5mL) was added dropwise over 15-20 minutes to a solution of bromoacetyl bromide (9.6mL) and potassium carbonate (11.4g) in dichloromethane (100mL), which caused the reaction mixture to warm and a white precipitate to form. After 4.5 hours, the reaction mixture was poured into water, shaken for a few minutes, and the phases were separated. The organic layer was washed with water and concentrated to a smaller volume which resulted in precipitation of a solid which was filtered off to give the sub-title compound (970mg) as a white solid.

¹H NMR(400MHz，CDCl₃)：δ8.10(s，1H)，7.53(d，2H)，7.40-7.33(m，2H)，7.17(t，1H)，4.03(s，2H).

To a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (50mg) in acetonitrile (1mL) was added 2-bromo-N-phenylacetamide (example 21a) (36 mg). The reaction mixture was stirred at room temperature for 3 days. Diethyl ether was added to the reaction mixture and the resulting solid was collected by filtration and dried to give the title compound as a colorless solid (39 mg).

m/e 461[M]⁺

¹H NMR(DMSO-D₆)：δ10.49(s，1H)，7.53-7.50(m，2H)，7.35-7.24(m，6H)，7.21-7.16(m，1H)，7.12-7.07(m，1H)，5.08(m，1H)，4.21-4.11(m，2H)，4.06(dd，1H)，3.64-3.49(m，4H)，3.27(s，1H)，2.37-2.21(m，2H)，2.18-2.04(m，2H)，1.98-1.88(m，3H)，1.77-1.66(m，1H)，1.70-1.30(m，9H).

Example 22: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (pyrimidin-4-yl) -acetamide

Chloroacetyl chloride (1.22mmol) in anhydrous CHCl at room temperature₃(2.4mL) solution was slowly added to 4-aminopyrimidine (1.11mmol) and Et₃N (1.66mmol) in anhydrous CHCl₃(22 mL). The bright yellow mixture gradually turned orange and after 4 hours the reaction mixture was washed with H₂O (1mL) quench. After stirring for 15 min, the mixture was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel (1-2% MeOH in dichloromethane) to give a yellow solid (122 mg).

¹H NMR(400MHz，DMSO-D₆)：δ11.21(s，1H)，8.93-8.90(m，1H)，8.70(d，1H)，8.03(dd，1H)，4.40(s，2H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.44mmol) and 2-chloro-N- (pyrimidin-4-yl) -acetamide (example 22a) (0.48mmol) in anhydrous MeCN (2mL) was stirred together at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (2-10% MeOH in dichloromethane) to give the title compound as a pale yellow solid (134 mg).

m/e 463[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.44(s，1H)，8.91(s，1H)，8.72(d，1H)，7.94(d，1H)，7.32-7.25(m，4H)，7.22-7.17(m，1H)，5.10-5.04(m，1H)，4.30(s，2H)，4.10-4.02(m，1H)，3.61-3.49(m，4H)，3.40-3.28(m，1H)，2.36-2.21(m，2H)，2.18-2.04(m，2H)，2.00-1.84(m，3H)，1.75-1.66(m，1H)，1.66-1.39(m，9H).

Example 23: (R) -1- [ (2-fluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (2-fluoro-phenyl) -acetamide

To a mixture of 2-fluoroaniline (2mL) and potassium carbonate (4.3g) in dichloromethane (50mL) was added bromoacetyl bromide (3.6 mL). The reaction mixture was stirred for 4 hours then water was added and the phases were separated. The organic layer was concentrated and the residue treated with ether and evaporated again to give the sub-title compound (4.98g) as a cream solid which was used without further purification.

¹H NMR(400MHz，CDCl₃)：δ8.38(s，1H)，8.26(t，1H)，7.18-7.09(m，3H)，4.05(s，2H).

A mixture of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (56mg) and 2-bromo-N- (2-fluoro-phenyl) -acetamide (example 23a) (44mg) in acetonitrile (1mL) was stirred at room temperature for 30 h. The resulting precipitate was collected by filtration, washed with diethyl ether and dried under vacuum at 50 ℃ to give the title compound (52mg) as a colorless solid.

m/e 479[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.34(s，1H)，7.83-7.77(m，1H)，7.32-7.16(m，8H)，5.12-5.03(m，1H)，4.25(s，2H)，4.10-4.02(m，1H)，3.63-3.51(m，4H)，3.41-3.29(m，1H)，2.37-2.23(m，2H)，2.17-2.06(m，2H)，1.98-1.88(m，3H)，1.79-1.67(m，1H)，1.66-1.39(s，9H).

Example 24: (R) -1- [ (2, 3-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (2, 3-difluoro-phenyl) -acetamide

To a mixture of 2, 3-difluoroaniline (630mg) and potassium carbonate (1.01g) in dichloromethane (30mL) was added bromoacetyl bromide (0.86 mL). The reaction mixture was stirred for 5 hours then water was added and the phases were separated. The organic layer was concentrated to give a 2: 1 mixture of the sub-title compound and bromoacetyl bromide. The residue was dissolved in dichloromethane and washed with water. The volatiles were evaporated to give the sub-title compound (1.15g) as an off-white solid which was used without further purification.

¹H NMR(400MHz，CDCl₃)：δ8.38(s，1H)，8.03(t，1H)，7.12-7.05(m，1H)，7.00-6.92(m，1H)，4.05(d，2H).

The title compound (colorless solid, 28mg, 31%) was prepared by analogous procedure to that used to prepare example 23 using 2-bromo-N- (2, 3-difluoro-phenyl) -acetamide (example 24a) instead of 2-bromo-N- (2-fluoro-phenyl) -acetamide.

m/e 497[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.54(s，1H)，7.58(t，1H)，7.32-7.16(m，7H)，5.13-5.04(m，1H)，4.26(s，2H)，4.10-4.02(m，1H)，3.62-3.49(m，4H)，3.42-3.29(m，1H)，2.37-2.23(m，2H)，2.17-2.06(m，2H)，1.98-1.85(m，3H)，1.79-1.67(m，1H)，1.66-1.40(m，9H).

Example 25: (R) -1- [2- (2, 3-dihydro-benzofuran-5-yl) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane formate

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [ 2.2.2)]A mixture of oct-3-yl) ester (example 14e) (126mg) and 5- (2-bromo-ethyl) -2, 3-dihydro-benzofuran (105mg, 0.46mmol) in acetonitrile (1.5mL) was stirred at room temperature for 22 h. The volatiles were evaporated and the residue was purified by silica gel chromatography (eluting with dichloromethane then 5% MeOH/dichloromethane then 10% MeOH/dichloromethane). The relevant fractions were combined and evaporated and the residue triturated with dichloromethane to give an off-white foam. Further purification was accomplished by reverse phase HPLC (5-98% MeCN/H with 0.1% formic acid₂O) to yield the title compound (70mg) as a white gummy solid.

m/e 474[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ8.35(s，1H)，7.35-7.26(m，4H)，7.24-7.18(m，1H)，7.12(s，1H)，6.95(d，1H)，6.68(d，1H)，5.08-5.01(m，1H)，4.46(t，2H)，3.87-3.78(m，1H)，3.47-3.25(m，5H)，3.20-3.06(m，3H)，3.04-2.97(m，1H)，2.86-2.75(m，2H)，2.39-2.23(m，2H)，2.18-2.10(m，2H)，2.01-1.78(m，3H)，1.69-1.44(m，10H).

Example 26: (R) -1- [2- (4-fluoro-phenoxy) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane formate

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [ 2.2.2)]A mixture of oct-3-yl) ester (example 14e) (50mg) and 1- (2-bromoethoxy) -4-fluorobenzene (50mg) in acetonitrile (1mL) was stirred at room temperature for 22 h. Purification by preparative HPLC (using 5-98% MeCN/H with 0.1% formic acid₂O elution) to give the title compound (19mg) as a colorless oil.

m/e 466[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ8.39(s，1H)，7.28-7.23(m，4H)，7.20-7.11(m，3H)，6.97-6.92(m，2H)，5.06-4.99(m，1H)，4.39-4.28(m，2H)，3.93(ddd，1H)，3.70-3.56(m，2H)，3.56-3.46(m，4H)，3.15-3.03(m，1H)，2.35-2.20(m，2H)，2.15-2.03(m，2H)，1.97-1.78(m，3H)，1.73-1.61(m，1H)，1.61-1.39(m，9H).

Example 27: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridazin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane formate

a) 2-chloro-N- (pyridazin-4-yl) -acetamide

A solution of pyridazin-4-ylamine (1.0g) in dry dichloromethane (10mL) was cooled to 0 ℃ in an ice bath under nitrogen, triethylamine (1.6mL) was added, followed by the slow addition of chloroacetyl chloride (0.92 mL). The ice bath was removed when the addition was complete and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25mL) and dichloromethane (30 mL). The solid was filtered off and washed with pentane, water and more pentane to give the sub-title compound (0.87g, 48%) as a brown solid.

¹H NMR(400MHz，DMSO-D₆)：δ11.17(s，1H)，9.33(dd，1H)，9.07(dd，1H)，7.94(dd，1H)，4.39(s，2H).

