TW200946529A - New compounds - Google Patents

Abstract

The invention provides named compounds of formula (I), pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions and their use in therapy.

Description

200946529 IX. Description of the Invention: The present invention relates to a cycloalkyl-substituted alkyl ester of a polycyclic amino alcohol, a process for preparing the same, a pharmaceutical composition containing the same, and a method for preparing a pharmaceutical composition • its use in therapy and its intermediates for its preparation. [Prior Art] The scorpion venom receptor is a G-pr〇tein coupled receptor (GPCR) family having five family members, %, %, β M3, % and 仏. Of the five muscarinic subtypes, three (M|, Μ3) are known to produce physiological effects on human lung tissue. β Parasympathetic nerves are used to reflect bronchoconstriction in human trachea and release acetaminophen to muscarinic receptors. Choline to regulate tracheal tension (airway t〇ne) 2 main path. Tracheal tension has increased in patients with respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason, steroid receptor antagonists have been developed for the treatment of tracheal diseases. It is commonly recognized as a first-line therapy for individuals with COPD, and is described in the literature (example 1st, cu-2)

Pharmacology 2001, 1, 223-229). When used to treat a respiratory condition, a muscarinic receptor antagonist is typically administered via inhalation. However, when administered via 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 of the herbicides have a relatively short duration of action, requiring them to be administered several times a day. The daily 131174.doc 200946529 eve-drug regimen is inconvenient for the patient' and there is a significant risk of inadequate treatment due to the patient's non-compliance with frequent repeated dosing schedules. Therefore, there is still a need for new compounds capable of blocking muscarinic receptors. In detail, it is necessary to produce high-efficiency and low systemicity when administered by inhalation. In addition, there is also a need for a new anti-drug agent that exhibits a long duration of action when administered by inhalation and can withstand one or two doses per day. Reference WO 98/045 17 describes aryl% propane, arylcyclobutane, arylcyclopentane and arylcyclohexanecarboxylic acid II which have antimuscarinic activity against bladder smooth muscle. The application of PCT/GB2007/004350 is based on the compound of formula (1):

Wherein: R1 and R2 together with the carbon atom to which they are directly attached form a 7-membered aliphatic carbocyclic ring, which may optionally be substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Cl_6 Alkoxy, Nh2, NH(Ci 6 alkyl), N(C,_6 alkyl^ and 匚!.6 alkyl, which may optionally be selected from halogen and one or more independently Substituted by a substituent of the radical; R3 represents a phenyl group or a 5 to 6 membered heteroaryl ring, each of which may optionally be substituted with one or more substituents independently selected from the group consisting of dentate, cyano, nitrate 131174 .doc ,7 200946529 Base, SH, S(O)0-2R9, NRWR11, s(o)2nr12r13, C(0)NR14R丨5, C(0)2R16, NR17S(0)2R〗8, NR丨9C (0) R2〇, nr21c(o)2r22, nr23c(o)nr24r25, OR26 and Ci6 alkyl, which may optionally be substituted by one or more substituents independently selected from the group consisting of halogen , hydroxy, C!·6 alkoxy, NH2, NHCCw alkyl) and NCC^alkyl)2; R4 represents a group of formula (II) or (Ilia) or (Illb):

Wherein Y is -CH2-, -CH2CH2- or -CH2CH2CH2- and the substitution on the ring in the group (II) may be at the 3 or 4 position; a is 1 or 2; b is 1 or 2;

Z is -CH2-; R5 represents a group of formula (IV):

(IV), wherein w is 0 or 1; R6 represents a c,.4 alkyl group, which is optionally substituted with a substituent selected from each group, a trans group, a C4 oxy group, 131174.doc 200946529 NH (CN6 yard base) and Νβκ alkyl)2; when w is 〇, y is 〇; when rated 1, y is 〇 or 1; Q is not 〇, 8 (〇) 0.2, >^8, -(:(^118-, -8〇 to 118-, ^118(:〇-, -NR8S〇2-, -〇c(〇)_, _C(0)0_,·Η( :=(::Η- or ethynyl; R7 represents a cyclic group Cyc1 or Cw alkyl, which may optionally be substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy , C!-4 alkoxy, NH2, NH(Ci4 alkyl), n(Ci4 alkyl) 2, cyclic group Cyc2 and -〇Cyc2; and additionally, when Q represents 〇, grab 8, -(: 0 when serving 8--, _S02NR8-, -C(〇)〇-,·η〇=(:Η- or ethynyl group, R7 may represent hydrogen;

Cyc1 and Cyc2 each independently represent an aryl group, a heteroaryl group, a 3 to 8 membered aliphatic carbocyclic ring or a 4 to 8 membered aliphatic heterocyclic ring, each of which may optionally be substituted by one or more of the following groups, respectively. Base substitution: element, cyano, nitro, SH, S(O)0-2R9, NRWr1 丨, S(0)2NR12R13, c(o)nr14r15, c(o)2r16, nr17s(o)2r!8 And NR19C(0)R2G, nr21c(o)2r22, NR23C(0)NR24R25, OR26, phenyl and cN6 alkyl, the phenyl group or the C.6 alkyl group may optionally be independently selected from one or more Substituents for the following groups are substituted: halogen, hydroxy, CN6 alkoxy, NH2, NHCCk alkyl) and ν((.6 alkyl)2; R8 represents hydrogen or Cw alkyl; R9 and R18 each independently represent Cl_6 alkyl, which may optionally be substituted by one or more substituents independently selected from the group consisting of dentate, hydroxyl, Cu alkoxy, NH2, NHCCu alkyl) and NCCm alkyl)2; And R10, R11, R12, R13, R]4, R15, R16, R17, R19, R2〇, 131174.doc 200946529 2 'R 'R 'R24HR26 each independently represents hydrogen or Cl.6 alkyl, the c" The alkyl group may optionally be selected from the following groups by one or more Substituent substitution: south, trans, alkoxy, nh2, NH(Ci_6 fluorenyl) and Nm)2; or ruler 1 and Rll, r, r13, rm and r]5 or R24 and R25M - together The nitrogen atom to which the two are attached may form a 4 to 8 membered aliphatic heterocyclic ring, and the heterocyclic ring may be optionally substituted with a substituent from a halogen, a hydroxyl group or a C丨6 alkyl group, and one or more independently selected The Ci_6 alkyl

a pharmaceutically acceptable anion substituted by one or more substituents independently selected from dentate and a thiol group; and X represents a pharmaceutically acceptable anion of a monovalent or polyvalent acid. [Invention] The present invention provides the above-mentioned ones. Compounds which are within the scope of the application PCT/GB2007/004350, but which are not specifically disclosed therein. Accordingly, the present invention provides a compound having a quaternary substance selected from the group consisting of: (i?)-l-[(6-fluorenyl-pyridine-3-ylaminecarbamyl)- -Phenyl-cycloheptanyloxycarbonyl)-1-nitrogen bisbicyclo[2.2.2]octaneX; β)-1-[(6-methylpyrazin-2-ylaminocarbazinyl) ) _ 曱 ] _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Carbonyloxytrifluoromethyl _ 噪 % 美 美 ) ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Azole_3_ylamine-mercaptopurinyl)_3_(1 • stupyl-cycloheptylcarbonyloxy)-1-nitrogen-bicyclo[2.2.2]octaneX; pyridazin-3-ylamine Mercaptomethyl)-3-(1-thiophen-2-yl-cycloheptane 131174.doc -10- 200946529 carbonyloxy)-1-nitrogen rust-bicyclo[2.2.2]octane oxime; -1-[(5-Methyl-isoxazol-3-ylaminecarbamimidylmethyl)_3_(1_thiophene-2-yl-cycloheptanoxy)-1-nitrogen rust bicyclo[2 22] 辛烧χ; (i?)-l-[(3-methyl-isoxazol-5-ylaminoindolyl)-methyl]_3_(1_thiophene_ • 2_yl-cycloheptane Oxygen)-1_nitrogen rust-bicyclic [2.2.2] 辛烧又; • (幻_1-[(3·Fluoro-phenylaminemethanyl)-methyl]-3-(1-thien-2-yl-cycloheptanecarbonyloxy)-1-nitrogen-bicyclo[2.2.2] Octane oxime; (/〇-1-[(5-fluorenyl-pyrazin-2-ylamine fluorenyl)-methyl]_3_(1•thiophene-2-yl)-cycloheptanyloxy 1 - Nitrogen-bicyclo[2.2.2] Xinxuan>X; (and)-1-(benzo[isopoxazol-3-ylaminecarbamimidylmethyl)_3_(1_thiophene-2-yl-ring Heptanecarbonyloxy)-1-nitrogen bisbicyclo[2.2.2]octaneX; (i?)-l-(»pyrazine-2-ylamine hydrazino)_3_(1_thiophene_ 2_yl-cycloheptaneoxyl-1-pyrene-bicyclo[2.2.2]octane X; (and) 3-[1-(3-f-o-yl)-cycloheptanthoxy ]_ 1 _(吼 · 2 2 2 2 2 2 2 2 2 2 双 双 双 双 双 双 双 双 2 2 2 2 2 2 2 2 2 2 2 ; ; ; ; ; ; ; ; ; ; ; ))·cycloheptanecarbonyloxy]-1-(isoxazol-3-ylaminemethanylmethyl)·1-nitrogen rust-bicyclo[2 2 2]octane oxime; (/0-3- (1-phenyl-cycloheptanecarbonyloxy)_〗_(„bipyridin-2-ylaminomethyl)-1-nitrogen-bicyclo[2.2.2]octaneX; stupid- Cycloheptanecarbonyloxy (pyridine-4-ylaminocarbamoylmethyl)-1-azaindole-bicyclo[2.2.2]octyl X; (phantom-l-[(5-fluoro-acrididine_2) _ 胺 醯 醯 ) ·Methyl]_3_(1_phenyl-cycloheptinoxy)-1-indolyl-bicyclo[2 22]octane X; (7〇-1-[(5-methyl-acrididine_2) _ 胺 醯 ) ) ) _ 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174 174本基-环庚院乳乳)_ι_(π ratio _3_ylamine amide methyl)-1-nitrogen rust-bicyclo[2.2.2]octane X; and (/?)-1 -[(2-methylbuty-4-ylaminocarbamoyl)-methyl]_3_(ι-phenyl-cycloheptanecarbonyloxy)-1_azaindole-bicyclo[2.2.2]octane Further, wherein X represents a pharmaceutically acceptable anion of a monovalent or polyvalent acid. The compound of the formula (I) mentioned above and the compound of the present invention contain an anion X associated with a positive charge of a quaternary nitrogen atom. The anion X can be any pharmaceutically acceptable anion of a monovalent or multivalent (e.g., divalent) acid. In one embodiment of the invention, X may be an anion of a mineral acid such as chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid, such as acetate, butene Diacid, fumarate 'citrate, oxalate, succinate, tartrate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, naphthalene disulfonate (naphthalene-1,5-disulfonate) (for example, heptaphthalenedisulfonate), 2,5-dichlorobenzenesulfonate or hydroxynaphthoate (1-hydroxy-2-naphthoate). According to the present invention, there is also provided a compound selected from the group consisting of:

131174.doc • 12- 200946529

131174.doc -13- 200946529

Wherein x represents a pharmaceutically acceptable anion of a monovalent or polyvalent acid. It will be appreciated that certain compounds of the invention may exist in solvated forms (e.g., in hydrated form) as well as unsolvated forms. It will be understood that the present invention encompasses all such solvated forms. Certain compounds of the invention may exist in tautomeric forms. Tautomers and mixtures thereof also form an aspect of the invention. The compounds of the invention exhibit advantageous pharmaceutical properties. For example, the compounds of the present invention exhibit higher potency than similar compounds containing cyclopentyl, cyclohexyl and cyclooctyl rings. In addition, these compounds also exhibit higher binding to gray polyproteins than similar compounds containing cyclohexyl and cyclodecyl rings. Higher blood group binding can be advantageous for compounds administered by inhalation because it can alleviate the effects of any systemic effects that the compound can have. The compounds of the invention have activity as "anti-cholinergic agents", including muscarinic receptor (M1, M2 & M3) antagonists, especially M3 antagonists. Treated diseases and;: Includes: 131174.doc -14- 200946529 i. Hu Meidao: obstructive diseases of the trachea, including: asthma, including bronchi, allergic 'intrinsic, extrinsic, exercise induced, drug induced (including Aspirin & NSAID induced) and dust-induced asthma, intermittent and persistent and all severity and other causes of tracheal overreaction; chronic obstructive pulmonary disease (C0PD); bronchitis including contagious And eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer lung disease and related diseases; allergic pneumonia;

