TW200848416A - Cyclic amine derivatives and their uses - Google Patents

Abstract

Compounds of formula (I) have muscarinic M3 receptor modulating activity; wherein R1 is C1-C6-alkyl or a hydrogen atom; and R2 is a hydrogen atom or a group -R5, or a group, -Z-Y-R5, or a group -Z-NR9R10, or a group -Z-N(R9)C(O)R11; and R3 is a lone pair, or C1-C6-alkyl; R4 is selected from one of the groups of formula (a), (b), (c) or (d); Z is a C1-C16-alkylene, C2-C16-alkenylene or C2-C16-alkynylene group; Y is a bond or oxygen atom; R5 is an C1-C6-alkyl, aryl, arylalkyl; aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl group; R6 is C1-C6-alkyl or a hydrogen atom; R7a and R7b are a C1-C6-alkyl group or halogen; n and m are independently 0, 1, 2 or 3; R8a and R8b are independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, C1-C6-alkyl, cycloalkyl and hydrogen; R8c is -OH, C1-C6-alkyl, hydroxy-C1-C6-alkyl, or a hydrogen atom; R8d is C1-C6-alkyl or a hydrogen atom; R9 and R10 are independently a hydrogen atom, C1-C6-alkyl, aryl, aryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)-, or heteroaryl (C1-C6-alkyl)- group; or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom; R11 is C1-C6-alkyl or a hydrogen atom; Ar1 is aryl, heteroaryl or cycloalkyl; Ar2 are independently aryl, heteroaryl or cycloalkyl; and Q is an oxygen atom, -CH2-, -CH2CH2- or a bond.

Description

200848416 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a bicyclo [2 2 11 忠ο # ^ v • 1-2] heptylamine derivative, a pharmaceutical group, a preparation method thereof, and a treatment method Use in diseases such as respiratory diseases mediated by νπ muscarinic receptors. [Prior Art] Anticholinergic (4) hinders the passage of a pulse through the parasympathetic nerve or hinders the effect produced by the pulse passing through the parasympathetic nerve. This is the result of the ability of these compounds to inhibit the action of acetylcholine by blocking the binding of acetylcholine (Ach) to the muscarinic cholinergic receptor. There are five muscarinic acetylcholine receptor (mAChR) subtypes, termed M5, and each is a product of a different gene and each exhibits unique pharmacological properties. mAChR is widely distributed in vertebrate organs and these receptors can mediate both inhibitory and stimulatory effects. For example, in smooth muscle visible in the trachea, bladder, and gastrointestinal tract, M3 mAChR mediates contractile responses (by

Caulfield, 1993, Pharmac. Ther., 58, 319-379.). In the lungs, it has been confirmed that the receptors Ml, M2 and M3 are important and are located in the ulmo, bronchial, submucosal and parasympathetic ganglia (discussed in and Jacoby, 1998, Am J Resp Crit Care Med, 158). (5 part 3) S 154-160). The M3 receptor on the smooth muscle of the trachea regulates contraction and thus contracts the bronchi. Stimulation of the M3 receptor located in the submucosal gland to secrete mucus 0 has been noted to increase signaling through the muscarinic receptor in a variety of different pathophysiological conditions, including asthma and COPD. In 121575.doc 200848416 C〇PD, the vagal tone may increase (Gross et al., 1989 'Chest; 96: 984-987) and/or if applied to the top of the edema or mucus-filled tracheal wall, For geometric reasons, a higher degree of blockage may be caused (Gross et al., 1984, Am Rev Respir Dis; 129: 856-870). In addition, A-type disease can lead to loss of inhibitory ship receptor activity, which increases the degree of release of the sacral nerve in the thorn (F) (Fryer et al., 1999, Life Sci., 64, (6_7) 4 455 ). The resulting increase in receptor activation is enhanced by obstruction of the trachea. Therefore, the identification of effective sputum receptor receptor antagonists will be suitable for the therapeutic treatment of disease conditions involving the enhancement of 受体 receptor activity 1±. In fact, concurrent treatment strategies currently support the regular use of M3 antagonist bronchodilators as the primary therapy for patients with C()pD and Eis et al., 2〇〇1, Am Rev Respir Cdt 163:1256-1276). Incontinence due to hypertrophy of the bladder has also been shown to be mediated by increased stimulation of M3 mAchR. Therefore, M3 mAChR antagonistic acid is useful as a therapeutic agent for such mAChR-mediated diseases. Although a large body of evidence supports the use of anti-codon therapy for the treatment of conditions of the tracheal disease, relatively few anti-neoplastic compounds are being used in the clinical use of pulmonary conditions. SUb's are still present for novel compounds that cause blockade of M3 sputum receptors, especially those compounds that have a long duration of action and are feasible for each dosing regimen. Since the sputum test receptor is widely distributed throughout the body, it is advantageous to be able to deliver the anticholinergic test directly to the respiratory tract, as this allows for the administration of lower doses of the drug. Design and use of localized activities with long duration of action and retention on the recipient or in the lungs 121575.doc 200848416 Sexual drugs reduce the inappropriate side effects seen by systemic administration of the same drug. Tiotropium (Spiriva ΤΜ) is a long-acting muscarinic antagonist currently marketed by the inhaled route for the treatment of chronic obstructive pulmonary disease.

Tiotropium In addition, ipratropium is a commercially available muscarinic antagonist for the treatment of COPD.

Isotropium has been mentioned as a other muscarinic receptor modulator. For example: US4353922 describes a muscarinic base regulator based on the [2.2.1] azabicycloheptane ring system. £? 418716 and 1^005610163 describe various [3.2.1] azabicyclooctane ring systems. W006/017768 describes the [3.3.1] azabicyclononane ring system. [2.2.2] Azabicyclooctane system (Acridine) has been previously described in, for example, US 2005/0209272 and WO 06/048225. [3.1.0] Azabicyclohexane system has been described, for example, in WO 06/035282. [3.2.1] Azabicyclooctane system has been described, for example, in W006/035303. SUMMARY OF THE INVENTION 121575.doc -10- 200848416 According to the present invention, a compound of formula (1) is provided:

(1), wherein R is an alkyl or a fluorene atom; and R, a hydrogen atom or a group -r5 or a group / or a group ζ withdraws 9r1〇 or a group _z_n(r9)c(〇)r1i : and

V is a lone pair or a Ci. in this case, the nitrogen atom to which it is attached is a quaternary nitrogen and is positively charged; r4 is selected from formula (a), (b), (c) or (4) Among the groups -

(9) (9) (6) (9) Z is (^-(:16), (:2-0:16 extended alkenyl or (:2-(:16) alkynyl; ί Y is a bond or oxygen atom; <^-(:6 alkyl, aryl, arylalkyl, aryl fused cycloalkyl, aryl fused heterocycloalkyl, heteroaryl, aryl (Cl_Cs alkyl) _, heteroaryl (<^-0:8 alkyl)·, cycloalkyl or heterocycloalkyl; alkyl or hydrogen atom; alkyl or halogen; η and m are independently 〇, 1, 2 or 3; R and R is independently selected from the group consisting of aryl, aryl fused heterocycloalkyl, hetero 12575.doc 200848416 aryl, CrG alkyl, cycloalkyl and hydrogen; R is -OH, Ci-C6 alkyl, By a radical -Ci_C6 alkyl or a hydrogen atom; R9 and r1g are independently a hydrogen atom, a CkC6 alkyl group, an aryl group, an aryl fluorene heterocycloalkyl group, an aryl fused cycloalkyl group, a heteroaryl group, an aryl group ( Ci_c6 alkyl)- or heteroaryl(CrC6 alkyl)- group; or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring containing from 4 to 8 atoms of another nitrogen or oxygen atom, as the case may be. ; <&11 is 〇1-〇6 alkyl or hydrogen atom;

Ar1 is an aryl group, a heteroaryl group or a cycloalkyl group;

Ar2 is independently aryl, heteroaryl or cycloalkyl; and Q is an oxygen atom, -CH2-, -CH2CH2- or a bond; or a pharmaceutically acceptable salt, solvate, N-oxide thereof Or a prodrug. In a subset of the compounds of the invention: an alkyl or hydrogen atom; and 112 is (: 1-〇6 alkyl, a hydrogen atom or a group -ZY-R5 or a group _Z_NR9R10 or a group _z_n (r9) c(〇)r11 ; R3 is a lone pair; *Ci_C6 alkyl, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and is positively charged; R is selected from formula (a) or (b) or (c) One of the groups:

575 为 -12 氧 -12匸丨-匕alkyl or halogen; η and m are independently 〇, i, 2 or 3; R8a& R8b are independently selected from the group consisting of aryl, heteroaryl, Ci_C6 alkyl, cycloalkyl or hydrogen. ; R8<^_〇H, Ci-C6 alkyl, hydroxy-Ci_c0 alkyl or hydrogen atom; R9 and R1G are independently a hydrogen atom, a Ci_C6 alkyl group, an aryl group, a heteroaryl group, an aryl group (CVC6 alkyl group); Or a heteroaryl (Ci_C6 alkyl) group, or γ, together with the nitrogen atom to which it is attached, forms a heterocyclic ring containing, as the case may be, another nitrogen or oxygen atom of 4-8 atoms; R is Ci-C: 6 alkyl or hydrogen atom. The compounds of the invention are present in the same or inverse form:

with

Or internal orientation. The compounds of the invention are also oriented outside the group NRlR2R3 at:

121575.doc -13- 200848416 It is presently preferred that the compounds of the present invention are mainly in the form of a reverse-ring bridge

The compounds of the invention also exist as optical isomers because substituted bicyclic systems lack a plane of symmetry. The absolute configuration of the numerator can be defined using the Cahn-Ingold-Prelog rule to assign the R or s name to the final user. To avoid confusion, use the ring number used below.

However, the compounds of the present invention include racemic forms, single enantiomers, and mixtures of enantiomers in any ratio, as all such forms have muscarinic M3 receptor modulating activity to varying degrees. A preferred class of one of the compounds of the present invention consists of a quaternary ammonium salt of formula (1) wherein the nitrogen of formula (I) is a positively charged quaternary nitrogen. The compounds of the invention are useful in the treatment or prevention of diseases involving the activation of muscarinic receptors, for example, the compounds of the invention are useful in the treatment of a variety of conditions including, but not limited to, respiratory disorders such as chronic obstructive pulmonary disease, all types Chronic bronchitis (including associated breathing difficulties), asthma (allergic and non-allergic;, wheezing infant syndrome), adult/acute respiratory syndrome (ARDS), chronic airway obstruction, bronchial function, lung Fibrosis, emphysema, and allergic rhinitis, caused by other medications, 121575.doc -14- 200848416, especially other inhaled drug therapy, increased tracheal hyperactivity, pneumoconiosis (such as stagnation, charcoal Sickness, asbestosis, end-stage disease, eyelash loss, iron deposition, powdery disease, tobacco endocrinosis and cotton stagnation; gastrointestinal disorders such as colonic irritable syndrome, spastic colitis, stomach Duodenal ulcer, gastrointestinal convulsion or peristalsis, diverticulitis, gastrointestinal smooth muscle spasm Pain; urinary tract disorders associated with dysuria, including neurological urinary frequency, neurogenic bladder dysfunction, nocturnal enuresis, psychogenic bladder dysfunction, incontinence associated with bladder spasm or chronic cystitis, urgency or frequent urination; And cardiovascular disorders, such as vagus nerve-induced sinus rhythm depression. For the treatment of respiratory conditions, administration by inhalation is generally preferred, and in such cases, the compound (1) administered as a quaternary ammonium salt is generally preferred. In many cases, the duration of action of the quaternary ammonium salt of the present invention administered by inhalation may be above 12 hours, or more than 24 hours, for a typical dose. For the treatment of gastrointestinal disorders and cardiovascular disorders, administration by parenteral route, usually by oral route, may be preferred. Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. Another aspect of the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition involving the detection of M3 receptor activity by sputum. [Embodiment] The terminology Unless otherwise specified in the context of the use of 丨m, the following terms have 121575.doc •15-200848416 The following meanings: π-mercapto-' means _co-alkyl, wherein alkyl is as herein Said. Exemplary thiol groups include -COCH3 and -COCH(CH3)2.醯Amino group '' means -NR-fluorenyl, wherein R and fluorenyl are as described herein. Exemplary guanamine groups include -nhcoch3 and _n(ch3)coch3. "Alkoxy" means - oxime-alkyl, wherein the alkyl group is as follows. Exemplary alkoxy groups include methoxy (-〇CH3) and ethoxy (-〇c2H5). 'Oxygen-burning base" Means -COO-alkyl, wherein the alkyl group is as defined below. Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. π alkyl π as a group or a part of a group means having 1 in the chain a straight or branched chain saturated hydrocarbon group of up to 12, preferably 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, 1-propyl and 2-propyl. π alkenyl hydrazine as a group or Part of a group refers to a straight or branched chain hydrocarbon group having 2 to i 2 , preferably 2 to 6 carbon atoms and a carbon-carbon double bond in the chain. Exemplary alkenyl groups include vinyl, i. propylene And a 2-alkyl group. The alkynyl group as a group or a part of a group means a straight or branched chain hydrocarbon group having 2 to 12, preferably 2 to 6 carbon atoms and a carbon-carbon double bond in the bond. Illustrative alkynyl groups include ethynyl, i-propynyl and propynyl. π alkylamino π means -NH-alkyl, wherein alkyl is as defined above. Exemplary alkylamino includes methylamine base Ethyl amine, burn extension group "means - burning group - a group wherein an alkyl group as previously defined. Exemplary extensible groups include -CH2-, -(CH2)2-, and -C(CH3)HCH2. The π-alkenyl group means an alkenyl- group in which an alkenyl group is as defined above. Exemplary alkenyl groups include -CH=CH-, -CH=CHCH2-, and _CH2CH=CH-. 16- 200848416 ''Extend alkynyl' means - alkynyl-, wherein alkynyl is as defined previously. Exemplary alkynyl groups include -CC-, -CCCH2-, and -CH2CC-. "Alkylsulfinyl" means a -so-alkyl group, wherein alkyl is as defined above. Exemplary alkyl sulfinylene includes sulfinyl and ethanesulfinyl. ''Alkyl sulfonate "Alkyl" means -so2-alkyl, wherein alkyl is as defined above. Exemplary alkyl sulfonyl groups include methylsulfonyl and ethenyl. ''Alkylthio'' means -S-alkyl, wherein alkyl is as defined above. Exemplary alkylthio groups include methylthio and ethylthio. f π Aminothio group '' means a -C0-NRR group, wherein R is as described herein. Exemplary amine sulfhydryl groups include -CONH2 and -CONHCH3. "Aminoalkyl" means an alkyl-nh2 group wherein the alkyl group is as previously described. Exemplary aminoalkyl groups include -CH2NH2. "Aminoalkylsulfonyl" means a -S〇2-NRR group, wherein R is as described herein. Exemplary amine sulfonyl groups include -so2nh2 and -so2nhch3. ''Aryl fluorene is a group or a group Part of the group represents optionally substituted monocyclic or polycyclic aromatic t-carbocyclic moieties of 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl or naphthyl. Substituted by one or more substituents; ''Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Cw alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthylquinone. The aryl moiety thereof may be substituted with one or more substituents. "Arylalkoxy" means an aryl-alkoxy- group in which the aryl and alkoxy moieties are as previously described. Preferred arylalkoxy groups contain an alkyl moiety. 121575.doc -17- 200848416 Exemplary arylalkoxy groups include benzyloxy. The aryl moiety thereof may be substituted with one or more substituents. The π aryl fused cycloalkyl group means a monocyclic ring-shaped base such as a phenyl group fused to a cycloalkyl group, wherein the aryl group and the ground alkyl group are as described herein. Exemplary aryl fused cycloalkyl groups include Tetrahydronaphthyl and dihydrogenated aryl. The aryl and cycloalkyl rings may each be substituted with one or more substituents. The aryl fused cycloalkyl group may be attached to the remainder of the compound via any available slave atom.

C

πAryl fused heterocycloalkyl" means a monocyclic aryl ring such as phenyl fused to a heterocycloalkyl group, wherein aryl and heterocycloalkyl are as described herein. Exemplary aryl fused Heterocycloalkyl includes tetrahydroquinolyl, porphyrinyl, benzoquinonedioxanyl, benzoquinone dioxapentyl, dihydrophenylfuranyl and isoindolyl. The heterocycloalkyl rings may each be substituted with _ or a plurality of substituents. The aryl fused heterocycloalkyl group may be attached to the remainder of the compound via any available carbon or nitrogen atom. "Frono" means aryl, wherein aryl As described above, the exemplary aryloxy group includes a phenoxy group. The aryl moiety in the oxime may be substituted with - or a plurality of substituents. The "oxime amine" is a "heterocycloalkyl group, or, a heterocyclic group, ...Ά 丨, 丨, 4 / W " 匕儿忍忍 The 3 to 8 member single-ring ring-burning base ring system replaced by the t-month condition, in which the ring carbon atom is replaced by nitrogen; and its visible The case contains another heteroatom selected from the group consisting of hydrazine, s or taken (here described herein). Exemplary cyclic amines include clopidogrel, bitumin, and _ methyl tour. The amine group may be substituted with one or more substituents. "Cycloalkyl" means 3 to 1 2 gamma mountain; s 7 ^ is a fluorene atom, preferably 3 to 8 carbon atoms and more 121,575. Doc -18- 200848416 A saturated monocyclic or bicyclic ring system of 3 to 6 carbon atoms m substituted. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclo' and j A cycloalkyl group may be substituted with one or more substituents. "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. An exemplary monocyclic cycloalkylalkyl group includes a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, and a cycloheptylmethyl group, wherein the alkyl moiety can be substituted with one or more substituents. ''Dialkylamino group'" means an alkyl group, wherein the alkyl group is as defined above. Exemplary dialkylamino groups include dimethylamino and diethylamino. " A dentate "or", meaning a fluoro, chloro, bromo or iodo group. Preferred is a fluoro or a thiol group. A π haloalkoxy group means an alkyl group wherein the alkyl group is substituted by one or Multiple halogen atoms substituted. The alkoxy group includes a trifluoromethoxy group and a difluoromethoxy group. "Haloalkyl•• means an alkyl group substituted with one or more halogen atoms. Exemplary haloalkyl groups include a trifluoromethyl group. Πheteroaryl" as a group or part of a group, an optionally substituted aromatic monocyclic or polycyclic organic moiety of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, wherein One or more of the ring atoms are elements other than carbon, such as nitrogen, oxygen or sulfur. Examples of such groups include benzoquinone, benzoxazolyl, benzothiazolyl, benzofuranyl Phenylthiophenyl, fluorenyl, imidazolyl, fluorenyl, pyridazinyl, isoxazolyl, isoindolyl, isoindole, chewing thiol, oxime, U 、, σ 秦 基, σ 唆 、, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, tetrazolyl, 1,3,4-oxadiazolyl, thiazolyl, thienyl And triazolyl. Heteroaryl 121575.doc -19- 200848416 may be substituted with one or more substituents. The heteroaryl group can be attached to the remainder of the compound of the invention via any available carbon or nitrogen atom. ''Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferably, the heteroarylalkyl group contains a lower carbon alkyl moiety. The arylalkyl group includes a pyridylmethyl group in which the heteroaryl moiety may be substituted with one or more substituents. ''Heteroarylalkoxy' means a heteroaryl-alkoxy- group, wherein The heteroaryl and alkoxy moieties are as previously described. Preferably, the heteroarylalkoxy group contains a lower alkyl moiety. Exemplary heteroarylalkoxy groups include acridinylmethoxy. The heteroaryl moiety thereof may be substituted with one or more substituents. "Heteroaryloxy" means a heteroaryloxy- group in which the heteroaryl is as previously described. An exemplary heteroaryloxy group includes an acridinyloxy group, wherein the heteroaryl moiety can be passed through a Or a plurality of substituents substituted. ''Heteroaryl fused cycloalkyl'' means a monocyclic heteroaryl group such as pyridyl or furyl group fused to a cycloalkyl group, wherein heteroaryl and cycloalkyl As described previously, exemplary heteroaryl fused cycloalkyl groups include tetrahydroquinolyl and tetrahydrophenylfuranyl. Each of the heteroaryl and cycloalkyl rings may be substituted with one or more substituents. The fused cycloalkyl group can be attached to the remainder of the compound via any available carbon or nitrogen atom. ''Heteroaryl fused heterocycloalkyl group' means fused to a heterocycloalkyl group such as pyridyl or furanyl. Monocyclic heteroaryl, wherein heteroaryl and heterocycloalkyl are as previously described. Exemplary heteroaryl fused heterocycloalkyl groups include dihydrodioxocyclopyridylpyridinyl, dihydropyrrolepyridinyl, dihydrofuran aridinyl and m-dioxolone. Each of the heteroaryl and heterocycloalkyl rings may be substituted with one or more of 121575.doc -20- 200848416 substituents. The heteroaryl fused heterocycloalkyl group can be attached to the remainder of the compound via any available carbon or nitrogen atom. "Heterocycloalkyl" or "heterocyclyl," meaning an optionally substituted cycloalkyl group containing one or more of 4 to 8 ring members selected from the group consisting of a hetero atom of hydrazine, s or NR. (Π) a cycloalkyl group containing 4 to 8 ring members of CONR and CONRCO (examples of such groups include amber quinone imine group and 2-side oxypyridinyl group). The heterocycloalkyl group may be substituted with one or more substituents. The heterocycloalkyl group can be attached to the remainder of the compound via any available carbon or nitrogen atom. The π heterocycloalkylalkyl group, or "heterocycloalkyl group" means a heterocycloalkyl-alkyl group, wherein the heterocycloalkyl group and the alkyl moiety are as previously described. Low-stone anthracyl, 'as a group, unless otherwise specified, means an aliphatic hydrocarbon group having from 1 to 4 carbon atoms in the chain which may be a straight or branched chain, ie, a fluorenyl group or an ethyl group. , propyl (propyl or isopropyl) or butyl (butyl, isobutyl or tert-butyl). Πsulfonyl π means -S〇2_alkyl, wherein alkyl is as described herein. Exemplary sulfonyl groups include methanesulfonyl. • 'sulfonylamino group π means -NR-sulfonyl, wherein r and sulfonyl are as described herein. Exemplary sulfonylamino groups include ·NHS〇2CH3. r means an alkyl, aryl or heteroaryl group as described herein. "πpharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, where appropriate, a pharmaceutically acceptable base addition salt, a pharmaceutically acceptable acid addition salt. And a pharmaceutically acceptable quaternary ammonium salt. For example, (i) when the compound of the invention contains one or more acidic groups (eg, a carboxyl group), a pharmaceutically acceptable base addition can be formed Salts include sodium 121575.doc • 21· 200848416 salts, potassium salts, calcium salts, magnesium salts and ammonium salts, or with such as diethylamine, hydrazine methyl-glucosamine, diethanolamine or amino acids (eg, amines) Salts and analogs of organic amines of acid); (ϋ) when the compound of the present invention contains a basic group such as an amine group, a pharmaceutically acceptable acid addition salt which can be formed includes a hydrochloride salt, Hydrobromide, sulfate, phosphate, acetate, citrate, lactate, tartrate, methanesulfonate, maleate, fumarate, porphyrin and the like (iii) When the compound contains a quaternary ammonium group, the acceptable counter ion may be, for example, chlorine. , bromide, sulfuric acid, methanesulfonate, benzenesulfonate, tosylate, naphthalene disulfonate, phosphate, acetate, citrate, lactate, tartarate, sulphate, cisplatin Alkoxide, fumarate, succinate and other salt forms are described in Handbook of Pharmaceutical Salts.