2-chloro-N- (pyridazin-4-yl) -acetamide (example 27a) (58mg) was added to 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [ 2.2.2.2)]Oct-3-yl) ester (example 14e) (100mg) in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 24 hours. Diethyl ether (2mL) was added to the reaction mixture and stirred for 15 min. The solid was filtered off, washed with diethyl ether and dried under vacuum at 40 ℃ overnight. The filtrate was evaporated, combined with the solid and purified by column chromatography (eluting with 0-15% MeOH in dichloromethane). Further purification by reverse phase preparative HPLC (using 15% MeCN/H containing 0.1% formic acid₂O was eluted with a gradient of 1% increase per minute) to give the title compound (19mg) as a colourless gum.

m/e 463[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ9.17(s，1H)，8.89(d，1H)，8.41(s，1H)，7.80(dd，1H)，7.32-7.25(m，4H)，7.21-7.15(m，1H)，5.08-5.02(m，1H)，4.28-4.14(m，2H)，4.04(dd，1H)，3.66(d，2H)，3.62-3.48(m，2H)，3.45-3.33(m，1H)，2.37-2.23(m，2H)，2.14-2.05(m，2H)，1.96-1.83(m，3H)，1.75-1.62(m，1H)，1.56-1.42(m，9H).

Example 28: (R) -1- [ (5-fluoro-pyridin-3-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (5-fluoro-pyridin-3-yl) -acetamide

A solution of 3-amino-5-fluoropyridine (1g) in anhydrous dichloromethane (10mL) was cooled to 0 ℃ in an ice bath under nitrogen. Triethylamine (1.36mL) was added followed by the slow addition of chloroacetyl chloride (0.78 mL). Upon completion of the addition, the ice bath was removed and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25mL) and dichloromethane (30 mL). The organic layer was washed with water (2 × 20mL) and dried (MgSO)₄) And evaporated to give the crude product. Purification by silica gel chromatography (eluting with 0-30% ethyl acetate/cyclohexane) gave the sub-title compound (1.0g) as a brown solid.

¹H NMR(400MHz，DMSO-D₆)：δ10.77(s，1H)，8.56(t，1H)，8.33(d，1H)，8.04(dt，1H)，4.33(s，2H).

2-chloro-N- (5-fluoro-pyridin-3-yl) -acetamide (example 28a) (53mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (84mg) in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The solid was filtered off and dried under vacuum at 40 ℃ to give the title compound (47mg, 35%) as a white solid.

m/e 480[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.53(s，1H)，8.58(s，1H)，8.34(d，1H)，7.99(dt，1H)，7.32-7.25(m，4H)，7.21-7.15(m，1H)，5.09-5.04(m，1H)，4.29(s，2H)，4.10-4.02(m，1H)，3.63-3.51(m，4H)，3.41-3.29(m，1H)，2.37-2.23(m，2H)，2.16-2.05(m，2H)，1.96-1.83(m，3H)，1.78-1.65(m，1H)，1.65-1.39(m，9H).

Example 29: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [2- (pyridin-3-yloxy) -ethyl ] -1-azonia-bicyclo [2.2.2] octane formate

a)2- (pyridin-3-yloxy) -ethanol

The sub-title compound (0.99g, 63%) was prepared according to the procedure described in WO 2004/000829.

b)3- (2-bromo-ethoxy) -pyridine

A solution of 2- (pyridin-3-yloxy) -ethanol (200mg) in 5mL dichloromethane was cooled to 0 deg.C and treated with carbon tetrabromide (524mg), followed by portions of triphenylphosphine (415 mg). The reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 45 minutes. The volatiles were evaporated and the residue was purified by silica gel chromatography (eluting with 0-100% EtOAc/pentane) to give the title compound (204mg) as a colourless liquid which was used without further purification.

¹H NMR(400MHz，CDCl₃)：δ8.34(dd，1H)，8.28-8.22(m，1H)，7.25-7.20(m，2H)，4.35(t，2H)，3.66(t，2H).

The title compound (10mg, 13%, colourless gum) was prepared using procedures analogous to those used to prepare example 25 using 3- (2-bromo-ethoxy) -pyridine (example 29b) instead of 5- (2-bromo-ethyl) -2, 3-dihydro-benzofuran.

m/e 449[M]⁺

¹H NMR(400MHz，DMSO-D6)：δ8.51(s，1H)，8.29(d，1H)，8.21(dd，1H)，7.38-7.33(m，2H)，7.28-7.24(m，4H)，7.19-7.14(m，1H)，5.06-4.99(m，1H)，4.51-4.39(m，2H)，3.99-3.90(m，1H)，3.74-3.59(m，2H)，3.57-3.37(m，3H)，3.14-3.05(m，1H)，2.36-2.22(m，2H)，2.14-2.05(m，2H)，1.98-1.82(m，3H)，1.74-1.62(m，1H)，1.62-1.38(m，9H).

Example 30: (R) -1- [ (6-methyl-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (6-methyl-pyridin-2-yl) -acetamide

The sub-title compound (0.95g, 58%, white solid) was prepared by analogous procedure as used to prepare example 28a using 2-amino-6-methylpyridine instead of 3-amino-5-fluoropyridine.

¹H NMR(400MHz，DMSO-D₆)：δ10.73(s，1H)，7.86(d，1H)，7.69(t，1H)，7.03-6.96(m，1H)，4.32(s，2H)，2.41(s，3H).

The title compound (34mg, 43%, white solid) was prepared using a method analogous to that used to prepare example 17 using 2-chloro-N- (6-methyl-pyridin-2-yl) -acetamide (example 30a) instead of 2-chloro-N- (5-fluoro-pyridin-2-yl) -acetamide.

m/e 476[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.01(s，1H)，7.79(d，1H)，7.71(t，1H)，7.32-7.25(m，4H)，7.23-7.16(m，1H)，7.02(d，1H)，5.09-5.04(m，1H)，4.24(s，2H)，4.06(ddd，1H)，3.63-3.50(m，4H)，3.38-3.29(m，1H)，2.38(s，3H)，2.38-2.23(m，2H)，2.17-2.04(m，2H)，2.00-1.82(m，3H)，1.78-1.66(m，1H)，1.65-1.40(m，9H).

Example 31: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (o-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-chloro-N-o-tolyl-acetamide

The sub-title compound (0.83g, 49%, off-white solid) was prepared using an analogous procedure to that used to prepare example 28a using o-toluidine instead of 3-amino-5-fluoropyridine.

¹H NMR(400MHz，DMSO-D₆)：δ9.62(s，1H)，7.39(d，1H)，7.23-7.08(m，3H)，4.29(s，2H)，2.23(s，3H).

The title compound (25mg, 35%, white solid) was prepared using a method analogous to that used to prepare example 17 using 2-chloro-N-o-tolyl-acetamide (example 31a) instead of 2-chloro-N- (5-fluoro-pyridin-2-yl) -acetamide.

m/e 475[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.26(s，1H)，7.34(dd，1H)，7.31-7.25(m，4H)，7.23-7.09(m，4H)，5.11-5.05(m，1H)，4.31(dd，2H)，4.07(ddd，1H)，3.68-3.52(m，4H)，3.40-3.31(m，1H)，2.38-2.22(m，2H)，2.19(s，3H)，2.17-2.06(m，2H)，1.97-1.84(m，3H)，1.79-1.67(m，1H)1.65-1.39(m，9H).

Example 32: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (2- (pyrazin-2-yl) -ethyl) -1-azonia-bicyclo [2.2.2] octane bromide

a)2- (2-bromo-ethyl) -pyrazines

To a solution of 2- (2' -hydroxyethyl) pyrazine (0.91g) in 30mL of dichloromethane was added carbon tetrabromide (2.65g) at 0 deg.C, followed by triphenylphosphine (2.1g) in portions. The solution became very dark. After stirring for 1 hour, the reaction mixture was adsorbed on HMN celite and purified by silica gel chromatography (eluting with 0-5% MeOH/dichloromethane) to give a cream solid (3.07g), which was further purified by silica gel chromatography (eluting with 0-50% EtOAc/pentane) to give the sub-title compound (0.47g, 34%) as a yellow oil.

¹H NMR(400MHz，CDCl₃)：δ8.56-8.48(m，3H)，3.78(t，2H)，3.37(t，2H).

2- (2-bromo-ethyl) -pyrazine (example 32a) (43mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (50mg) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 68 hours. The volatiles were evaporated and the product was purified by silica gel chromatography (eluting with 0-20% MeOH in dichloromethane). The relevant fractions were combined and concentrated, taken up in dichloromethane, filtered and evaporated to give the title compound (30mg) as a yellow colloidal glass.

m/e 434[M]⁺

¹H NMR(400MHz，CD₃OD)：δ8.60(d，1H)，8.54(dd，1H)，8.51(d，1H)，7.31-7.24(m，4H)，7.21-7.15(m，1H)，5.05-4.98(m，1H)，3.86(ddd，1H)，3.57(t，2H)，3.49-3.30(m，3H)，3.24-3.12(m，3H)，3.08-2.97(m，1H)，2.36-2.19(m，2H)，2.15-2.06(m，2H)，1.97-1.78(m，3H)，1.71-1.59(m，1H)，1.57-1.37(m，9H).

Example 33: (S) -1- (3-phenoxy-propyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane formate salt

a) 1-phenyl-cycloheptanecarboxylic acid (S) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester

A solution of (S) - (+) -3-quinuclidinol (299mg) and methyl 1-phenyl-cycloheptanecarboxylate (example 14d) (455mg) in 6.5mL of anhydrous toluene was treated with a dispersion of 60% sodium hydride (94mg) under nitrogen and the mixture was heated to reflux and held for 24 hours then cooled to room temperature and left to stand over the weekend. EtOAc and saturated NaHCO were added₃(aq) and the phases are separated. The aqueous phase was extracted with EtOAc (× 3) and the combined organic layers were washed with brine, dried (MgSO)₄) And evaporated to give the crude product. Purification by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) afforded the sub-title compound (384mg) as a yellow oil.