Dimensionalization, including unexplained fibrotic alveolitis, idiopathic interstitial pneumonia, anti-neoplastic therapy, complicated fibrosis and chronic infection, including tuberculosis and sputum and other fungal infections; lung transplantation complications; lung vascular Structural vascular and thrombotic disorders and high blood pressure in the pulmonary circulation; antitussive activity, including treatment of chronic cough-like procedural cough associated with tracheal inflammatory and secretory conditions; acute and chronic rhinitis, including drug-induced rhinitis and blood vessels Soreing rhinitis; long-term and seasonal allergic rhinitis, including neuropathic rhinitis (hay fever); nasal polyposis; acute viral sensation, including the common cold and due to respiratory fusion virus, influenza, coronavirus (including Sars) and adenovirus infection; 2. with or associated with (for example) congenital dysplasia of primary plaque secondary osteoarthritis / non-inflammatory osteoarthrosis or its joints; Anhdtide; cervical and lumbar spondylitis and lower back and neck pain; rheumatoid arthritis and Still's disease (StiUis-ca); serum-negative spondyloarthropathy , including ankylosing spondylitis, psoriasis and arthritis and undifferentiated spondyloarthropathy; septic arthritis and other infection-related joint money and bone disorders, such as tuberculosis, including Porter's disease 131174.doc 200946529 (Potts' disease) and Poncet's syndrome; acute and chronic crystallization-induced synovitis, including urate goutut, pyrophosphate #弓 deposition disease, and ash-filled 腱, mucous sac and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and local scleroderma; systemic lupus erythematosus, Mixed connective tissue disease and undifferentiated connective tissue disease; inflammatory myopathy, including dermatomyositis and polymyositis; polymalgia rheumatica; juvenile arthritis, including all joints of idiopathic inflammatory joints Inflammatory rash and related syndromes and rheumatic fever and its systemic complications; vasculitide, including giant cell arteritis, high Anteremia (Takayasu's arteriti) s), Churg-Strauss syndrome, nodular polyarteritis, microscopic polyarteritis, and vasculitis associated with viral infections, allergic reactions, cryoglobulin and diseased proteins; lower back pain Familial Mediterranean fever, Muckle_Wells syndrome and familial Hami Hibernian Fever, Kikuchi disease; drug-induced joint pain (arthalgia) ), tendonitis (tend〇nititide) and myopathy; · musculoskeletal disorders due to injury (such as sports injuries) or disease, phlegm and phlegm. Syria, scales 堃. Arthritic rash (such as Rheumatoid arthritis, lunar arthritis, gout or crystalline joint disease), other joint diseases (such as disc degeneration or sacroiliac joint degeneration), bone remodeling diseases (such as urethrosis, Paget's disease) (paget's disease) or osteonecrosis), polychondritis, scleroderma, polychondritis, scleroderma, mixed connective tissue disease 131174.doc -16- 200946529 disease, spondyloarthropathy or periodontal disease Disease (such as periodontitis); 4. 犮 | .. psoriasis, atopic dermatitis, contact dermatitis or other eczema skin disease and delayed allergic reactions; plant and photodermatitis; seborrheic dermatitis, herpes Dermatitis, lichen planus, sclerosing atrophic moss (lichen. scler〇sus et atrophica), gangrenous pyoderma, cutaneous sarcoma, discoid lupus erythematosus, pemphigus, pemphigus, bullous epidermis Urticaria, angioedema, vasculitis, erythema, skin eosinophilia, alopecia areata, male pattern baldness, Sweet's syndrome, Weber_Christian syndr〇me, multi-liter J Sexual erythema, infectious and non-infectious cellulitis; panniculitis; cutaneous lymphoma, non-melanoma skin cancer and other dysplastic lesions; drug-induced conditions, including fixed drug therapy; 5_殡锖.·睑Inflammation; conjunctivitis, including allergic conjunctivitis in the years and spring, iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disease infecting the retina; Inflammation, including sympathetic sacral ophthalmitis; sarcoidosis; including viral, fungal and bacterial infections; 6. 'system.. glossitis, gingivitis, periodontal disease; esophagitis including reverse. · flow; eosinophilic gastrointestinal Inflammation, granulomatosis, Crohn's disease, colitis (including ulcerative colitis), proctitis, anal pruritus (prudtis ani); celiac disease, colonic urgency, and food-related Allergies, these conditions may have effects away from the intestinal tract (such as migraine, rhinitis or eczema); 7. crotch: hepatitis, including autoimmune, alcoholic and viral; liver fibrosis and cirrhosis; cholecystitis Acute and chronic adrenitis; 131174.doc -17- 200946529 8. Secreted to the shoulder, silk · nephritis, including interstitial and spheroid nephritis; renal syndrome; cystitis, including acute and chronic (interstitial · cystitis and Hulun's ulceration (HAnner, s ulcer); acute and chronic urethritis, prostatitis', ' epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; Erectile dysfunction (male Female). 9. Prescription gift transfer #斤. Acute and chronic rejection after (for example) kidney, heart, liver, lung, bone marrow, skin or corneal transplantation or after transfusion; or chronic graft versus host disease;

Ίο. Aizheimer's disease and other dementia conditions, including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndrome; cerebral atherosclerosis and vasculitis; Inflammation, myasthenia gravis; acute and chronic pain (acute, intermittent or persistent from central or peripheral sources), including visceral pain, headache, migraine, tri-analgia, atypical facial pain, joint and bone pain Pain caused by cancer and tumor invasion, neuropathic pain syndrome 'including diabetes, post-herpetic and HIV-related neuropathy; neurosarcoma disease (neur〇sarc〇id〇sis); malignant, infectious or autoimmune process Central and peripheral nervous system complications; 11. Other autoimmune and allergic conditions 'Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes, Idiopathic thrombocytopenic purpura, eosinophilic fasciitis, high IgE syndrome, antiphospholipid syndrome; 1 2. Other conditions with inflammatory or immunological components, Including acquired immune deficiency syndrome (131174.doc -18» 200946529 AIDS), leprosy, Sezary syndrome and paraneoplastic syndrome; 1 3 · ~ ▲ reward. Infected coronary artery and peripheral circulation Atherosclerosis; pericarditis; myocarditis, inflammatory and autoimmune cardiomyopathy, including myocardial sarcoma 'ischemic reperfusion injury; endocarditis, heart disease and aortitis' including contagious ( For example, syphilis; vasculitis; proximal and peripheral venous conditions 'including phlebitis and thrombosis, including deep vein thrombosis and variceal complications; β. honing. · Treatment of common cancers, including prostates, Malignant tumors of the breast, lung, ovary, pancreas, intestine and colon, stomach, skin and brain tumors and the sensation of the cerebral medulla (including leukemia) and malignant tumors infected with lymphoid tissue such as Hodgkin's lymphoma and non-hoof Chikin's lymphoma; includes prevention and treatment of metastatic disease and tumor recurrence and paraneoplastic syndrome; and 15. f靡.. celiac disease Proctitis, eosinophilic gastroenteritis, hypertrophic Q-cell hyperplasia, Crohn's disease, ulcerative colitis, microscopic colitis, uncertain colitis, large intestine irritability, large intestine irritability, non-inflammatory ventral diarrhea, Food-related allergies (such as migraine, rhinitis, and eczema) that have an effect away from the gut. Accordingly, the invention further provides a compound of the invention as defined above for use in therapy. In another aspect, the invention provides the use of a compound of the invention as defined above for the manufacture of a medicament for therapy. In the context of this specification, 'unless there is the opposite specific #8,|131174.doc -19- 200946529 The term "therapy" also includes "prevention". The term "treatment" should be interpreted accordingly. Another aspect of the invention provides a method of treating a condition of a disease in a mammal suffering from or at risk of the disease, comprising administering to the mammal in need of the treatment a " A compound of the invention as defined above. The invention also provides a compound of the invention as defined above for use in the treatment of chronic obstructive pulmonary disease (c〇pD), such as irreversible COPD. The 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 for the treatment of chronic obstructive pulmonary disease (COPD), such as irreversible c〇pD. The invention also provides the use of a compound of the invention as defined above for the treatment of asthma. The invention also provides the use of a compound of the invention as defined above for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (c〇PD), such as irreversible c〇pD. The invention also provides the use of a compound of the invention as defined above for the manufacture of a medicament for the treatment of asthma. The invention further provides a method of treating chronic obstructive pulmonary disease (COPD), such as irreversible COPD, in a warm-blooded animal, such as a human, comprising administering to the mammal in need of such treatment an effective amount of a formulation as defined above Inventive compound. The invention further provides a method of treating asthma in a warm-blooded animal, such as a human', which comprises administering to a mammal in need of such treatment an effective amount of a compound of the invention as defined above, e.g., 131174.doc -20-200946529. In order to use the compounds of the invention for therapeutic treatment of the genus), it is generally according to standard pharmaceutical practice: (such as a character. X-knife is formulated as a pharmaceutical combination spoon: this: in another aspect, the invention provides a pharmaceutical composition The compound of the present invention and the agent or the carrier are defined by the two p X. In another aspect, the present invention provides a method for preparing a drug comprising a living ingredient and a pharmaceutical Second, such as dilution: or carrier mixing. Depending on the mode of administration, the pharmaceutical composition ... contains 0.05 to 99% w (% by weight) (such as 〇〇 5 to 80 / 〇 w, such as 〇 1 〇 to 7 〇 〇 w, all weight percentages are based on the total composition. I) Activity Costs The pharmaceutical composition of the invention can be administered in a standard manner for the treatment required; a disease such as 'by' local (such as administration to the lungs) And/or trachea or) 4-port, rectal or parenteral administration. For these purposes, the compounds of the invention may be formulated into the following forms, such as aerosols, dry powder formulations, in a manner known in the art. , key, capsule, sugar, powder, granule, aqueous or oily solution Or a suspension, a (lipid) emulsion, a dispersible powder, a suppository, an ointment, a cream, a drop, and a sterile injectable aqueous or oily solution or suspension. The human pharmaceutical composition is suitable for oral administration in a unit dosage form. A composition for administration, an early dosage form such as a tablet or capsule containing between 0.1 mg and 1 g of the active ingredient. The heart of the invention is a pharmaceutical composition of the invention suitable for intravenous, dermal 131174.doc 200946529 Or a composition for intramuscular injection. Each patient may receive, for example, from 1 mg mg/kg to 100 mg/kg of the compound of the invention under intravenous endothelium or intramuscular administration, for example (U mg/kg to 2 mg) In the range of /kg, the composition is administered 1 to 4 times a day. Intravenous, subcutaneous and intramuscular doses can be administered by rapid injection. Alternatively, the intravenous dose can be administered by continuous infusion/main time over a period of time. Alternatively, each patient will receive a daily oral dose which is approximately equal to the daily parenteral dose and is administered to the composition four times a day. ❹ 另一 Another suitable pharmaceutical composition of the invention is suitable for inhalation Composition with it, when treating Inhalation is a particularly suitable method of administering a compound of the present invention in the case of obstructive pulmonary disease (c〇pD) or respiratory disease of asthma. When administered by inhalation, the compounds of the present invention can be effectively administered in doses in the microgram range, Such doses are, for example, 0(1)(9), 〇, 〇1 4〇, 0.1 to 30, n2〇, 〇" to 1 〇, 5 to 1 〇, 5 to 5, 5 to 40, 5 to 3 〇 5 to 2"g, (1) squeaking, to 50, 1 to 4, 1 to 3, or 1 to 2, the active ingredient. In the present invention, a pharmaceutical composition is provided. It comprises a compound of the invention as defined above together with a pharmaceutically acceptable adjuvant, diluent or dressing which is formulated (iv) for administration by inhalation. When administered by inhalation, a metered dose inhaler device can be used to administer active ingredients dispersed in a suitable propellant with or without other excipients such as ethanol, surfactants, lubricants or stabilizers. . Suitable propellants include mixtures of warp, carbon and hydrogen, such as heptafluoride propellant materials. Preferably, the propellant is ρΐ34_227, each of which is used alone or in combination with other simplifications/propellants and/or surfactants and/or other forms of morphing 131174.doc •22·200946529. A spray may also be employed which may or may not contain a suitable pH and/or/= liquid or preferably a solution or a multi-dose formulation. —, $ 节剂, as a unit agent The dry powder inhaler can be used alone or in combination with the active ingredient, and administered in the form of a carrier composition which is acceptable in the following. Dry powder inhalation two: single:: powdered powder or ordered mixed powder or capsule containing powder. Single or multiple doses and available

Dosing inhalers, nebulizers, and dry powders are available and a variety of such devices are available. 》The device is. It is well known that a hair-step is a combination therapy, wherein one or more of a combination of one or more therapeutic agents is formed, or a medical compound comprising a compound of the present invention. Oral substances or formulations are listed for treatment, in particular for treatment such as, without limitation, rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease, psoriasis and inflammatory bowel disease Inflammatory diseases, the compounds of the invention may be combined with the agents listed below. Non-steroidal anti-inflammatory agents (NSAm below) include non-selective for topical or systemic application! • Ring-forming oxygenase cox_1/c〇x_2 inhibitors (such as piroxicam (Pir〇XiCam); diclofenac (diclofenac); propionic acid , such as naproxen, fibiprofen (fiurbipr〇fen), fenoprofen (fenoprofen), ketoprofen (ket〇pr〇fen) and ibuprofen (ibuprofen); fenamic acid Fenamate, such as mefenamic acid; indomethacin; sulindac I31174.doc •23· 200946529 (sulindac); azapropazone; dihydrogen Ratio. sit _ class, such as phenylbutazone; salicylate 'such as aspirin; selective C〇x 2 inhibitors (such as meloxicam, celecoxib, ros Rofecoxib, valdecoxib, lumarocoxib, parecoxib, and etoricoxib; cyclooxygenase inhibitory nitric oxide donor ( ciNOD); glucocorticoids (whether administered by topical, oral, intramuscular, intravenous or intra-articular routes); amidoxime (metho) Trexate); leflunomide; hydroxychloroquine; d-penicillamine; auranoHn or other parenteral or oral gold preparation; analgesic; double vinegar Diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine. The invention further relates to a combination of a compound of the invention with an agonist or antagonist of cytokine or cytokine function, including an agent acting on a cytokine signal transduction pathway, such as a SOCS system modulator, including alpha_, beta- and Γ-interferon; type I insulin-like growth factor GGFd); interleukin (IL), including IL1 to 17 and an interleukin antagonist or inhibitor, such as anakinra; tumor necrosis factor a ( TNF-a) inhibitors, such as anti-TNF monoclonal antibodies (eg, infliximab; adalimumab and CDP-87) and TNF receptor antagonists, including immunoglobulin molecules (such as etanercept and low molecular weight agents, such as pentox Xyfyiiine. In addition, the present invention relates to compounds of the invention and monoclonal antibodies targeting 1 lymphocyte (such as CD20 (Rituto) a combination of imazumab, rituximab), mrA_131174.doc -24- 200946529 aIL16R and T-lymphocytes, CTLA4-Ig, HuMax Il-l 5). The invention further relates to the compounds of the invention and chemokine receptors Combination of functional regulators , such modulators as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the CC family), CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for CXC Family of) and antagonists of CX3CR1 (for the c-x3-c family). The invention further relates to a combination of a compound of the invention and a matrix metalloproteinase (MMP) inhibitor, a matrix metalloproteinase, ie, a matrix lysin, Collagenase and gelatinase and aggrecanase, in detail collagenase-1 (ΜΜΡ·1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), matrix lysin-1 (ΜΜΡ-3), matrix lysin-2 (MMP-10) and matrix lysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline. Still further relates to a combination of a compound of the invention and a leukotriene biosynthesis inhibitor, a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist, Such as zileuton, ABT-761, fenleuton, tepoxalin, Abbott-79175, Abbott-85761; N-(5-take 〇 〇 吩 -2- -2-alkyl sulfonamide; 2,6-di-t-butyl phenol hydrazine; methoxytetrahydropyran, such as Zeneca ZD-2138; compound SB-210661; substituted by pyridyl 2-cyanonaphthalene compound such as L-739, 010; 2-cyanoquinoline compound such as L-746, 530; or hydrazine or quinoline compound such as MK-591, MK-886 and BAY X 1005. 131174.doc -25- 200946529 The invention further relates to a combination of a compound of the invention with a receptor antagonist of leukotrienes (LT) B4, LTC4, LTD4 and LTE4, the antagonist being selected from the group consisting of: phenol Pyridazine-3-1, such as L-651, 392; a mercapto compound such as CGS-25019C; benzoxalamine 'such as ang. Ontaz〇iast; benzodiazepine amines such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast , pranlukast, verlukast (MK-679), RG-12525, R〇-245913, iralukast (CGP 45715A) 'BAY X 7195. The invention further relates to a combination of a compound of the invention and a combination of phosphodiesterase (PDE) inhibitors, such as methylxanthine, including theophylline and amine theophylline; selective PDE isozyme inhibitors, including A PDE4 inhibitor (an inhibitor of the isoform PDE4D) or an inhibitor of PDE5. The invention further relates to a combination of a compound of the invention and a histamine type 1 receptor antagonist, such as cetirizine, loratadine, desloratadine ), fexofenadine, acriVastine, terfenadine, astemizole, azelastine, levocabastine , chlorpheniramine, promethazine, cyclizine or mizolastine; it is administered orally, topically or parentally. The invention further relates to a combination of a compound of the invention and a proton pump inhibitor 131174.doc -26- 200946529 (such as omePrazole) or a gastric protective histamine type 2 receptor antagonist. The invention further relates to the combination of a compound of the invention and a histamine type 4 receptor antagonist. The invention further relates to a combination of a compound of the invention and an ι/α_2 adrenergic agonist vasoconstrictive sympathomimetic agent, such as propylhexedrine, phenylephrine, benzene Phenylpropanolamine, ephedrine, pseudoephedrine (pSeud〇ephedrine), naphazoline hydrochloride, oxymetaz〇Hne hydrochloride, tetrahydrofuran hydrochloride (tetrahydrozoline hydrochloride), celec hydrochloride. Xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride » The present invention further relates to a compound of the invention and a β-adrenergic receptor agonist (including β-acceptor) a combination of subtypes 1-4), such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, Occerine (〇rciprenaline), bitolterol mesylate, pirbuterol or indacaterol or its antagonistic enantiomer. The invention further relates to a combination of a compound of the invention and a color, such as sodium cromoglycate or nedocromil sodium, 131174.doc -27-200946529. The invention further relates to the compounds of the invention Glucocorticoid combination 'glucocorticoids such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, cecaxine propionate Fluticasone propionate, ciclesonide or mometasone furoate The present invention further relates to a combination of a compound of the invention and an agent that modulates a nuclear hormone receptor, such as PPAR.