Properties, selection and use',, P. Heinrich Stahl and Camille G. Wermuth, Wiley-VCH, 2002. It will be understood that reference to a compound of the invention as used herein is also intended to include pharmaceutically acceptable salts.

C "prodrug" means a compound which can be converted in vivo to a compound of the invention by metabolic means (for example by hydrolysis, reduction or oxidation). For example, an ester prodrug of a compound of the invention containing a hydroxyl group It can be converted into a parent molecule by hydrolysis in vivo. Suitable esters of the compound of the invention containing a hydroxyl group are, for example, acetate, citric acid ester, lactate, barium tartrate, strontium, malonate , oxalate, salicylate, propionate, succinate, butyl quinone _ _ acid ester, maleic acid ester, methylene-dihydroxy-caiene, gentisic acid, hydroxy Ethyl phthalate, di-p-tolylhydrazide tartaric acid 7-alkanesulfonic acid 121575.doc -22- 200848416 xi, sulphuric acid sulfonic acid S, phenylphosphinic acid, p-toluene acidity, cyclohexyl Sulfonate and quinate. As another example, an ester prodrug of a compound of the invention containing a Wei group can be converted into a parent molecule by hydrolysis in vivo. Prodrugs described by FJ Leinweber, Drug Metab. Res., 1987, 18, 379. It should be understood that The reference to the compounds of the present invention is intended to also include prodrug forms. π-saturated π is a compound and/or group which does not have any carbon-carbon double bond or carbon-carbon bond. The case is substituted with up to four substituents. Optional substituents include fluorenyl (eg -COCH3), alkoxy (eg -OCH3), alkoxycarbonyl (eg -COOCH3), alkylamino (eg -NHCH3), An alkylsulfinyl group (eg, -SOCH3), an alkylsulfonyl group (eg, -so2ch3), an alkylthio group (eg, -SCH3), -NH2, an amine fluorenyl group (eg, -CON(CH3)2), Aminoalkyl (eg -CH2NH2), arylalkyl (eg -CH2Ph or -CH2-CH2-Ph), cyano, dialkylamino (eg -N(CH3)2), halo, halo Oxyl (e.g., -OCF3 or -OCHF2), haloalkyl (e.g., _CF3), alkyl (e.g., -CH3 or -CH2CH3), _OH, -N02, aryl (optionally alkoxy, i alkoxy) , ii, alkyl or _alkyl substituted), heteroaryl (optionally substituted by alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, amino fluorenyl ( For example -CONH2, -CONHCH3), amine Sulfhydryl (eg, -so2nh2, -so2nhch3), amidino (eg, -nhcoch3), sulfonylamino (eg, -nhso2ch3), heteroarylalkyl, cyclic amine (eg, morpholine), aryloxy, Heteroaryloxy, arylalkoxy (eg benzyloxy) and 121575.doc -23- 200848416 heteroarylalkoxy. The alkyl, alkenyl or alkynyl group may be optionally substituted. Optional substituents in the aforementioned groups include alkoxy groups (e.g., -0Ch3), alkylamino groups (e.g., -NHCH3), alkyl sulfinyl groups (e.g., _s〇CH3), alkyl sulfonyl groups (e.g., -so2ch3), alkylthio (eg _SCH3)...NH2, aminoalkyl (eg -ci^NH2), arylalkyl (eg _CH2P1^_CH2_CH2 Ph), cyano, dialkylamine ( For example -N(CH;3)2), fluorenyl, haloalkoxy, (eg -OCF3 or -OCHF2), _alkyl (eg CF3), alkyl (eg -Ch3 or -CH2CH3), -oh And -N02. The compounds of the invention may exist in one or more geometric forms, optical forms, enantiomeric forms, diastereomeric forms, and tautomeric forms, including but not limited to, cis and trans, five and two , indole, type and meso form, keto form and enol form. Unless otherwise stated, reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate, the isomers can be separated from their mixtures by the application or modification of known methods, such as chromatographic techniques and recrystallization techniques. Where appropriate, the isomers can be prepared by applying or modifying known methods, such as asymmetric synthesis. Base R1, R2 and R3 alkyl or hydrogen atom; and R2 is a hydrogen atom or a group _rS or a group -ZY-R5 or a group -Z_NR9R10 or a group _z_n(r9)c(〇)r1i •' And r3 is a lone pair, or Cl-(:6 alkyl, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and is positively charged; when the group _R5 or the group _Z_Y_R5 or a group - Z_NR9R10 or group _Z_ 121575.doc -24· 200848416 When N(R9)C(〇)Rn is present in R2, Z can be (for example, the latter is optionally substituted with methyl groups in up to three carbons in the chain; Y is a bond or; r5 may be, for example, an optionally substituted aryl group such as phenyl or naphthyl; or an aryl fused heterocyclic group such as 3,4·methylenedioxyphenyl , 3, a penetrating ethyl-oxy-based group or a monohydroquinone biting a south group; a substituted heteroaryl group such as pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl , benzoxazole, benzoquinone, fluorenyl, benzoyl, fluorenyl, phenyl, phenylthiophenyl, furyl, benzofuranyl, imidazolyl, benzoquinone Micylene, isothiazolyl, benzoquinoneisothiazolyl, pyrazolyl, Isothiazolyl, oxazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, fluorenyl, pyridazinyl, triazinyl, fluorenyl and carbazolyl; The group (CrC6 alkyl)-, such as those in which the aryl moiety is any of the above-mentioned specifically mentioned aryl groups, especially phenyl and C6 alkyl)- moiety is _CH2. or _CH2CH2_; Substituted aryl fused cycloalkyl, such as dihydrogenated or 1,2,3,4-tetrahydronaphthyl; substituted heteroaryl (Ci_C8 alkyl) _, such as The aryl group moiety is any of the above-mentioned specific heteroaryl groups and the -(Cl-C6 alkyl) moiety is a group of -CH"t-CH2CH2-; 6 a substituted cycloalkyl group such as a cyclopropyl group , cyclobutyl, ring 121575.doc •25· 200848416 pentyl, cyclohexyl, cycloheptyl or cyclooctyl; or optionally substituted heterocycloalkyl (CrCr alkyl)-, such as those in which The alkyl moiety is azetidinyl, piperidinyl, bufferyl, n-substituted piperazinyl (such as methyl piperazinyl) or oxazolidinyl and _yl)- moiety is -CH2- or -CH2CH2- Group; R9 and R10 Independently selected from hydrogen; Cl_c0 alkyl, such as methyl, ethyl, or n-propyl or isopropyl; or any optionally substituted aryl or aryl group as specifically mentioned in the discussion of R5 above a fused heterocycloalkyl, aryl fused cycloalkyl, heteroaryl or aryl (Cl_C8 alkyl) group; or R9 and R10 together with the nitrogen atom to which they are attached may form another nitrogen or a heterocyclic ring of 4-8 ring atoms, preferably 4-6 ring atoms of an oxygen atom, such as azetidinyl, piperidinyl, piperazinyl, piperidinyl-substituted piperazinyl (=methylpiperazinyl), pyrrole Pyridyl, morpholinyl and thiomorpholinyl;

Rl1 can be, for example, methyl, ethyl or n-propyl or isopropyl. Preference is now given to compounds of the invention in which, in the group _nr1r2r3, R1 is methyl or ethyl; R2 is a group of the above-mentioned groups ζγ·κ5, in particular wherein R5 is a cyclic lipophilic such as phenyl a group, 丫 is a bond or _〇_, and is, for example, up to 12, for example, up to 9 carbon atoms are bonded to nitrogen and _yr5 is a straight or branched chain extension; and ^^ is a methyl group, The nitrogen is quaternized and positively charged. The base ring R4 R is selected from one of the groups (a), (b) ' (c) or (d): 121575.doc -26- 200848416

(9) (6) (9). In the group (4), 'R6 may be a (tetra)alkyl group such as a methyl group or an ethyl group, or a hydrogen atom, and Ar1 may be an aryl group such as a phenyl group, such as a heteroaryl group such as a porphinyl group, especially a 2-phenylene group. a cycloalkyl group of a cyclohexyl group, a cyclopentyl group, a cyclopropyl group or a cyclobutyl group; the ring substituents R7a and R7b may independently be, for example, a*, an ethyl group,

a burnt earth of n-propyl or isopropyl, n-butyl, t-butyl or t-butyl <halogen such as a fluorine group, a chloro group or a bromo group; and m and η may independently be 〇, 1, 2 or 3. In the groups (8) and (4), R^R8b may be independently selected from any of the aryl, aryl fused heterocycloalkyl, aryl fused cycloalkyl groups specifically mentioned in the discussion of R5 above, Heteroaryl, Cl_C0 alkyl or cycloalkyl. Further, RSb may also be a hydrogen atom. R8c may be -OH, a hydrogen atom, a C^-C:6 alkyl group such as a methyl group or an ethyl group or a hydroxy-Ci_c0 alkyl group such as a hydroxymethyl group. At present, it is preferable that R8e is ·OH. Anti ^ and! A preferred combination of ^ (especially when R8. is _〇h) includes combinations thereof, wherein (i) R8a & RU are each optionally substituted monocyclic heteroaryl groups of 5 or 6 ring atoms, such as Pyridyl, oxazolyl, thiazolyl, indolyl and especially thienyl (such as 2-thienyl); (ii) R8a and R8b are optionally substituted phenyl; one of them is optionally substituted a phenyl group, and the other is a cycloalkyl group such as cyclopropyl, cyclobutyl, cycloheptyl, cyclooctyl or especially cyclopentyl or cyclohexyl; and (iv) one of R8a and R8b is a monocyclic heterocyclic ring substituted with 5 or 6 ring atoms as appropriate. 121575.doc -27- 200848416 aryl, such as pyridinyl, thienyl, oxazolyl, thiazolyl or furyl, and the other is a ring-burning The base 'such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. In group (c), ruler 8. It may be -OU, a hydrogen atom, a <^-0:6 alkyl group such as a methyl group or an ethyl group or a hydroxyl group -Ci_C6 alkyl group such as a hydroxymethyl group. It is presently preferred that R8e is -OH. Ar2 is each an aryl, heteroaryl or cycloalkyl ring and may be, for example, any of the aryl, heteroaryl, alkyl or cycloalkyl rings specifically mentioned in the discussion of R5 above. Preferably, the Ar2 ring comprises a phenyl group. The bridge _q between the two Ar2 rings is _〇_, -Ch2kh2Ch2_. In R4 options (a), (b), (c) and (d), it is presently preferred that R4 is a group (a) or (b) or (c). A preferred subclass of a compound of the invention consists of a compound of the formula (IA):

X- (IA) wherein ring A is optionally substituted phenyl ring, or 5 or 6 ring atom monocyclic heterocyclic ring, or phenyl fused heterocycloalkyl ring system, wherein the heterocyclic ring The alkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R8a is a stupid group, a thienyl group, a cyclopentyl group or a cyclohexyl group; and R8b is a phenyl group, a thienyl group, a cyclopentyl group or a cyclohexyl group; Is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7, with the constraint that s+t is not greater than 10; Y is a bond or _ 〇 _ 121575.doc -28 - 200848416 'and x is a pharmaceutically acceptable anion. In the compound (IA), it is preferred that the ring A is an optionally substituted phenyl group, wherein the optional substituent is selected from the group consisting of an alkoxy group, a halogen group (especially a fluorine group or a gas group), and a Cl-c3 alkane. Base, amine CVC3, amino-Ci-C3 alkyl, _CN and amine sulfonyl. At present, preferred R8a&R8b groups are: R8a = phenyl, R8b = phenyl; R8a = 2_thienyl, R8b = 2-nonyl; phenyl, fluorene 8, cyclohexyl. Another preferred subclass of a compound of the invention consists of a compound of formula (IB):

IB· (IB) wherein ring B is optionally substituted phenyl ring, or 5 or 6 ring atom monocyclic heterocyclic ring, or aryl fused heterocycloalkyl ring; s is 1, 2 , 3, 4, 5, 6 or 7 and t is 〇, 1, 2, 3, 4, 5, ό or 7, with the constraint that S + t is not more than 1 〇; γ is a bond or _〇_; And Rule 6, Arl, R7a and R7b are as defined for the above group (4); and χ- is a pharmaceutically acceptable anion. In the compound (ΙΒ), it is presently preferred that the ring β is (1) optionally substituted phenyl' wherein the optional substituent is selected from alkoxy, halo (especially fluoro or chloro), CVC3 alkyl, Amine Cl-C3 fluorenyl, amine Ci-Cs alkyl, -CN and aminosulfonyl; another preferred subclass of a compound of the invention consists of a compound of the formula (IC): 121575.doc -29- 200848416