¹H NMR(300MHz，CD₃OD)：δ7.39-7.27(m，4H)，7.25-7.14(m，1H)，4.80(dt，1H)，3.16(ddd，1H)，2.83-2.64(m，3H)，2.56-2.34(m，4H)，2.15-2.04(m，2H)，1.91-1.86(m，1H)，1.72-1.44(m，11H)，1.38-1.25(m，1H).

A mixture of 3-phenoxypropyl bromide (0.026mL) was added to 1-phenyl-cycloheptanecarboxylic acid (S) - (S) -) (1-aza-bicyclo [2.2.2]Oct-3-yl) ester (example 33a) (50mg) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 72 hours and then heated to 50 ℃ and held for 3 days. The volatiles were evaporated and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give 57mg of a hygroscopic foam. Further purification was accomplished by reverse phase HPLC over 30 min using a C18 column (5-95% MeCN/H with 0.1% formic acid)₂O elution) to give the title compound (43mg) as an oil.

m/e 462[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ8.38(s，1H)，7.34-7.24(m，6H)，7.23-7.17(m，1H)，6.94-6.87(m，3H)，5.07-4.97(m，1H)，3.98(t，2H)，3.87-3.77(m，1H)，3.44-3.26(m，5H)，3.16-3.09(m，1H)，3.01-2.90(m，1H)，2.38-2.23(m，2H)，2.16-1.77(m，7H)，1.69-1.43(m，10H).

Example 34: (R) -1- { [2- (3-fluoro-phenoxy) -ethylcarbamoyl ] -methyl } -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- [2- (3-fluoro-phenoxy) -ethyl ] -acetamide

A mixture of 2- (3-fluorophenoxy) ethylamine (0.93g) and potassium carbonate (1.24g) in dichloromethane (20mL) was treated with bromoacetyl bromide (1.04mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 6 hours. Water was added and the mixture was stirred until bubbling ceased. The organic layer was separated and evaporated to give the crude product which was purified by silica gel chromatography (eluting with 0-50% EtOAc/pentane) to give the sub-title compound (1.17g) as a brown oil.

¹H NMR(400MHz，CDCl₃)：δ7.24(dt，1H)，6.90(s，1H)，6.71-6.66(m，2H)，6.63(dt，1H)，4.06(t，2H)，3.90(s，2H)，3.71(q，2H).

The title compound (70mg, 76%, yellow foam) was prepared via an analogous method to that used to prepare example 32 using 2-bromo-N- [2- (3-fluoro-phenoxy) -ethyl ] -acetamide (example 34a) instead of 2- (2-bromo-ethyl) -pyrazine.

m/e 523[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ8.74(t，1H)，7.33-7.23(m，5H)，7.23-7.16(m，1H)，6.79-6.71(m，3H)，5.09-5.02(m，1H)，4.03-3.94(m，5H)，3.57-3.40(m，6H)，3.33-3.22(m，1H)，2.35-2.20(m，2H)，2.10(d，2H)，1.96-1.82(m，3H)，1.74-1.62(m，1H)，1.62-1.40(m，9H).

Example 35: (R) -1- [ (3, 5-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (3, 5-difluoro-phenyl) -acetamide

The subtitle compound (2.02g, a colorless waxy solid) was prepared using a similar procedure to that used to prepare example 38a using 3, 5-difluoroaniline in place of 2, 6-difluoroaniline.

¹H NMR(400MHz，CDCl₃)：δ8.17(s，1H)，7.16(d，2H)，6.63(td，1H)，4.02(s，2H).

A mixture of 2-bromo-N- (3, 5-difluoro-phenyl) -acetamide (42mg) (example 35a) and 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (50mg) in MeCN (1mL) was stirred at room temperature for 72 h. The solid precipitate was filtered off, washed with diethyl ether and dried under vacuum at 50 ℃ overnight. The mother liquor was evaporated, treated with diethyl ether and the resulting solid was filtered off. The solids were combined and crystallized from hot isopropanol to give the title compound (15mg) as a colourless solid.

m/e 497[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.89(s，1H)，7.33-7.17(m，7H)，7.01(tt，1H)，5.13-5.06(m，1H)，4.26-4.14(m，2H)，4.10-4.01(m，1H)，3.63-3.49(m，4H)，3.43-3.32(m，1H)，2.38-2.23(m，2H)，2.18-2.06(m，2H)，1.98-1.86(m，3H)，1.79-1.67(m，1H)，1.65-1.41(m，9H).

Example 36: (R) -1- [2- (4-methoxy-benzyloxy) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane formate

1- (2-bromo-ethoxymethyl) -4-methoxy-benzene (42mg) and 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [ 2.2.2)]Octa-3-A mixture of the yl) ester (example 14e) (50mg) in MeCN (1mL) was stirred at room temperature for 16 hours and then heated to 80 ℃ under nitrogen overnight. An additional 1.1 equivalents of 1- (2-bromo-ethoxymethyl) -4-methoxy-benzo was added and the mixture was heated at 80 ℃ for an additional 48 hours. The volatiles were evaporated and the crude product was purified by silica gel chromatography (using 0-10% concentrated NH₃/MeOH in dichloromethane) gave 61mg of oil, which was further purified by reverse phase HPLC over 30 minutes (Gemini 5 μ M C6 phenyl column) (with 5-95% MeOH/H containing 0.1% formic acid)₂O elution, UV detection at 220 nm). The relevant fractions were combined and evaporated to give the title compound (34mg) as an oil.

m/e 492[M]⁺

¹H NMR(400MHz，CD₃OD)：δ8.48(s，1H)，7.31-7.16(m，7H)，6.91-6.86(m，2H)，5.09-5.03(m，1H)，4.44-4.39(m，2H)，3.92-3.63(m，6H)，3.46-3.29(m，5H)，2.99-2.88(m，1H)，2.43-2.28(m，2H)，2.24-2.20(m，1H)，2.15-1.86(m，4H)，1.75-1.51(m，10H).

Example 37: (R) -1- (2-Phenylethyloxy-ethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

The title compound (68mg, 77% as a gummy solid) was prepared according to a similar procedure as used for the preparation of example 36 using [2- (2-bromo-ethoxy) -ethyl ] -benzene instead of 1- (2-bromo-ethoxymethyl) -4-methoxy-benzene.

m/e 476[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ7.32-7.11(m，10H)，5.00-4.92(m，1H)，3.80-3.65(m，3H)，3.60(t，2H)，3.41-3.11(m，6H)，2.99-2.88(m，1H)，2.77(t，2H)，2.38-2.21(m，2H)，2.17-2.04(m，2H)，1.99-1.89(m，1H)，1.84-1.67(m，2H)，1.67-1.32(m，10H).

Example 38: (R) -1- [ (2, 6-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (2, 6-difluoro-phenyl) -acetamide

To a mixture of 2, 6-difluoroaniline (1.12g) and potassium carbonate (1.8g) in 50mL of dichloromethane was added bromoacetyl bromide (1.5mL) and the mixture was stirred at room temperature for 17 hours. Water was added and the mixture was stirred for several hours then the phases were separated on a hydrophobic frit (hydrophic frit) and the organic layer was evaporated. The crude product was purified by silica gel chromatography (eluting with 0-100% EtOAc/cyclohexane) to give the sub-title compound (0.92g) as a white solid.

¹H NMR(400MHz，CDCl₃)：δ7.74(s，1H)，7.31-7.21(m，1H)，6.98(t，2H)，4.08(s，2H).

A mixture of N- (2, 6-difluoro-phenyl) -acetamide (example 38a) (42mg) and 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (50mg) in MeCN (1mL) was stirred at room temperature for 19 h. An additional 20mg of 2-bromo-N- (2, 6-difluoro-phenyl) -acetamide was added and stirring was continued for an additional 22 hours. The volatiles were evaporated and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound (41mg) as a colourless foam.

m/e 497[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.40(s，1H)，7.42-7.35(m，1H)，7.31-7.25(m，4H)，7.22-7.16(m，3H)，5.12-5.05(m，1H)，4.32-4.27(m，2H)，4.10-4.02(m，1H)，3.66-3.49(m，4H)，3.43-3.31(m，1H)，2.36-2.21(m，2H)，2.17-2.06(m，2H)，1.99-1.85(m，3H)，1.77-1.66(m，1H)，1.68-1.25(m，9H).

Example 39: (R) -1- [ (methyl-phenyl-carbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane formate salt

a) 2-bromo-N-methyl-N-phenyl-acetamide

To a mixture of N-methylaniline (5mL) and potassium carbonate (9.6g) in 100mL of dichloromethane was added bromoacetyl bromide (8.1mL) (exothermic). The mixture was stirred for 4.5 hours and then water was added. The phases were separated and the organic layer was concentrated. The crude product was purified by silica gel chromatography (eluting with 0-100% EtOAc/cyclohexane). The relevant fractions were combined and evaporated and the residue was taken up in dichloromethane and washed with water. The organic layer was stirred with an additional portion of water for a few minutes and then the layers were separated. The organic layer was evaporated to give the sub-title compound (10.2g) as a pale yellow solid.

¹H NMR(400MHz，CDCl₃)：δ7.50-7.36(m，3H)，7.31-7.26(m，2H)，3.67(s，2H)，3.31(s，3H).