The present invention further relates to a combination of a compound of the present invention with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody that modulates Ig function, such as an anti-IgE (e.g., omalizumab). The invention further relates to a combination of a compound of the invention and another systemic or topical anti-inflammatory agent 'anti-inflammatory agent such as thalidomide or a derivative thereof, retinoid, dithranol or | calcipotriol. The invention further relates to a combination of a compound of the invention and a combination of an amine salicylate and a reductive acridine, such as sulfasalazine, mesalazine, and baliu Nitrogen (balsalazide and olsalazine); and immunomodulators such as thiopurine; and corticosteroids such as budesonide. The invention further relates to a combination of a compound of the invention and the following: an antibacterial agent, such as a penicillin derivative, tetracycline, macrolide, beta-indoleamine (beta-131174. Doc -28 - 200946529 lactam), fluoroquinolone, metronidazole, aminoglyc〇side; antiviral agents, including acyclovir, famciclovir (famcici〇vir), valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin ), zanamavir and oseltamavir; protease inhibitors such as indinavir, nelfinavir, ritonavir and sand Saquinavir; nucleoside reverse transcriptase inhibitors such as didanosine, lamivudine, stavudine, zalcitabine or ziduo Zidovudine Or a non-nucleoside reverse transcriptase inhibitor, such as nevirapine or efavirenz. The invention further relates to a combination of a compound of the invention and the following: a cardioin agent, such as a calcium channel blocker, a beta-adrenergic receptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, vasoconstriction a receptor 2 antagonist; a lipid lowering agent such as statin or a cellulose ester; a blood cell morphological regulator such as pentoxoxineine; a thrombolytic or anticoagulant such as platelet aggregation Inhibitor. The invention further relates to a combination of a compound of the invention and a CNS agent, such as an anti-depressant (such as sertraUne); an anti-shock palsy (such as deprenyl hydrochloride; L-dopa; Ropinirole; pramipex〇ie; MAOB inhibitors, such as selegine and rasagUine; comp inhibitor, 131174.doc •29- 200946529 such as hiss? (tasmar); A-2 inhibitor, dopamine reuptake inhibitor, NMDA antagonist; agonist; dopamine agonist or neuronal nitric oxide synthase inhibitor); or anti-Alzheimer's ( Alzheimer) drugs, such as winterepazole (donepezil), remizine (7), 丨丨 丨 (4), tacrine, C0X 2 inhibitor, propentofylline or methotrexate (metrifonak) ). The invention further relates to a combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a central or peripherally acting analgesic (e.g., opioid or a derivative thereof), carbamazepine, phenytoin (phenyt〇in), sodium valproate, amitrypti Hne or other antidepressant paracetamol or nonsteroidal anti-inflammatory agents. The invention further relates to a combination of a compound of the invention and a parenteral or topical application (including inhalation) of a local anesthetic such as lignocaine or a derivative thereof. The compounds of the present invention may also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene or a dibasic acid salt such as alendronate. A further advancement relates to a combination of a compound of the invention and: (1) a tryptase inhibitor; (ii) a platelet activating factor (pAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) IMpD_formulation; " (7) Adhesion Molecular Inhibitors' include VLA_4 anti-Qi; (vi) cathepsin; (VH) kinase inhibitors, such as tyrosine kinases (such as Btk, Itk, Jak3 or MAP) Inhibitors (eg, Gefitinib or Physician Zebra 131174.doc • 30. 200946529 # b (Imatimb mesylate)), a serine/threonine kinase inhibitor (such as MAP kinase inhibitor) a kinase such as p38, a protein kinase A, B or C or IKK) or a kinase involved in cell cycle regulation (such as a -dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibition | (ix) Excimer _ B 1 or B2 reconstituted antagonist, (χ) anti-gout agent, such as colchicine; (xi) xanthine oxidase inhibitor, such as allopurinol (all〇purinol); (xii ) uric acid, such as pr〇benecid, sulfinpyrazone or benzbromarone (be (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFp); (χν) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor, such as basic fiber Maternal growth factor (bFGF); (xvii) granule macrophage community stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK1 or NK3 receptor antagonism Agents such as NKP-608C, SB-233412 (tanatant, talnetant) 4D_4418; (XX) elastase inhibitors such as UT-77 or ZD-0892; (xxi) TNF-a converting enzyme inhibitor (TACE); (xxii) an inducible nitric oxide synthase (iNOS) inhibitor; (xxiii) a chemoattractant receptor homologous molecule (such as a CRTH2 antagonist) expressed on TH2 cells; (xxiv) a P38 inhibitor; (xxv) modulation Toll-like receptor (TLR) functional agent; (xxvi) an agent that modulates the activity of a sputum receptor (such as Ρ2Χ7:); or (xxvii) an inhibitor 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, for example, suitable agents include: (0 anti-proliferative/anti-neoplastic drugs used in medical oncology or groups thereof 131174.doc -31 - 200946529 Including, for example, a burning agent (such as cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil) ), busulphan or nitrosourea; antimetabolites (eg, antifolates such as fluoropyrimidine 5-fluorouracil or pyrithione, raltitrexed, A Aminoguanidine, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel; antitumor antibiotics (eg anthracycline) such as doxorubicin (such as doxorubicin) Adriamycin), bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin -C), Dactinomycin or mithramycin; anti-mitotic agents (eg, vinca alkaloid, such as vincristine, vinblastine, vindesine) Vindesine) or vinorelbine or taxoid, such as taxol or taxotere; topoisomerase inhibitor (for example, epipodophyllotoxin, Such as etop〇side, teniposide, amsacrjne, topotecan or camptothecin; (ii) cytostatics such as Anti-estrogen (anti〇estr〇gen) (eg tamoxifen, toremifene, raloxifene > droloxifene or idoxifene ( Iodoxyfene)); estrogen receptor down-regulation (eg fulvestrant 131174.doc -32- 200946529 (fulvestrant)); anti-androgens (eg bicalutamide, flutamide, niru) Nilutamide or cyproterone acetate; LHRH antagonism Agent or LHRH agonist (eg, goserelin, leuprorelin or buserelin); progestin (eg megestrol acetate); aromatase Inhibitors (eg, anastrozolium <» sitting (anastr〇zole), letrozole, vorazole or exemestane

(exemestane)) or a 5α-reductase inhibitor, such as finasteride; (iii) an agent that inhibits cancer cell invasion (eg, a metalloproteinase inhibitor such as marimastat; or urokinase fiber) Lysozyme activator receptor function inhibitor); 玍 U 千 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , [C225]); a farnesyl transferase inhibitor; a glutamate kinase inhibitor or a serine/threonine kinase inhibitor; an epidermal gene production factor inhibiting woven, for example, a sedative family of lysine kinases, such as (d)H Gas diyl) 7 Ai group _6 ♦ 琳 基 propyl propoxy giini, AZD1839), Ν _ (3, branch i material first Λ - (acetylene base) _6,7-bis (2-methoxy B Oxy) quinazolin-4-amine (Errot 袪 milk (3-chloro 4 t 1 、, 匕, 〇S1-774) or 6-propylene guanamine _N_ U 乳-4-乱本基)-7-(3-^ w , —

1033)) · jk I is ^ propoxy)quinazolin-4-amine (CI, platelet-derived v long-factor family inhibitor; long-factor steroid inhibitor 丨 or hepatocyte-derived (v) anti-angiogenic agent , P-type vascular endothelial growth factor effect agent 131174.doc • 33 · 200946529

Antibody, bevacizumab, WO 97/22596, WO (eg, anti-vascular endothelial growth factor (bevacizumab), which is disclosed in

Compounds of 97/30035, WO 97/32856 or WO A and wu 98/13354) or by another mechanism (eg, linomid (H_ide), integrin ανβ3 functional inhibitor or angiostatin );

❹ (10) vascular damaging agent 'such as Compos ^ TA4 (c () mbretastatin Α 4) or disclosed in WO 99/02166, W 〇〇〇 / 4 〇 529, purchase 〇〇 / 41669, alone (H / 92224, rush 0 a compound of 02/04434 or 霄〇〇2/〇8213; (vii) an agent for use in reverse therapy, such as an agent for one of the above listed targets, such as ISIS 2503, an anti-ras antisense molecule; (V111 An agent used in gene therapy, such as a method of replacing an abnormal gene such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-mediated enzyme prodrug therapy) methods, such as using cytosine deaminase, thymidine a method of kinase or bacterial nitroreductase; and a method of increasing tolerance of a patient to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; or (IX) an agent used in an immunotherapy method, such as an increase in immunotherapy Immunogenic in vitro and in vivo methods of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granule macrophage colony stimulating factor; methods for reducing T cell non-denatured Use such as cells Method for transfecting immune cells with transfected dendritic cells; method for using tumor cell lines transfected with cytokines; and method for using anti-genetic antibodies 0 In another embodiment, the present invention provides pharmaceutical products a combination comprising 131174.doc-34-200946529 active ingredient and at least one other active ingredient selected from the compounds of the invention as described above: • citrate s-enzyme inhibitor; • β2 adrenal gland Receptor agonist; • chemokine receptor function regulator; * kinase function inhibitor; * protease inhibitor;

Ο • steroid glucocorticoid receptor agonists; and • non-steroidal glucocorticoid receptor agonists. The pharmaceutical product of this embodiment may, for example, be a pharmaceutical composition comprising the first and other active ingredients in a mixture as a mixture. Alternatively, the pharmaceutical product may be (for example, suitable for simultaneous, sequential or separate administration of a patient in need thereof). The pharmaceutical preparation form comprises the first and other active ingredients. The pharmaceutical product of this embodiment is particularly suitable for the treatment of respiratory diseases such as asthma, COPD or rhinitis. Examples of phosphodiesterase inhibitors which can be used in the pharmaceutical products of this embodiment include PDE4 Inhibitors (such as inhibitors of isoform PDE4D), PDE3 inhibitors, and PDE5 inhibitors. Examples include the following compounds: (Z)-3-(3,5-diox-4-.pyridyl)-2 -[4-(2-dihydroindolyloxy-5-methoxy-2-ene) octyl] acrylonitrile; N-[9-amino-4-oxo-oxime-phenyl·3 , 4,6,7_tetrahydropyrrole[3,2,bj][i,4]benzodiazepine_3(r)-yl]. than bite_3 -decylamine (ci_i 〇44 3_(hydroxyl)-1-(4-fluorobenzyl)·Ν_[3_(methylsulfonyl)phenyl]·1H_吲哚-2-carboxamide; I31174.doc -35- 200946529 (1S_外)_5-[3-(Bicyclo[2.2.1]hept-2-yloxy)-4-A Oxyphenyl]tetrahydro-2(1H)-octidine _ (attiram); N_(3,5_diox-4-pyridyl)-2-[l-(4- Fluorobenzyl)-5-hydroxy-1H-indole-3-yl]-2-oxoethoxyacetamide (Awd-12-281); β-[3-(cyclopentyloxy)_4_ Methoxyphenyl μι% dihydro-U3_di- oxy-2H-isoindole-2-propanol (CDC-801); N-[9-fluorenyl-4-yloxyphenyl _ 3,4,6,7_tetrahydropyrrole•ik][l,4] stupid and diazeph _3(R)_yl]π than 唆_4_ methotrexate (ci_i 〇1 8); [4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-indole-carboxylic acid (Cilomilast); 8-amino-1,3- Bis(cyclopropylmethyl)xanthine (sipanphylline, Cipamfylline); N-(2,5-dichloro-3-indenyl)-8-decyloxy-5-indole D-4418); 5-(3,5-di-t-butyl-4-hydroxybenzylidene)-2-imidothiazolidine-4-one (Darbufelone); 2-methyl- L-[2-(l-methylethyl)"biazolium[iSa].pyridyl_3_yl]-bu-propyl _ (Ibidilast); 2-(2,4-di (A)-(R) -5-(4-decyloxy-3-propoxyphenyl)_5-methyloxazolidine-2-one (Mesoprama, Mesopram); (-Bushun-^ethoxy^-曱氧基-之-曱基^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Doc -36- 200946529