Wherein ring C is optionally substituted phenyl ring, or 5 or 6 ring atoms of a monocyclic heterocyclic ring or an aryl fused heterocyclic ring; Q is an oxygen atom, -CH2_, -CH2CH2 Or one button; 3 is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7, with the constraint that s + t is not greater than 10 and Y is a bond or ·0-; and X- is a pharmaceutically acceptable anion. In the compound (1C), it is presently preferred that the ring C is an optionally substituted phenyl group, wherein the optional substituent is selected from the group consisting of an alkoxy group, a halogen group (especially a fluorine group or a chlorine group) cvc3 alkyl group, an amine group. Cl_c3 fluorenyl, amine Ci_C3 alkyl, _cn and aminosulfonyl; more preferably ring C is phenyl ring. In subclasses (ΙΑ), (IB) and (IC), s+t can be ( For example M, 2, 3, 4 5 6 or 7 and may produce a suitable combination of t and s, such as (yes, 2、, 1, 2, 3, 4, 5 or 6 and 鸿卜^卜蜮^ in the compound...) In (IB) and (1C), the currently preferred combination of t and YAs is #〇, $ is 2 or 3, and ¥ is -〇-. Another-currently preferred combination Y is a bond and s+t 2, 3 or 4 〇, as in the 'I subclass (ΙΑ), (IB) and (IC) of the compounds of the invention, it is generally preferred that the compound be predominantly in a reverse-ring bridge configuration. By way of non-limiting example provided herein, in a practical example, the invention provides a formula Ci) selected from the following: 121575.doc -30- 200848416: inverse (earth)-biphenyl-2-yl- Aminocarbamic acid 2-dimethylamino-bicyclo[221]hept-7-yl ester; inverse (1S, 2S Hydroxy-di-thiophen-2-yl-acetic acid 2-[methylphenyl-propyl)-amino]-bicyclo[2·2·1]hept-7-yl ester; inverse (IS, 2S) [ 7-(2-Hydroxy-2,2·di-thiophene-2-yl-ethenyloxy)-bicyclo[2 ·2·1]hept-2-yl]-dimethyl-(3-phenyl- Propyl)-ammonium bromide; inverse (1R, 2R) hydroxy-di-thiophen-2-yl-acetic acid 2_[mercapto-(3-phenyl-propylaminol-bis-bicyclo[2·2·1] Hg-7-yl ester; inverse (1R, 2R) [7-(2-trans-base_2,2-___σ-sept-2-yl-ethenyloxy)-bicyclo[2·2·1]g -2-yl]-dimethyl-(3.phenyl-propyl)-bromination; inverse (1S, 2S) (7-benzyloxybicyclo[2.2.1]hept-2-yl)_ Mercapto-(3_phenyl-propyl)-invitronation; inverse (1S,2S)hydroxy-di-thiophen-2-yl-acetic acid 2-[methyl-(3-phenoxy-propyl) -amino]-double soil [2·2·1]hept-7-yl _ ; inverse (18,28)[7-(2_hydroxy-2,2-disesten-2-yl-ethoxime ))-bicyclo[2·2·1]hept-2-yl]-dimethyl-(3-phenoxy-propyl)-ammonium bromide; inverse (1S, 2S)^i-based-^_ σ塞特-2-yl-acetic acid 2-[methyl-(4-phenyl-butyl)-amino]-bicyclo[2·2·1]hept-7-yl ester; inverse (1S, 2S) [7-(2-Pheptyl-2,2-di-nonyl-2-yl-) Ethyloxy))bicyclo[2.2.1]hept-2-yl]-didecyl-(4•phenyl-butyl)_invitrogen; inverse (1S,2S)hydroxy-di-thiophene-2 -yl-acetic acid 2-(methyl-phenethyl-amino)-bicyclo[2.2.1]hept-7-yl ester; inverse (1S,2S)7-(2-^yl-2,2-di - 叹 -2- -2-yl-ethoxycarbonyl) _ bicyclic 121575.doc -31- 200848416 [2.2.1] hept-2-yl] dimethyl-phenethyl-alkaline ammonium; inverse (1S, 2S) hydroxy-diphenyl-acetic acid 2-(methyl-phenethyl-amino-y-bicyclo[2.2.1]hept-7-yl ester; inverse (1S,2S)[7-(2-hydroxy-2 ,2-diphenyl-ethoximeoxybicyclo[2·21]hept-2-yl]-dimethyl-phenethyl-ammonium bromide; reverse (1S,2S)hydroxy-diphenyl-acetic acid 2-[Methyl-(3-phenoxy-propyl)-aminol-bicyclo[2.2.1]hept-7-yl ester; inverse (1S,2S)[7-(2-hydroxy-2, 2·Diphenyl-ethoxycarbonylbicyclo[2.21]heptan-2-yl]monomethyl-(3-propoxy-propyl)-molybdenum; inverse (1S,2S) 9-hydroxy-9H - Diphenylhydrazone -9-carboxylic acid 2-[methyl-(4-phenyl-butyl)-amino]-bicyclo[2.2.1]hept-7-yl ester; inverse (1S, 2S) [ 7-(9-Hydroxy-9H-dibenzoquinone- 9-carbonyloxy)bicyclo[2.2.1]hept-2-yl]-dimethyl- (4-phenyl-butyl)-ammonium bromide; inverse (1S,2S).yl-di-thiophene-2-yl-acetic acid 2-{[8-(t-butoxy-yl-methyl) -amino)-octyl]-mercapto-aminobibicyclo[2 ·2·1]hept-7-yl ester; inverse (1S,2S)[8·(t-butoxycarbonyl-methyl) Amino) _ octylbu [7_(2_ hydroxy-2,2-di-thiophene-2-yl-ethoxycarbonyl)-bicyclic oxime ^heptyl]-diyl]-didecyl-ammonium bromide; (1S,2S)[7-(2•hydroxy-2,2-di-thiophen-2-yl-ethyloxy)bicyclo[2.2.1]hept-2-yl]-monomethyl-(8_ Methylamino-octyl)·ammonium; anti-(1S,2S)[3_(4•gas-propenyloxy)-propyl]_[7-(2-trans-base_2,2·2 -σcephen-2-yl-acetoxy)-bicyclo[2.2.1]hept-2-yl]-dimethylammonium; trans-(IS,2S)hydroxy-di-thiophene-2-yl- Acetic acid 2·{[3-(3,4_dioxa-phenoxy)-propyl]-indolyl-aminobicyclobicyclo[2.2.1]hept-7-yl ester; 121575.doc -32- 200848416 Anti-(1 S,2S)[3-(3,4-Dichloro-phenoxy)-propyl H7_(2-hydroxy-2,2-di-thiophen-2-yl-ethenyloxy)-bicyclic ^么^hg-^kib dimethyl-ammonium'; anti-(1S,2S) 9-hydroxy-9H-dibenzoquinonecarboxylic acid hydrazine [mercapto _(3_benzene) --propyl)-amino]-bicyclo[2·2·1]hept-7-yl g; anti-(1S,2S)[7-(9-trans-yl-9H-dibenzoquinone _ 9_Herocyclobicyclo[2.2.1]hept-2-yl]-dimethyl-(3-phenyl-propyl)-ammonium; trans-(1S,2S) 9-hydroxy-9H-diphenylhydrazine Piper _9_carboxylic acid 2_[methyl gas(penta)-4-phenyl-but-3-enyl)-amino]-bicyclo[2·2·1]hept-7-yl g; -(1S,2S)[7-(9-·yl-9H-diphenylindole·9-carbonyloxy)-bicyclo[2.2.1]heptan-2-yl]-dimethyl-((five -4-phenyl-buty-3-alkenyl)_kg; anti-(1S,2S)hydroxy-di-thiophen-2-yl-acetic acid 2_{[4_(4-aminocarboxamyl)-phenyl) -butyl]-fluorenyl-amino}-bicyclo[2.2.1]hept-7-yl g; trans-(1S,2S)[4-(4-aminoindenyl-phenyl)-butyl ]_[7_(2_Phyl 2,2_di-thiophen-2-yl-ethyloxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl-ammonium; anti-(1S, 2S) hydroxy-di-thiophen-2-yl-6-acid 2-{[4-(4· ··phenyl)-butyl l-decyl-amine b-cyclo[2·2·1]hept-7 · base ester; (trans-(1S,2S)[4-(4-gas-phenyl)-butyl]-[7·(2_hydroxy-2,2-di-thiophen-2-yl-ethoxime Base)-bicyclo[2.2.1]heptan-2-yl]-dimethylammonium; anti-(1S,2S Hydroxy-di-thiophen-2-yl-acetic acid 2-[methyl-(4-p-toluyl)-butyl)-amino]-bicyclo[2·2·1]hept-7-yl ester; -(1S,2S)[7-(2-hydroxy-2,2-di-thiophen-2-yl-ethyloxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl-( 4-p-phenylphenyl-butyl)ammonium; anti-(IS,2S) 9-light-based -9-fluorene-9-carboxylic acid 2-[methyl-(3-phenoxy-propyl) )-aminol.bicyclo[2·2·1]heptyl ester; 121575.doc -33- 200848416 anti-(1S,2S)[7-(9-hydroxy-9H-diphenylpyrene)_9_ Carbonyloxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl-(3-phenoxy-propyl)-ammonium; anti-(1S,2S) 9-hydroxy-9H-- 9-formic acid 2_[indenyl-(4-phenyl-butyl)-aminol·bicyclo[2·2·1]hept-7-yl ester; anti-(1S,2S)[7-(9 _______ methoxy) _bicyclo[2 2.m2_ yl l-dimethyl-(4-phenyl-butyl)-ammonium; anti-(1S,2S)hydroxy-diphenyl -acetic acid 2·[indenyl-(4-phenyl-butyl)-aminol·bicyclo[2·2·1]heptyl-7-yl ester; anti(1S, 2S)[7-(2-| ^ -2-2,2-Phenylethoxycarbonyl)-bicyclo[2·2·1]hept-2-yl]-dimethyl-(4·phenylbutyl)ammonium; anti-US , 2S) thio-di-porphin_2-based _ Acetic acid 2_{[4_(4_aminophenyl)-butyl]-methyl-amino}-bicyclo[2.2.1]hept-7-yl ester; anti-(1S,2S)[4-( 4-cyano-phenyl)-butylindole 7♦yl 2,2-di-nonyl-2-yl-ethyloxy)-bicyclo[2.21]hept-2-yl]-dimethylammonium ; anti-us, 2sm-di-anthracene-2-yl-acetic acid 2_{[3-(4. cyano-phenoxy)-propyl; I-fluorenyl-amino}•bicyclo[2· 2·1]g_7_based vinegar; anti-(1S,2S)[3-(4-cyano-phenoxy)-propylhydroxy-2,2_di-thiophene-2-yl-acetone Oxy))bicyclo[2.2.1]hept-2-yl]-dimethyl-ammonium; trans-(1S,2S) 9-methyl-9H-diphenylpyridinium-9-carboxylic acid methyl-( 4•Phenyl-butyl)-amino]-bicyclo[2.2.1]hept-7-yl ester; trans-(1S,2S)dimethyl-[7-(9-fluorenyl-9H_diphenyl)幷piperidinyloxy)bicyclo[2.2.1]hept-2-yl H4-phenyl-butyl)-record; trans-(IS, 2S)-[hydroxy-mono-thiophen-2-yl-acetic acid 2 -[indenyl-(2-phenoxy-ethyl)-amino]-bicyclo[2·2·1]hept-7-yl ester; 121575.doc -34- 200848416 anti-(1S,2S)7 -(2.hydroxy-2,2_di-thiophen-2-yl-ethyloxy)-bicyclo[2·2·1]hept-2-yl]-didecyl-(2-phenoxy- Ethyl ammonium; anti-(1S, 2S) hydroxy·di-thiophene-2·yl-acetic acid 2-[(2-benzyloxyethyl)-methyl-amino]-bicyclo[2·2·1]hept-7-yl ester; _(1S,2S)(2-Benzyloxy-ethyl)-[7-(2-hydroxy-2,2-di-thiophen-2-yl-ethyloxy)-bicyclo[2.2.1]g -2-yl]-dimethyl-ammonium; trans-(IS, 2S)hydroxy-di-thiophen-2-yl-acetic acid 2-{[3-(4-chloro-phenyl)-propyl]-indole -Amino}-bicyclo[2.2.1]hept-7-yl ester; anti-(1S,2S)[3-(4-Gasylphenyl)-propyl]_[7_(2_hydroxy-2, 2-di-porphin-2-yl-ethyloxyl l-bicyclo[2.2.1]hept-2-yl]-dimethyl-ammonium; trans-(1S,2S)hydroxy-di-thiophene_2 _ base·acetic acid 2_{[3_(3-chloro-phenyl)-propyl]-indolyl-amino}•bicyclo[2.2.1]hept-7-yl ester; anti-(1 S,2S)[ 3-(3-Gas-phenyl)-propyl]_[7_(2_hydroxy-2,2_di-nonyl-2-yl-ethyloxy)-bicyclo[2.2.1]heptan-2-yl Dimethyl-ammonium; anti-(1S,2S)hydroxy-di-thiophene-2-yl-acetic acid 2_{[3_(2_qi_phenyl)-propyl]-methyl-amino}- Bicyclo[2.2.1]hept-7-yl ester; trans-(1S,2S)[3_(2-chlorophenyl)-propyl b[7-(2-hydroxy-2,2-di-thiophene- 2-yl-acetoxy)·bicyclo[2·2·1]hept-2-yl]-dimethyl ·Ammonium; anti-(1S,2S)2,2-diphenyl-propionic acid 2-[methyl-(phenylphenyl-butyl)-amino]-bicyclo[2·2·1]hept-7 -yl ester; anti-(1S,2S)[7_(2,2-diphenyl-propenyloxy)bicyclo[221]hept-2-yl]-dimethyl-(4-styl-butyl )_ammonium; anti-(is, 2sm-di-secretenophene-2-acetic acid 2_{[2-(3_gas_phenoxy^ethyl)-methyl-amino}•bicyclo[2.2.1 Hg-7-yl ester; 121575.doc -35 - 200848416 trans-(1S,2S)[2-(3-Gas-phenoxy)-ethyl]-[7·(2-hydroxy-2,2 · bis-thiophen-2-yl-ethoxycarbonyl)bicyclo[2·2·1]hept-2-yl]-dimethyl-ammonium; trans-(1S,2S)hydroxy-di-thiophene-2- 2-acetic acid 2-{[2-(2-chloro-phenoxy)-ethyl]-methyl-aminobicyclobicyclo[2.2.1]hept-7-yl ester; anti-(IS, 2S)[ 2-(2-Gas-phenoxy)-ethyl]-[7-(2.hydroxy-2,2-di-thiophen-2-yl-ethyloxy)bicyclo[2.2.1]hept-2 -yl]: dimethyl-ammonium; anti-(1S,2S)-transyl-di-σ-secen-2-yl-acetic acid 2-{[2-(4_气·本乳基)_ethyl] -Methyl-aminodibicyclo[2.2.1]hept-7-yl ester; anti-(1S, 2S)[2-(4-chloro-phenoxy)-ethyl]-[7·(2- Hydroxy-2,2-di-thiophen-2-yl-ethyloxy)-bicyclo[2 .2.1]hept-2-yl]-dimethyl-ammonium; trans-(1S,2S)hydroxy-di-thiophen-2-yl-acetic acid 2-{methyl-[4-(1-methyl- 2 -Sideoxy-1,2-dihydropiperidin-4-yl)-butyl]•amino}-bicyclo[2·2·1]hept-7-yl; anti-(1S,2S) -[7_(2-hydroxy-2,2-di-thiophen-2-yl-ethenyloxy)_double jade [2.2.1]g-2 -yl]·«-曱-[4_(1 _Methyl-2_sideoxy-1,2-diazabipyridin-4-yl)-butyl]-ammonium; anti-(1S,2S)-[7-(2R-cyclohexyl-hydroxy-benzene 2-acetic acid 2-[indenyl-(4-phenyl-butyl)-amino]-bicyclo[2·2·1]hept-7-yl ester; anti-(1 S,2 S) - [7 -(2R- ί-hexyl- 2-3⁄4yl-2-phenyl-ethenyloxy)·bicyclo[2·2·1]hept-2-yl]-dimethyl-(4•phenyl-butyl _) ammonium; anti-(18,2SH7-(2S-cyclohexyl-trans-phenyl-acetic acid 2_[methyl-(phenylphenyl-butyl)-amino]-bicyclo[2.2.1]g -7-yl ester; and trans-(1S,2S)-[7-(2S-cyclohexyl-2-yl-2-phenyl-ethoxycarbonyl)-bicyclo[2·2·1]g- 2-yl]-dimethyl-(4-phenylbutyl) Ammonium. 121575.doc -36· 200848416 In another embodiment, the invention provides a compound of formula (1) selected from the group consisting of: (S, 2S)[7-(2•hydroxy-2,2-di-thiophene-2) —yl-ethoxycarbonyl]-bicyclo[2.2.1]hept-2-yl]-dimethyl-(3-phenoxy-propyl)-ammonium; inverse (1S,2S)[7-(2 -hydroxy-2,2-di-thiophene-2-yl-ethoxycarbonyl)-bicyclo[2.2.1]hept-2-yl]-diindenyl-(4-phenyl-butyl)-ammonium; Inverse (IS, 2S) [7-(9-hydroxy-9Η-diphenylpyridiniumcarbonyloxy)-bicyclo[2.2.1]hept-2-yl]-didecyl-(4_phenyl-butyl) Base); anti-(1S,2S)[3-(4-chloro-phenoxy)-propyl-[7-(2-hydroxy-2,2-di-thiophen-2-yl-ethoxime) ))-bicyclo[2.21]hept-2-yl>-dimethylammonium; anti-(1S,2S)[7-(9-hydroxy-9H-diphenylpyridinium-9-carbonyloxy)-bicyclic [2·2·1]heptan-2-yl]-didecyl-(3-phenoxy-propyl)-ammonium; anti-(IS,2S)[7-(9-hydroxy-9Η-diphenyl Piperazine·9-carbonyloxybicyclo[2·2·1]heptyl-2-yl]-dimethyl-((penta)-4-phenyl-but-3-enyl)-ammonium; (1S,2S)[4-(4-Chloro-phenyl)-butyl]-[7-(2-hydroxy-2,2-di-thiophene-2-yl-ethenyloxy)-bicyclic [2.2.1]Hept-2-yl]-dimethylammonium; trans-(18,28)[7-(9-hydroxy-state-第9-carbonyloxy)-bicyclo[2.2.1] Hept-2-yl]-dimethyl-(4-phenylbutyl)ammonium; anti-(1 S,2S)-[7-(2R-cyclohexyl_2_yl-2-phenyl Ethyloxy))bicyclo[2.2.1]hept-2-yl]-dimethyl-(4-phenyl-butyl)-ammonium; anti-(IS,2S)dimethyl-[7-( 9·methyl-9H-diphenyl fluorenyl-9-methoxy-)bicyclo[2.2.1]hept-2-yl]-(4-phenyl-butyl)-ammonium; anti- (IS, 2S) 7-(2-trans)-2,2-di-nonyl-2-ylethoxycarbonyl)-bicyclo[2.2.1]hept-2-yl]-dimethyl-(2-ben Oxy-ethyl)_record; 121575.doc -37- 200848416 anti-(1S,2S)[3-(4-chloro-phenyl)-propyl]_[7 (2·ionyl-2,2_嗟-嗟-phen-2-yl-ethyl oxy)·bicyclo[2 21]hept-2-yl]-dimethylhepta-(1S,2S)[3-(2·chloro·phenyl)_ Propyl]_[7_(2·carbyl_2,2_di-indol-2-yl-ethyloxy)-bicyclo[221]hept-2-yl]-dimethyl-bell; and anti- (1S,2S)[3-(3-Phenylphenyl)-propyl]·[7_(2_(yl) 2,2_di-porphin-2-yl-ethenyloxy)-bicyclo[基卜工曱基#. The present invention is also directed to a paeoniflorin formulation comprising a compound of the invention as an active ingredient. Other compounds can be used in combination with the compounds of the present invention for the prophylaxis, treatment of pulmonary inflammatory diseases. Accordingly, the present invention is also directed to pharmaceutical compositions for the prevention and/or oral treatment of the following sputum tract disorders: such as chronic obstructive pulmonary disease, colitis, asthma, chronic airway obstruction, pulmonary fibrosis, emphysema, and Allergic rhinitis, the pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention and one or more additional therapeutic agents. Other compounds can be used in combination with the compounds of the present invention for the prevention and treatment of pulmonary inflammatory diseases. Accordingly, the present invention includes a medicament of the present invention as described above (::: or a combination of a plurality of anti-inflammatory agents, bronchodilators, antihistamines, vasoconstrictors or scuttles, such as described above) The medicament of the present invention and the combination medicaments are present in the same or different pharmaceutical compositions, separately or simultaneously. The preferred combination should have two or three different pharmaceutical compositions. Suitable for combination therapy with the compounds of the present invention. Therapeutic agents include: one or more other bronchodilators, such as PDE3 inhibitors; methylxanthine, such as theophylline; other muscarinic receptor antagonists; pice steroids, such as fluticasone propionate (7) 121575.doc -38- 200848416 propionate), ciclesonide, mometasone furoate or budesonide, or WO02/88167, WO02/12266, W002/100879 'W002/00679 , steroids as described in WO 03/35668, WO 03/48181, WO 03/62259, WO 03/64445, WO 03/72592, WO 04/39827 and W004/66920; non-steroidal glucocorticoid receptor agonists; β2-adrenal Receptor agonists such as salbutamol or salbutamol, salmeterol, metaproterenol, terbutaline, fenoterol, procaterol ), carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK- 597901, GSK-159802, GSK-64244, GSK-678007, TA-2005, and EP1440966, JP05025045, W093/18007, WO99/64035, US2002/0055651, US2005/0133417, US2005/5159448, WO00/075114, WO01/42193 , WOOL/83462, WO02/66422, W002/70490, WO02/76933, WO03/24439, W003/42160, WO03/42164, WO03/72539, W003/91204, WO03/99764, WO04/16578, W004/016601, WO04 /22547, WO04/3292, WO04/33412, WO04/37768, WO04/37773, W004/37807, WO0439762, WO04/39766, WO04/45618, W004/46083, WO04/71388, W004/80964, EP1460064, W004/087142 , 121575.doc -39- 200848416

WO04/89892, US2004/0229904 W005/033121 W004/071388 W005/065650 W005/092840 WO05/092887 W005/092087 US20050182091 W005/077361 W005/11 1005, W005/110359, W006/016245 WO06/032627 - EP01477167, W004/ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 /070908 W005/092860 W005/090288 W005/080313, W005/092870 W005/111002 US2005/0272769 US2006/0019991 W006/031556 US2006/0106213 W006/051373, W006/056471 compounds;

Leukotriene modulators, such as montelukast, zafirlukast or pranlukast; protease inhibitors such as, for example, MMP12 inhibitors of matrix metalloproteinases and such as Marima Tamar inhibitors of marimastat, DPC-333, GW-3333; human neutrophil elastase inhibitors, such as sivelestat and WO04/043942, W005/021509, W005/021512, W005 /026123, W005/026124, W004/024700, W004/024701, W004/020410, 121575.doc -40- 200848416 W004/020412, W005/080372, WO05/082863, WO05/082864, W003/053930 Inhibitors; phosphodiesterase-4 (PDE4) inhibitors, such as roflumilast, arofylline, cilomilast, ONO-6126 or IC-485; a diesterase-7 inhibitor; an antitussive, such as codeine or dextramorphan; a kinase inhibitor, especially a P38 MAP kinase inhibitor; a P2X7 antagonist; an iNOS inhibitor; a nonsteroidal anti-inflammatory agent (NSAID), such as ibuprofen Ibuprofen) or ketoprofen; dopamine receptor antagonist; TNF-α inhibitors, such as anti-TNF monoclonal antibodies such as infliximab (Remicade) and CDP_870, and such as Enbo (Enbrel) TNF receptor immunoglobulin molecule; A2a agonist, such as those described in EP1052264 and EP1241176; A2b antagonists, such as those described in WO2002/42298; chemotaxis Modulators of hormone receptor function, such as antagonists of CCR1, CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB-265610, SB-225002, MCP-1 (9-76) ), RS-504393, MLN-1202, INCB-3284; compounds that modulate the action of prostaglandins, such as PGD2 (DP1 or 121575.doc • 41 - 200848416 CRTH2), or coagulation such as ramatroban Mutant A2 antagonist; a compound that modulates Th1/Th2 function, such as a PPAR agonist; an interleukin 1 receptor antagonist, such as anakinra (Kineret); an interleukin 10 agonist, such as Ai Ilodecakin; HMG-CoA reductase inhibitor (statin) Statin)), such as rosuvastatin, mevastatin, lovastatin, svastatin, simvastatin, pravastatin and fluvastatin; mucus Regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, gefitinib Anti-infectives (antibiotics or antivirals), and anti-allergic agents, including but not limited to antihistamines. The weight ratio of the first and second active ingredients can vary and will depend on the effective dose of each ingredient. The effective dose of each should generally be used. Any suitable route of administration can be used to provide a mammal, especially a human, with an effective amount of a compound of the invention. In therapeutic use, the active compound can be administered by any convenient, suitable or effective route. Suitable routes of administration are known to those skilled in the art and include oral, intravenous, rectal, parenteral, topical, transocular, nasal, buccal and pulmonary administration. Of course, the amount of the prophylactic or therapeutic dose of the compound of the invention will vary depending on a number of factors, including the activity of the particular compound employed, the age, weight, diet, general health and sex of the patient, cast 121575 .doc -42- 200848416 Pharmacy time 'dosing route, rate of excretion, use of any other drug, and severity of disease treated by scripture. In general, the daily dose for inhalation in a single or divided dose should be in the range of from about 0.1 pg to about 1 mg per kg of body weight, preferably from the mother kilogram of body weight 〇·ι call to about 〇·5 ^^ and better per kilogram of body weight 〇·1 pg to 5〇pg. On the other hand, in some cases it may be necessary to use doses outside of these ranges. Compositions suitable for administration by inhalation are known and may include carriers and/or diluents known for use in such compositions. The composition may contain from 1 to 99% by weight of active compound. Preferably, the unit dose contains the active compound in an amount of from 1 Mg to 10 mg. The appropriate dose for administration to the I port is 10 Mg/kg to 100 mg/kg, preferably 40 pg/kg to 4 mg/kg.