2-bromo-N-methyl-N-phenyl-acetamide ((example 39a) (38mg) and 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [ 2.2.2)]A mixture of oct-3-yl) ester (example 14e) (50mg) in 1mL of MeCN was stirred at room temperature for 48 hours. The volatiles were evaporated and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane). Further purification by reverse phase HPLC (using 20-90% MeCN/H containing 0.1% formic acid₂O elution) to give the title compound (17mg) as a colourless gum.

m/e 475[M]⁺

¹H NMR(400MHz，DMSO-D₆With one drop of TFA-D): Δ 8.08(s, 1H), 7.47(t, 2H), 7.39(dd, 3H), 7.32-7.23(m, 4H), 7.20-7.15(m, 1H), 5.09-4.98(m, 1H), 4.01-3.83(m, 3H), 3.61-3.34(m, 5H), 3.16-3.09(s, 3H), 2.37-2.21(m, 2H), 2.16-2.05(m, 2H), 1.96-1.75(m, 3H), 1.71-1.36(m, 10H).

Example 40: (R) -1- [3- (4-cyano-phenoxy) -propyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

A mixture of 4- (3-bromo-propoxy) -benzonitrile (41mg) and 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (52mg) in MeCN (1mL) was stirred at room temperature for 16 hours then heated to 80 ℃ under nitrogen and held for a further 16 hours. The volatiles were evaporated and the residue triturated with ether to give an off-white solid, which was triturated with EtOAc and dried in vacuo to give the title compound (61mg) as a white solid.

m/e 487[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ7.78-7.73(m，2H)，7.33-7.26(m，4H)，7.22-7.17(m，1H)，7.09-7.04(m，2H)，5.05-4.99(m，1H)，4.08(t，2H)，3.82(ddd，1H)，3.43-3.26(m，5H)，3.21-3.08(m，1H)，3.02-2.90(m，1H)，2.39-2.22(m，2H)，2.17-2.00(m，4H)，1.99-1.78(m，3H)，1.68-1.43(m，10H).

Example 41: (R) -1- [ (2, 5-difluoro-phenylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (2, 5-difluoro-phenyl) -acetamide

The sub-title compound (3.6g, 90%, orange solid) was prepared by analogous operation to that used to prepare example 38a using 2, 5-difluoroaniline in place of 2, 6-difluoroaniline.

¹H NMR(400MHz，CDCl₃)：δ8.42(s，1H)，8.13(ddd，1H)，7.08(ddd，1H)，6.82-6.75(m，1H)，4.04(s，2H).

A mixture of 2-bromo-N- (2, 5-difluoro-phenyl) -acetamide (example 41a) (47mg) and 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (56mg) in MeCN (1mL) was stirred at room temperature for 30 h. The resulting precipitate was filtered off, washed with diethyl ether and dried under vacuum at 50 ℃ overnight to give the title compound (65mg) as a colourless solid.

m/e 497[M]⁺

¹H NMR(400MHz，DMSO-d₆)：δ10.51(s，1H)，7.82-7.75(m，1H)，7.38-7.26(m，5H)，7.21-7.16(m，1H)，7.09-7.01(m，1H)，5.12-5.06(m，1H)，4.25(s，2H)，4.05(ddd，1H)，3.61-3.48(m，4H)，3.42-3.29(m，1H)，2.36-2.23(m，2H)，2.17-2.06(m，2H)，1.98-1.85(m，3H)，1.76-1.67(m，1H)，1.66-1.41(m，9H).

Example 42: (R) -1- [2- (4-cyano-benzyloxy) -ethyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

A mixture of 4- (2-bromo-ethoxymethyl) -benzonitrile (41mg, 0.17mmol) and 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (51mg) in MeCN (1mL) was stirred at room temperature for 16 h and then heated to 80 ℃ under nitrogen overnight. The resulting solid was filtered off, washed with diethyl ether and dried in vacuo to give the title compound (70mg) as a white solid.

m/e 487[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ7.80(dd，2H)，7.48(d，2H)，7.31-7.22(m，4H)，7.22-7.16(m，1H)，5.06-4.96(m，1H)，4.57(s，2H)，3.94-3.78(m，3H)，3.56-3.35(m，5H)，3.27-3.18(m，1H)，3.11-3.00(m，1H)，2.36-2.18(m，2H)，2.08(d，2H)，1.98-1.77(m，3H)，1.72-1.60(m，1H)，1.60-1.38(m，9H).

Example 43: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [ (6-trifluoromethyl-pyridin-2-ylcarbamoyl) -methyl ] -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (3-trifluoromethyl-phenyl) -acetamide

The sub-title compound (1.1g, aliquot, white solid) was prepared by analogous procedures to those used to prepare example 14f using 2-amino-6- (trifluoromethyl) pyridine instead of 2-amino-pyridine and adding chloroacetyl chloride at room temperature instead of at 0 ℃.

¹H NMR(300MHz，CDCl₃)：δ8.90(s，1H)，8.42(d，1H)，7.92(t，1H)，7.48(d，1H)，4.22(s，2H).

The title compound (66mg, 76%, white solid) was prepared by analogous procedure to that used to prepare example 14 using 2-chloro-N- (3-trifluoromethyl-phenyl) -acetamide (example 43a) instead of 2-chloro-N-pyridin-2-yl-acetamide.

m/e 530[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.48(s，1H)，8.25(d，1H)，8.14(t，1H)，7.67(d，1H)，7.33-7.26(m，4H)，7.22-7.17(m，1H)，5.12-5.05(m，1H)，4.28(s，2H)，4.11-4.03(m，1H)，3.66-3.49(m，4H)，3.41-3.29(m，1H)，2.36-2.23(m，2H)，2.18-2.06(m，2H)，2.00-1.82(m，3H)，1.79-1.66(m，1H)，1.66-1.40(m，9H).

Example 44: (R) -1- [ (4-methyl-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (4-methyl-pyridin-2-yl) -acetamide

The sub-title compound (1.3g, 74% solid) was prepared by analogous procedures to those used to prepare example 14f using 2-amino-4-methylpyridine instead of 2-amino-pyridine and adding chloroacetyl chloride at room temperature instead of at 0 ℃.

¹H NMR(400MHz，CDCl₃)：δ8.77(s，1H)，8.17(d，1H)，8.03(s，1H)，6.93(d，1H)，4.19(s，2H)，2.39(s，3H).

To a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (100mg) in 1mL MeCN was added 2-chloro-N- (4-methyl-pyridin-2-yl) -acetamide (example 44a) (62mg) and the mixture was stirred at room temperature for 21 hours. The precipitate was filtered off and dried in vacuo at 50 ℃ to give the title compound (80mg) as a white solid.

m/e 476[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.98(s，1H)，8.18(d，1H)，7.85(s，1H)，7.33-7.26(m，4H)，7.22-7.17(m，1H)，7.02-7.00(m，1H)，5.11-5.04(m，1H)，4.24(s，2H)，4.10-4.02(m，1H)，3.64-3.50(m，4H)，3.40-3.29(m，1H)，2.42-2.20(m，5H)，2.17-2.06(m，2H)，1.98-1.84(m，3H)，1.79-1.67(m，1H)，1.73-1.31(m，9H).

Example 45: (R) -1- [ (5-chloro-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (5-chloro-pyridin-2-yl) -acetamide

The sub-title compound (0.33g, 20%) was prepared by analogous procedures to those used to prepare example 14f using 2-amino-5-chloropyridine instead of 2-amino-pyridine and adding chloroacetyl chloride at room temperature instead of at 0 ℃.

¹H NMR(400MHz，CDCl₃)：δ8.80(s，1H)，8.28(d，1H)，8.19(d，1H)，7.70(dd，1H)，4.20(d，2H).

The title compound (103mg, 63%, white solid) was prepared by analogous procedure to that used to prepare example 44 using 2-chloro-N- (5-chloro-pyridin-2-yl) -acetamide (example 45a) instead of 2-chloro-N- (4-methyl-pyridin-2-yl) -acetamide.

m/e 496[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.26(s，1H)，8.41-8.39(m，1H)，8.02-7.94(m，2H)，7.32-7.25(m，4H)，7.22-7.17(m，1H)，5.12-5.03(m，1H)，4.27(s，2H)，4.09-4.02(m，1H)，3.63-3.50(m，4H)，3.42-3.32(m，1H)，2.37-2.23(m，2H)，2.17-2.05(m，2H)，1.99-1.84(m，3H)，1.78-1.65(m，1H)，1.65-1.39(m，9H).

Example 46: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (p-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N-p-tolyl-acetamide

To a solution of p-toluidine (2.35g) in 100mL of dichloromethane was added potassium carbonate (6.21 g). The reaction mixture was flushed with argon and bromoacetyl bromide (1.6mL) was then added dropwise and the reaction mixture was stirred for 17 hours. Water was added and the layers were separated. The organic layer was treated with cyclohexane and reduced in volume under vacuum, which caused a solid to precipitate, which was filtered off to give the sub-title compound (2.67g) as an off-white solid.

¹H NMR(400MHz，CDCl₃)：δ8.06(s，1H)，7.40(d，2H)，7.16(d，2H)，4.01(s，2H)，2.33(s，3H).