Pumafentrine); 3_(cyclopropylmethoxy)-N-(3,5-diox-4-"pyridyl)-4-(difluorodecyloxy) azelaamine (Rofluentast) , Rofliimilast), N-oxide of Roflumilast; 5'6_-ethoxybenzo[b]thiophene-2-carboxylic acid (Tibenelast); Ο ❹ 2,3,6'7- Tetrahydro- 2_(菜imino)-9,10-dimethoxy-3_methyl-4H-°°[[,1-a]isoquinolin-4-one (Quacquine) Xin, treqUinsin); and 3_[[3-(cyclopentyloxy)_4_methoxyphenyl]methyl]·Ν·ethylmercaptoethyl)-311-嘌呤_6-amine (乂- 11294 eight). Examples of β-adrenergic receptor agonists which can be used in the pharmaceutical products of this embodiment include hydroxyisoproterenol, isoproterenol, and isoprenaline. , albuterol, albuterol (for example in the form of a sulfate), formoterol (for example in the form of fumarate), salmeterol (for example in the form of a hydroxynaphthoate), terbuta Lin, Ocinarin, Bitoterol (for example in the form of the mesylate salt) than Buttero or Indatrate. The β2_adrenoreceptor agonist of this embodiment may be a long-acting β2-agonist, such as salmeterol (for example in the form of hydroxynaphthoate) or formoterol (for example in the form of fumarate) "Bambuterol (for example in the form of the hydrochloride); Carm〇terol (TA 2005, chemically identified as 2 (1H) phenoxone, 8_ hydroxy-5-[l -hydroxy-2-[[2-(4-decyloxy)]-methylethyl]-amino]ethyl]-monohydrochloride, [MR'r*)], also by the United States Chemical Abstract Service Registration No. 137888_u_〇 Identification and Disclosure 131174.doc • 37· 200946529 in U.S. Patent No. 4,579,854); Introduction to Catalo (CAS No. 3 12753-06-3; QAB- 149); an aniline derivative, for example, as disclosed in WO 2002/70933, 3_(4_{[6_({(2R)_2 [3_(甲醯美4-hydroxyphenyl]-2-hydroxyethyl) Alkyl hexyl hexyl oxy butyl sulfonamide; benzene sulfonamide derivative, for example, 3-(4-{[6-({) as disclosed in W〇2〇〇2/88167 (2R)-2-carbyl-2-[4-carbyl-3-((yl)methyl)phenyl]ethyl}amino)hexyl]oxy} butyl An aryl aniline receptor agonist as disclosed in WO 02/032921 and WO 2005/025555, as disclosed in WO 2004/032921 and US 2005/222144. Derivatives, and compounds GSK 159797, GSK 159802, GSK 597901, GSK 642444, and GSK 678007. Examples of chemokine receptor function modulators that can be used in pharmaceutical products of the sage embodiment include CCR1 receptor antagonists. Examples of the kinase function inhibitor of the medical product of the embodiment include a p38 kinase inhibitor and an IKK inhibitor. Examples of the protease inhibitor which can be used for the pharmaceutical product of this embodiment include a neutrophil elastase inhibitor or a MMP12 inhibitor. Examples of steroid glucocorticoid receptor agonists useful in the pharmaceutical products of this embodiment include budesonide; fluticasone (e.g., in the form of a propionate); mometasone (e.g., in the form of a phthalate) ); beclomethasone (for example in the form of 17-propionate or 17,21-diacid S); ciclesonide; loteprednol (eg, carbon-based) Acidic acetonate form; etiprednol (for example in the form of dicloacetate); Trienin 131174.doc -38- 200946529 Triamcinolone (for example in the form of a condensed acetonide) ; flunisolide; zoticasone; flomoxonide; rofieponide; butixocort (for example in the form of propionate); Nylon (prednis〇i〇ne); prednisone; tipredane; steroid vinegar, such as 6α, 9α-difluoro-17α-[(2-furylcarbonyl)oxy]-ΐΐβ -hydroxy-16α-mercapto-3-oxo-androst-1,4-diene-17β-thiocarbonate S-fluorodecyl ester, 6α,9α-difluoro-11 β-hydroxy-16α- Methyl-3-oxooxy-17α-propoxyl-androst-1,4-diene-17β-thiocarbonate S-(2-o-oxy-tetrahydro-furan-3S-yl) ester And 6α,9α-difluoro-11β·hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazol-5-carbonyl)oxy]-3-oxo-androst-1 , 4-dien-17β-thiocarbonate S-fluoromethyl ester, steroid ester according to DE 4129535, according to WO 2002/00679, WO 2005/041980, etc. Sterols or Steroids GSK 870086, GSK 685698 and GSK 799943 ° Examples of non-steroidal glucocorticoid receptor agonist modulators which can be used in the pharmaceutical products of this example include the modulators described in WO 2006/046916. [Embodiment] The present invention will now be described by way of the following examples. In the example, at a proton frequency of 300 MHz or 400 MHz or 500 MHz on a Varian Unity Inova spectrometer, or a proton frequency of 400 MHz or 500 MHz on a Bruker DRX spectrometer, or 600 MHz on a Bruker Avance spectrometer The NMR spectra were measured at a proton frequency or on a Bruker Avance DPX 300 spectrometer at a proton frequency of 300 MHz. At 131174.doc -39- 200946529

MS spectra were measured on an Agilent 1100 MSD G1946D spectrometer or a Hewlett Packard HP1100 MSD G1946A spectrometer. The name is generated using the Autonom 2000 (version 4.01.305) software supplied by MDL. Example 1: Gasification of (i?)-l-[(6-methyl-nt-pyridine-3-ylaminocarbamoyl)-methyl b- 3_(1-phenyl-cycloheptanecarbonyloxy)_1_ Nitrogen-bicyclo[2 2.2]octane a) 1-phenyl-cycloheptanol

碘 Under a nitrogen atmosphere, iodine crystals were added to magnesium (1.2 g) in anhydrous tetrahydrofuran (60 mL) at a rate to maintain a steady reflux of the reaction, followed by the addition of bromobenzene (7·85 g). The reaction mixture was stirred for 20 minutes, then cycloheptone (4.48 g) was carefully added. After stirring for 10 minutes, 'saturated gasification aqueous solution mL was added, and the reaction was allowed to dissolve between water (1 〇〇 mL) and isohexane (1 〇〇 mL). The organic layer was dried (MgSO.sub.4). NMR (299.946 MHz, CDC13) δ 7.53-7.47 (m, 2Η), η 36- 7.29 (m, 2Η), 7.26-7.19 (m,1Η), 2.07 (ddd,2Η), 1.97-1 50 (m, 11H). b) 1-decyloxy-1-phenyl-cycloheptane

131174.doc -40- 200946529 1 benzyl-% heptanol (Example 1 a) (76 g) was dissolved in tetrahydrogen. In the south (1 〇〇 mL), sodium hydride (6 〇% in oil, 2 〇) was added. The reaction was stirred for 5 minutes and iodomethane (7" g) was added. The mixture was maintained at 6 Torr (3 (:: overnight) and then a certain amount of sodium hydride (60% in oil, 2.0 g) and methyl iodide (7.1 g) were added and the reaction was refluxed for 7 hrs. The reaction mixture was partitioned between EtOAc (3 mL) (EtOAc) , CDC13) δ 7.43-7.37 (m5 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 decanoic acid

The clock (2.62 g) and nano (0.52 g) were heated in a mineral oil at 120 ° C for 30 minutes in a chaotic atmosphere and then cooled to room temperature. The oil was removed and replaced with ether (100 mL) and EtOAc <RTI ID=0.0>>> The reaction was cooled to -78 ° C and solid carbon dioxide (about 2 g) was added with stirring. The reaction was allowed to warm to room temperature and water (15 mL) was carefully added under nitrogen. The aqueous layer was separated, neutralized with concentrated hydrochloric acid and extracted with diethyl ether (15 mL). The organic layer was dried (MgSO.sub.4). 131174.doc 41 200946529 NMR (300 MHz, CDC13) δ 7.40-7.20 (m, 5H), 2.49-2.35 (m, 2H), 2.16-2.03 (m, 2H), 1.76-1.47 (m, 8H). d) methyl 1-phenyl-cycloheptane decanoate

1- Ο ο 1-Phenyl-cycloheptanoic acid (Example lc) (4.1 5 g) was refluxed for 24 hours in methanol (1 50 mL) and concentrated hydrochloric acid (5 mL). The solvent was evaporated, and the residue was dissolved in EtOAc (EtOAc) (EtOAc) (EtOAc) And evaporated to give the subtitle compound (3.5 g). ]H NMR (300 MHz, CDC13) δ 7.37-7.18 (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) Phenyl-cycloheptanecarboxylic acid (and)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester

In the Dean and Stark apparatus, 1-phenyl-cycloheptanoic acid methyl ester (Example ld) (1.0 g) and (R)-acridin-3-ol (0.39) were used. g) refluxed for 24 hours in heptane (5 〇 mL) containing sodium (about 5 mg). The heptane (20 mL) was replaced with a block of 131174.doc •42-200946529 (20 mL) and reflux was continued for 3 days. The reaction was partitioned between water (50 mL) and ether (50 mL) and the ether layer was separated, dried (MgSCU) and evaporated. The crude product was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) NMR NMR (300 MHz, CDC13) δ 7.35-7.27 (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), 1.91-1.8〇(ιη? 1H), ^70^.34 (m| 12H). f) 2-Chloromethyl-pyridine-3-yl)-acetamide

Will be 6_methyl ° ratio. A mixture of dimethylamine (1 g) and triethylamine (2.2 mL) in dry THF (20 mL) was stirred and cooled to -6 (TC). Chlorine (1·567 g) was added to form a yellow suspension. The mixture was stirred at -60t: until the analysis showed the 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 with EtOAc EtOAc EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ), 8.60 (1H, d), 7.91 (1H, dd), 7.22 (1H, d), 4.27 (2H, s), 2.42 (3H, s) 〇 Example 1. Gasification 丨 (6_methyl_咐) Acridine_3_ylaminemethanylmethyl] 131174.doc -43- 200946529 (1_phenyl-cycloheptanecarbonyloxy)-1-azaindole_bicyclo[2.2.2]octane

1-Phenyl-cycloheptanoic acid (foot)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (example le) (52 mg) was dissolved in acetonitrile (2 mL) 2-Gas-N-(6-methylpyridin-3-yl)acetamide (Example lf) (29 mg) was added. The reaction was stirred for 10 days and diluted with ethyl acetate (4 mL) and EtOAc (14 mL). The mixture was allowed to stand for 5 days, then the crystals crystals crystals crystals crystals m/e 476 [M]+. *H NMR (400 MHz, DMSO-D6) δ 11.33 (s, 1H), 8·7 〇 (d, 1 Η), 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, ih) 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), 2.〇l_ 1.86 (m, 3H), 1.83-1.71 (m, 1H), 1.69-1.41 (m, 8H). Example 2: Bromide (/f)-l-[(6-methyl-pyridin-2-ylaminocarbamoyl)-methyl]_3·(1-phenyl-cycloheptanyloxy)- 1- atmosphere town - double ring [2.2.2] Xin Xuan a) 2-molyl methyl ratio 0 Qin-2·yl)-acetamide

I31174.doc -44- 200946529 6-Methyl-pyrazin-2-ylamine (150 mg) and potassium carbonate (571 mg) were added to dioxane (25 mL). 2_Bromide (0.120 mL) was added to the suspension with stirring. The reaction was spoiled overnight and then water (0 1 mL) was added under further mixing. A certain amount of potassium carbonate (571 mg), 2-bromoethyl bromide (0.120 mL) and water (〇·ΐ mL) were added over 2 hours until the reaction progressed to completion. The reaction was diluted with water (100 mL), EtOAc (EtOAc)EtOAc. !H NMR (400 MHz, CDC13) δ 9.45 (s, 1 Η), 9.37 (s, 1H), 8.33 (s, 1H), 4.05 (s, 2H), 2.51 (s, 3H). Example 2: Bromo(Λ)-1-[(6-fluorenyl-nfc »hom-2-ylaminocarbamic acid)-methyl b 3_(1-phenyl-cycloheptanecarbonyloxy)-1- Nitrogen-bicyclic guanidine 2.2.2]octane

1-Phenyl-cycloheptanoic acid (R)-(l-aza-bicyclo[2 2 2]oct-3-yl) ester (example le) (70 mg) and 2-bromo-N-(6 -Methylpyridin-2-yl)acetamide (Example 2a) (49.2 mg) was dissolved in acetonitrile (1 mL) and stood overnight. The crystals were separated upon standing and filtered and washed with acetonitrile (2×1 mL), ethyl acetate (2×3 mL), and ethyl ether (2×3 m) to afford the title compound (2 4 m). m/e 477 [M]+. *H NMR (400 MHz, DMSO-D6) δ 11.33 (s, 1H), 9.09 (s, 131174.doc -45- 200946529 ) ' 8.37 (S, 1H), 7.38·7.31 (m, 4Η), 7· 27-7.22 (m,1H), 5.15-5.09 (m, 1H)5 4.36-4.25 (m, 2H), 4.16-4.07 (m, 1H) 3-68-3.56 (m, 4H), 3.46-3.33 ( m, !H), 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) 〇 Example 3. 帛化(斗(一)1-Phenyl-cycloheptanthoxy)-l-[(6·Trifluoroindolizine·3_ylamine 曱 ugly Base)_methyl]Small gas town double ring [η]]octane ❹ a) 2, odor (6-difluoromethyl _ 琏 _3_ base) _ acetamide