Another aspect of the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The term "composition" as used in the pharmaceutical composition is intended to cover the product comprising the active ingredient and the inert ingredients which comprise the carrier (pharmaceutically acceptable excipients), and directly or indirectly by any two or two Combination, complexation or agglutination of the above ingredients, <dissociation of one or more components, or any product resulting from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by the compound of the present invention, other active ingredients, and pharmaceutically acceptable excipients. The pharmaceutical composition of the present invention comprises, as an active ingredient, a compound of the present invention or a pharmaceutically acceptable compound thereof, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients. % language, pharmaceutically acceptable

Salt '' refers to pharmaceutically acceptable substances including I 狡 and 栝 inorganic bases or acids and organic bases or 121575.doc •43· 200848416 无 无 无 或 or acid and 里 right S5 minus &^; A salt prepared from the salt of a tetraammonium compound of a balanced ion that is acceptable for the study. The active compound is preferably in the form of microparticles for delivery by inhalation. It can be prepared by a variety of techniques including spray drying, freeze drying and micronization. For example, 3, the composition of the present invention can be suspended. Form preparation for delivery from a nebulizer or as an aerosol in a liquid propellant for use, for example, in a pressurized metered dose inhaler (PMDI). Propellants suitable for use in pmDi are familiar to the art. It is known and includes CFC-12, HFA_134a, HFA-227, HCFC-22 (CC12F2) and HFA_152 (C2H4F2) and isobutane. In a preferred embodiment of the invention, the composition of the invention is a dry powder. Form for delivery using a dry powder inhaler (Dpi). Many types of DPI are known to be delivered by delivery of microparticles that can be formulated with excipients that facilitate delivery and release. For example, in dry powder blending The microparticles may be formulated with large carrier particles that aid in the influx of DPI into the lung. Suitable carrier particles are known and include lactose particles; which may have a mass median aerodynamics greater than 9 〇 μηη Diameter. In the case of an aerosol-based formulation, an example is a compound of the invention 24 mg per can of lecithin, an NF liquid concentration of 1.2 mg per can of a gas, a NF 4 025 g per can of a gas Burning, NF 12 15 g / can. 121575.doc -44- 200848416 The active mouth can be dosed as described in the inhaler system used. In addition to the active compound, the dosage form may additionally contain excipients. For example, push it hU, for example, in the case of aerosols, it is gas root, surface activity [biobaining agent, stabilizer, preservative, flavoring agent, filler (for example, lactose in the case of inhalation device) Or, where appropriate, other active compounds 0, for the purpose of inhalation, a number of systems utilizing an inhalation technique suitable for the patient to produce and entangle an aerosol of optimal particle size. , expanders, and pear-shaped containers (such as NebuUt〇r8, Wti, and automatic devices that emit jet-type sprays (10) (10), 8) for metering aerosols (especially in the case of powder inhalers), many techniques are available Solutions (eg Diskhaler®, Rotadi) Sk®, Turbohaler® or, for example, an inhaler as described in EP-A-0505321. In addition, the compounds of the invention can be delivered in multiple chambers to the device, thereby allowing delivery of the combined agent. The preparation of the appropriate materials is carried out according to the procedures of the following schemes and examples, and is further exemplified by the following specific examples. Further, by using the procedures described in the disclosure contained herein, those skilled in the art can readily prepare the claims herein. Other compounds of the invention. However, the compounds illustrated in the examples should not be construed as forming the only genus of the invention. These examples further illustrate the details of preparing the compounds of the invention. Those skilled in the art will readily appreciate that such compounds can be prepared using known variations in the conditions and procedures of the following preparation procedures. The compounds of the present invention can be isolated in the form of their pharmaceutically acceptable salts, such as those described herein before. It may be necessary to protect the reactive functional groups (e.g., hydroxyl, amine, thio or carboxy groups) used in the preparation of the compounds of the present invention to avoid their undesired involvement in the reaction leading to the formation of the compound. Conventional protection can be used, as described by T. W. Greene and P. G. M. Wilts in "protective gr〇ups in organic chemistry" John Wiley and Sons, 1999. The compounds of the invention can be prepared according to the route illustrated in Scheme 1.

Ra", Rb (IV) Scheme 1 A compound of the formula (1) wherein Ra, Rb and RC&R4 are as defined for R1, R2, R3 and R4 in the compound of the formula (1), by allowing the compound of the formula (H):

Prepared by reacting with a compound of the formula (III): Rc-x (III) 121575.doc -46 - 200848416 wherein X is a leaving group such as a halogen, tosylate-methanesulfonate group. The reaction can be carried out in a large amount of a solvent such as acetonitrile, chloroform, DMF or DMSO, optionally in the presence of a base such as diisopropylethylamine (DIPEA), from 〇 ° C to the reflux temperature of the solvent, preferably ambient temperature to solvent It is carried out at the temperature of the reflux temperature. The compounds of formula (I) exist in two enantiomeric forms which can be prepared in the same palm form by the same pair of palms (χπ). Alternatively, it is possible to perform palmar separation from racemic substances other than palm hplc.岑.: a compound of the formula (II) wherein R4 is a group of the formula (4) as defined above and R6 is fluorene, by allowing the compound of the formula (IV):

Among them Ra and Rb#m敎, react with the compound of (10)) to prepare··

(V) Definition. The reaction can be carried out at a temperature between 0 ° C and the reflux temperature of the solvent, such as in a range, preferably wherein R 7a, R 7b, η and m are in a large amount of non-nucleophilic organic solvent such as DMF or toluene of formula (1). Compounds which are well known in the art and which are readily available or can be obtained by formula (V) are prepared by known methods by the known methods. A compound of the formula (II) wherein R4 is as defined above for the group of formula (b) 121575.doc -47- 200848416 can be prepared by reacting a compound of the formula (ιν) with a compound of the formula (VI): D8a Ή, 0 (VI) wherein R 8a, RSb and R 8c are as defined for formula (1) and LG is a leaving group such as an anthracene group, an isin or a fluorenyl imidazolyl group. The reaction is in the presence of a strong base such as NaH or NaOMe in a solvent such as toluene, THF or dihalomethane, to some extent, preferably oxime. Execution at a temperature between 〇 and solvent reflux temperature. a compound of the formula (VI) wherein, ruthenium and R8e are as defined in the formula (1) and Y is a 0-alkyl, halogen or oxime-imidazolyl group, which can be prepared from a compound of the formula (VII) by a known method. . P8a H〇rtr 0 (VII) The compounds of formula (VII) are well known in the art and are readily available commercially or can be prepared by known methods, such as those described in WO 01/04118. A compound of the formula (II), wherein R4 is a group of formula (c) as defined above, which is reacted with a compound of the formula (IV) and a compound of the formula (VIa):

(Via) wherein Ar, R, hydrazine and LG are as defined above, using conditions similar to those described above for the preparation of a compound of formula (π) by reacting a compound of formula (IV) with a compound of formula (VI) preparation. 121575.doc -48- 200848416

(Vila) A compound of the formula (Via) can be produced from a compound of the formula (Vila) by a method similar to the above-mentioned method for producing a compound of the formula (VI) from the compound of the formula (VII). Compounds of formula (VII) are well known in the art and are readily available commercially or can be prepared by known methods. The compound of the formula (IV) can be obtained from the compound of the formula (VIII):

Da, N, nb RR (VIII) is prepared by reacting with hydrogen in the presence of a catalyst, preferably palladium hydroxide/carbon, in a polar solvent such as MeOH or EtOAc, optionally in the presence of a protic acid such as sulfuric acid or acetic acid. . The compound of the formula (VIII) can be obtained from the compound of the formula (IX):

(IX) with the general formula (X) amine:

RaRbNH(X) is prepared in the presence of a reducing agent such as sodium triethoxysulfonate in a polar solvent such as THF or DCE, optionally in the presence of acetic acid. The compound of the formula (IX) can be obtained from the compound of the formula (XI): 121575.doc -49- (XI) 200848416 〇

Injury is carried out in response to a tin reagent, preferably BusSnH and a free radical initiator, preferably aibn. The reaction is carried out in a variety of solvents, preferably toluene, at a temperature between a range, preferably room temperature and the reflux temperature of the solvent. The compound of the formula (XI) can be obtained from the compound of the formula (XII):

Brx>°

Br Η (XII) is prepared by reacting with a benzyl alcohol. The reaction is carried out in the presence of a strong base such as NaH in a variety of solvents, preferably THF or DMF, at a temperature which is within a certain range, preferably at -78 ° C and ambient temperature. Compounds of formula (XII) are known in the art and can be prepared as individual enantiomers by bromo-bicyclic [3.2.0]heptenone by bromination (Synthesis (1977), 155-166) ). The resolution of bicycloheptanone is described in EP0074856. Those skilled in the art will recognize that a particular enantiomer of a compound of formula (1) can be obtained by starting with a particular enantiomer of bicycloheptanone. Further, a compound, wherein R4 is a group of formula (b) as defined above and Rb is as defined in formula (1) and R6 is η, may be a compound of formula (XIII): R4

Ra N, Η (Χίπ) 121575.doc -50- 200848416 wherein Ra and R4 are as defined above, and are reacted with a compound of the formula (VI): with a compound of the formula (XIV).

Rb-X (XIV) wherein X is a leaving group such as a halogen, a tosylate group or a mesylate group. The reaction can be carried out in a variety of solvents such as acetonitrile, chloroform, DMF or DMSO, optionally in the presence of a third amine base such as DIPEA, at a temperature from 0 ° C to the reflux temperature of the solvent, preferably from ambient temperature to solvent reflux temperature. The compound of formula (XIV) is well known in the art and is readily available or can be prepared by known methods. The compound of the formula (XIII) is a compound of the formula (XV) wherein Ra and R4 are as defined above:

b0C (XV) is prepared by reacting with an acid such as trifluoroacetic acid or better hydrochloric acid. A suitable solvent is a two-gas methane or, more suitably, a mixture of water, dioxane and tetrahydrofuran. The compound of the formula (XV) can be a compound of the formula (XVI) wherein the Ra system is as defined above.

(XVI) is prepared by reacting with a compound of the formula (νι) under the conditions described above for the preparation of the compound of the formula (II) from the compound of the formula (IV), 121575.doc -51 - 200848416. The compound of the formula (XVI) can be obtained from the compound of the formula (XVII):

(XVII) wherein the Ra is reacted with hydrogen in the presence of a catalyst, preferably palladium hydroxide in the presence of a catalyst, preferably palladium hydroxide in the presence of a solvent such as MeOH or EtOAc in the presence of di-tert-butyl dicarbonate. To prepare. The compound of the formula (XVII) is obtained by the above-mentioned method for producing a compound of the formula (VIII) from the compound of the formula (IX). General Experimental Details: All reactions were carried out under a nitrogen atmosphere unless otherwise specified. The NMR spectroscopy is a Bruker Avance DRX with a 5 mm reverse detection triple resonance TXI probe operating at 400 MHz on a Varian Unity Inova 400 spectrometer with a 5 mm reverse detection triple resonance probe or at 400 MHz. Obtained on a 400 spectrometer or a Bruker Avance DPX 300 spectrometer with a standard 5 mm dual-frequency probe operating at 300 MHz. The displacement system is given in ppm relative to tetramethyl sulphate. When the product is purified by column chromatography, 'quick cerium oxide f means 0.035 mm to 0.070 mm (220 mesh to 440 mesh) chromatography tannin (such as Fluka silicone 60) and accelerated column dissolution up to 10 Nitrogen applied pressure at psi. When thin layer chromatography (TLC) has been used, it refers to the use of a plate of TLC, which is a 3x6 cm silicone on an aluminum foil plate often having a fluorescent indicator (254 nm), for example, 121575.doc -52 - 200848416 (eg Fluka 60778). All solvents and commercial reagents are used as received. All compounds containing a basic center purified by HPLC were obtained as TFA salt unless otherwise stated. LC-MS Method 1 Waters Micromass ZQ with a C18 reverse phase column (3 〇 x 4.6 mm Phenomenex Luna 3 μιη particle size), dissolved in the following materials: A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid . Gradient: Gradient-time flow rate (ml/min) %A %B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5 Detection - MS, ELS, UV (100 μΐ shunt to have series MS for UV Detector MS Ionization - Electrospray (Cation and Anion) LC-MS Method 2 Waters Micro mass ZQ with C18 reverse phase column (Higgins Clipeus 5 μιη C18 100x3.0 mm or equivalent) Dissolved with the following materials: A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient: 121575.doc -53- 200848416 Gradient-time flow rate (ml/min) %A %B 0.00 1.0 95 5 1.00 1.0 95 5 15.0 1.0 5 95 20.0 1.0 5 95 22.0 1.0 95 5 25.0 1.0 95 5 Detection - MS , ELS, UV (100 μΐ split to MS with tandem UV detector) MS ionization - electrospray (cation and anion) LC - MS method 3 with C18 reverse phase column (C18 100x3.0 mm Higgins Clipeus 5 Micromass Platform LCT of μηι particle size, dissolved by: A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient: Gradient-time flow rate (ml/min) %A %B 0.00 1.0 95 5 1.00 1.0 95 5 15.00 1.0 5 95 20.00 1.0 5 95 22.00 1.0 95 5 25.00 1.0 95 5 Detection - MS, ELS, UV (100 μΐ Divided to MS with tandem UV detector) MS ionization method - electrospray (cation) 121575.doc -54- 200848416 Abbreviations used in the experimental part: DCM = dichloromethane; EtOH = ethanol; DIPEA = two different Propylethylamine; EDCI = 1-(3-dimethylaminopropyl)-3.ethylcarbodiimide hydrochloride; DMAP = dimethylaminopyridine; RT = room temperature; HATU =0-(7-azabenzoquinone-tris-s-l-yl)-oxime, oxime, Ν', Ν'-tetramethyl saw hexafluorophosphate; TFA = trifluoroacetic acid; MgS04 = barium sulfate; THF = four Hydrogen oxime; Et2 〇 = diethyl ether; DCE = 1,2-dichloroethane; NaHC03 = sodium bicarbonate; EtOAc = ethyl acetate; AIBN = 2,2'-azobis(2-mercaptopropionitrile) ; Rt = residence time; Na2S04 = sodium sulfate; NH4C1 = ammonium chloride; N2 = nitrogen; H2S 〇 4 = sulfuric acid. Example 1 Inverse (earth)-biphenyl-2-yl-amino decanoic acid 2-dimethylamino-bicyclo[2·2·1]hept-7-yl ester. (II) : Ra, Rb=CH3, R4=biphenyl-2-ylamine carbenyl

a·(土)·7-benzyloxy_5·bromobicyclo[2.2.1]heptan-2-one (XI) to H2 to NaH (60% dispersion in oil; 433 mg, 10-8 mmol) Benzyl alcohol (1.07 mL, 10.4 mmol) was added dropwise to a suspension of anhydrous THF (7 mL). The mixture was stirred for 30 min, then cooled to -3 0 ° C and EtOAc (EtOAc) <RTI ID=0.0> The solution in mL) was treated dropwise and the reaction mixture was allowed to warm to 0 °C over 2 h. The light brown heterogeneous mixture was diluted with ethyl acetate and then washed with aq. 10% aqueous EtOAc, water and brine, dried over magnesium sulfate and evaporated. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) 4 NMR (CDC13) 400 MHz): δ 1.79 (1H? ddd5 J=14.3 Hz5 4.2 Hz, 1·5 Hz), 2·15 (1H, m), 2·65 (1H, m), 2.80 (1H, m), 2.82 (1H, d, /=19.1 Hz), 2.86 (1H, m), 4.03 (1H, q, J=l.8 Hz), 4.50 (1H, d, J=11.7 Hz), 4.53 ( 1H,d,J=11.7 Hz), 4.71 (1H, m), 7.27-7.40 (5H,m) 〇

Χί b· (±)·7_benzyloxy·bicyclo[2.2.1]heptan-2-one (IX): to (soil)-7-benzyloxy-5_indo-bicyclo[2.2.1]heptane- 2-ketone (609 mg, 2.06 mmol) and AIBN (34 mg, 0.21 mmol) were added dropwise to a mixture of 30 mL of anhydrous degassed benzene, and tributyltinhydride (0.72 mL, 2.68 mmol) was added and the solution was heated. Up to 80 ° C for 1.5 h. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj 4 NMR (CDC13, 400 MHz): δ 1.49 (2H, m), 1·99 (1H, d, J = 18.5 Hz), 2.10 (3H, m), 2·62 (1H, m), 2.67 (1H , m), 3.91 (1H, s), 4.51 (1H, d, /=11.7 Hz), 4.53 (1H, d, J = 11.7 Hz), 7.27-7.39 (5H, m).

c·(±)-(7-Benzyloxy-bicyclo[2.2.1]hept-2-yl)-dimethyl-amine. (¥111): Ra, Rb=CH3; R4=Bn 121575.doc -56- 200848416 To (soil)-7-benzyloxy-bicyclo[2·2·1]heptan-2-one (262 mg, 1 • 21 mmol) and didecylamine (2 Μ solution in THF, 1.21 mL, 2.42 mmol) in 2 mL of dry DCE with acetic acid (69 pL, 1.21 mmol), followed by triethyl hydrazine Sodium hydride sodium hydride (385 mg, 1.82 mmol) and a small amount of 3A molecular sieve. The mixture was stirred at ambient temperature for 6 h. The reaction was quenched with 10 mL of saturated aqueous sodium bicarbonate and stirred for 10 min. The reaction mixture was extracted with EtOAc EtOAc EtOAc. LC-MS (Method 1): Rt 1.73 min, m.

d·(士)_2_ Dimercaptoamine-bicyclo[2·2·1]hept-7-alcohol. (IV): Ra, Rb=CH3 (7-benzyloxy-bicyclo[2.2.1]hept-2-yl)-didecylamine (236, mg, 0.96 mmol) in anhydrous MeOH ( The solution in 8 mL) was added to 20 wt% palladium hydroxide on carbon (50 mg). The reaction vessel was evacuated and flushed 3 times with nitrogen and then a 25% solution of sulfuric acid in MeOH (320 kL, 1.5 mmol) was added. The reaction was stirred under a hydrogen atmosphere (hydrogen balloon) for 20 h. The reaction was quenched with 200 mg of solid sodium carbonate and 3 mL of water and evaporated. The residue was partitioned between DCM and brine and the layers separated. The aqueous phase was re-extracted 4 times with DCM and the combined organics dried over sodium sulfate and evaporated to give a 3:1 mixture (105 mg) of the title compound as a colourless oil. .doc -57- 200848416 One step of purification is ready to use.