To a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (51mg) in acetonitrile (1mL) was added 2-bromo-N-p-tolyl-acetamide (example 46a) (39 mg). The reaction mixture was stirred at room temperature overnight and acetonitrile was removed under reduced pressure. The material was recrystallized from acetonitrile/ethyl acetate to give the title compound as a colourless solid (16 mg).

m/e 475[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.40(s，1H)，7.40(d，2H)，7.33-7.25(m，4H)，7.21-7.16(m，1H)，7.13(d，2H)，5.11-5.04(m，1H)，4.13(q，2H)，4.09-4.00(m，1H)，3.64-3.48(m，4H)，3.42-3.36(m，1H)，2.37-2.23(m，2H)，2.23(s，3H)，2.17-2.04(m，2H)，1.95-1.86(m，3H)，1.78-1.66(m，1H)，1.65-1.40(m，9H).

Example 47: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (m-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N-m-tolyl-acetamide

To a solution of m-toluidine (5.35g) in 150mL of dichloromethane was added potassium carbonate (17.3 g). The reaction mixture was flushed with argon and bromoacetyl bromide (3.6mL) was added dropwise over 15 minutes and the reaction mixture was stirred for 2.5 hours. Water was added and the layers were separated. The organic layer was evaporated and the residue was treated with EtOAc/cyclohexane. The precipitate was filtered off and discarded. The mother liquor was evaporated and purified by silica gel chromatography (eluting with 0-100% EtOAc/cyclohexane) to give the sub-title compound (6.13g) as an off-white solid.

¹H NMR(400MHz，CDCl₃)：δ8.06(s，1H)，7.38-7.28(m，2H)，7.27-7.21(t，1H)，6.98(d，1H)，4.02(s，2H)，2.36(s，3H).

To a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (50mg) in acetonitrile (1mL) was added 2-bromo-N-m-tolyl-acetamide (example 47a) (38 mg). The reaction mixture was stirred at room temperature for 26 hours and acetonitrile was removed under reduced pressure. The material was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound (37mg) as a colorless foam.

m/e 475[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.40(s，1H)，7.39(s，1H)，7.32-7.25(m，5H)，7.22-7.15(m，2H)，6.92(d，1H)，5.11-5.05(m，1H)，4.14(q，2H)，4.11-4.01(m，1H)，3.64-3.48(m，4H)，3.42-3.30(m，1H)，2.39-2.21(m，5H)，2.18-2.05(m，2H)，1.97-1.84(m，3H)，1.77-1.66(m，1H)，1.65-1.39(m，9H).

Example 48: (R) -1- (oxazol-2-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N-oxazol-2-yl-acetamide

Bromoacetyl bromide (0.44mL) in anhydrous CHCl₃(5mL) solution was added dropwise to 2-amino-1, 3-oxazole (0.39g) and triethylamine (0.96mL) in anhydrous CHCl at room temperature₃(92 mL). The brown mixture was stirred for 16 hours and then with H₂O (2mL) was quenched and stirred for 20 minutes before being concentrated under reduced pressure to a light brown solid. The crude product is purified by chromatography on silica gel (using1-3% MeOH in dichloromethane) to give the title compound (0.56g) as an off-white solid.

¹H NMR(400MHz，DMSO-D₆)：δ11.61(s，1H)，7.89(s，1H)，7.12(s，1H)，4.11(s，2H).

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.31mmol) and 2-bromo-N-oxazol-2-yl-acetamide (example 48a) (0.31mmol) were stirred at room temperature in anhydrous MeCN for 18 h. The reaction mixture was concentrated in vacuo and the yellow solid was purified by flash silica gel column chromatography (eluting with 0-15% MeOH in dichloromethane) to give the title compound (100mg) as a white solid.

m/e 452[M]⁺

¹H NMR(400MHz，DMSO-D₆，353K)：δ7.67(s，1H)，7.35-7.29(m，4H)，7.26-7.18(m，1H)，7.02(s，1H)，5.14-5.05(m，1H)，4.17-4.04(m，3H)，3.66-3.56(m，4H)，3.52-3.40(m，1H)，2.42-2.29(m，2H)，2.24-2.12(m，2H)，2.10-1.86(m，3H)，1.82-1.70(m，1H)，1.70-1.47(m，9H).

Example 49: (R) -1- [ (6-methyl-pyridazin-3-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

a) 2-bromo-N- (6-methyl-pyridazin-3-yl) -acetamide

Bromoacetyl bromide (0.22mL) in anhydrous CHCl₃(4mL) solution was slowly added to 3-amino-6-methylpyridazine (0.24g) and triethylamine (0.47mL) in anhydrous CHCl at room temperature₃(45mL) in suspension. The brown mixture was stirred for 3.5 hours and then with H₂O (1.5mL) was quenched and stirred for 20 minutes before being concentrated under reduced pressure to a brown solid. The crude product was purified by silica gel chromatography (eluting with 1-2% MeOH in dichloromethane). The relevant fractions were combined and evaporated to give the title compound (0.20g) as a pink/beige solid.

¹H NMR(400MHz，DMSO-D₆)：δ11.41(s，1H)，8.18(d，1H)，7.59(d，1H)，4.17(s，2H)，2.57(s，3H).

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.20mmol) and 2-bromo-N- (6-methyl-pyridazin-3-yl) -acetamide (example 49a) (0.20mmol) were stirred together at room temperature in anhydrous MeCN for 18 h. The reaction mixture was concentrated in vacuo and the yellow solid was purified by flash silica gel column chromatography (eluting with 0-15% MeOH in dichloromethane) to give the title compound (65mg) as a brown solid.

m/e 477[M]⁺

¹H NMR(400MHz，CDCl₃)：δ8.19(d，1H)，7.38(d，1H)，7.27(d，4H)，7.20-7.12(m，1H)，5.18-4.96(m，3H)，4.41(dd，1H)，4.11-3.95(m，3H)，3.81(d，1H)，3.47-3.37(m，1H)，2.66(s，3H)，2.45-2.27(m，2H)，2.26-2.13(m，2H)，2.08-1.96(m，3H)，1.81-1.68(m，1H)，1.69-1.30(m，9H).

Example 50: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (pyrimidin-2-yl) -acetamide

A solution of 2-amino-pyrimidine (2.0g) in anhydrous dichloromethane (17mL) was treated with triethylamine (2.6mL) under nitrogen at 0 deg.C, followed by the slow addition of chloroacetyl chloride (1.5mL, 18.4 mmol). The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water, the phases were separated and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with 10% MeOH in dichloromethane). The relevant fractions were combined and evaporated to give the title compound (1.20g) as a green solid.

¹H NMR(400MHz，CDCl₃)：δ8.84(s，1H)，8.65(d，2H)，7.09(t，1H)，4.46(s，2H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e, 0.30mmol) and 2-chloro-N- (pyrimidin-2-yl) -acetamide (example 50a) (0.36mmol) in MeCN (1.5mL) was stirred together at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound as a white solid (90 mg).

m/e 463[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.19(s，1H)，8.66(d，2H)，7.32-7.24(m，4H)，7.23-7.14(m，2H)，5.09-5.03(m，1H)，4.48(s，2H)，4.06(ddd，1H)，3.65-3.51(m，4H)，3.45-3.34(m，1H)，2.37-2.21(m，2H)，2.15-2.07(m，2H)，1.96-1.80(m，3H)，1.75-1.64(m，1H)，1.63-1.38(m，9H).

Example 51: (R) -1- [ (5-cyano-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (5-cyano-pyridin-2-yl) -acetamide

A solution of 2-amino-5-cyanopyridine (2.0g) in dry dichloromethane (17mL) was treated with triethylamine (2.6mL) under nitrogen at 0 deg.C followed by the slow addition of chloroacetyl chloride (1.5 mL). The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with 50% EtOAc/cyclohexane). The relevant fractions were combined and evaporated to give the title compound (2.17g) as a light brown solid.

¹H NMR(400MHz，CDCl₃)：δ8.99(s，1H)，8.61(dd，1H)，8.36(dd，1H)，8.00-7.97(m，1H)，4.23(s，2H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.30mmol) and 2-chloro-N- (5-cyano-pyridin-2-yl) -acetamide (example 51a) (0.36mmol) in MeCN (1.5mL) was stirred together overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound as a white solid (60 mg).

m/e 487[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.56(s，1H)，8.81(dd，1H)，8.31(dd，1H)，8.09(d，1H)，7.32-7.25(m，4H)，7.23-7.17(m，1H)，5.11-5.04(m，1H)，4.32(s，2H)，4.10-4.01(m，1H)，3.63-3.50(m，4H)，3.42-3.29(m，1H)，2.37-2.23(m，2H)，2.17-2.05(m，2H)，2.00-1.82(m，3H)，1.78-1.65(m，1H)，1.65-1.40(m，9H).

Example 52: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N-pyrimidin-5-yl-acetamides

5-aminopyrimidine (450mg) was suspended in DCE (2mL) and acetonitrile (2mL) in a microwave vial. Chloroacetyl chloride (0.377mL) was added with stirring. The vial was sealed and the reaction mixture was heated in a microwave at 80 ℃ for 5 minutes. The solid was filtered off, washed with acetonitrile (2 × 5mL), DCE (2 × 5mL) and pentane (2 × 30mL) and then partitioned between saturated sodium bicarbonate and DCE (50mL/50mL), which ensures that the aqueous layer was still basic. The organic layer was separated and the aqueous layer was extracted with DCE (2 × 75 mL). The combined organic layers were dried over magnesium sulfate and evaporated to give the sub-title compound (200mg) as a yellow solid.