CF3 fluoromethylpyridazin-3-ylamine (〇.042 g) (prepared by a procedure similar to the procedure described in wo 2 007048779) dissolved in dioxane (training mL) and decomposed with carbonic acid _4 g) _ start mixing. Add 乙乙漠 (0.12 mL) and stir for 5 hours. Water (〇24) was added, and the reaction was stirred for 1 and 5 hours, after which water (40 mL) was added and the mixture was stirred for 15 hours. The di-methane was separated, dried and evaporated to give subtitle title: Compound (0.053 g). m/e 284/286 [M+H]+. </ RTI> <RTIgt; Example 3: Bromide (;?)-3-(l-phenyl-cycloheptanecarbonyloxytrifluoromethyl-pyridazin-3-ylaminecarbamyl)-methyl b 1_azaindole_bicyclo [2.22] Octane 131174.doc -46· 200946529 B"

1-Phenyl-cycloheptanoic acid (R)-(i-aza-bicyclo[2 2 .2]oct-3-yl) ester (example le) (61.1 mg) and 2-bromo-N- ( 6-Trifluorodecyl-pyridazine_3_yl)-acetamide (Example 3a) (53.0 mg) was dissolved in acetonitrile (2 mL) and left overnight. The solvent was evaporated and the product was purified eluting with EtOAc EtOAc (EtOAc) m/e 531 [M]+. H NMR (400 MHz, DMSO-D6) δ 12.17 (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. Bromide (and)-1_(benzo[rf]isoxazole-3-ylaminocarbamoylmethyl)_3_(1-phenylcycloheptanecarbonyloxy)-1_azaindole-bicyclo[ 2 2 2]octane a) benzo[oxaisoxazole-3-yl-2-oxo-acetamide

To the benzo[d]isoxazole_3 _ group 131174.doc -47- 200946529 amine (1 g) and cesium carbonate (2.42 g) in anhydrous DMF (20 mL) with stirring at the bottom The mixture of Molybdenum (〇·62 mL) was added to the mixture. After stirring for 8 h, lc/ms showed the completion of the reaction and the bromide was changed to a vapor in the final product. The reaction was poured into water (1 mL) and the product was extracted in &amp;| (2 χ 200 mL). The combined extracts were dried over magnesium sulfate and concentrated to dryness. The crude product was purified with EtOAc (EtOAc/EtOAc (EtOAc) m/e 210 [M+H]+. Example 4: gasified benzo(4)isoxazole-3-ylamine-methylmethyl)_3_(1-phenyl-cycloheptylcarbonyloxy)_i_azepine-bicyclo[2 2 2]octane

1-(R)-cycloheptanecarboxylic acid (R)-(l-aza-bicyclo[2.2.2]octyl) vinegar (example le) (114 mg) and hydrazine-benzo[d]isoxazole_ 3_Base_2_Gas-acetamide (Example 4a) (89 mg) was dissolved in acetonitrile (10 mL) and left to stand for 1 week. The obtained crystals were filtered and washed with diethyl ether (3×10 mL) to give the title compound (1 20 mg) as a solid. m/e 502 [M]+. 4 NMR (400 MHz, DMSO-D6) δ 12.15 (s, 1H), 8 16 (d 1H), 7.74 (d, 1H), 7.72-7.67 (m, 1H), y.44-7.39 (m, 1H) )| 7.38-7.30 (m,4H), 7.27-7.19 (m,1H), 5.mu (m,1H)', 4.63-4.46 (m, 2H), 4.17 (ddd, 1H), 3.76-3.61 ( m, 4H), 3.49 131174.doc -48- 200946529 (dd,1H),2.43-2.29 (m,2H),2.24-2.12 (m,2H), 2.〇3-ι·89 (m,3H) , 1.86-1.74 (m, 1H), 1_7〇-1·44 (m, 9H). Example 5: Pyridazine bromide _3_ylamine methyl hydrazinomethyl thiophenyl-cycloheptanecarbonyloxy)-1-azaindole-bicyclic guanidine 2.2.2]octane a) 2-but-3-ene Ethyl-2-thiophene-2-yl-hex-5-enoic acid ethyl ester

Ethyl 2-(thien-2-yl)acetate (2.35 g) was dissolved in tetrahydrofuran (3 mL) and cooled to -78. Lithium bis(trimethyldecyl) guanamine (2 3 i g) in THF (1 Μ solution, 13.8 mL) was added, and the solution was stirred for 3 Torr. 4-Bromo-but-1-ene (1·4 mL) was added and the reaction was allowed to warm to room temperature and stirred for one hour. The reaction was re-cooled to _78t, and a solution of THF(M), bis(trimethyl decyl) guanamine (231 g) in 138 mL) was added and the solution was stirred &lt;RTIgt; Add 4m · dilute (1.4 mL) and allow the reaction to warm to room temperature and overnight HPLC-MS analysis means that the reaction is not completed, so the reaction is cooled again ~ to - thief and according to the procedure outlined above, add bis (trimethyl stone) Xiyuan. Base) An aliquot of the amine-amine clock (1 Μ solution, 1 () mL) and 4 Ding Xiaohe 〇 machine. After 2 hours of mixing, the water was added (3 〇 and the organic extract of the reaction mixture was extracted with (2) 6 〇 m) and dried (10) and evaporated. The resulting oil was purified by EtOAc (EtOAc) elut elut elut elut 131174.doc -49· 200946529 'H NMR (400 MHz, DMSO-D6) δ 7.21 (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) Ethyl 1-thiophen-2-yl-cyclohept-4-enecarboxylate

Add Grubbs touch to 2-but-3-enyl-2-phenyl-2-phenyl-hexa-5-diacetate (Example 5a) (3.18 g) in di-methane (100 mL) Media (Grubbs

Catalyst) (second generation, Sigma-Aldrich Company Ltd) (0.100 g). The mixture was warmed to reflux under a gas atmosphere. After 20 hours, the mixture was cooled to room temperature and evaporated to an oil. The title compound (2.60 g) was obtained as a white oil. ❹ NMR NMR (400 MHz, DMSO-D6) δ 7.19 (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) Ethyl 1-thiophen-2-yl-cycloheptanecarboxylate

Ethyl 1-thiophen-2-yl-cyclohept-4-enecarboxylate (Example 5b) (2 86 g) was dissolved in 131174.doc -50 - 200946529 ethanol (30 mL) and ginsyl (triphenylphosphine) was added Gasification 铑(i)(〇i〇〇The reaction was rapidly stirred overnight under 5 hydrogen pressures. Add ginseng (triphenylphosphine) gasification hydrazine (1) (0.050 g), and at 5 hydrogen pressures The reaction was stirred for 3 days. A third addition of bis(diphenylphosphine)phosphonium chloride (1) (〇〇5〇g) was carried out, and the reaction was stirred overnight under 3 hydrogen pressure. The reaction was evaporated to dryness. The title compound (2.500 g) was obtained as a sub-title compound (m.p.). 400 MHz, DMSO-D6) δ 7.17 (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-thiophen-2-yl-cycloheptane decanoic acid (&amp;_〇_aza-bicyclo[2 2 2]oct-3-yl) ester

Ethyl 1-thiophen-2-yl-cycloheptanecarboxylate (Example 5c) (2.5 g) and (R)^-bun-3-pre (2.08 g) were dissolved in toluene (350 mL) and Sodium hydride (0.1 g) was added under nitrogen. The mixture was heated to reflux for 2 hours, after which time the toluene was carefully distilled to leave approximately 1 〇〇 mL, which was cooled and washed with water (1 〇〇 mL), dried (MgSCU) and evaporated. The crude product was purified by silica gel column chromatography eluting with ethyl acetate/triethylamine (99/1) to afford subtitle compound 131174.doc -51 - 200946529 (2.84 g). m/e 334 [M+H.]. lHNMR (4〇° MH^ C^l3) δ 7.18 (t, 1H), 6.95.6&gt;92 (m&gt; 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&gt; 2U), 1.95-1.90 (m, iH), 1.71-1.44 (m, 11H), 1.34-1.23 (m, 1H). ' e) 2-Bromo-Λ/&quot;-pyridazin-3-yl-acetamide

Add dioxin to the pyridazine _3_ylamine (27 phantom and diisopropylethylamine (6.3 mL) in dioxane ((10) in suspension at 〇 °c Bromoacetic anhydride (9 〇g) in methane (10 mL). The mixture was stirred for 0.5 hrs and then allowed to warm to room temperature. The resulting suspension was filtered, washed with methylene methane and dried to give Subtitle compound (2.0 g) 0 'Η NMR (400 MHz, DMSO-D6) δ 11.51 (s, 1H), 9.00 (dd, 1H), 8.28 (dd, 1H), 7.74-7.68 (m, 1H) , 4.15 (s, 2H) ° Example 5: pyridazine bromide·3_ylamine-methylmethylthiophene-2-yl-cycloheptyl carbonyloxy)-1-nitroso-bicyclo[2 2 2] octane alkyl

200946529 ^^-phen-2-yl-cyclo(tetra)carboxylic acid (RHl•aza-bicyclo[2 2 2]octyl_3_yl)a (Example 5d) (80 mg) and 2-brook-N-azine 3_Base-acetamide (Example 5e) (52 mg) was dissolved in acetonitrile (3 mL) and was taken overnight. Add acetic acid (9 mL) and isohexan (4 mL) and search overnight. The crystals obtained were filtered off and then triturated with ethyl acetate to give the title compound (14 g) m/e 469 [M+]. iH NMR (400 MHz, DMS〇-D6) S U.68 (s,1H),9 〇5 (10),

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 , 2,,,,, -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: Bromination (/〇_i-[(5-methyl-isoxazole_3_ylaminecarbamimidyl)methyl]_ 3-(1-嗟-phen-2-yl-cycloheptane Oxy)_ι_氮镇_双环 [2 2 2]辛炫 a) 2-bromo-7V-(5-methyl-isoxazol-3-yl)-acetamide

Add 2_ &gt to a stirred suspension of sodium bicarbonate (1.242 g) and 5-methyl-isooxazin-3-amine (1.45 g) in dichloromethane (5 mL) by dropwise addition ; stinky 醯 醯 (1.28 mL). The reaction was stirred overnight and then washed with water (2×50 mL). The organic solvent was dried over MgSO.sub.4 and evaporated. 131174.doc •53· 200946529 H NMR (400 MHz, DMSO-D6) δ 11 ”, ^ U·32 (s, 1H), 6.62 (s, 1H), 4.06 (s, 2H), 2.38 (s, 3H) Example 6: deciding W-spectrum methyl-iso-methylamine methyl) _ 3-(1-p-phen-2-yl-cycloheptanyloxy) 4-nitrogen- Double ring [2 2 2] Xin Shao

Ethyl acetate (Example 5d) (68 mg) and 2_Mo-N-(5-methyl-isoxazole·3_yl)acetamide (Example 6a) (45 mg) dissolved in acetonitrile (2 mL) Stir in the middle of the night. Ethyl acetate (10 mL) and isohexane (9 mL) were added and stirred overnight. The obtained crystals were filtered, and the methylene chloride was washed with ethyl acetate to give the title compound (82 mg). m/e 472 [M+]. !H NMR (400 MHz, DMSO-D6) δ 11.55 (s, 1 Η), 7.44 (dd,

1Η), 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, lH), 1.63-1.48 (m, 8H). Example 7: Bromination (i〇-l-[(3-methylisoisoxazolaminecarboxylidene)-methylbu-3-(1-喽-phen-2-yl-cycloheptanecarbonyloxy) Aza-bicyclo[2 2 2]octane 131174.doc -54- 200946529 a) 2-bromo-iV-(3-methyl-isoxazol-5-yl)-acetamide

3- At room temperature, 3-methyl-isoxazole _5-ylamine (2.9 g) and potassium bromate (9.8 g) were suspended in a gas (100 mL) and added 2-dif dropwise B brewing desert (6 g). The mixture was disturbed overnight. Water (〇.3 mL) and a further quantity of potassium carbonate (3 g) were added and the reaction was stirred for a further 3 minutes. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and evaporated EtOAc. ). H NMR (300 MHz, CDC13) δ 11.97 (s, 1 Η), 6.16 (s, 1H), 4.09 (s, 2H), 2.19 (s, 3H). Example 7: Bromination (i〇-l-[(3-indolyl-isoxazole-5-ylaminomethylglycosyl)-methylbu3-(1-thiophen-2-yl-cycloheptanecarbonyloxy) Base)-I-nitrogen-bicyclo[2.2.2]octane

1-Thien-2-yl-cycloheptanecarboxylic acid aza-bicyclo[2 2 2]oct-3-yl) ester (Example 5d) (50 mg) and 2-bromo-indole-(3-indolyl) Oxazol-5-yl)acetamide (Example 7a) (32 mg) was dissolved in acetonitrile (2 mL) and was taken overnight. I31174.doc -55· 200946529 Ethyl acetate (10 mL) and EtOAc (1 mL) were evaporated. m/e 472 [M+]. !H NMR (400 MHz, DMSO-D6) δ 12.21 (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,old), 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: Bromination (|?)·ι_[(3_gas·phenylaminemethanyl)methyl] Wintersporin_2-yl·cycloheptanecarbonyloxy)_1_azaindole-bicyclo[ 2 2 2]octane a) 2-difluoro-phenyl)-acetamide