八 e· (earth) trans-biphenyl-2-yl-carbamic acid 2-dimethylamino-bicyclo[2.2.1]hept-7-yl ester. (II) : Ra, Rb=CH3 ; R4 = benzidine carbenyl group (s) · 2-didecylaminobicyclo[2·2·ΐ]hepta-7-ol with (士)_(7_ A solution of a 3:1 mixture of benzyloxy-biguanidine [2·2·1]heptan-2-yl)-didecylamine (96 mg) in anhydrous toluene (2 mL) with biphenyl isocyanate Treated with ester (145 mg, 〇 74 mmol) and the mixture was heated at EtOAc (2 s s s s s s s s s s s s s s s s s s s s s s s s s s s The title compound (125 mg) was obtained as a colorless sugar. LC_MS (method 1): Rt 7.05 min, m/z 351.16 [MH+]. LC-MS (method 1): Rt 2.01 and 2·09 min, m/ z 351.27 [MH+]. 4 NMR (CDC13, 400 MHz): δ 0.99 (1H? dd5 /=12.7 Hz, 4.9 Hz), 1.34 (1H, m), 1.51 (1H, m), 1.73 (1H, m) , 1.83 (2H, m), 2.13 (6H, s), 2.20 (2H, m), 2·39 (1H, m), 4·72 (1H, s), 6·57 (1H, s, br) , 7.13 (1H, td, J=7.5, 1·2 Hz), 7.22 (1H, dd, J=7.5, 1.7 Hz), 7.36 (3H, m), 7·40 (1H, m), 7 · 48 (2H, m), 8.06 (1H, s, br) o Example 2 α·Inverse (1S, 2S)-based-di-ex-phen-2-yl-acetic acid 2-[methyl-(3 -phenyl-propyl)-amino]-bicyclo[2.2.1]hept-7-yl ester.(11) : Ra=CH3 ; Rb=3-benzene-58- 121575.doc 200848416 base-1-propene Base; R4=radio-di-sex-2-a base

H.p. (1S, 2S) 2-[Methyl-(3-phenyl-propyl)-amino]bicyclo[2.2.1]hept-7-ol. (IV): Ra=CH3; Rb=3-phenylpropylpropyl ruthenium compound is obtained by a method similar to that of the example 由(丨R)_ 2,3-dibromo-bicyclo[3.2.0] Preparation of hept-6-one and methyl-(3-phenylpropyl)-amine. 111丽11(€〇(:13,400]^): 3 0.91-0.95(111,111), 1.32·1·38 (1Η,m), 1.54-1.62 (2Η,m),1.68-1.89 (6Η, m), 1.98 (1H, m), 2·08 (3H, m), 2.26-2.29 (3H, m), 2.59-2.63 (2H, m), 3.97 (1H, m), 7.15-7.19 ( 3H, m), 7.25-7.29 (2H, m).

c·Reverse (1S,2S)hydroxy-di-porphin-2-yl-acetic acid 2-[methyl-(3-phenyl-propyl)-aminobicyclo[2.2.1]hept-7-yl ester . (II): Ra=CH3; Rb=3-phenyl-1-propyl; R4=hydroxy-diphenen-2-ylcarbonyl at the ambient temperature under a nitrogen atmosphere, inverse (1S, 2S)2- Solution and hydrogenation of [methyl-(3-phenyl-propyl)-amino]bicyclo[2·2·1]hept-7-ol (165 mg, 0.63 mmol) in anhydrous benzene (10 mL) Sodium (76 mg in 60% dispersion in mineral oil) was stirred together. When the gas evolution has subsided, the reaction will be added immediately after 5 minutes of adding 121-. Place in a preheated oil bath at 80 °C. After 1 h, the reaction was allowed to cool, after which it was quenched with saturated ammonium sulfate solution. The reaction was extracted into EtOAc and EtOAc (EtOAc) Purification by chromatography using MeOH <RTI ID=0.0># </ </RTI> <RTIgt; LC-MS (Method 2): Rt 7.90 min, m/z 482 [MH]+. iH NMR (CDC13, 400 MHz): δ 0.88-1.01 (1H, m)5 1.21-1.34 (2H,m)5 1·46_1·59 (1H,m), 1.68-1.87 (4H,m),2.01- 2.09 (3H, s), 2.18-2.27 (3H, m), 2.30-2.37 (2H, m), 2.54-2.60 (2H, m), 4.75-4.97 (1H, m), 4.83 (lH, m), 6.93-6.97 (2H,m),7"2-7.18(5H,m),7.22-7.28 (4H,m) 〇Example 3 Inverse (18,28)[7-(2-Ph-based-2, 2-Di-indol-2-yl-ethyloxy)-bicyclo[2.2.1]heptyl-2-methylbyl-(3-phenyl-propyl)-brominated. (1): Ra, Rb=CH3; Rb=3-phenyl-1-propene; R4=carboxydithiophene-2-yl group

Reverse (1S,2S)hydroxy-di-thiophene-2-yl-acetic acid 2-[methyl-(3-phenyl-propyl)-amino]-bicyclo[2.2.1] at 50 °C The hept-7-yl ester (33 mg, 0.069 mmol) was heated in a sealed tube for 2 days in a 30% w/w solution of methyl bromide in acetonitrile (1 mL). The solvent was removed and purified by chromatography using EtOAc EtOAc EtOAc (EtOAc) LC-MS (Method 2): Rt 7.45 min, m/z 495 [M]+, lH NMR (CDC135 400 MHz) 61.33-1.41 (1H, m) 1.45-1.56 (1H, m), 1.57-1.67 (2H , m), 1.69-1.79 (1H, m), 2.04-2.21 (3H, m), 2·43 (1H, m), 2.64-2.79 (3H, m), 3.23 (3H, s), 3.25 (3H ,s),3.43-3.55 (1H,m)5 3.56-3.68 (1H,m), 4.31 (1H, m)5 4.89-4.92 (1H5 m)5 5.02-5.05 (1H5 m)5 6.93-6·99 (2H, m), 7.10-7.30 (9H, m) The following examples were prepared in a manner similar to that described in Examples 1-3. Instance name structure ~~^~ Ί---- Ή NMR (400 MHz) Rt/min (method 2); [MH]+ or 4 inverse (1R, 2R) hydroxy---σ-cephen-2-yl- 2-[Methyl-(3-phenyl-propyl)-amino]-bicyclo[2.2.1]hept-7-yl ester poly(λ) (CD3OD) 0·83-0·93 (1Η, m ), 1.15 - 1.30 (2H, m), 1.43-1.54 (1H, m) 51.6 〇. 1.81 (4H, m), 2.06 (3H, m), 2.10-2.15 (lH, m), 2.19-2.30 (3H5 m)? 2.33-2.40 (1H, m)5 2.51-2.59 (2H,m),4·75_4·78 (1H, m),4·78-4·83 (1H,m), 6.90-6.98 (2H ? m)? 7.06-7·25 (7H, m), 7.29-7.36 (2H? m) 〇μνΐ| 十7.29; 482 5 inverse (1R, 2R)[7-(2-经基-2,2_二- 叹 phen-2-yl-ethoxycarbonyl)-bicyclo[2.2.1]hept-2-yl]-dimethyl-(3-system Χίο (CDCls) 1.33-1.42 (1H5 m)5 1.44-1.57 (1H, m), 1.58-1.80 (2H? , 7.95 ; 496 121575.doc -61 - 200848416 Phenyl-propyl)-&gt; Ammonium streak 3.27 (3Η, s), 3·29 (3Η, s), 3.44-3.59 (lH, m), 3.59- 3.71 (lH,m),4.24-4.34 (1Η,m),4.87-4.92 (2Η, m)5 6.93-6.99 (2H? m)? 7.11-7.30 (9H, m). 6 Inverse (1S, 2S) (7-Benzyloxybicyclo[2.2.1]heptan-2-yl)-didecyl-(3-phenyl-propyl)-alkaline ammonium 1 Br (CDC13) 1.28- 1.36 (1H? m), 1.43-1.52 (lH, m), 1.65-1.74 (13⁄4 m)? 1.9-2.2 (5H, m), 2.33-2.38 (1H, m)5 2.61-2.66 (lH, m) , 2.72-2.79 (2H? m)? 3.26 (3H, s), 3.29 (3H, s), 3.54-3·66 (2H, m), 3·87 (1H, m), 4.23-4.32 (1H, m), 4.46 (2H, s), 7.18-7.37 (10H) 〇7.37; 364 7 inverse (1S, 2S) hydroxy-^^-σ-cephen-2-yl-acetic acid 2-[indenyl-(3- Phenoxy-propyl)-amino]-bicyclo[2.2.1]hept-7-yl ester (CDC13) 0.94-1.00 (1H, m), 1.12-1.20 (lH, m), 1.20-1.30 (lHm ), 1.43-1.54 (lH,m),1.73-1.84 (2H,m),1.84-1.92 (2H, m),2.06 (3H,s),2.16-2.21 (1H3 m)5 2.28-2.48 (4H5 m ), 3.92-4.04 (2H, m), 4.74 (1H, s), 4.84 (lH, s), 6.84-6.96 (5H? m) 5 7.12-7.15 (2H, m), 7.22-7.27 (4H, m 〇7.97; 498 8 inverse (1S,2S)[7-(2-hydroxy-2,2-di-σ-sec-2-yl-ethyloxy)-bicyclo[2.2.1]hept-2- ]]-dimethyl-(3-phenoxy-propyl)-ammonium bromide Q &lt;Λ\βγ (CDC13) 1.37-1.45 (1H5 m), 1.5 6-1.73 (3H,m), 1.79-1.87 (1H? m)? 2.20-2.37 (3H? m)? 2.48-2.52 (1H,m),2.88-2.92 (1H, m), 3.30-3.35 (6H ,m), 3.74-3.90 (2H, m)5 4.06-4.11 (2H? m)? 4.26-4.34 (1H,m),4.77 (1H,s),4.93 (1H,s),6.81-6.85 (2H , m), 8.07; 512 121575.doc -62- 200848416 6.93-6.97(3H,m),7.11· 7.13 (2Η, m)5 7.22-7.28 (4Η, m) 〇9 inverse (1S, 2S) hydroxyl group - Di-thiophen-2-yl-acetic acid 2-[indolyl-(4-phenyl-butyl)-amino]-bicyclo[2.2.1]hept-7-yl ester (CDC13) 0.95-1 ·00 ( 1Η, m), 1.23-1.33 (2H? m), 1.39-1.65 (5H, m)?1.73-1.85(2H,m), 2.01 (3H,s), 2.15-2.24 (3H?m)? 2.29- 2.38 (2H, m)5 2.56-2.61 (2H,m), 4.75 (1H,s), 4.84 (1H,s)5 6.93-6.97 (2H,m), 7.12-7.17 (5H? m)? 7.22- 7.27 (4H, m). 8.27 ; 496 10 Inverse (1S,2S)[7-(2-Pheptyl-2,2-di-α-cephen-2-yl-ethyloxy)-bicyclo[2.2.1]hept-2-yl] - Dimercapto-(4-phenyl-butyl)-alkaline ammonium ring. ' (CDC13) 1·35·1·43 (1H, m), 1.50-1.80 (8H, m), 2.10- 2.20 (1H5 m)? 2.45-2.49 (1H, m), 2.63-2.70 (2H, m ), 2.73-2.77 (1H, m)? 3.24 (6H5 s)5 3.47-3.58 (2H,m), 4.18-4.25 (1H, m), 4.73 (1H, s), 4·87 (1H, s) , 6.93-6.97 (2H, m), 7.10- 7.17 (53⁄4 m), 7.21-7·28 (4H, m). 8.40 ; 510 11 inverse (1S, 2S) hydroxy *-p-phen-2-yl-acetic acid 2-(indolyl-ethyl-amino-amino)-bicyclo[2·2·1]hept-7-yl ester ( CDC13) 0.89-0.94 (1H, m), 1.16-1.33 (2H, m), 1.44-1.55 (1H5 m), L72-1.82 (2H, m), 2.16 (3H, s), 2.17-2.21 (1H5 m ), 2.35-2.39 (1H, m)5 2.40-2.50 (3H,m),2·63-2·76 (2H, m), 4.74 (1H,s),4·84 (1H, s), 6.93 -6.97 (2H,m), 7.13-7.19 (53⁄4 m), 7.23-7.27 («1,m). 7.70 ; 468 121575.doc •63- 200848416 12 Inverse (1S,2S)7· (2·hydroxy-2,2-dicetax-2-yl-ethyloxy)-bicyclo[2·2·1] Hept-2-yl]-dimercapto-phenethyl-bromide oxime. ' ΒΓ - (CDC13) 1.33-1.41 (1H? m), 1.46-1.68 (3H, m), 1.73-1.81 (1H, m)? 2.12-2.23 (1H, m), 2.37-2.41 (1H, m) , 2·77-2·81 (1H, m), 3.08-3.16 (2H, m), 3·30 (6H, s), 3.64-3.73 (2H, m), 4.40-4.48 (1H, m), 4.91 (1H, s), 5.04 (1H, s), 6.89-6.94 (2H, m), 7.07-7.11 (2H, m), 7.15-7.26 (5H, m), 7.30-7.34 (2H, m) 〇 7.84; 482 13 reverse (1S, 2S) hydroxy-diphenyl-acetic acid 2-(methyl-phenethyl-amino)-bicyclo[2.2.1]hept-7-yl ester (3⁄4 (CDCI3) 0.84- 0.91 (1H? m), 1.04-1.15 (2H, m), 1.20-1.36 (lH, m), 1.65-1.80 (2H5 m)? 2.11-2.18 (4H, m), 2.29-2.34 (1H, m) , 2.39-2.49 (3H, m), 2.62-2.75 (2H3 m), 4.23 (1H, s), 4.85 (1H, s), 7.11-7.19 (3H, m), 7.21-7.34 (8H, m), 7.36-7.42 (4H, m) 0 8.06 ; 456 14 Inverse (1S,2S)[7-(2-Pheptyl-2,2-diphenyl-ethenyloxy)-bicyclo[2.2.1]heptane- 2-yl]-dimethyl-phenethyl ammonium bromide Αν (CDCI3) 1.22-1.45 (3H, m), 1.62-1.71 (2H, m), 2.13-2.23 (1H, m)? 2.38-2.41 (1H, m)5 2.73-2.76 (1H, m), 3.08-3.15 (23⁄4 m), 3.31 (3H, s), 3 .34 (3H, s), 3.71-3.77 (2H, m), 4.17 (1H, s), 4.32-4.39 (1H, m), 4.91 (1H, s)? 7.17-7.37 (15H, m) 8.14 ; 470 121575.doc 64- 200848416 15 Inverse (1S,2S)hydroxy-diphenylacetic acid 2-[methyl-(3-phenoxy-propyl)-amino]-bicyclo[2.2.1]g -7-yl ester meaning (CDC13) 0.90-0.96 (1H5 m), 1.01-U1 (2H, m), 1.22-1.34 (1H, m)5 1.67-1.80 (2H, m), 1.82-1.90 (2H, m),2·04 (3H,s), 2.11-2.15(13⁄4 m)5 2.26-2.45 (4H,m),3.90-4.01 (2H,m),4·23 (1H,s),4.85 (1H ,s),6·82·6·92 (3H,m), 7.21-7.33(8H,m),7.36-7.40 (4H,m) 〇7.40 ; 486 16 inverse (1S,2S)[7-(2 -hydroxy·2,2-diphenylethyloxy)-bicyclo[2·2·1]hept-2-yl]-didecyl-(3·phenoxy-propyl)-ammonium bromide Name V 々 ♦ Ί〇 (CDCI3) 1.24-1.47 (3H5 m), 1.60-1.73 (2H, m), 2.15-2.34 (3H? m), 2.39-2.43 (1H, m) 5 2.79-2.83 (1H , m), 3·28 (6H, s), 3.66-3.83 (2H, m), 4.02-4.07 (2H, m), 4.22-4.31 (2H, m), 4.93 (1H, s), 6.79-6.83 (2H? m)5 6.89-6.94 (1H? m)? 7.19-7.38 (UH,m) 〇8.50 ; 500 17 (1S,2S)9-Hydroxy-9H-dihydromethane-9-decanoic acid 2-[methyl-(4•phenyl-butyl)-amino]-bicyclo[2·2·1]g -7-yl ester 13⁄4) (CDCI3) 0.68-0.79 (1H, m), 0.80-0.87 (1H, m), 0.88-1.05 (2H, m), 1.35-1.45 (2H, m), 1.50-1.70 ( 4H, m), 1.90-1.98 (4H? m), 2.05-2.23 (4H, m), 2.55-2.60 (2H, m)5 4.55 (1H, s), 4.90 (1H, s), 7.10-7.20 ( 7H? m), 7.22-7.30 (2H, m), 7.32-7.39 (2H, m)5 7.50-7.55 (2H, m). 8.35; 498 18 reverse (1S, 2S) [7-(9-hydroxy-9H-diphenylpyridin-9-carbonyloxy)-bicyclo[2·2·1]heptyl]-dimethyl- (4- ^ °^6 (CDC13) 1.00-1.19 (3H5 m), 1.42-1.56 (2H, m), 1.59-1.77 (4H, m), 1.96-2.10 (1H, m), 2.15-2.19 (1H , m), 2.40-2.43 (1H, m), 2·59·2.64 (2H, m), 8.01; 512 121575.doc -65- 200848416 Phenyl-butyl)-arcified ammonium 3.13 (6H? s) 3.35-3.50 (2H, m), 4.17-4.22 (1H, m), 4.60 (1H, s) 5 5.00 (1H, s), 7.10-7.28 (9H, m), 7.32-7.40 (2H? m) ? 7.51-7·59 (2H, m). 19 reverse (1S,2S)hydroxy-di-11-cephen-2-yl-acetic acid 2-{[8-(t-butoxy-yl-methyl-amino)-octyl]-methyl-amine }}-bicyclo[2.2.1]hept-7-yl ester 1 (CDC13) 0.98-1.02 (1H, m), 1.20-1.60 (24H, m), 1.75-1.90 (2H, m), 2.05 (3H, s), 2.10-2.30 (3H, m), 2.32-2.40 (2H, m)? 2.85 (3H, s), 3.15-3.25 (2H, m), 2.78 (1H, s), 4.88 (1H, s) , 6.95-7.0 (2H, m), 7.15-7.20 (2H, m), 7.25-7.30 (2H, m) 〇 9.02; 605 20 inverse (1S, 2S) [8-(t-butoxycarbonyl-fluorene) -Amino)-octyl H7-(2-transyl-2,2-di-σ-sec-2-yl-ethenyloxy)-bicyclo[2.2.1]hept-2-yl]-di Methyl-ammonium bromide Λ〇Λ〇Br- (CDCls) 1.20-1.95 (26H? m), 2.20-2.30 (1H, m), 1.55 (lH, s), 2.40 (3H, s), 3.85 (1H s)5 3.15-3.20 (2H,m), 3.35 (3H,s), 3.37 (3H,s), 3.50-3.60 (2H,m), 4.30-4.40 (1H,m),4.90 (1H,s ), 4.95 (1H, s), 6.95-7.00 (2H5 m)? 7.10-7.15 (2H, m), 7.28- 7.30 (2H, m) 0 8.86; 619 21 Reverse meridian · 2,2-di-σ Desphen-2-yl-acetoxy)bicyclo[2.2.1]hept-2-yl]-dimethyl-(8-methyl Base-octyl)-&gt; stinky money 1.99; 519 (method 1) Example 22 trans-(1S,2S)[3-(4-phenoxy)-propyl]-[7-(2-hydroxy- 2,2-di-thia 121575.doc •66- 200848416 phen-2-yl-acetoxy)-bicyclic guanidine 2·2·1]heptan-2-yl]-dibromoammonium methane

a. (1R,7S)-7-Benzyloxybromo-bicyclo[2·2·1]heptan-2-one to sodium hydride under Ν2 (6〇% dispersion in oil; 4 · 5 3 g, 113·21 mmol) benzyl alcohol (11.18 g, 108.07 mmol) was added dropwise to a suspension in anhydrous THF (120 mL). The reaction was warmed to 35 °C for 30 min and then cooled to -30 °C. A solution of (lR)-2,3-dibromo-bicyclo[3.2.0]hept-6-one (13.79 g, 51.46 mmol) in dry THF (60 mL). Ambient temperature. The reaction was quenched with EtOAc / EtOAc (EtOAc)EtOAc. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) NMR (CDC13,400 ΜΗζ): δ 1.75-1.85 (1 H, m), 2.20-2.30 (1H, m), 2.60-2.65 (1H, m), 2.75-2.90 (2H, m), 4.05 (1H, s), 4.45-4.55 (2H, m), 4.65-4.75 (1H, m), 5.3 (1H, s), 7.3-7.4 (5H, m) 〇