¹H NMR(400MHz，DMSO-D₆)：δ10.71(s，1H)，9.00(s，2H)，8.93(s，1H)，4.35(s，2H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (115mg) in acetonitrile (2mL) was treated with 2-chloro-N-pyrimidin-5-yl-acetamide (example 52a) (66mg) to give a dark brown solution which was stirred at room temperature overnight. The resulting solid was filtered off, washed with cold acetonitrile (2mL) and pentane (3mL) and dried under vacuum at 45 ℃ to give the title compound as a brown solid (151 mg).

m/e 463[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.70(s，1H)，9.01(s，2H)，8.93(s，1H)，7.33-7.26(m，4H)，7.22-7.16(m，1H)，5.11-5.05(m，1H)，4.34(s，2H)，4.12-4.04(m，1H)，3.67-3.52(m，4H)，3.43-3.31(m，1H)，2.37-2.22(m，2H)，2.17-2.06(m，2H)，1.99-1.83(m，3H)，1.79-1.67(m，1H)，1.65-1.40(m，9H).

Example 53: (R) -1- [ (3-fluoro-pyridin-2-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (3-fluoro-pyridin-2-yl) -acetamide

2-amino-3-fluoropyridine (1.5g) was dissolved in DCE (15mL) and chloroacetyl chloride (1.1mL) was added dropwise. The reaction mixture was heated in a microwave at 80 ℃ for 5 minutes. The reaction mixture was cooled and the resulting solid was filtered off, washed with DCE, MeCN and pentane and then suspended in dichloromethane and NaHCO was added₃Aqueous solution (saturated). The organic phase was separated and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (eluting with 0-100% EtOAc/cyclohexane) to give the title compound as a white solid (800 mg).

¹H NMR(400MHz，DMSO-D₆)：δ10.61(s，1H)，8.27(dt，1H)，7.83-7.77(m，1H)，7.41-7.35(m，1H)，4.37(s，2H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.30mmol) and 2-chloro-N- (3-fluoro-pyridin-2-yl) -acetamide (example 53a) (0.36mmol) in MeCN (1.5mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound as a white solid (86 mg).

m/e 480[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.07(s，1H)，8.25(dt，1H)，7.81(ddd，1H)，7.39(ddd，1H)，7.31-7.24(m，4H)，7.22-7.15(m，1H)，5.11-5.04(m，1H)，4.36(s，2H)，4.11-4.04(m，1H)，3.66-3.52(m，4H)，3.44-3.32(m，1H)，2.37-2.21(m，2H)，2.19-2.06(m，2H)，1.99-1.82(m，3H)，1.77-1.65(m，1H)，1.65-1.38(m，9H).

Example 54: (R) -1- [ (3-fluoro-pyridin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (3-fluoro-pyridin-4-yl) -acetamide

A solution of 3-fluoro-pyridin-4-ylamine (0.2g) in dry dichloromethane (2mL) was treated with triethylamine (0.28mL) under nitrogen at 0 deg.C followed by the slow addition of chloroacetyl chloride (0.16 mL). The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with 0-100% EtOAc/cyclohexane). The relevant fractions were combined and evaporated to give the title compound (0.11g) as a pink solid.

¹H NMR(400MHz，DMSO-D₆)：δ10.55(s，1H)，8.56(d，1H)，8.35(d，1H)，8.16(dd，1H)，4.44(s，2H).

Example 54: (R) -1- [ (3-fluoro-pyridin-4-ylcarbamoyl) -methyl]-3- (1-phenyl-cycloheptanecarbonyloxy) -1-nitrogen-bicyclo [2.2.2]Octane chloride

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.30mmol) and 2-chloro-N- (3-fluoro-pyridin-4-yl) -acetamide (example 54a) (0.36mmol) in MeCN (1.5mL) was stirred together overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound as a white solid (110 mg).

m/e 480[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ10.92(s，1H)，8.56(d，1H)，8.35(d，1H)，8.03(dd，1H)，7.32-7.26(m，4H)，7.21-7.16(m，1H)，5.11-5.05(m，1H)，4.41-4.29(m，2H)，4.10-4.02(m，1H)，3.63-3.50(m，4H)，3.42-3.30(m，1H)，2.36-2.23(m，2H)，2.17-2.06(m，2H)，1.98-1.82(m，3H)，1.78-1.65(m，1H)，1.66-1.40(m，9H).

Example 55: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {2- [ (pyrazin-2-ylcarbonyl) -amino ] -ethyl } -1-azonia-bicyclo [2.2.2] octane bromide

a) Pyrazine-2-carboxylic acid (2-bromo-ethyl) -amides

A solution of 2-pyrazinecarboxylic acid (1g) in dichloromethane (30mL) was treated with triethylamine (1.27mL) HATU (3.6g) and the mixture was stirred for 10 min. A solution of 2-bromoethylamine hydrobromide (1.5g) and triethylamine (1.27mL) in dichloromethane (20mL) was added and the reaction mixture was stirred for 3 hours. Water (50mL) was added and the organic layer was separated and washed with water (3 × 50 mL). The organic layer was dried over magnesium sulfate and evaporated to give the crude product, which was purified by silica gel chromatography (eluting with 0-100% EtOAc/dichloromethane). The relevant fractions were combined and evaporated to give a residue which was dissolved in EtOAc (40mL) and washed with saturated sodium bicarbonate, which ensured that the aqueous layer was basic. The organic layer was dried over magnesium sulfate and evaporated to give the sub-title compound (1.0g) as a white solid.

¹H NMR(400MHz，DMSO-D₆)：δ9.21(d，1H)，9.14(t，1H)，8.90(d，1H)，8.75(dd，1H)，3.75-3.69(m，2H)，3.66-3.60(m，2H).

Pyrazine-2-carboxylic acid (2-bromo-ethyl) -amide (example 55a) (87mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (113mg) in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The solid precipitated out and was filtered off, washed with cold acetonitrile and dried in vacuo at 40 ℃ to give the title compound (96mg) as a white solid.

m/e 477[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ9.22(t，1H)，9.17(d，1H)，8.88(d，1H)，8.72(dd，1H)，7.33-7.25(m，4H)，7.22-7.16(m，1H)，5.01-4.96(m，1H)，3.89(ddd，1H)，3.73-3.57(m，2H)，3.51-3.28(m，5H)，3.22(dt，1H)，3.13-3.02(m，1H)，2.38-2.30(m，1H)，2.30-2.20(m，1H)，2.17-2.06(m，2H)，1.97-1.76(m，3H)，1.69-1.37(m，10H).

Example 56: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- ([1, 2, 4] thiadiazol-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- [1, 2, 4] thiadiazol-5-yl-acetamides

A solution of [1, 2, 4] -thiadiazol-5-ylamine (3.0g) in anhydrous dichloromethane (30mL) was treated with triethylamine (4.6mL) under nitrogen at 0 deg.C, followed by the slow addition of chloroacetyl chloride (2.6 mL). The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel chromatography (eluting with 50-75% EtOAc/cyclohexane) to give the title compound (1.00g) as a yellow solid.

¹H NMR(400MHz，DMSO-D₆)：δ13.32(s，1H)，8.51(s，1H)，4.52(s，2H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.30mmol) and 2-chloro-N- [1, 2, 4] thiadiazol-5-yl-acetamide (0.36mmol) (example 56a) in MeCN (1.5mL) was stirred at room temperature overnight. The reaction mixture was filtered and the resulting solid was washed with cold MeCN to give the title compound (30mg) as a solid.

m/e 469[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ13.70(s，1H)，8.51(s，1H)，7.34-7.27(m，4H)，7.22-7.17(m，1H)，5.11-5.05(m，1H)，4.54-4.43(m，2H)，4.12-4.05(m，1H)，3.67-3.53(m，4H)，3.45-3.33(m，1H)，2.38-2.24(m，2H)，2.18-2.05(m，2H)，1.99-1.83(m，3H)，1.80-1.67(m，1H)，1.67-1.40(m，9H).

Example 57: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {3- [ (pyridin-2-ylcarbonyl) -amino ] -propyl } -1-azonia-bicyclo [2.2.2] octane bromide

a) Methanesulfonic acid 3- [ (pyridin-2-ylcarbonyl) -amino ] -propyl ester

Isobutyl chloroformate (3.35mL) was added to a solution of 2-pyridinecarboxylic acid (2.10g) and N-methylmorpholine (2.82mL) in dry THF (85mL) at 0 ℃. After 15 minutes, 3-amino-1-propanol (1.31mL) was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo to a pink solid and passed through a plug of silica gel (1-5% MeOH in dichloromethane). The resulting brown oil was taken up in dichloromethane (85mL) and cooled to 0 ℃. Et was added to the solution₃N (4.75mL) and methanesulfonyl chloride (2.0 mL). After 30 minutes, the reaction mixture was warmed to room temperature and stirred for 2.5 hours, then with H₂O (50mL) quench. The layers were separated and the organic phase was washed with saturated NaHCO₃(aq) washed and dried (MgSO₄). Concentration under reduced pressure gave an orange oil which was purified by silica gel chromatography (eluting with 90% EtOAc/cyclohexane) to give the sub-title compound (2.06g) as an orange oil.