To a suspension of sodium hydrogencarbonate (1 §) and 3-fluoroaniline (0.46 g) in dichloromethane (100 mL) was added dropwise 2-bromoethyl bromide (0.36 mL). After stirring overnight, the reaction was washed with H~~~~~ m/e 232 [M+H+]. H NMR (300 MHz, CDC13) δ 8.14 (s, 1H), 7.50 (dt, 1H), 7.31 (td, 1H), 7.18 (ddd, 1H), 6.87 (tdd, 1H), 4,03 (s, 2H). 131174.doc 56- 200946529 Example 8: Bromo(Λ)-1-[(3-fluoro-phenylaminemethanyl)-methyl]_3_(1-thiophene-2-yl-cycloheptanecarbonyloxyl )-1-nitroindole-bicyclo[2.2.2]octane

1-Thien-2-yl-cycloheptanecarboxylic acid (phantom-(1-aza-bicyclo[2,2 2]octyl-3-yl) ester (Example 5d) (96 mg) and 2-bromo-indole 3 -Fluoro-phenyl)-acetamide (Example 8a) (67 mg) was dissolved in acetonitrile (2 mL) and left overnight. Diethyl ether (1 mL) and iso-hexane (8 mL) were added and the mixture was taken overnight. The obtained crystals were filtered and washed with diethyl ether to give sub-title compound (9 </ RTI> mg). m/e 485 [M+]. !H NMR (400 MHz, DMSO-D6) δ 10.84 (s, 1 Η), 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), ❹ 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 · Bromination (/?)·ι·[(5-methyl-pyrazine-2-ylaminecarboxamidine)·methyl]_3_ (1-thiophen-2-yl-cycloheptanylcarbonyloxy) Nitrogen-bicyclo[2·2 2]octane a) 2-bromo-#-(5-methyl-pyrazine-2-ylacetamide

N

〇N 131174.doc 57· 200946529 Add bromide bromide to a mixture of 5-methylpyridin-2-ylamine and carbonic acid planer (11.2 g) dissolved in anhydrous DMF (30 mL) by dropwise addition. (2 89 g), and the mixture was stirred at room temperature for 2 hours. Water was added (2 Torr and the mixture was extracted with ethyl acetate (2 EtOAc) and dried over magnesium sulfate. The extract/e.g. to about 50 mL and iso-hexane (1 mL) was added to give Subtitle compound (1,64 g) as a solid. H NMR (400 MHz, DMSO-D6) δ 11.06 (1 Η, s), 9.17 (1H, s), 8, 31 (1H, d), 4.16 (2H, s ), 2_46 (3H, s). Example 9: Bromination (/?)_i_[(5_indolyl e-pyridin-2-ylaminocarbamoyl)methyl]_3_ (1-thiophen-2-yl) -cycloheptanecarbonyloxy)azinium-bicycloindole 2·2·2]octane

Η Η .Χλ Dissolve 1-thiophen-2-yl-cycloheptylcarboxylic acid (and)·(ι_aza-bicyclo[2 2 2]octyl-3-yl) ester (Example 5d) (48 mg) Acetonitrile (2 mL) was added with 2-bromo-iV-(5-mercapto-pyridazin-2-yl)-acetamide (Example 9a) (33 mg). After 1 week of stirring, diethyl ether (8 mL) and isohexane (5 mL) were added. The crystals were collected by filtration, washed with ethyl acetate (2×4 mL) and dried to give the title compound (26 mg). m/e 483 [M+]. *H NMR (400 MHz, DMSO-D6) δ 11.26 (s, 1H), 9.15 (s, 1H), 8.36 (s, 1H), 7.44 (dd, 1H), 7.04 (dd, 1H), 6.99 (dd , 131174.doc -58- 200946529 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) 〇 Example 10: Gasification (/〇·1·(benzo[rf]isoxazole_3_ylaminecarbamyl) Methyl)-3-(1-thiophen-2-yl.cycloheptanecarbonyloxy)azinium-bicyclo[2.2.2]octane

1-Thien-2-yl-cycloheptanecarboxylic acid aza-bicyclo[2.2.2]oct-3-yl)ester (Example 5d) (71 mg) and TV-benzo[4isoxazole·3- Base-2-gas-acetamide (Example 4a) (54 mg) was dissolved in acetonitrile (10 mL) and allowed to stand for 6 days. The crystals were filtered and washed with diethyl ether (3×10 mL) m/e 509 [M+]. 4 NMR (400 MHz, DMSO-D6) δ 12.16 (s, 1H), 8 17 (d 1 Η), 7.74 (d, 1 Η), 7.72-7.67 (m, 1 Η), 7.44-7.39 (m, 2 Η) 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 (ddj 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, 131174.doc • 59- 200946529 1H), 1.64-1, 47 (m, 8H). Example 11: sulphate (and) _l_(puppyrazin-2-ylamine decyl fluorenyl) sold phenanthrene-2·yl-cycloheptanecarbonyloxy)·1-nitroindole-bicyclic fluorene 2 2 2 Octane a) 2-bromo-iV-e ratio 嗓_2_yl-acetamide

Add 2-bromoethyl bromide (1 72) to a stirred suspension of pyrazin-2-ylamine (1.87 g) and potassium carbonate (8.19 g) in dioxane (25 mL) by dropwise addition. mL). The reaction was stirred overnight and then washed with water (2 χ 5 〇 mL). The organic phase was dried over MgSO.sub. 'H NMR (400 MHz, CDC13) δ 9.51 (d, 1H)S 8.63 (s, 1H), 8.42 (d, 1H), 8.30 (dd, 1H), 4.06 (s, 2H). Example 11: Bromide (pyrazine-2-aminoamine-methylmethyl) 3 (1 thiophene-2-yl-cycloheptanecarbonyloxy)-1-azaindole-bicyclo[2.2.2]

1-Thien-2-yl-cycloheptanoic acid (Λ)_(1•aza-bicyclo[2 2 2]octyl) ester (Example 5d) (116 mg) &amp; Pyrazin-2-ylacetamide (Example lla) (75 mg) was dissolved in acetonitrile (2 mL) and left overnight. Diethyl ether (10 mL) and iso-hexane (8 mL) were added and the mixture was stood overnight. The obtained crystals 131174.doc-60-200946529 were taken out and washed with diethyl ether to give the title compound (117 mg). m/e 469 [M+]. !H NMR (400 MHz, DMSO-D6) δ 11.38 (s, 1 Η), 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) 〇 Example l2: Desalination (i〇-3_[l-(3-fluoro-phenyl)-cycloheptanecarbonyloxy]_i ·(吼嗓-2-ylaminocarbamoylmethyl)_ι_azepine_bicyclic guanidine 2.2·2]octane a) 2-but-3-enyl-2-(3-fluoro-phenyl)_ _5-enoic acid ester

(3-Fluoro-phenyl)-acetic acid methyl ester (4.30 g) was dissolved in tetrahydrofuran (2 mL) and cooled to -78 °C. A bis(trimethyl sulfanyl) guanamine chain (25 6 mL '1 M THF solution) was added and the solution was stirred for 30 minutes. 4_Bromobutane 1-ene (2.60 mL) was added, and the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was again cooled to -78 °C. Lithium bis(tridecyldecylalkyl) guanamine (25 6 mL, 1 M in THF) was added and the solution was stirred for 30 min. 4_Bromo-indene-butene (2.60 mL) was added and the reaction was allowed to warm to room temperature and stirred for hrs. The reaction was re-cooled to -78 ° C and bis (trimethylnonane 13 ll 74.doc • 61 - 200946529 base) guanamine chain (25.6 mL '1 M THF solution) and 4 bromine were added according to the procedure outlined above. An aliquot of -丨_butene (26〇mL). After stirring overnight, water (2 mL) was added and the mixture was extracted with diethyl ether (2 X 60 mL). The combined organic extracts were dried over magnesium sulfate and evaporated. The resulting liquid was purified by chromatography on silica gel eluting with ethyl acetate/isohexane (1/99) to give subtitle compound (5 g). m/e 277 [M+H]+. b) 1-(3-Fluoro-phenyl)-cyclohepta-4-carboxylic acid formazan

Adding Gera to 2-but-3-ylidene-2-(3-fluoro-phenyl)-hexa-5-dicarboxylic acid methyl vinegar (Example 12a) (5.0 g) in a gas (1 mL) Booth Catalyst (second generation, Sigma-Aldrich Company Ltd) (0,05 g). The mixture was warmed to reflux under nitrogen. After 20 hours, the reaction was cooled to EtOAcqqqqqqqm The product analysis shows the presence of a large amount of the starting material in the mixture, so that the mixture is subjected to repeated reaction conditions and purification to give the subtitle compound 6 </RTI> as a coloured oil. m/e 249 [M+H]. 〇 c) methyl i-P-fluoro-phenyl)-cycloheptanecarboxylate

131174.doc -62 - 200946529 1-(3-|11-Phenyl)-cyclohepta-4-carboxylic acid decyl ester (Example 1213) (1.098) was dissolved in methanol (20 mL) with palladium/carbon ( 50 mg), and the mixture was stirred overnight under 4 hydrogen pressures. The solution was filtered and evaporated to give subtitle compound (1.09 g). m/e 251 [M+H]+. d) 1-(3-Fluoro-phenyl)-cycloheptane decanoic acid (and) • aza-bicyclo[2 2.2] xin_3_yl)

Ethyl 1-(3-fluoro-phenyl)-cycloheptanecarboxylate (Example 12c) (0.280 g) was dissolved in toluene (100 mL) and &lt;RTI ID=0.0&gt; 320 g). Toluene (10 mL) was distilled off in a Dean-Stark apparatus and after cooling, sodium carbonate (10 mg) was added. The reaction was refluxed for 4 hours in a Dean-Stark apparatus, after which an additional amount of sodium hydride (10 mg) was added and the reaction was refluxed for further 4 hours. After allowing to cool to room temperature, the toluene was washed with water, dried and evaporated. The residue was purified by column chromatography eluting with ethyl acetate / hexane / triethylamine (5 </ </RTI> <RTIgt; 0.200 g) ° m/e 346 [M+H]+. !H NMR (399.824 MHz, CDC13) δ 7.26 (td, 1H), 7.1〇-7.〇7 (m,1H), 7.04 (dd,1H), 6.90 (ddd,1H),4.78-4.73 (m, Ijj) 131174.doc * 63 - 200946529 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). Example 12: Bromination (i〇-3-[l-(3-fluoro-phenyl)-cycloheptanecarbonyloxy]-1-(»pyrazine-2-ylaminecarbamimidylmethyl)-1 -N-hydrazine-bicyclic guanidine 2.2.2]octane

Dissolving 1-(3-fluoro-phenyl)-cycloheptanoic acid (iJ)-(l-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 12d) (0.100 g) in Acetonitrile (8 mL) was added with 2-bromopyrazin-2-yl-acetamide (Example lla) (〇.〇5 g). The reaction was stirred for 3 days, diluted with EtOAc EtOAc (EtOAc) (EtOAc) Crystallization gave the title compound (〇. 〇 8 1 g) as a solid. m/e 481 [M+].丨H NMR (399.826 MHz, DMSO-D6) δ 11.42 (s, 1H), 9.28 (s, 1 Η), 8.49-8.45 (m, 2 Η), 7.40 (td, 1 Η), 7.19-7.12 (m, 2 Η) , 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: xihua (i?)-3-[l-(3-fluoro-phenyl)-cycloheptanecarbonyloxy] small (isocausine 131174.doc-64-200946529 oxazol-3-ylaminecarboxamidine Methyl group 双 双 双 2 2 2 2] octane a) 2- 溪-iV- 鸣 ° ° 基 基 基 基 乙

Η Br & &&quot; oxazin-3-ylamine (1.14 g) was dissolved in dioxazole (5 ()) and potassium carbonate (3.74 g) was added. Molybdenum (i i2 mL) was slowly added with stirring and the suspension was dropped overnight. The reaction was washed with water (2 x 50 mL), dried and evaporated. The product was recrystallized from dichloromethane/isohexane to give sub-title compound (2.3 g). NMR (299.946 MHz, CDci3) s 8 94 (s, iH), 8 34 (s, 1H), 7·06 (s, 1H), 4.03 (s, 2H). Example 13 Kb (and)-3-U ♦ gas-phenyl) cycloheptin deoxyl group] small (isoxazol-3-ylamine methyl hydrazinomethyl)-1 hydrazine-bicyclic guanidine 2 2 2 Octane

1-(3-Fluoro-phenyl)-cycloheptanecarboxylic acid (i〇_〇_aza-bicyclo[2 2 2]oct-3-yl)S (Example 12d) (50 mg) and 2_ Desert is different. evil. The solution was dissolved in acetonitrile (4 mL) and stirred overnight. The solution was diluted with ether (12 mL) and stirred overnight. The obtained crystals, (4), EtOAc (EtOAc) m/e 470 [M+] 〇131174.doc -65- 200946529 H NMR (399.826 MHz, DMSO-D6) δ 11.69 (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, ih), 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: gasification (/?)·3_(1•phenyl-cycloheptanecarbonyloxy)4 (acridin-2-ylaminocarbazylmethyl)_1-azaindole-bicyclo[2.2.2] xin Alkane a) cycloheptyl-stupyl·a

Phenylmagnesium bromide (3.0 μL in ether) was added dropwise to a stirred (overhead stirrer) solution of cycloheptanenitrile (5 μg) in 229 mL of diethyl ether under nitrogen at a slight reflux rate. Solution) (271 mL). Subsequently, the reaction mixture was heated under reflux for 3 hours. TLC indicates the absence of starting material in the reaction mixture. The reaction mixture was cooled to room temperature and stood overnight under nitrogen. - Cool the reaction mixture to 〇 ° C and use 102 mL· 4 N HC1 (aqueous solution) dropwise

• Handle while maintaining the temperature below 2 (TC. Quickly add 4 N sulfuric acid (203 mL) dropwise to start the reaction and then near the end more quickly. Remove the ice bath and distill off the ether. 8 〇 _ 9 〇 (&gt; c under heating for 35 hours, then allowed to cool to room temperature and allowed to stand overnight. The mixture was diluted with ether (about 450 mL) and water (1 〇〇 mL). Separate the layers and use The organic layer was combined and washed with saturated aqueous sodium bicarbonate (600 mL) and brine (600 mL), dried over magnesium sulfate, filtered and evaporated. The subtitle compound (86.5 g) was obtained as an orange liquid. NMR (300 MHz, CDC13) δ 7.96-7.91 (d, 2 Η), 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-Wind*-cycloheptyl)-phenyl-indole