(1R,7S)·7-Benzyloxy·bicyclo[2.2.1]heptan-2-one 121575.doc •67- 200848416 to (1R,7S&gt;7-benzyloxybromo-bicyclo[22]]g- 2-ketone (5·19 g, 17·58 mmol) and AIBN (289 mg) were added dropwise to tetrahydrogenated tributyltin (6·15 mL, 22.86 mmol) in 210 mL of anhydrous degassed toluene. The solution was heated to 80 ° C for 6 to 5 hours. The reaction mixture was concentrated under reduced pressure and purified eluting eluting eluting eluting eluting eluting with NMR (CDC13, 400 ΜΗζ): δ 1.40-1.55 (2Η, m), 1.95-2.20 (4Η, m), 2.60-2.65 (1Η, s), 2.65-2.70 (1H, m), 3.90 (1H) ,m), 4.50 (2H,m), 7.20-7.40 (5H,m) 〇

c·trans-(1S,2S)benzyl-(7-benzyloxybicyclo[2.2.1]hept-2-yl)-methyl-amine (1R,7S)-7-benzyloxy-bicyclo[ 2.2.1] A solution of hept-2-one (387 mg, 1.79 mmol) in anhydrous DCE was stirred with activated 3A (1.0 g). I added benzylmethylamine (434 mg, 3.58 mmol), sodium triethoxysulfonate (570 mg, 2.69 mmol) and acetic acid (1〇2 pL, 1.79 mmol) and will

Stir at ambient temperature for 18 hours. The reaction was quenched with 6 mL aq. EtOAc (EtOAc)EtOAc. Purification by chromatography using 0-1% MeOH / EtOAc (EtOAc) 4 NMR (CDC13, 400 ΜΗζ): δ 1·05-1·12 (1H, m), 1.35-1.43 (1H, m), 1·6 (Μ·72 (1H, m), 1.75-1.85 (1H , m), 1.87-2.08 (5H, m), 121575.doc -68- 200848416 2.20-2.25 (1H, m), 2.35-2.46 (2H, m), 3.29-3.45 (2H, m), 3.78 (1H , s), 4.50 (2H, s), 7.20-7.39 (10H, m).

Today

OH d. trans-(1S,2S)(7-hydroxy-bicyclo[2.2.1]hept-2-yl)-methyl-carbamic acid tert-butyl ester using argon to make anti-(1S, 2S) Benzyl-(7-benzyloxy-bicyclo[2.2.1]hept-2-yl)methyl-amine (446 mg, 1.38 mmol) and di-tert-butyl dicarbonate (333 mg, 1.52 mmol) The solution in anhydrous EtOH (10 mL) was degassed and 20 wt% palladium oxide/carbon (45 mg) was added. The reaction was stirred under a hydrogen atmosphere (hydrogen balloon) for 20 hours. The reaction was flushed with EtOAc (3 mL). 1H NMR (CDC13,400 ΜΗζ): δ 1.30-1.65 (13Η, m), 1.70 face 1·80 (1Η, m), 1.85-1.98 (2Η, m), 2.05-2.09, (1H, m), 2.33 -2.38 (1H,m),2·88 (3H,s),4.03-4.10 (2H, m) o

e·trans-(1S,2S)hydroxy-di-thiophen-2-yl-acetic acid 2-(t-butoxycarbonyl-fluorenyl-amino)-bicyclo[2.2.1]hept-7-yl ester 121575 .doc -69- 200848416 Counter-(1 S,2S) (7-hydroxy-bicyclo[2.2.1]hept-2-yl)-methyl-carbamic acid dibutyl hydrazine in a round bottom flask A solution of 480 mg, 2.0 mmol) in toluene (50 mL) was equipped with a short-distance distillation apparatus. Hydroxy-di-thiophene-2-yl-acetic acid B (108 mg '2.0 mmol) was added and the mixture was gradually heated until methanol distillation (bpt 70 ° C, external temperature 130 ° C) was observed. After distilling off the fraction, the mixture was further heated until toluene began to distill (external temperature 140 C). After about 10 mL of toluene had been distilled off, the mixture was allowed to cool to room temperature. The mixture was poured into aq. EtOAc (EtOAc) (EtOAc) The combined organics were dried & dried over anhydrous Na 2 SO 4 and evaporated. The title compound (680 mg, 73%) was obtained eluted elute elut elut elut elut elut 4 NMR (CDC13, 400 MHz): δ 1.25-1.35 (2H, m), 1.43 (9H, S), 1.44-1.55 (3H, m), 1.93-2.02 (1H, m), 2.31 (1H, m) , 2.60 (1H, m), 2·85 (3H5 s)5 4.06-4.12 (1H5 m)? 4.74 (1H, s)5 4.91 (1H5 s), 6.95- 6.99 (2H, m), 7.14-7.17 ( 2H, m), 7·26-7·29 (2H, m).

f·trans-(1S,2S)hydroxydi-thiophen-2-yl-acetic acid 2-mercaptoaminobicyclo[2·2·1]hept-7-yl vinegar will be trans-(1S,2S)hydroxy- Dithiophen-2-yl-acetic acid 2-(t-butoxycarbonyl-methyl &quot;amino)-bicyclo[2.2.1]hept-7-yl ester (1.4 g, 3.0 mmol) dissolved 121575.doc • 70· 200848416 in THF (10 mL) and 1,4-dioxane (2 mL). Hydrochloric acid (2 Torr, 10 mL) was added and the mixture was stirred vigorously and warmed to 5 for 2 hours. The mixture was allowed to cool to room temperature then carefully neutralized with NaHCO3 (50 mL). The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc. The title compound (800 mg, 73%) was obtained as a solid in the form of a creamy solid. 4 NMR (CDC13,400 ΜΗζ): δ 0.82 (1Η, dd), 1·23·1·30 (1Η, m), 1·32·1·41 (1Η, m), 1.52-1.61 (1H, m ), 1.64-1.71 (1H, m), 1.96-2.05 (1H, m), 2·24 (1H, m), 2·30 (3H, s), 2·45 (1H, m), 2·99_3 ·04 (1H,m),4.87 (1H,s),6.96-6.99 (2H, m)5 7.16-7.18 (2H,m), 7.27-7.29 (2H,m) 〇

〇

g. trans-(IS,2S)hydroxy-di-thiophen-2-yl-acetic acid 2-{[3·(4-Gasphenoxy)-propyl]-methyl-amino}-bicyclo[2.2 .1]hept-7-yl ester will be trans-(1S,2S)hydroxy-di-thiophen-2-ylacetic acid 2-methylaminobicyclo[2·2·1]hept-7-yl ester (50 mg , 0.14 mmol) was dissolved in acetonitrile (4 mL). 1-(3-Mo-propoxy)-4-gas-benzene (69 mg, 0.28 mmol) and triethylamine (40 g, 0.28 mmol) were added and the mixture was stirred at 80 ° C for 16 hours. The reaction was allowed to cool to room temperature and the solvent was removed. The title compound (55 mg, 74%) was obtained eluted eluting eluting eluting eluting H NMR (CDC13,400 ΜΗζ): δ 〇·95-0·99 (1H, dd), 1.13-1.20 (1Η, m), 1.22-1.30 (1Η, m), ΐ·46-1·55 (1Η ,m),1.76-1.84 (2H,m),1.85-1.92 (2H,m),2.08 (3H,s),2_21 (1H,m)5 2.29-2.47 (4H,m),3.91-4.02 (2H , m), 4.77 (1H, s), 4.86 (1H, s), 6.80 (2H, m), 6.97 (2H, m), 7.15-7.17 (2H, m), 7·22 (2H, m), 7.26-7.29 (2H, m).

h·trans-(1S,2S)[3_(4-chloro-phenoxy)-propyl]_[7·(2-hydroxy-2,2·di-thiophene-2-yl-ethenyloxy) - Bicyclo[2·2·1]hept-2-yl-dimethyl-ammonium bromide A solution of 30% w/w methyl bromide in acetonitrile is added to the anti-(1S,2S) hydroxy-di-thiophene. 2-yl-acetic acid 2-{[3-(4-chloro-phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]hept-7-yl ester (55 mg, 0.10 Mm). The mixture was heated in a sealed tube at 55 ° C for 3 days, then cooled to room temperature and concentrated. Purification by flashing on a Teledyne ISCO companion eluting with 0-20% MeOH / DCM as a solvent to afford title compound (50 mg, 80%). 4 NMR (CDC13,400 ΜΗζ): δ 1.27-1.50 (2H, m), 1.52-1.61 (lH, m), 1.66 (lH, dd), 1.90-1·98 (1H, m), 1.99-2.08 ( 1H,m),2_15-2·22 (2H,m),2·38 (1H,m), 2.79 (1H,m),3.01 (3H,s),3.09 (3H,s), 3.40-3.47 ( 2H,m),4.01-4.08 (3H,m),4.86 (1H,s),6.94-7.02 (4H, 121575.doc -72- 200848416 m),7.08 (2H,m),7.33-7.39 (2H, m), 7.40 (1H, s), 7. 51 (2H, m); LCMS (Method 3): Rt 8.67 min, m/z 546 [M-Br]+. The following examples were prepared in a manner similar to that described in Example 22. Example name structure ^NMR (400 MHz) δ (method); Rt/min ; [MH]+ or [M-Br|+ 23 trans-(1S,2S)hydroxy-di-σ-cephen-2-yl-acetic acid 2-{[3-(3,4-Dichloro-phenoxy)-propyl]-indolyl-amino}-bicyclo[2.2.1]hept-7-yloxime (CDC13) 0.92-0.99 ( 1H, m)? 1.12-1.21 (1H? m)? 1.20-1.31 (1H? m)? 1.46-1.56 (lH,m),1.74-1.93 (4H,m),2.07 (3H,s), 2.19- 1.24 (1H5 m)? 2.28-2.47 (4H,m), 3.90-4.02 (2H,m), 4.78 (1H,br s), 4.85 (1H? s)5 6.70-6.75 (1H,m),6.94- 6.99 (3H, m), 7.14-7.18 (2H, m), 7.25-7.31 (3H, m). (Method 2); 2.72; 566 24 trans-(1S,2S)[3-(3,4-dioxa-phenoxy)-propyl]-[7-(2-hydroxy-2,2-di- σ塞-phen-2-yl-ethyloxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl-ammonium bromide (CDCla) 1.40-1.50 (1H, m), 1.60-1.80 ( 3H,m), 1.80- 1.85 (1H, m)? 2.20-2.40 (3H,m), 2.58 (1H, m), 2·98 (1H,m), 3.37 (3H,s), 3.39 (3H, s), 3.80- 4.00 (2H? m)? 4.10-4.20 (2H,m), 4.28-4.36 (1H,m),4·73 (1H,s), 4.97 (1H?s)5 6.73-6.80 ( 1H, m), 6.98-7.02 (3H, m), 7.16-7.20 (2H, m), 7.23-7.40 (3H, m). (Method 3); 9.04; 580 25 Anti-(1S,2S)9-hydroxy-9H-diphenyl hydrazine-9-decanoic acid 2-[mercapto-(3-CX^^N Λα (CDC13) 0.68 -0.83 (2H? m), 0.88-1.05 (2H, m), 1.50-1.75 (4H, m)? 1.90-1.99 (4H5 m)? 2.05-2.23 (method 3); 7.95; 484 121575.doc -73 - 200848416 Example name structure 1H NMR (400 MHz) δ (method); Rt/min; [MH]+ or [M-Br]+ phenyl-propyl)-amino]-bicyclo[2.2.1]hept-7 -yl ester (4Η5 m)? 2.50-2.58 (2Η? m), 4·55 (1Η, s), 4·93 (lH, s), 7.10-7.28 (9Η, m), 7.30-7.40 (2Η, m), 7.50-7.55 (2Η, m). 26 trans-(1S,2S)[7-(9-Hydroxy-9H-diphenyl fluorenyl-9-carbonyloxy)-bicyclo[2.2.1]hept-2-yl]-didecyl-(3 -Phenyl-propyl)-&gt;Smelling money CCo夂Br_ Λα (Method 2); 7.81; 498 27 Anti-(1S,2S)9·Hydroxy-9H-diphenyl hydrazine-9-carboxylic acid 2- [Methyl-((6)-4-phenyl-but-3-yl)-amino]-bicyclo[2.2.1]hept-7-yl ester °^Χα (CDC13) 0.65-1.05 (4H? m) , 1.50-1.75 (2H, m), 1.90 (lH, s), 2.05 (3H, s), 2.15 (lH, s), 2.20-2.40 (4H, m), 4.60 (1H, s), 4.90 (1H , s), 6.05-6.20 (1H5 m), 6.33-6.40 (1H, m), 7.10-7.40 (llH, m), 7.50-7.60 (2H, m). (Method 2); 7.95; 496 28 trans-(1S,2S)[7-(9-Hydroxy-911-diphenylpyridin-9-carbonyloxy&gt;bicyclo P.2.1]heptan-2-yl] - Dimercapto-((6)-4-phenyl-but-3-yl)-&gt; Ammonium Oxide (d4-MeOD) 1.05-1.25 (3H, m), 1.50-1.60 (1H, m), 1.70 -1.80 (lH,m), 2.00-2.10 (1H5 m)5 2.20 (1H,m), 2.60 (1H,m), 2.65- 2.70 (2H, m), 3.02 (3H,s),3.10 (3H, s), 3.30-3.40 (2H, m)? 3.80-3.95 (1H, m), 4.68 (1H, s), 6.08-6.15 (lH, m), 6.58-6.64 (lH, m), 7.13-7.40 ( llH,m), 7.60-7.62 (2H,m). (Method 3); 8.42; 510 121575.doc -74- 200848416 Example name structure 1HNMR (400MHz) 6 (method); Rt/min; [MH]+ or [M-Br]+ 29 anti-(1S,2S)hydroxy-di-σ-secen-2-yl-acetic acid 2-{[4-(4-aminoindenyl-phenyl)butyl]-anthracene --Amino}-bicyclic Ρ.2.1]hept-7-yl ester (CDC13) 0.95-1 ·05 (1Η, m), 1.23-1.37 (2H, m), 1.40-1.75 (5H? m), 1.77 -1.90 (2H,m),2.04 (3H, s)? 2.15-2.41 (5H? m)? 2.63-2.70 (2H,m),4.81 (1H,s),4.85 (1H,s)5 5.55-6.20 (2H? m)? 6.95-7.00 (2H? m)5 7.17-7.20 (2H,m), 7.22-7 .30 (4H, m), 7.70-7.75 (2H, m). (Method 2); 6.63; 539 30 Anti-(lS,2S)[4-(4-Aminomethylphenyl-phenyl)-butyl ]-[7-(2-3⁄4yl-2,2-di-σ-secen-2-yl-ethenyloxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl-bromination Ammonium (CDC13) 1.43-1.47 (2H, m), 1.58-1.99 (8H, m), 2.08-2.18 (1H? m)? 2.43-2.47 (lH, m), 2.75-2.81 (2H5 m)5 2.82- 2.85 (1H? m), 3.02-3.13 (6H, m), 3.30-3.39 (2H? m)? 3.95-4.02 (1H, m), 4·93 (1H, s), 6.98-7.01 (2H, m ), 7.15-7.17 (2H? m)? 7.30-7.41 (4H, m), 7.79-7.83 (2H, m). (Method 3); 7.12; 553 31 trans-(1S,2S)hydroxy-di-σ-secen-2-yl-acetic acid 2-{[4·(4-Gas-phenyl)-butyl]-methyl -amino}-bicyclo[2.2.1]hept-7-yl ester (CDC13) 0.96-1.04 (1H, m)? 1.25-1.35 (3H5 m)? 1.42-1.61 (4H? m)31.77-1.87 (2H , m), 2.04 (3H, s), 2.19-2.27 (3H, m), 2.33-2.41 (2H? m)? 2.58 (2H, t), 4.78 (1H, s), 4.86 (1H, s), 6.96-7.00 (2H, m), 7.08-7.11 (2H, m), 7.16-7.19 (2H? m)5 7.22-7.30 (4H, m). (Method 1); 2.82; 530 121575.doc -75· 200848416 Instance name structure ^NMR (400 MHz) δ (method); Rt/min ; [MH]+ or [M-Brl+ 32 inverse·(lS,2S) [4-(4-Chloro-phenyl) butyl]-[7-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2·2·1]heptane- 2·yl]-dimethyl-alkaline ammonium (d6-DMSO) 1.35-1.76 (9H, m), 1.87-2.04 (2H, m)5 2.34 (1H, m), 2.62 (2H, t), 2 · 75 (1H, m), 2·92 (3H, s), 3.01 (3H, s), 3.22-3.35 (1H5 m)? 3.90-3·99 (1H, m), 4.82 (1H, s), 6.99-7.01 (2H,m), 7.08-7.10 (23⁄4 m)? 7.24 (2H,d),7·36 (2H,d), 7.40 (1H,s), 7.50 (2H, d). (Method 3); 8.80; 544 33 &_(1S,2S)hydroxy-di-11-cephen-2-yl-acetic acid 2-[methyl-(4-p-tolyl-butyl)-amino] -bicyclo[2.2.1]hept-7-yl ester (CDC13) 0.97-1.03 (1H5 m), 1.25-1.35 (3H, m), 1.41-1.63 (4H? m)? 1.76-1.87 (2H? m) 5 2.04 (3H? s), 2.19-2.25 (3H, m), 2.31 (3H? s)? 2.31-2.40 (2H, m), 2·57 (2H, t), 4·78 (1H, s) , 4.86 (1H, s), 6.96-7.00 (2H, m)? 7.04-7.10 (4H? m)? 7.16-7.18 (2H, m), 7.26-7.29 (2H, m) ο (Method 1); 2.80 ; 510 34 thio-2,2-di-π-cephen-2-yl-ethoxycarbonyl)-bicyclo[2.2.1]hept-2-yl]-didecyl-(4-p-tolyl- Butyl)ammonium bromide (d6-DMSO) 1.34-1.75 (8H, m), 1.87-2.03 (2H, m), 2.25 (3H, s), 2·34 (2H, m) 5 2.58 (2H, t ), 2.74 (1H, m), 2.93 (3H, s), 3.01 (3H? s)3 3.22-3.31 (lH, m), 3.90-3.98 (1H, m), 4.83 (lH, s), 6.99- 7.02 (2H, m), 7.07-7.12 (6H, m), 7·39 (1H, s), 7.50 (2H, m). (Method 3); 8.70; 524 121575.doc -76- 200848416 f Instance name structure! ΗΝΜΚ (400 MHz) δ C method:); Rt/min ; [MH]+ or [M-Br]+ 35 anti-( 1S,2S)9·hydroxy-9H-dibenzoquinone-9-decanoic acid 2-[methyl-(3-phenoxy-propyl)-amino]-bicyclo[2.2.1]hept-7- Base ester σ