¹H NMR(400MHz，CDCl₃)：δ8.55(ddd，1H)，8.29(s，1H)，8.17(dt，1H)，7.88-7.83(m，1H)，7.45(ddd，1H)，4.35(t，2H)，3.63(q，2H)，3.07(s，3H)，2.11(p，2H).

b) Pyridine-2-carboxylic acid (3-bromo-propyl) -amide

Methanesulfonic acid 3- [ (pyridin-2-ylcarbonyl) -amino]A mixture of propyl ester (example 57a) (1.96g) and lithium bromide (3.29g) in acetone (19mL) was heated to reflux and held for 2 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was taken up in EtOAc/H₂Partition between O (60mL, 1: 1). The phases were separated and the aqueous phase was further extracted with EtOAc (2 × 25 mL). The combined organics were dried (MgSO)₄) And concentrated in vacuo to a brown oil which solidified on standing. Purification by silica gel chromatography (eluting with 0-100% EtOAc/cyclohexane) afforded the sub-title compound (1.5g) as a white solid.

¹H NMR(400MHz，CDCl₃)：δ8.55(ddd，1H)，8.25-8.12(s，1H)，8.19(dt，1H)，7.85(td，1H)，7.43(ddd，1H)，3.64(q，2H)，3.50(t，2H)，2.22(p，2H).

1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.31mmol) and pyridine-2-carboxylic acid (3-bromo-propyl) -amide (example 57b) (0.31mmol) were stirred together in anhydrous MeCN (3mL) at room temperature for 16 days. The reaction mixture was concentrated in vacuo and the solid was purified by silica gel chromatography (eluting with 0-15% MeOH in dichloromethane) to give the title compound (145mg) as a white solid.

m/e 490[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ8.94(t，1H)，8.62(ddd，1H)，8.03-7.95(m，2H)，7.58(ddd，1H)，7.31-7.24(m，4H)，7.19-7.13(m，1H)，5.01-4.95(m，1H)，3.76(ddd，1H)，3.51-3.09(m，7H)，3.09-3.01(m，1H)，2.93-2.82(m，1H)，2.36-2.22(m，2H)，2.14-2.06(m，2H)，1.99-1.90(m，1H)，1.92-1.71(m，4H)，1.68-1.39(m，10H).

Example 58: (R) -1- [ (2-methyl-pyrimidin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (2-methyl-pyrimidin-4-yl) -acetamide

2-methyl-pyrimidin-4-ylamine (545mg) was suspended in DCE (5mL) and chloroacetyl chloride (0.4mL) was added dropwise. The reaction mixture was heated in a microwave at 80 ℃ for 5 minutes. The reaction mixture was cooled to give a solid which was filtered, washed with dichloromethane then suspended in dichloromethane and saturated NaHCO was added₃(aq). The organic phase was collected and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to afford the sub-title compound as a yellow solid (70mg, 7.5%).

¹H NMR(400MHz，DMSO-D₆)：δ11.16(s，1H)，8.58(d，1H)，7.84(d，1H)，4.37(s，2H)，2.53(s，3H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e, 0.29mmol) and 2-chloro-N- (2-methyl-pyrimidin-4-yl) -acetamide (example 58a) (0.35mmol) in MeCN (2.0mL) was stirred together at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound as a white solid (55 mg).

m/e 477[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.40(s，1H)，8.61(d，1H)，7.75(d，1H)，7.32-7.25(m，4H)，7.23-7.17(m，1H)，5.10-5.03(m，1H)，4.28(s，2H)，4.09-4.01(m，1H)，3.62-3.48(m，4H)，3.40-3.30(m，1H)，2.50(s，3H)，2.36-2.24(m，2H)，2.17-2.05(m，2H)，1.98-1.84(m，3H)，1.78-1.65(m，1H)，1.64-1.41(m，9H).

Example 59: (R) -1- [ (6-methyl-pyrimidin-4-ylcarbamoyl) -methyl ] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane chloride

a) 2-chloro-N- (6-methyl-pyrimidin-4-yl) -acetamide

6-methyl-pyrimidin-4-ylamine (545mg) was suspended in DCE (5mL) and chloroacetyl chloride (0.4mL) was added dropwise. The reaction mixture was heated in a microwave at 80 ℃ for 5 minutes. The reaction mixture was cooled, filtered and a solid was obtained. The reaction was repeated a second time and the two solid batches were combined, washed with dichloromethane and then suspended in dichloromethane and saturated NaHC0 was added₃(aq.). The organic phase was collected and the aqueous layer was extracted with dichloromethane (× 2). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluting with 0-10% MeOH in dichloromethane),the sub-title compound was obtained as a yellow solid (120 mg).

¹H NMR(400MHz，DMSO-D₆)：δ11.11(s，1H)，8.76(d，1H)，7.91(s，1H)，4.38(s，2H)，2.44(s，3H).

A solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (0.30mmol) and 2-chloro-N- (6-methyl-pyrimidin-4-yl) -acetamide (example 59a) (0.36mmol) in MeCN (2mL) was stirred together at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound as a white solid (125 mg).

m/e 477[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ11.39(s，1H)，8.76(d，1H)，7.83(s，1H)，7.34-7.26(m，4H)，7.22-7.17(m，1H)，5.10-5.04(m，1H)，4.32(s，2H)，4.10-4.01(m，1H)，3.64-3.50(m，4H)，3.43-3.31(m，1H)，2.42(s，3H)，2.37-2.23(m，2H)，2.18-2.06(m，2H)，1.98-1.81(m，3H)，1.78-1.66(m，1H)，1.65-1.39(m，9H).

Example 60: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {2- [ (pyridin-2-ylcarbonyl) -amino ] -ethyl } -1-azonia-bicyclo [2.2.2] octane bromide

a) Pyridine-2-carboxylic acid (2-bromo-ethyl) -amide

A solution of pyridine-2-carboxylic acid (0.99g) in dichloromethane (30mL) was treated with triethylamine (1.27mL) and HATU (3.6 g). The mixture was stirred for 10 minutes, then a solution of 2-bromoethylamine hydrobromide (1.5g) and triethylamine (1.27mL) in dichloromethane (20mL) was added. The reaction mixture was stirred for 3 hours. Water (50mL) was added and the layers were separated. The organic layer was washed with water (3 × 50mL), dried over magnesium sulfate and evaporated to give the crude product, which was purified by silica gel chromatography (eluting with 0-100% EtOAc/dichloromethane). The relevant fractions were combined and evaporated, taken up in EtOAc (40mL) and washed with saturated sodium bicarbonate solution, which ensures that the aqueous layer remained basic. The organic layer was dried over magnesium sulfate and evaporated to give the sub-title compound (0.88g) as a white solid.

¹H NMR(400MHz，DMSO-D₆)：δ9.01(t，1H)，8.66(ddd，1H)，8.07-7.98(m，2H)，7.62(ddd，1H)，3.70(q，2H)，3.62(t，2H).

Pyridine-2-carboxylic acid (2-bromo-ethyl) -amide (example 60a) (75mg) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [2.2.2] oct-3-yl) ester (example 14e) (98mg) in acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 16 hours. An additional 10mg of pyridine-2-carboxylic acid (2-bromo-ethyl) -amide was added and the reaction mixture was stirred for 8 hours. The volatiles were evaporated and the residue was purified by silica gel chromatography (eluting with 0-10% MeOH in dichloromethane) to give the title compound (55mg) as a white solid.

m/e 476[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ9.12(t，1H)，8.64-8.62(m，1H)，8.05-7.97(m，2H)，7.61(ddd，1H)，7.32-7.25(m，4H)，7.22-7.15(m，1H)，5.02-4.96(m，1H)，3.88(ddd，1H)，3.71-3.55(m，2H)，3.49-3.27(m，5H)，3.22(dt，1H)，3.12-3.02(m，1H)，2.38-2.20(m，2H)，2.17-2.07(m，2H)，1.96-1.75(m，3H)，1.69-1.38(m，10H).

Example 61: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (3- (pyridin-4-yl) -propyl) -1-azonia-bicyclo [2.2.2] octane bromide

a)4- (3-bromo-propyl) -pyridinium bromide

A solution of 3- (pyridin-4-yl) -propan-1-ol (2.88mL) in hydrobromic acid (16mL, 141.43mmol) was heated at 135 ℃ at reflux for 18 h. The cooled solution was concentrated in vacuo and the residue was redissolved in isopropanol and re-concentrated (this operation was repeated 3 more times). The residue was dissolved in isopropanol, decolorized by boiling with activated carbon, filtered, and the clear solution was crystallized by standing in a refrigerator over 48 hours. The resulting crystals were removed by filtration, washed with isopropanol/diethyl ether (1: 1) followed by diethyl ether and then dried under vacuum at 40 ℃ and room temperature to give the sub-title compound as a light brown solid (3.55 g).

¹H NMR(400MHz，D₂O): δ 8.64(d, 2H), 7.96(d, 2H), 3.52(t, 2H), 3.12(t, 2H), 2.30 (quintuple, 2H).