Thiopurine (21 〇 mL) was added dropwise to pure cycloheptyl-phenyl-methanone (Example 14a) (86.5 g) at about 0 hr. Gas evolution and exotherm were observed. Keep the internal temperature at 丨5 during the addition. 〇 ,, and the evolved gas was purified by passing through a 10.2 M aqueous NaOH solution. The reaction mixture was heated to reflux overnight. TLC indicates no starting material remaining. The reaction mixture was cooled to 0 C and slowly poured onto ice (1 L) with stirring. The layers were separated and the aqueous layer was extracted with ether (2 &lt;&lt;&gt;&lt; The combined organic layers were washed with EtOAc (EtOAc) (EtOAc) Compound (100 g). XH NMR (400 MHz, CDC13) δ 8.10-8.06 (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). 131174.doc •67· 200946529 C) 1-phenyl-cycloheptanecarboxylic acid

The turbid solution of silver nitrate (1 37 g) in water (85 mL) was quickly treated dropwise (1-a-cycloheptyl)-phenyl ketone (Example 14b) (1 g) at 75 〇. A solution in mL of dioxane to form a precipitate. The reaction mixture was heated to 75 C for 4.5 hours. TLC showed no starting material remaining. The reaction mixture was cooled to room temperature then filtered and concentrated to ~2 mL. Water (2 〇〇 mL) and ether (300 mL) were added and the layers were separated. The aqueous layer was extracted with ether (2 χ 25 〇 mL). The combined organic layers were extracted with a 10% aqueous solution of sodium carbonate (3 x 250 mL). The combined alkaline extract was heated to 9 (Γ, and then cooled to warmness and acidified with concentrated hydrochloric acid (aq) over 40 min. The obtained brown solid was filtered, washed with water (X2) and Drying under vacuum, crystallization from EtOAc (4 mL), ield (yield: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 1Η), 2·43_2·35 (m, 2Η), 2.07-1.98 (m, 2Η), 1.70-1.53 (m, 8H) d) 1-phenyl-cycloheptane decanoate

131174.doc -68. 200946529 Add three dropwise to a solution of 1-phenyl-cycloheptanecarboxylic acid (Example 14c) (98 phantom in decyl alcohol (85 mL) and toluene (300 mL) under a nitrogen atmosphere. Methyl oxime-based diazo-carbazide (29.2 mL) in 2.0 Μ solution. After 45 minutes, TLC showed no starting material. The reaction mixture was concentrated in vacuo and purified by column chromatography. The crude product was purified by EtOAc/EtOAc EtOAc (EtOAc: EtOAc (EtOAc) 7.21-7.12 (m,1Η),3·60 (s,3Η),2.43-2.32 (m,2Η),2.07-1.96 (m, 2H),1.65-1.58 (m,8H) e) 1-benzene Base-cycloheptanecarboxylic acid (i〇-(l-aza-bicyclo[2.2.2]oct-3-yl) ester

In the Dean-Stark trap, (R)_(3)- acridinol (1〇.13 g, 0.0798 mol) and 1-phenyl-cycloheptanoic acid methyl ester (example) 14d) (9 25 solution in hydrazine (90 mL) was heated to reflux for 3 〇 min. The reaction mixture was cooled to room temperature and the water separator was removed. Sodium hydride was added portionwise under nitrogen (mineral oil) 60% dispersion) (3.19 g), and the reaction mixture was heated to reflux overnight under nitrogen. TLC showed no starting material remained. The reaction mixture was cooled in ice bath and ethyl acetate (2 mL) Dilute with water (2 mL). The mixture was filtered and the layers were separated. ethyl acetate (2 </ br> 25 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> And evaporating to give the crude product, which was purified by silica gel chromatography eluting with 1% triethylamine. The related fractions were combined and evaporated to give subtitle compound (7 63 as colorless oil). NMR (400 MHz, CD3OD) δ 7.34-7.28 (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, ❹ 1H), 1.69-1.54 (m, l〇H), 1.54-1.42 ( m,1H), 1.35-1.24 (m, 1H). ' Ο 2-Chloro-#-吼°-2-yl-acetamide Η

Cl A solution of 2-amino-pyridine (1. g) in anhydrous dichloromethane (10.6 mL) was treated with triethylamine (1·63 mL) under EtOAc. Helium (0.93 mL). The reaction mixture was allowed to warm to room temperature. After 2 hours, the mixture was partitioned between diqi methane and water. The phases were separated and the aqueous layer was extracted with chloroform (x2). The combined organic layers were washed with brine, dried over sulphuric acid &lt;RTI ID=0.0&gt;&gt;&gt;&&&&&&&&&&&&&& The relevant fractions were combined and evaporated to give the title compound as a pink solid. Further purification of the desired product by 湿 叮Ν 1·15 g was carried out by wet milling with 40-60 petroleum ether. The G.94 g portion of the material f was crystallized from EtOAc (EtOAc: EtOAc: EtOAc (EtOAc: EtOAc) , 1H), 8.32 (ddd, 1H), 8.21 (d, 1H), 7.76 (ddd, 1H), 7.12 (ddd, 1H), 4.20 (s, 2H). Example 14: Gasification of phenyl-cycloheptanecarbonyloxy)-1-(pyridin-2-ylamine decylmethyl)-1-azaindole-bicyclo[2.2.2]octane

1- 1-Phenyl-cycloheptanecarboxylic acid (R)-(l-aza-bicyclo[2.2.2]oct-3-yl) (Example l4e) (254 mg) in acetonitrile (5 mL) The solution was treated with 2-p-pyridin-2-yl-acetamide (Example l4f) ( 146 mg) and the obtained yellow solution was stirred at room temperature overnight, during which solids precipitated. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Purification was carried out by crystallization from EtOAc (2 mL) to afford 98 mg of the title compound as white crystals. m/e 462 [M]+. *H NMR (400 MHz, DMSO-D6): δ 11.09 (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). 131174.doc 71 200946529 Example l5: 溪化(Ι?)·3-(1-phenyl-cycloheptanecarbonyloxy)-1-(pyridin-2-ylamine-methylmethyl)-1-nitrogen铕-bicyclic guanidine 2.2.2]octane a) 2-bromo-N-indole-2-yl-acetamide

To the 2-amino group at room temperature. Et3N (58.6 mmol) and bromoacetam bromide (58.6 mmol) were added dropwise to a solution of the mixture (4 8.8 mmol) in anhydrous THF (9 8 mL). The mixture was stirred overnight and quenched with saturated NaHC EtOAc (aq). EtOAc was added to the mixture and the layers were separated. The aqueous phase was extracted with EtOAc and EtOAc (EtOAc m. Purification by flash chromatography on EtOAc EtOAc (EtOAc) lH NMR (400 MHz, CDC13): δ 8.75 (s, 1H), 8, 26 (ddd, 1H) 8.10 (d, 1 Η), 7.67 (ddd, 1 Η), 7.03 (ddd, 1 Η), 3.94 (s, 2Η). Example 15: Bromide (and)-3-(1·phenyl-cycloheptazepine)-j (吼 基 胺 胺 醢 甲基 甲基 -1- -1- -1- 双 双 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2 2.2

1-Phenyl-cycloheptanecarboxylic acid aza-bicyclo[2.2.2] osin-3-yl) ester (Example 14e) (〇.79 mmol) and 2-bromopyridine-2_131174.doc -72- 200946529 base-acetamide (Example 15a) (0.87 mmol) - dropped for 2.5 days in anhydrous MeCN "Concentrate the reaction mixture under vacuum and chromatographic column chromatography with 2-8% MeOH The title compound (211 mg) was obtained as a white solid. m/e 462 [M]+. NMR (400 MHz, DMSO-D6) δ 11.02 (s, 1 H), 8.33 (ddd, 1 H), 7.97 (d, 1 H), 7.86-7.80 (m, 1 H), 7.32-7.25 (m, 4 H), 7.23-7.12 (m, 2 H), 5.09-5.04 (m, 1 H), 4.23 (s, 2 H), 4.06 (ddd, 1 H), 3.63-3.49 (m, 4 H), 3.41-3.29 (m, 1 H), 2.37-2.22 (m, 2 H), 2.17-2.04 (m, 2 H), 1.98-1.83 (m, 3 H), 1.78. 1.66 (m, 1 H), 1.65-1.39 (m, 9 H). Example l6: gasification (/?)-3-(l-phenyl-cycloheptanecarbonyloxy)-1 (pyridine-4-ylamine-mercaptomethyl)-1-azaindole-bicyclo[2.2. 2]octane a) 2-pyridine pyridine-4-yl-ethylamine

The suspension of the 4-amino group (0.96 g) in anhydrous dioxane (1 mL) was cooled to hydrazine in an ice bath under nitrogen. Hey. Triethylamine (5% mL) was added, followed by the slow addition of gas-brewed chlorine (〇 89 mL). The ice bath was removed and the reaction mixture was allowed to reach room temperature. TLC showed a small amount of starting material remaining. The reaction mixture was diluted with water (20 mL) and di-methane (25 mL). The solid was filtered, washed with EtOAc EtOAc (EtOAc) The filtrate layer was separated and the organic layer was washed with water, dried and evaporated to give a dark brown glass. Another batch of title compound (0.91 g) was obtained by wet milling with pentane. 'H NMR (400 MHz, DMSO-D6) δ 10.79 (s, 1H), 8.47 (d, 2H), 7.59 (d, 2H), 4.33 (s, 2H). Example 16: Gasification of phenyl·cycloheptanecarbonyloxy)-1-(pyridine·4-ylaminocarbamimidylmethyl)-1_nitrogenbicyclo[2.2.2]octane

2-Ga-indole-pyridin-4-yl-acetamide (Example 16a) (30 mg) was added to 1-phenyl-cycloheptane decanoic acid (R)-(aza-bicyclo[2.2.2 </RTI> oct-3-yl) ester (Example 14e) (53 mg) in EtOAc (1 mL). The reaction mixture was stirred at room temperature for 24 hours. Diethyl ether (2 mL) was added and the mixture was filtered to give a pale brown solid. The solid was washed several times with diethyl ether and at 4 Torr. Dry under the vacuum under the armpits. Purification was achieved by column chromatography using 0-10% MeOH / dioxane. The desired fractions were combined and evaporated to give the title compound (20 mg). m/e 462 [M]+. *H NMR (400 MHz, DMSO-D6) δ H.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. 131174.doc -74- 200946529 (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 l7: gasification (i?)-l-[(5-fluoro-acridin-2-ylaminemethanyl)-methyl]_3-(1-phenyl-cycloheptanoxy)_1_镇镇_双环 [2.2.2] 辛烧 a) 2-Chloro-2-yl)-Ethylamine

The title compound (0-99 g, 73%, white solid). </ RTI> <RTIgt; Example 17: Chlorinated (/〇-l-[(5-fluoro-pyridin-2-ylaminemethanyl)·methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1- Nitrogen-bicyclo[2.2.2]octane

2-Gas-indole-(5-fluoro-pyridin-2-yl)-acetamide (Example 17a) (31 mg) was added to 1-phenyl-cycloheptanecarboxylic acid aza-bicyclo[2.2.2] Oct-3-yl) ester (Example 14e) (49 mg) in EtOAc (1 mL). The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added diethyl ether (2 mL), EtOAc, EtOAc (EtOAc) The residue was dried to give the title compound (49 mg). m/e 480 [M]+. 〇NMR (400 MHz, DMSO-D6) δ 11.19 (s, 1H), 8.36 (d, 1H), 8.02 (m, 1H), 7.81 (ddd, 1H), 7.33-7.26 (m, 4H), 7.22- (7, 1H) 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: gasification (and)-1-[(5-fluorenyl-pyridin-2-ylaminocarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)- 1azepine_bicyclo[2.2.2]octane a) 2-chloro-#-(5-methyl-pyridin-2-yl)-acetamide

The title compound (0.50 g) was obtained from m. 'H NMR (400 MHz, DMSO-D6) δ 10.69 (s, 1H), 8.17 (dt, 1H), 7.95 (d, 1H), 7.63 (dd, 1H), 4.32 (s, 2H), 2.25 (s , 3H). Example 18: Gasification of [(5-methyl-pyridin-2-ylaminocarbamimidyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)-1-azaindole-bicyclo[ 2.2.2] Octane 131174.doc -76· 200946529

According to the method used in Preparation Example 17, 2-chloro-N-(5-methyl-pyridin-2-yl)-acetamide (Example 18a) was used instead of 2- gas-purine (5-fluoro-pyridine- The title compound (36 mg) was prepared from 2-ethyl-ethylamine. m/e 476 [M]+. [H NMR (400 MHz, DMSO-D6) δ 10.98 (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)S 2.37-2.22 (m&gt; 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: gasified hydrazine R)-3-(l-phenyl-cycloheptanecarbonyloxypyridin-3-ylaminecarbamimidylmethyl)-1-azaindole-bicyclo[2.2.2]octane a 2 - gas-iV- ° ratio 0 -3 -yl-ethylamine

A mixture of 3-aminopyrazine (350 mg) and sodium hydroxide (0.6 g) was dissolved in water (8 mL) and the mixture was cooled in ice. Vj acetonitrile (1.19 mL) was added dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with dichloromethane, and the organic layer was concentrated and passed through a tube layer _ 131174.doc -77· 200946529 The title compound was obtained as a white solid (yield: 1 〇gj. 1H NMR (4 〇° MHz &gt; DMSO-D6) δ 10.51 (s&gt; 1 Η)). 8.73 (d, 1Η), 8.30 (dd, 1H), 8.03 (ddd, 1H), 7.40-7.35 (m, 1H), 4.30 (s, 2H) 〇' Example 19: gasification (Λ)-3_(1 • phenyl-cycloheptanecarbonyloxy acridine·3·ylamine-mercaptomethyl)-1-azaindole_bicycloindole 2·2·2]octane

By the method similar to the method used in Example 15, 2-gas was used as -pyridyl. The title compound (78 mg) was prepared by substituting <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; m/e 462 [M]+. ^ NMR (400 MHz, DMSO-D6) δ 11.27 (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: Chlorinated (/?)_i_[(2_methyl-indenyl-4-methylamine)-methyl]_3·(1-phenyl-cycloheptanecarbonyloxy)_1• Nitrogen-bicyclo[22.2]octane 131174.doc • 78- 200946529 a) 2-Gas-iV-(2-indolyl-pyridin-4-yl)-acetamide according to the method used in Example 14f 4-Amino-2-methylpyridine The title compound (1.0 g) was obtained. 'H NMR (400 MHz, DMSO-D6) δ 10.64 (s, 1H), 8.32 (d, 1H), 7.44 (d, 1H), 7.38-7.35 (m, 1H), 4.30 (s, 2H), 2.42 (s, ❹ 3H). Example 20: Gasification of (ii)-l-[(2-methyl-nb-pyridin-4-ylaminocarbamoyl)-methyl]-3-(1-phenyl-cycloheptanecarbonyloxy)- 1-azaindole-bicyclo[2.2.2]octane

标题 The title compound was prepared using a procedure similar to the one used to prepare Example 17. The title compound (57 mg) was obtained as a white solid. m/e 476 [M]+. XH NMR (400 MHz, DMSO-D6) δ 11.32 (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 131174.doc -79- 200946529 (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 ). Pharmacological analysis of M3 receptor activity assay in scintillation proximity assay (SPA) format by [3H]N-methylpurine (NMS) and performance of human muscarinic acetylcholine M3 receptor (M3-ACh) The competitive binding of the CHO-Kl (Chinese hamster ovary) cell membrane to the affinity of the compound for the M3 receptor (pIC50).