(CDC13) 0.65-0.75 (1H, m), 0.80-0.94 (3H, m), 1.50-1.58 (1H? m)? 1.62-1.70 (1H, m)? 1.81-1.90 (2H, m), 1.92 ( lH, s), 2.00 (3H, s), 2.10 (lH, s), 2.21-2.30 (2H? m) 5 2.30-2.40 (1H, m), 3.89-4.00 (2H, m), 4·57 ( 1H, s), 4.91 (1H, s), 6.83 (2H, d), 6.92 (lH, t), 7.10-7.20 (4H, m), 7.21-7.28 (2H, m), 7.30-7.39 ( 2H, m), 7.49-7.53 (2H, m). (Method 2); 7.62; 500 36 trans-(1S,2S)[7-(9-hydroxy-9H-diphenyl fluorene ρ南-9-carbonyloxy)-bicyclo[2.2.1]hept-2- Base]-dimethyl-(3-phenoxy-propyl)-molybdenum

(d6-DMSO) 0.93-1.01 (2H, m), 1.10.10.20 (1H, m), 1.52 (lH, dd), 1.68-1.79 (1H?m)5 1.82-1.93 (lH, m), 2.03- 2.17 (3H, m), 2.46 (1H, s), 2.90 (3H, s), 3.01 (3H, s), 3.29-3.40 (2H5 m), 3.88 (1H, m), 4.00 (2H, m), 4.59 (1H, s), 6.88 (2H, d), 6.95 (lH, t), 7.10 (lH, s), 7.17-7.25 (4H? m)? 7.27-7·32 (2H, m), 7.38-7.42 (2H, m), 7.60 (2H, d). (Method 2); 7.81; 514 37 trans-(1S,2S)9-hydroxy-9H-indole-9-carboxylic acid 2-[methyl-(4-phenylbutyl)-amino]-bicyclo[2.2 .1]hept-7-yl ester

(CDC13) 0.65-0.73 (1H, m), 0.81-1.02 (3H, m), 1.35-1.45 (2H? m)? 1.48-1.59 (3H, m), 1.63-1.71 (2H, m), 1.95 ( 3H, s), 2·06·2·24 (4H, m), 2.57 (2H, t), 4·27 (1H, s), 4.61 (method 1); 2.64; 482 121575.doc -77- 200848416 Example name structure 1H NMR (400 MHz) 5 (method); Rt/min; [MH]+ or [M-Br]+ (lH, s), 7.12-7.18 (3H, m), 7.23-7.32 (4H, m) , 7.38-7.45 (4H? m)? 7.66 (3⁄4 d). 38 anti-(1S,2S)[7-(9-hydroxy-9H-indol-9. oxy)·bicyclo[2.2.1]hept-2-yl]-dimethyl-(4-phenyl- Butyl)-ammonium bromide 4th "6 (d6-DMSO) 0.88-1.02 (2H, m), 1.04-1.13 (1H, m), 1.41-1.51 (3H, m), 1.56-1.64 (3H? m ) 1.79-1.85 (lH, m), 2.05 (1H, m)? 2.39 (1H? m)? 2.53 (2H, t), 2.80 (3H, s), 2·88 (3H, s), 3.10- 3.19 (2H, m), 3.70-3.80 (lH, m), 4.52 (1H, s), 6.70 (1H, s), 7.11-7.16 (3H? m)? 7.20-7·30 (4H, m), 7.39 (2H, t), 7.42 (2H, d), 7.77 (2H, d) 0 (method 3); 8.12; 496 39 trans-(1S,2S)hydroxy-diphenyl-acetic acid 2-[indenyl- (4-Phenyl-butyl)-amino]-bicyclo[2.2.1]hept-7-yl ester (CDC13) 0.94-0.99 (1H?m)5 1.07-1.27 (2H,m), 1.31-1.40 (lH, m), 1.41-1.50 (2H, m), 1.54-1.63 (2H? m)? 1.70-1.83 (2H5 m), 2.02 (3H, m), 2.15-2.23 (3H, m)? 2.35 (2H,m), 2.60 (2H,t), 4·28 (1H,s),4.88 (1H,s), 7.14-7.18 (3H, m)? 7.24-7·29 (2H,m), 7.29-7.36 (6H,m),7.39-7.44 (4H, m) 0 (method 1); 2.79 ; 484 40 anti-(1S,2S)[7-(2-radio-2,2- Phenyl-acetoxy)-bicyclic (d6-DMSO) 1.23-1.34 (2H,m),1·35-1·43 (1H, m), 1.54-1.62 (3H,m), 1.66-1.78 ( 2H,m), 1.80- (method 3); 8.65; 498 121575.doc -78- 200848416 Example name structure ^NMR (400 MHz) δ (method); Rt/min ; [MH]+ or [M-Brl+ [ 2.2.1]hept-2-yl]-dimercapto-(4-phenylbutyl)-ammonium bromide 1.86 (1H?m)5 1.94-2.01 (1 Η, m), 2.30 (1 Η, m), 2.61 (2H, t), 2.68 (1H, m), 2.93 (3H, s), 3.00 (3H, s), 3.22-3.30 (2H, m), 3.90-3.97 (lH, m), 4· 85 (1H, s), 6.69 (1H, s), 7.15-7.24 (3H, m)? 7.25-7.38 (12H, m). 41 trans-(1S,2S)hydroxy-dicetin-2-yl-acetic acid 2-{[4-(4-cyano-phenyl)-butyl]-indolyl-amino}-bicyclo[2.2. 1]hept-7-yl ester (CDC13) 0.95-1.05 (1H, m), 1.20-1.37 (2H, m), 1.40-1.65 (5H? m)5 1.77-1.85 (2H, m), 2.04 (3H , s), 2.15-2.28 (3H, m), 2.33-2.42 (2H, m), 2.63-2.70 (2H, m), 4.80-4.88 (2H, m), 6·95-7·00 (2H, m), 7.17-7.20 (2H, m), 7.24-7.30 (4H? m)? 7.55-7·59 (2H, m). (Method 2); 7.68; 521 42 trans-(1S,2S)[4-(4-cyano-phenyl)-butyl]-[7-(2-pyridyl-2,2-di-σ Phen-2-yl-ethoxycarbonyl)-bicyclo[2.2.1]hept-2-yl]-didecyl-alkaline ammonium Y% (d4-MeOD) 1.40-1.50 (lH, m), 1.55- 1.75 (5H, m), 1.78-1.89 (2H, m), 1.90-1.99 (1H5 m)? 2.10-2.20 (1H? m)? 2.42-2.47 (1H, m), 2.78-2.85 (3H, m) , 3.01-3.15 (6H, m), 3.30-3.40 (2H5 m)? 3.95-4·02 (1H, m), 4·93 (1H, s), 6.98-7.01 (2H, m), 7.12-7.17 (2H,m), 7.38-7.45 (4H5 m)? 7.62-7.66 (2H,m). (Method 2); 7.80; 535 121575.doc -79- 200848416 Instance name structure! ΗΝΜΚ(400ΜΗζ)δ (method); Rt/min ; [MH]+ or [M-Br]+ 43 anti-(1S,2S Hydroxy-di-σ-secen-2-yl-acetic acid 2-{[3-(4-cyano-phenoxy)-propyl]-methyl-amino}-bicyclo[2.2.1]g- 7-yl ester (CDC13) 0.90-1.00 (1H, m)5 1.05-1.35 (2H, m), 1.45-1.65 (1H5 m)? 1.70-1.85 (2H, m), 1.86-2.00 (2H, m) , 2.01-2.15 (3H, m), 2.18-2.25 (lH, m), 2.26-2.55 (4H5 m)5 4.00-4.15 (2H? m)5 4.77 (1H? s), 4.86 (1H, s), 6.90-7.00 (4H, m), 7.15-7.20 (2H, m)5 7.23-7.30 (2H? m)3 7·55·7·60 (2H, m). (Method 2); 7.88; 523 44 trans-(1S,2S)[3·(4-cyano-phenoxy)-propyl]-[7-(2-hydroxy-2,2-di-σ Benz-2-yl-ethoxycarbonyl)-bicyclo[2.2.1]hept-2-yl]-dimethyl-alluted ammonium (d4-MeOD) 1.43-1.52 (lH,m), 1.58-1.78 ( 3H, m), 1.95-2.02 (lH, m), 2.15-2.25 (1H? m)3 2.30-2.40 (2H5 m), 2.45-2.50 (1H, m), 2.90-2.94 (1H, m), 3.10 -3.22 (6H,m), 3.56-3.62 (2H? m)? 4.05- 4.12 (lH,m),4.18-4.22 (2H,m),4.97 (1H,s), 6.98-7.01 (2H? m) ? 7.05- 7.12 (2H? m)? 7.13-7.18 (2H? m)? 7.39-7.41 (2H? m), 7.63-7.70 (2H, m). (Method 2); 7.52; 537 45 Anti-(1S,2S)9-methyl_9Η·diphenyl hydrazine. 2-[methyl-(4-phenyl-butyl)-amino]-bicyclo[2.2.1]hept-7-yl ester TO (CDC13) 0.80-0.99 (2H, m) ,1.00-1.10 (2H,m), 1.35-1.49 (2H3 m)5 1.50-1.77 (5H,m),1.90 (3H, s),1.92-2.03 (3H,m), 2.05-2.30 (4H? m ) 5 2.57-2.61 (2H, m), 4.60 (1H, s) 5 7.00-7.30 (13H, m). (Method 2); 9.66; 496 121575.doc -80 - 200848416 Instance name structure ^NMRC^O MHz) δ (method); Rt/min ; [MH]+ or [M-Brl+ 46 anti-(1S,2S) Dimercapto-[7-(9-fluorenyl-9H-diphenylanthracene-9-Moxy)-bicyclo[2.2.1]hept-2-yl]-(4-phenyl-butyl) -&gt;Smelling ββγ (d4-MeOD) 1.17-1.25 (3H,m), 1.49-1.58 (1H, m)5 1.60-1.80 (5H,m), 1.90(3H,s),1.95-2.03 ( lH,m), 2.17-2.20 (1H, m), 2.49-2.55 (1H, m), 2.62-2.70 (2H? m)5 2.90-3.02 (6H, m), 3.20-3.32 (2H? m)? 3.80-3.90 (1H?m), 4.66 (lH, s), 7.05-7.35 (13H, m). (Method 2); 9.35; 510 47 trans-(1S,2S)-[transyl-di-nonyl-2-yl-acetic acid 2-[methyl-(2-phenoxy-ethyl)-amino group ]•Bicyclo[2.2.1]hept-7-yl ester CX〇-^N (CDC13) 1.00-1.08 (1H, m), 1.20-1.40 (2H, m), 1.50-1.60 (13⁄4 m)? 1.80- 1.95 (2H, m), 2.20 (3H, s), 2.25 (1H, m), 2.45 (1H, m), 2.50-2.60 (1H, m), 2.60-2.80 (2H, m), 4.00-4.10 ( 2H, m), 3.78 (1H, s), 4.90 (1H, s), 6.83-7.00 (5H? m) 5 7.17-7.20 (2H, m), 7.22-7.30 (4H, m). (Method 2); 7.57; 484 48 trans-(1S,2S)7-(2-hydroxy-2,2-di-D-cephen-2-yl-ethenyloxy)·bicyclo[2.2.1]g -2-yl]-dimercapto-(2-phenoxy-ethyl)-&gt; stinky 〇d〇^〇N^. ΒΓ (CDC13) 1.40-1.55 (1H, m), 1.60-1.65 ( lH,m), 1.65-1.80 (2H5 m)51.83-1.95 (lH,m),2.23-2.38 (lH,m),1.58-1.60 (1H, m),3.0-3.10 (lH,m), 3.43 ( 3H, s), 3.50 (3H, s), 4.23-4.38 (1H5 m)? 4.39-4·42 (1H, m), 4.46-4.60 (3H, m), 4.68 (1H, s), 4.93 (1H , s), 6.90-7.08 (5H, m), 7.16-7.18 (2H, (Method 3); 7.99; 498 121575.doc -81 - 200848416 Example name structure 1HNMR (400 MHz) δ (method); Rt/min ; [MH]+ or [M-Br]+ m), 7.20-7.40 (4Η, m). 49 trans-(1S,2S)hydroxy-di-σ-secen-2-yl-acetic acid 2-[(2-benzyloxy-ethyl)-indolyl-amino]-bicyclo[2.2.1]g- 7-Dylester (CDC13) 1.03 (1H, dd), 1.25-1.36 (23⁄4 m)? 1.51-1.59 (1H? m)? 1.77-1.91 (2H, m), 2·14 (3H, s), 2.24 (1H, m)5 2.40-2.58 (4H,m),3.53-3.59 (2H, m), 4.52 (2H,s), 4.78 (1H,s),4.87 (1H,s), 6.95-6.99 (2H m)5 7.16-7.18 (2H,m), 7.26-7.29 (3H,m),7.31-7.34 (4H, m) o (method 1); 2.60 ; 498 50 anti-(lS,2S)(2- Benzyloxy-ethyl)-[7-(2-hydroxy-2,2-dicetaxan-2-ylethyloxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl -ammonium bromide (d6-DMSO) 1.33-1.59 (3H, m), 1.62-1.68 (1H, m) 51.88-2.06 (2H, m), 2.35 (lH, m), 2.79 (1H, m), 3.03 (3H, s), 3.10 (3H, s), 3.56 (2H, m), 3.87-3.90 (2H? m)? 4.02-4.10 (lH, m), 4.55 (2H, s)5 4.81 (lH, s ), 6.99-7.01 (2H, m), 7·07-7·09 (2H, m), 7.27-7.38 (5H, m), 7.40 (1H, s), 7.50 (2H, d). (Method 2); 7.73; 512 51 trans-(1S,2S)hydroxy-di-σ-secen-2-yl-acetic acid 2-{[3-(4-chloro-phenyl)propyl]-methyl- Amino}-bicyclo[2.2.1]hept-7-yl ester Clxx^ (CDC13) 0.94 (1H, dd), 1.25-1.32 (2H, m)? 1.51-1.65 (lH, m), 1.67-1.87 ( 4H,m),2.05 (3H,s), 2.19-2.26(3H,m),2.33-2.39 (2H,m)5 2·57 (2H, t),4.77 (1H,s),4·86 ( 1H, s)5 6.96-7.00 (2H? m)5 7.10(2H,d),7.16-7.18 (method 1); 2.71; 516 121575.doc -82- 200848416 Instance name structure!ΗΝΜΚ(400 ΜΗζ)δ ( Method); Rt/min; [MH]+ or (2Η,m), 7.21-7.30 (4Η, m) ο 52 anti-(1S,2S)[3·(4-gas-phenyl)-propyl] -[7-(2-hydroxy-2,2-di-thiophen-2-yl-ethenyloxy)-bicyclo[2.2.1]hept-2-yl]-didecyl-alkaline ammonium (d4- MeOD) 1.39-1.47 (lH,m), 1.50-1.75 (4Η5 m), 1.83-1.93 (lH,m), 2.05-2.16 (3H,m), 2.45 (1H,m),2.63-2.75 (2H, m), 2.79 (lH, m), 3.03 (3H, s), 3.06 (3H, s), 3.30-3.38 (1H? m)? 3.94-4.01 (1H, m), 4.92 (1H, s), 6.98 -7.01 (2H,m), 7.14 (2H,m), 7.25 (2H, d), 7. 31 (2H,d), 7.40 (2H5 d) 〇(Method 2); 8.27 ; 530 53 --(1S,2S)hydroxy-di-π-cephen-2-yl-acetic acid 2-{[3· (3 -Chloro-phenyl)-propyl]methyl-amino}-bicyclo[2.2.1]hept-7-yl ester Cl (CDC13) 0.90-0.98 (1H5 m), 1.20-1.35 (3H, m), 1.65-1.90 (4H, m), 2.06 (3H, s), 2.18-2.28 (3H, m), 2.30-2.40 (2H, m), 2.55-2.61 (2H, m), 4.78 (1H, s), 4.85 (1H, s), 6.95-7.01 (2H5 m)5 7.03-7.08 (lH, m), 7.13-7.21 (5H, m), 7.23-7.30 (2H, m) 0 (method 2); 7.97; 517 54 gas-phenyl)-propyl]-[7-(2-carbamic-2,2-dicetax-2-yl-ethenyloxy)&gt;bicyclo[2.2.1]hept-2-yl] - dimethyl-alkaline ammonium Β "(CDCI3) 1.35-1.46 (1 H? m), 1.50-1.72 (3 H, m), 1.75-1.85 (1 H? m)? 2.08-2.28 (3 H5 m)? 2.46-2.52 (1 H5 m)? 2.67-2.82 (3 H? m), 3.25-3.35 (6 H,m), 3.55-3.78 (2 H? m)? 4.28-4.38 (1 H,m ), 4.85 (1 H, s), 4.92 (1 H, s), 6.95- (method 1); 2.79; 530 121575.doc -83 - 200848416 Example name structure 1HNMR (400MHz) 5 (method); Rt/min ; [MH]+ or [M-Brl+ 7.00 (2 H,m),7 .10-7.30 (8 Η, m). 55 trans-(1S,2S)hydroxy-di-σ-secen-2-yl-acetic acid 2-{[3·(2-chloro-phenyl)-propyl]-methyl-amino}-bicyclo[2.2 .1]hept-7-yl ester (CDC13) 0.98-1 ·02 (1Η, m), 1.22-1.38 (3H,m), 1.71-1.97 (4H? m)5 2.09 (3H,s), 2.22 ( 1H,m), 2.26-2.34 (2H?m)? 2.36-2.41 (2H,m),2.66-2.75 (2H,m),4.78 (1H,s), 4·86 (1H,s),6.96- 7.00 (2H, m), 7.09-7.22 (4H, m), 7.23-7.35 (4H, m). (Method 1); 2.72; 516 56 anti-(lS^Sp-iS·chloro-phenyl)-propyl]-[7-(2-hydroxy-2,2-di-nonyl-2-yl·B Aromatic oxy)-bicyclo[2.2.1]hept-2-yl]-dimethyl-brominated oc〇^Br% (d4-MeOD) 1.39-1.46 (lH,m), 1.52-1.62 (1H, m), 1.63-1.74 (2H, m), 1.87-1.94 (lH, m), 2.06-2.18 (3H, m), 2.45 (lH, m), 2.77 (lH, m), 2.81-2.87 (2H, m), 3.05 (3H, s), 3.12 (3H, s), 3.34-3.47 (2H, m), 3.97-4.03 (1H, m), 4.91 (lH, s), 6.98-7.01 (2H, m) , 7.13 - 7.15 (2H, m), 7.20-7.29 (2H, m), 7.36-7.41 (4H, m). (Method 1); 2.75; 530 57 trans-(1S, 2S) 2,2-diphenyl-propionic acid 2-[methyl-(4-phenyl-butyl)-amino]-bicyclo[2.2. 1]hept-7-yl ester °ΓΧ) (CDC13) 0.90-0.98 (1H, m), 1.10-1.22 (2H, m), 1.35-1.50 (3H? m)? 1.53-1.62 (2H, m), 1.65-1.82 (2H,m), 1.90 (3H,s), 2.02 (3H5 s\ 2.10-2.36 (5H? m)5 2.56-2.62 (2H? m)5 4.78-4.81 (lH,m), 7.12- 7.32 (15H, m). (Method 2); 9.49; 482 121575.doc -84- 200848416 Example name structure 1HNMR (400MHz) 5 (method); Rt/min; [MH]+ or [M-Brl+ 58 anti- (lS,2S)[7-(252-diphenyl-propenyloxy)-bicyclo[2.2.1]hept-2-yl]dimethyl-(4-phenyl-butyl)-ammonium bromide Br&quot; (CDC13) 1.25-1.52 (3 Η? m)5 1.60-1.83 (6 H,m), 1.89 (3 Η, s)5 2.08-2.19 (1 Η, m), 2.31-2.39 (1 Η, m), 2.60-2.72 (3 Η, m), 3.20-3.30 (6 Η 5 m)? 3.40-3.62 (2 Η, m)? 4.13-4.24 (1 Η, m), 4.82 (1 Η, s), 7.10-7.36 (15 Η,m). (Method 2); 3.00; 496 59 Anti-(1S,2S)hydroxy-di-σ-cephen-2-yl-acetic acid 2-{[2_(3-gas-benzene Oxy)-ethyl]-methyl-amino}-bicyclo[2.2.1]hept-7- Ester Cl (CDC13) 1.00 (lH, m), 1.23-1.38 (3H, m)5 1.80-1.95 (2H, m), 2.20 (3H, s), 2.22-2.30 (1H, m), 2.42-2.48 ( 1H? m)5 2.50-2.60 (1H, m), 2.60-2.80 (2H, m), 3.98-4.03 (2H, m), 4.75 (1H, s), 4.88 (1H, s), 6.73-6.80 ( 1H, m), 6.83-6.93 (2H, m), 6.95-7.00 (2H5 m)5 7.15-7.20 (3H, m), 7.22-7.30 (2H, m). (Method 2); 7.98; 518 60 trans-(1S,2S)[2-(3-Gas-phenoxy)-ethyl]-[7·(2-diyl-2,2_di-anthracene- 2-yl-acetoxy)bicyclo[2.2.1]hept-2-yl]-dimethyl-&gt; ammonium odorate Cl ΒΓ % (CDC13) 1.20-1.95 (5H, m), 2.23 - 2.38 ( 1H,m), 2.55-2.60 (1H5 m)? 3.00-3·05(1Η,ηι),3·44(3Η, s),3·48 (3H,s),4.24-4.36 (lH,m) , 4.38-4.42 (1H, m), 4.42-4.58 (3H, m), 4.73 (1H, s), 4.93 (1H, s)5 6.80-6.88 (1H? m)? 6.93-7.05 (4H, m) , 7.16-7.20 (2H, m)5 7.23-7.35 (3H, m) 0 (method 2); 8.05; 532 121575.doc -85- 200848416 instance name structure ^NMRC^O MHz) δ (method); Rt/ Min; [MH]+ or [M-Brl-f 61 trans-(1S,2S)hydroxy-dicetin-2-yl-acetic acid 2-{[2-(2-a-phenoxy)-ethyl ]-Methyl-amino}-bicyclo[2.2.1]hept-7-ylindole 0::~~ (CDC13) 1.02-1.10 (1H5 m)5 1.24-1.38 (2H,m), 1.50-1.60 (1H5 m), 1.80-1.95 (2H, m), 2.23 (3H, m), 2.23-2.28 (1H, m), 2.46-2.50 (1H3 m)3 2.59-2.65 (1H5 m)? 2.76-2.80 ( 2H, m), 4.08-4.16 (2H, m), 4.78 (1H, s), 4.90 (1H, s), 6.83-6 .94 (2H, m), 6.95-7.00 (2H, m)5 7.18-7.21 (3H5 m)? 7.23-7.30 (2H5 m)? 7.37-7.40 (1H, m). (Method 2); 7.84; 518 62 trans-(1S,2S)[2-(2-chloro-phenoxy)-ethyl]_[7_(2-hydroxy-2,2-cephen-2-yl) -Ethyloxy)bicyclo[2.2.1]heptan-2-yl]-dimethyl-alkaline ammonium ruthenium (CDCls) 1.20-1.49 (2H?m), 1.61-1.77 (3H,m), 1.83- 1.92 (1H? m)5 2.26- 2.37 (1H? m)5 2.54-2.58 (1H,m), 2.97-3.02 (1H, m),3·47 (3H,s), 3.49 (3H,s), 4.28-4.36 (1H, m), 4.43-4, 52 (1H, m), 4.54-4.66 (3H, m), 4.96 (1H, s), 6.93-7.02 (4H, m), 7.10-7.14 (2H , m), 7.22-7.30 (3H, m), 7.32 - 7.37 (1H, m). (Method 3); 8.30; 532 63 trans-(1S,2S)hydroxy-dicetin-2-yl-acetic acid 2-{[2-(4-chloro-phenoxy)ethyl]-indenyl- Amino}-bicyclo[2.2.1]hept-7-yl ester C, xx0^ (CDC13) 0.99-1.08 (1H? m), 1.25-1.37 (3H, m), 1.51-1.62 (1H? m)? 1.79-1.92(2H,m), 2.19(3H, s)5 2.24-2.28 (1H,m), 2.42-2.47(lH,m), 2.50-2.58 (1H?m)? 2.60-2.75 (2H,m ), 3.95-4.06 (2H, (Method 2); 2.58; 518 121575.doc -86 - 200848416 f Instance name structure! ΗΝΜΚ (400 MHz) δ (method); Rt/min ; [MH]+ or [M- Brl+ m), 4.78 (1Η, s), 4.88 (1H, s), 6.78-6.84 (2H, m), 6.95-7.00 (2H, m), 7·14-7.31 (5H, m). 64 anti-(1S,2S)[2-(4-Gas-phenoxy)-ethyl H7-(2-transyl-2,2--cephen-2-yl-ethenyloxy)·bicyclic [2.2.1] Hept-2-yl]-dimercapto-brominated molybdenum Br_c, Ol. ~^ (CDC13) 1.20-1.40 (1H, m), 1.41-1.50 (lH,m), 1.70-1.83 (3H? m)5 1.83-1.95 (lH,m),2.23-2.35 (1H,m), 2.55-2.60 (1H, m), 3·00-3·08 (1H, m), 3·44 (3H, s), 3·48 (3H, s), 4.20-4.30 (1H5 m), 4.30- 4.40 (1H, m), 4.45-4.60 (3H, m), 4.95 (1H, s), 6.85-6.93 (2H? m) 5 6.98-7.03 (2H, m), 7.16-7.20 (2H, m)5 7.22-7.35 (4H, m)o (Method 2); 2.66; 532 Example 65 Anti-(IS, 2S)hydroxy-di-thiophene-2-yl-acetic acid 2-{methyl-[4_(1-methyl) -2-Sideoxy_1,2-diaropyridinyl)-butyl]-amino}•bicyclo[2.2.1]heptyl ester OBn