4- (3-bromo-propyl) -pyridine hydrobromide (example 61a) (0.210g) was added to diethyl ether (10mL) and sodium hydroxide solution (4mL) (10%) in a separatory funnel and the mixture was shaken and separated. The ether layer was washed with water (2X 10mL) and dried (MgSO)₄) And evaporated to give the free base as an oil. To the residue was added 1-phenyl-cycloheptanecarboxylic acid (R) - (1-aza-bicyclo [ 2.2.2)]Oct-3-yl) ester (example 1e) (0.245g) and acetonitrile (2mL) and left to stand for 2 days. Ether (20mL) was added to give an oil, the supernatant was decanted off and the residue was washed with ethyl acetate (2 × 20 mL). The oil was crystallized by stirring with diethyl ether (20mL) and the solid was washed twice with diethyl ether (2 × 20mL) to give the title compound as a solid (0.094 g).

m/e 447[M]⁺

¹H NMR(400MHz，DMSO-D₆)：δ8.51(d，2H)，7.35-7.30(m，4H)，7.30-7.27(m，2H)，7.24-7.18(m，1H)，5.07-5.01(m，1H)，3.81(ddd，1H)，3.43-3.27(m，2H)，3.21-3.14(m，1H)，3.10(d，1H)，2.97-2.88(m，2H)，2.59(t，2H)，2.40-2.27(m，3H)，2.18-2.10(m，2H)，2.04-1.76(m，5H)，1.72-1.43(m，10H).

Pharmacological analysis

M3 receptor Activity assay

In the form of a Scintillation Proximity Assay (SPA) consisting of³H]N-methylscopolamine (NMS) on expression of human muscarinic acetylcholine M₃Receptor (M)₃-ACh) of CHO-K1 (Chinese hamster ovary) cell membranes, determining the M-binding of the compounds₃Affinity of the receptor (pIC)₅₀)。

SPA beads were precoated with cell membrane, and then a serial dilution of the compound of the present invention, 0.2nM, at a concentration of 2mg beads/well³H]NMS, half Kd (dissociation constant determined experimentally) and assay buffer (20)mM HEPES pH 7.4, containing 5mM MgCl₂) And (5) culturing. The assay was performed in a final volume of 200. mu.L in the presence of 1% (v/v) Dimethylsulfoxide (DMSO). Measured in the absence of a competitive compound³H]Total binding of NMS, determined in the presence of 1. mu.M atropine³H]Non-specific binding of NMS. Plates were incubated at room temperature for 16 hours, then normalized³H protocol in Wallac Microbeta^TMAnd (4) reading. Determining pIC₅₀Value, pIC₅₀Is defined as specific [ 2]³H]Negative logarithm of compound concentration required for 50% reduction of NMS binding. Table 1 shows pIC of some representative examples₅₀Numerical values.

TABLE 1

Table 2 gives the IC's of the compounds of the examples₅₀Strength.

TABLE 2

M3 binding IC₅₀< 2nM means "+ + +"; IC (integrated circuit)₅₀2-10nM represents "+"; IC (integrated circuit)₅₀> 10nM represents "+"; NT-was not tested.

Plasma protein binding measurements

The extent of plasma protein binding was determined by equilibrium dialysis of the compound between human plasma and buffered water solution at 37 ℃ and the concentration of the compound in plasma and buffer was determined by HPLC-MS/MS.

Method

Dialysis cells (cut-off 5000) were prepared by rinsing with water and then soaking in dialysis buffer for a minimum of 1 hour. The dialysis buffer was isotonic buffered saline at pH 7.4. A stock solution of the compound in dimethyl sulfoxide was prepared at a concentration of 0.5 mM. Frozen pooled human plasma (frozen pelleted human plasma) was obtained from volunteer subjects.

DMSO stock solutions of compounds were added to plasma at a rate of 10 μ Ι DMSO solution per ml plasma. This resulted in a 1% DMSO plasma solution containing various compounds at a concentration of 5 μ M.

Dialysis cells were then prepared and half of the cells were filled with 750. mu.l dialysis buffer and the other half with 750. mu.l plasma solution of the compound. Once prepared, the cells were sealed and placed in an incubator at 37 ℃. These cells were then spun for at least 4 hours to equilibrate.

After equilibration, 500. mu.l of the buffer sample was removed and added to the HPLC vial with 100. mu.l of plasma (sample in 6-fold diluted plasma), and 100. mu.l of the plasma sample was removed and added to the HPLC vial with 500. mu.l of dialysis buffer (sample in 6-fold diluted plasma).

The samples were then analyzed by HPLC-MS/MS. A four-point calibration curve was obtained as follows: the stock solution was diluted with 6-fold diluted plasma at concentrations of 0.013. mu.M, 0.05. mu.M, 0.25. mu.M and 1.25. mu.M, and the diluted stock solution, buffer sample and plasma sample were injected in this order.

Computing

The concentration of the compound in the sample was determined using MassLynx software (produced by Waters/Micromass) with version number 4.1, which automatically calculates the calibration curve and the concentration of the compound in the cells. Plasma protein binding, the percentage of compound bound in human plasma (percent bound,% bound), was determined from the calibration curve using the following equation;

table 3 shows the human plasma protein binding values measured using the procedure described above for some representative examples.

TABLE 3

Numbering of the Compounds of the examples	% binding
		11	95.2
13	93.2
		15	96.1
17	97.6
		20	98.2
21	99.4

Acetylcholine induced bronchoconstriction in vivo

Dunkin-Hartley guinea pigs (300-. Test compounds or excipients were administered to conscious guinea pigs either by inhalation or by intratracheal instillation (0.5ml/kg) under recoverable gas anesthesia (5% halothane). The guinea pigs were allowed to recover from anesthesia, and the degree of bronchoconstriction was measured. At up to 48 hours post-administration, guinea pigs were subjected to peripheral anesthesia using sodium pentobarbital (60mg/kg), catheterized into the trachea for artificial ventilation, and into the jugular vein for intravenous administration of methacholine. During the surgical preparation procedure, guinea pigs were ventilated with a constant volume respiratory pump (Harvard Rodent Ventilator model 683) at a rate of 60 breaths/min with a tidal volume of 5 mL/kg. Lung function (lung resistance and lung compliance) was measured in anesthetized and ventilated guinea pigs using the lung measurement Flexivent system (SCIREQ, Montreal, Canada) connected to an endotracheal tube. Guinea pigs were ventilated (in a half-sinusoidal ventilation mode) at a rate of 60 breaths/min and a tidal volume of 5 mL/kg. Is applied at 2-3cmH₂Positive end of breath pressure (positive end expiration pressure) of O. Respiratory resistance was measured using a Flexivent "snapshot" device (duration 1 second, frequency 1 Hz). Pulmonary resistance and lung compliance were measured before and after intravenous administration of methacholine (3, 10 and 30 μ g/kg), respectively. The increase in the peak of resistance following methacholine stimulation was calculated, and the effect of the test compound on methacholine-induced changes in lung function was calculated.

The percent inhibition of bronchoconstriction by methacholine was calculated for each dose according to the following formula:

intranasal administrationInhibition of pilocarpine-induced salivation by compounds

Guinea pigs (450-. Guinea pigs were randomly divided into treatment groups and weighed. Each guinea pig was lightly anesthetized (4% halothane) and was stimulated with pilocarpine by intranasal administration of the compound or vehicle (0.5ml/kg) for up to 24 hours. At this test time point, polyurethane (25% H) for guinea pigs was used₂O solution, 1.5g/kg) was subjected to peripheral anesthesia. Once adequate anesthesia had developed (i.e., no longer had the toe pinch reflex), an absorbent pad was placed in the mouth of each guinea pig to dry the remaining saliva, removed, and replaced with a new absorbent pad pre-weighed and held for 5 minutes, thereby forming a baseline reading of saliva production. At the end of this 5 minutes, the absorbent pad was removed and weighed. A pre-weighed new absorbent pad was inserted into the mouth of the guinea pig, and then pilocarpine (0.6mg/kg, 2ml/kg) was administered subcutaneously to the guinea pig under the skin of the neck. The absorbent pad was removed, weighed, and replaced with a new absorbent pad that was pre-weighed every 5 minutes for a total of 15 minutes.

The amount of saliva produced was calculated by subtracting the previously weighed absorbent pad weight from the weight of the absorbent pad after every 5 minutes, and these weights were added up to obtain the cumulative amount of saliva produced over a period of 15 minutes. Analysis can be performed every 5 minutes time, except for the entire 15 minute recording time. Assuming that the baseline value of saliva produced is constant, this baseline value is multiplied by 3 to give a baseline reading of saliva produced over a 15 minute period.

The inhibition of saliva production by the compounds was calculated by the following formula: (1- (test value-baseline value)/(vehicle value-baseline value)). 100.

Claims

1. A compound selected from the group consisting of:

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (3- (pyridin-4-yl) -propyl) -1-azonia-bicyclo [2.2.2] octane X,

2. The compound of claim 1 selected from:

3. A pharmaceutical composition comprising a compound according to claim 1 or claim 2 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

4. A process for the preparation of a pharmaceutical composition as claimed in claim 3 which comprises mixing a compound as claimed in claim 1 or claim 2 with a pharmaceutically acceptable adjuvant, diluent or carrier.

5. A compound according to claim 1 or claim 2 for use in therapy.

6. Use of a compound according to claim 1 or claim 2 in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease.

7. A method of treating chronic obstructive pulmonary disease in a warm-blooded animal such as man, comprising administering to a mammal in need of such treatment an effective amount of a compound as claimed in claim 1 or claim 2.

8. A pharmaceutical product comprising a combination of a first active ingredient and at least one further active ingredient, wherein the first active ingredient is a compound according to claim 1 or claim 2 and the further active ingredient is selected from:

● A phosphodiesterase inhibitor for the treatment of chronic hepatitis,

● beta 2-adrenoceptor agonists,

● modulators of chemokine receptor function,

● an inhibitor of the function of a kinase,

● A protease inhibitor is provided, which is useful as a protease inhibitor,

● a steroidal glucocorticoid receptor agonist, and

● non-steroidal glucocorticoid receptor agonists.