The SPA beads were pre-coated with a membrane and then buffered with 2 mg beads per well with serial dilutions of the compound of the invention, 0.2 nM, half Kd (dissociation constant determined in the experiment) [3H] NMS and assay buffer The solution (containing 5 mM MgCl2i 20 mM HEPES (pH 7.4)) was incubated. The assay was performed in the final volume of 200 pL in the presence of 1% (v/v) dimethyl hydrazine (DMSO). The total binding of [3H]NMS was determined in the absence of competing compounds and non-specific binding of [3H]NMS was determined in the presence of 1 μΜ atropine. Plates were incubated for 16 hours at room temperature and subsequently read on a Wallac MicrobetaTM using standard 3H protocol. pIC5G was determined as the negative logarithm of the concentration of the compound required to reduce the specific [3H]-NMS binding by 50%. Table 1 shows the pIC5G values for some representative examples. Table 1 Example Compound No. pICsO 1 9.1 5 9.4 13 10.1 131174.doc -80- 200946529 Table 2 gives the IC5〇 intensity of the example compounds. Table 2 Example number M3 Combined with IC5Q Example number M3 Combined with IC50 Example number M3 Combined with IC5Q 1 +++ 8 +++ 15 2 +++ 9 +++ 16 +++ 3 ++ 10 +++ 17 +++ 4 +++ 11 +++ 18 +++ 5 +++ 12 +++ 19 +++ 6 +++ 13 +++ 20 7 ++ 14 +++ M3 combined with IC50&lt;2 nM '&quot;++ +&quot;; ic50 2-10 nM,&quot;++";IC50:&gt;i〇nM," + "; NT-not tested. Measurement of plasma protein binding via human plasma and water at 37 °C Analytical dialysis of compounds between buffers and determination of compound concentrations in plasma and buffer by HPLC-MS/MS to determine the plasma protein binding process. Preparation method ^ Rinse with water, then immerse in dialysis buffer The dialysis cells were prepared in the liquid for at least 丨 hours (molecular weight cutoff 5000). The dialysis buffer was an isotonic buffered physiological saline solution (pH 7.4). A stock solution of the compound at a concentration of 〇5 mM in the diterpenoid was prepared. Volunteers get cold; East collects human plasma. Add a compound DMSO solution to the blood pool at a ratio of 1〇μΐ面(5)(6) blood group. This produces 1% dms in the blood solution. Each compound 131174.doc •81 - 200946529 The concentration of the substance is 5 μΜ. Then dialysis cells are prepared, and half of the cells are filled with 75 〇 dialysis buffer, and the other half of the cells are filled with 750 μl of the compound plasma solution. The cells, ie, the cells are sealed and placed in a 3&lt;rc incubator. Then the cells are allowed to rotate for a minimum of 4 hours to reach equilibrium. After equilibration, 500 μM buffer sample is removed and together with 1 〇〇 plasma Add together to the HPLC vial (sample in 6-fold diluted plasma) and remove ❹

The μ blood sample was added to the HpLc vial along with 500...dialysis buffer (sample in sputum dilution plasma). Subsequently, the samples were analyzed using HPLC-MS/MS. A four-point calibration curve was obtained by diluting a stock solution containing 6 times diluted Μ 5 μΜχ 〇 25 μΜΑ 1 25 μΜ 'these dilutions were injected in this order' with the injection of the sputum sample and subsequent injection of sputum Slurry samples. Calculate the concentration of the compound in the sample using the MassLynx version 4.1 software that automatically calculates the calibration curve and concentration of the compound in the cell (manufactured by partial milk/(4)(d)). According to the calibration curve, the following equation is used to select the compound in human plasma. Percentage (% combined) to determine hemoprotein binding: Binding % = 1 00-1 00 product / buffer injection 艚 (5 (plasma plasma; product) The institution supplies Dunkin Hadley guinea pigs (7) her 丨-乂g). By inhalation (0.5 ml/kg) by conscious rats by inhaling or under reversible anesthesia (5° money) Animal 13I174.doc -82- 200946529 Administration of test compound or vehicle. Before the bronchoconstriction is measured, the animal is recovered from anesthesia. Up to 48 hours after administration, and finally sodium pentobarbitone (sodium pentobarbitone) 60 mg/kg) anaesthetized guinea pigs, insert a cannula into the trachea for artificial ventilation, and insert a cannula into the jugular vein for intravenous administration of methotrexate. During the surgical preparation, use an isovolumic breathing pump (Harvard) Rodent Ven The tilator model 683) ventilates guinea pigs at a rate of 60 breaths per minute and a tidal volume of 5 ml/kg. The anesthetized and ventilated guinea pigs were measured using the Flexivent system (SCIREQ, Montreal, Canada) attached to the tracheal cannula. Lung function (lung tolerance and compliance). Aerated animals at 60 breaths/min at 5 ml/kg tidal volume (quasi-sinus ventilation mode). Application of 2-3 cm H20 positive end expiratory pressure Respiratory tolerance was measured using a Flexivent&quot;snapshot&quot; device (1 second duration '1 Hz frequency). Before and after intravenous administration of methotrexate (3, 10 and 3 〇pg/kg), The lungs were measured for compliance and compliance. The peak value of tolerance after acetylcholine challenge was calculated, and the effect of the test compound on the change of lung function induced by methotrexate was calculated. Percentage inhibition of bronchoconstriction at doses of choline. Tolerance of group t _ _ resistance change in compound treatment group] Tolerance change in vehicle treatment group x intranasal (ί·η·) Inhibition of pilocarpine-induced drooling by compounds by Harlan UK or D Avid Hall, Staffs UK supplies guinea pigs (450-550 g) and is trained in indoor equipment for a minimum of 3 days. The guinea pigs are randomly placed in the treatment group and weighed. Each animal is lightly anesthetized with halothane. And the compound or 13ll74.doc-83 - 200946529 vehicle (〇·5 W/kg) was administered intranasally up to 24 hours before challenge with pilocarpine. At the time of the test, the knees were finally numb with a urethane (25% solution in η2〇, 1.5 g/kg). One s presents adequate anesthesia (no toe contraction), placing an absorbent pad in the mouth of each animal for 5 minutes to dry the residual saliva &amp; remove the pad and replace it with a new one for 5 minutes To establish a baseline saliva production reading. At the end of the 5-minute period, the cockroaches were removed and weighed. The new pre-weighed _ population wealth, then each animal under the skin behind the neck to receive subcutaneous (sc.) hairy musk test (〇 6 mg / kg 'at 2 ml / kgT) e every 5 minutes Remove the sputum, weigh it and replace it with a new pre-weighing pad for up to 15 minutes.

Saliva production was calculated by subtracting the pre-weighed weight of the sputum from the weighing after each 5 minute period, and the values were added to produce salivary accumulation over a minute. In addition to the entire 15-minute recording period, each $85 period can also be analyzed. It is assumed that the baseline production of saliva is constant and multiplied by a reading of 15 minutes of baseline saliva production. The inhibition of saliva produced by the compound can be calculated using the following equation (1 · (test baseline) / (media baseline)) x i 〇〇. 131174.doc 84-

Claims (1)

200946529 X. Patent application scope: 1. A compound 'selected from the group consisting of: (i〇-l-[(6-methyl-D-pyridyl_3_ylaminecarbamyl)) Base]_3_(1_phenyl-cycloheptanyloxycarbonyl)·〗_Nitrogen rust_bicyclo[2 2 octane X ; β)-1-[(6-methyl-pyridazine-2-aminoamine Mercaptopurine]_3_(1-phenyl-cyclohungylcarbonyloxy)-1_azaindole-bicyclo[2.2.2]octane; phenyl-cycloheptanecarbonyloxy)-1-[( 6-trifluoromethyl-pyridazin-3-ylamine fluorenyl)-fluorenyl]-1-nitrogen-bicyclo[2.2.2]octaneX; Ο(Α)-1-(benzopyrene) Isoxazol-3-ylamine-mercaptopurinyl)-3-(1-phenyl-cycloheptanecarbonyloxy)-1_nitrogen rust-bicyclo[2.2.2]octane; (i?) -l-(pyridazin-3-ylaminecarbamimidylmethyl)-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy)-1-nitrogen-bicyclo[2.2.2]octane X ; (/?)-1-[(5-Methyl-isoxazol-3-ylaminocarbamoyl)-methyl]-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy ) _ 氮 nitrogen rust - bicyclo [2.2.2] octane X; (i〇-l-[(3· decyl-isoxazol-5-ylamine carbamoyl)-fluorenyl]-3-(1 -thiophen-2-yl-cycloheptanecarbonyloxy)-b-azindole-bicyclo[2.2.2]octane X; ® (/〇-l-[(3-fluoro-benzene) Aminomethylmercapto)-methyl]-3-(1 thiophen-2-yl-cycloheptanecarbonyloxy)-1-indolyl-bicyclo[2.2.2]octaneX; • (magic-l- [(5-Methyl-pyrazin-2-ylaminoindolyl)-methyl]-3-(1-thiophene-2-yl-cycloheptanecarbonyloxy)_i-nitrogen rust-bicyclo[2.2. 2] octane X; (/〇-1-(benzoxazino-3-ylaminomethyl)-3-(1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azaindole-bicyclo[2.2.2]octaneX; (/〇-1-(吼嗓_2_ylamine-mercaptomethyl)-3-(1-indol-2-yl-cyclo) Heptanecarbonyloxy)-1-nitrogen-bicyclo[2.2.2]octaneX; 131174.doc 200946529 β)-3-[1-(3-Fluoro-phenyl)·cycloheptanecarbonyloxy] _b (&lt;1-pyridin-2-ylamine-mercaptomethyl)-1-indolyl-bicyclo[2 2 2]octane X; (/?)-3-[1-(3-fluoro- Stupid)_cycloheptanecarbonyloxy]_丨_(isoxazole_3_ylamine fluorenyl)-1_nitrogen rust-bicyclo[2 22]octane X ; (Λ)-3_( 1-phenyl-cycloheptanecarbonyloxy)-1-(carbidin-2-ylamine-methylmethyl)-1-indolyl-bicyclo[2,2.2]octane X; (/^)- 3-(1-Phenyl-cycloheptanecarbonyloxy)_丨_(pyridine-4-ylaminecarbamimidylmethyl)-1-indolyl-bicyclo[2.2.2]octaneX; (/? )-1-[(5-fluoropyridinium_2_) Amidoxime methyl]_3_〇-stupyl-cycloheptanecarbonyloxy)·1-azaindole bicyclo[2.2.2]octane X ; (/?)-1-[(5-曱phenyl-D-pyridyl-2-ylaminomethylmercapto)-indenyl-phenyl-cycloheptanylcarbonyloxy)-1-nitrogen rust-bicyclo[2.2.2]octaneX; phenyl-cycloheptane Carbonyloxy)-1-(acridine-3-ylaminecarbamimidino)-1-nitrogen-bicyclo[2.2.2]octaneX; and (and)-1-[(2-fluorenyl) -pyridine·4-ylaminodecyl fluorenyl]_3_(1_phenyl-cycloheptylcarbonyloxy)-1-nitrogen rust-bicyclo[2.2.2]octane X; wherein X represents unit price or multivalent A pharmaceutically acceptable anion of acid. 2. The compound of claim 1 which is selected from the group consisting of: 131174.doc 200946529 131174.doc 200946529 〇 where x is the price of a monovalent or multi-valent acid. 3. A pharmaceutical composition comprising a compound such as sputum s - claim 1 or 2 and a discretionary adjuvant, diluent or carrier. 4. A method of preparing a pharmaceutical composition as claimed in claim 3, which comprises mixing a compound as claimed in claim 1 or 2 with a pharmaceutically acceptable or carrier. A suppository adjuvant, diluent 5_a compound of claim 1 or 2 is used in therapy. 6. A medicament for use in a compound of claim 1 or 2 for the treatment of cold obstructive obstructive pulmonary disease. , for use in the manufacture of a chronic obstructive disease for treating warm-blooded animals, such as humans, the method comprising (iv), the warm-blooding effective amount of the mammal as claimed in the request = Investing in a pharmaceutical product, the combination of which is the first active ingredient! 5 ^ The compound of the compound of item 1 or 2 and at least one selected from the group consisting of: other active compounds of various substances; phosphoric acid enzyme inhibitor; I3II74.doc 200946529 · β2 adrenergic receptor agonist; • chemokine receptor Functional modulators; • Kinase inhibitors; • Protease inhibitors; • Steroid glucocorticoid receptor agonists; and • Non-steroidal glucocorticoid receptor agonists. 131174.doc 200946529 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 131174.doc