Η a· 4-(4-Benzyloxy-butan-1·ynyl)-1Η-pyridine-2-one forms 2-hydroxy-4-bromoindole in a 1:1 mixture of DMF and Et3N (70 mL) 121575.doc -87- 200848416 Precipitate (2·00 g, 11.49 mmol), cuprous iodide (219 mg, i l5 _ and butyl-3-alkynyloxymethyl-benzene (2·〇3 g, a solution of 12·64 mm 〇1). Degas the system using a rat gas and add hydrazine (triphenylphosphine) to the hydrazine (mg, 1 1 $ mmol). Degas the system with argon and apply it. It was sealed and stirred for 5 hours under 5 Torr. Thereafter, the reaction was reduced to dryness and the residue was dissolved/suspended in ethyl acetate (30 mL) to remove any inorganic material by filtration and the solvent was reduced to water. The title compound (2.91 g) was obtained as crystals eluted eluted eluted eluted eluted eluted eluted eluted eluted with (2H,m) 3.65-3.71 (2H,m), 4.57-4.63 (2H,m),6.20-6.27 (1H,m), 6 · 5 8 - 6.6 2 (1H,m),7 · 2 0 · 7 · 7 0 (6 H, m). OBn

b. 4-(4-Ethoxy-buty-l_fast) small methyl ketone-2-one 4-(4-benzyloxy-but-1-ynyl)-1Η under nitrogen atmosphere Pyridine-2-one (400 mg, 1.58 mmol) was dissolved in dry THF. Potassium tert-butoxide (195 mg, 1.73 mmol), tetrabutylammonium iodide (29 mg, 0.08 mmol) and methyl iodide (147 g, 2.37 mmol) were added and the reaction was stirred at ambient temperature for 18 hours. . Thereafter, the reaction was stopped by adding 0 (about 5 mL) and the reaction mixture was concentrated to a gel, which was partitioned between DCM and H20. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The title compound (300 mS) was obtained as a yellow gum eluting eluting elution elution elution elution elution elution elution elution lH NMR (CDC135 400 MHz): δ 2.69-2.75 (2Η5 m), 3.49-3.53 (3Η,m),3·63-3·70 (2Η,m),4.59 (2Η,s),6.08-6.12 ( 1Η, m), 6.60-6.62 (1H, m), 7.16-7.20 (1H, m), 7·75-7·90 (5H, m) 〇

c. 4_(4-Hydroxy-butyl)-1-indenyl-1H-pyridin-2-one using nitrogen to give 4-(4-benzyloxy-but-1-ynyl)-1·methyl-1H A solution of pyridin-2-one (300 mg, 1.12 mmol) in MeOH (2.5 mL) andEtOAc. 10 wt% palladium on carbon (30 mg) was added and the reaction mixture was stirred under hydrogen for 18 h. The reaction was filtered through EtOAc and concentrated. The residue was degassed with MeOH (2.5 mL) andEtOAc. 20 wt% palladium hydroxide on carbon (30 mg) was added and the reaction was stirred under hydrogen for a further 18 h. The reaction was filtered through EtOAc (EtOAc) elute NMR (CDC13, 400 ΜΗζ): δ 1.45-1.75 (4H, m), 2.45-2.60 (2Η, m), 3·45-3·65 (5Η, m), 6.25-0.45 (2Η, m), 7 ·50-7·70 (1H,m) 〇

121575.doc -89- 200848416 d· 4-(4-Mo-butyl)-l_曱 比 咬 -2- 纲 纲 纲 4- 4-(4-hydroxy-butyl)-ΐ•methyl dH-pyridine· A solution of 2-ketone (200 mg, 1 mmol) in EtOAc (EtOAc)EtOAc. The reaction was cooled to rt and was taken to aq. EtOAc (aq. The organic layer was dried over anhydrous MgSO.sub.4 and evaporated. The title compound (120 mg) was obtained as a yellow gum eluting eluting eluting eluting eluting eluting eluting 4 NMR (CDC13, 400 MHz)·· δ 1.70-1.95 (4H, m), 2·42-2·50 (2H, m), 3.38-3.45 (2Η, m), 3.48-3.53 (3Η, m) , 5.99-6.05 (1Η, m), 6.35-6.40 (1H, m), 7.17-7.23 (1H, m).

e·trans-(1S,2S)hydroxy·di-thiophen-2-yl-acetic acid 2-{methyl-[4-(1_methyl-2)-oxy-1,2-di-argonpyridine_4 _yl)-butyl]-aminodibicyclo[2丄1]heptyl-7-yl ester title compound was obtained by the method described in Example 22 from trans-(is, 2S)-based bis-thiophene-2- Preparation of 2-methylaminobicyclo[2·2·1]hept-7-yl acetate. lU NMR (CDC135 400 MHz): δ 0.95-1.05 (1 Η 5 m) 3 1.20-1.36 (3 Η, m), 1.38-1.70 (5 Η, m), 1.75-1.90 (2 Η, m), 1.95- 2.05 (3 Η, m), 2.15-2.27 (3 Η, m), 2.30-2.44 (4 Η, m), 3.50 (3 Η, s), 4.70-4.90 (2 Η, m), 5.97-6.03 ( 1 Η,m),6·37-6·4〇(1 Η, 121575.doc -90- 200848416 m),6·95-7·01 (2 H,m),7.15-7.21 (3 H,m ), 7.23-7.30 (2 H, m). LC-MS (method 3) Rt 6.64 min; m/z 527 [mh]+. ' / Example 66 anti-(IS, 2S)-[7_(2_trans-base_2,2-di-porphin-2-yl-ethenyloxy)-bicyclo[2·2·1]g-2 -yl]-di-f-group*(1-methylj-side oxy-t-dihydro-piperidin-4-yl)-butylammonium bromide

The title compound was obtained by the method described in Example 22, i 々 method from trans-(1S, 2S) via thio-di-thiophen-2-yl-acetic acid 2-{methyl-[4 servoyl-2-_2 side Oxy.···························· iH NMR (CDCI3, 400 MHz): 1.38-1.5〇〇^ (? (3 H,m), 2.81-2.87 (1 H,m), 2·19-2·30 (1 H,m), 2.50- 2.60

Η, m), 3.25-3.35 (6 Η, m), 3.45-3.53 (4 Η? m), 3.65-3.85 (2 Η, m), 4.20-4.30 (1 Η, (4), 4·9 〇 (1 Η, s), 4.99 (1 Η, s), 6.11-6.16 (1 Η, m), 6.32-6.36 (1 Η, m), 6.95.7. 〇〇 (2 Η, m), 717.)9 (2 Η, m), 7.20-7.33 (3 Η, m). Lc ms (method 2) Rt 2·27 min ; m/z 541 [M-Br]+ ο Example 67 trans-(IS, 2S)-[7-(2R-cyclohexyl-hydroxy-phenyl-acetic acid 2 [ Methyl _(4_phenylbutyl)-amino]-bicyclo[HI]hept-7-yllo 121575.doc -91- 200848416

a·trans-(1S,2S)(7-benzyloxy-bicyclo[2·2·1]hept-2-yl)-methyl-(4-phenyl-butyl)-amine as described in Example 22c The condition is (1R,7S)-7-benzyloxy-bicyclo[2·2·1]heptan-2-one (1.00 g, 4.62 mmol) and ethyl-(4-phenyl-butyl)-amine (1.51 g, 9.25 mmol) of the reaction. 4 NMR (CDC13, 400 MHz): δ 0.92-1.01 (1H, m), 1.25-1.35 (1H, m), 1.43-1.53 (2H, m), 1.56-1.68 (3H, m), 1.69-1.78 ( 1H,m), 1.79-1.91 (2H,m), 2.05(3H,s),2.14-2.35(5H,m),2.59-2.65 (2H,m),3.69-3.72 (1H,m),4· 49 (2H, s), 7.14-7.20 (3H, m), 7.22-7.38 (7H, m).

b·反_(18, 2S)2·[Methyl-(4-phenyl-butyl)-amino]bicyclo[2·2·1]hept-7-ol using nitrogen to make anti-(1S, 2S (7-Benzyloxy-bicyclo[2.2.1]hept-2-yl)-indolyl-(4-phenylbutyl)-amine (1.28 g, 3.52 mmol) in MeOH (5 mL), EtOH The solution in (15 mL) and H2S〇4 (200 μΐ^) was degassed. Palladium hydroxide on carbon (128 mg) was added and the reaction mixture was scrambled for 48 h under hydrogen. After 24 h, H2S04 (200 μM) and Pd(OH)2/C (128 mg) were added. The reaction was filtered through HyFlo 121575.doc-92-200848416 and concentrated. The residue was partitioned between NaHC〇3 and DCM. The organic phase was concentrated to give the title compound (9 <RTIgt; 4 NMR (CDC13, 400 MHz): δ 0·92_1·〇ΐ (iH,m), 1.30-1.40 (1Η,m), 1.42-1.90 (8Η,m),1·95_2_35 (8Η,m), 2.58 -2.66 (2H, m), 3.95-4.00 (1H, m), 7.13-7.20 (3H, m), 7.22-7.30 (2H, m).

c·trans-(1S,2S)-[7_(2R-cyclohexyl.hydroxy-phenyl-acetic acid 2_[methyl-(4-phenyl-butyl)-amino]bicyclo[2.2.1]g The 7-base ester title compound was obtained by the method described in Example 22 from the reverse _(1 §, 2 §) 2-[methyl-(4-phenyl-butyl)-amino]-bicyclo[2.2.1] Preparation of -7-ol. (CDC13, 300 MHz): δ 0.98-2.31 (29H5 m)5 2.57-2.63 (2Η3 m)? 3.73 (1Η, s), 4.76 (1Η, s), 7.15-7.37 (8Η, m), 7.60-7.64 (2Η, m); LC-MS (method 1) Rt 2.93 min; m/z 490 [MH]+. </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -2-hydroxy-2-phenyl-ethoxycarbonyl)-bicyclo[2.2.1]hept-2-yl]-dimethyl-(4-phenyl-butyl)_invitro

The title compound was obtained by the method described in Example 22 from s-(s,2SH7_(2R-cyclohexyl-carbamic-phenyl-acetic acid 2-[methyl-(4-phenyl-butyl)-amino]- 121575.doc -93- 200848416 Bicyclo[2.2.1]heptyl ester preparation. (CDC13) δ 1.02-1.91 (19 H,m), 2.08-2.19 (2 Η,m), 2.47-2.49 (1 Η,m ), 2.55-2.57 (1 Η, m), 2.62-2.66 (2 Η, m), 3.23 (3 Η, s), 3.25 (3 Η, s), 3.40-3.58 (3 Η, m), 3.95, 4·00 (1 Η, m), 4.70 (1 Η, s), 7.08-7.33 (8 Η, m), 7·52-7·56 (2 η, m) ; LC-MS (method 3) Rt 9·49 min ; m/z 504 [M-Br]+ 〇 Example 69 Anti-(1S,2S)-[7_(2S-cyclohexyl·hydroxy-phenyl·acetic acid 2-[methyl-(4-benzene) Ketobutyl)-aminodibicyclo[2·2·1]hept-7-yl ester

The title compound was prepared from the compound <RTI ID=0.0># </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; (CDCl3,): 5〇.8〇-l.68(l7H,m) 1.70-1.85 (2H,m),1.88-1.98 (1H,m),2.05 (3H,s),2.06-2.12 (1H, m), 1.13-2.30 l (3H? m)? 2.30-2.38 (1H5 m)5 2.39-2.42 (1H5 m), 2.55-2.64 (2H, m), 3.72 (lH, s), 4.73 (lH, s ), 7.10-7.20 (3H, m), 7.20-7·35 (5H, m), 7.60-7.65 (2H, m); LC-MS (method l) Rt 2.86 min; m/z 490 [MH]+ 〇Example 70 trans-(1S,2S)-[7-(2S-cyclohexyl-2-hydroxy_2_phenyl-ethoximeoxybicyclo[2·2·1]hept-2-yl]-di Methyl-(4-phenyl-butylammonium bromide 121575.doc -94- 200848416

The title compound was obtained by the method described in Example 22 from p-(1S,2S)-[7-(2S-cyclohexyl-hydroxy-phenyl-acetic acid 2-[methyl-(4-phenyl-butyl)-amine Preparation of bis-[2·2·1]heptyl ester. (CDC13) δ 〇·99_1·94 (19H,m), 2.01-2.21 (2H5 m)5 2.34-2.41 (1H, m)5 2.64- 2.73 (2H5 m)? 2.74-2.80 (1H5 m)5 3.27 (3H5 s)? 3.29 (3H? s)5 3.53-3.66 (3H,m),4·07-4·16 (ih,m),4 · 72 (1H, s), 7.12-7.20 (3H, m), 7·21-7·36 (5H, m), 7.50-7.57 (2H, m); LC_MS (method 3) Rt 9.53 min ; m/ z 504 [M-Br]+ Biological example The inhibitory effect of the compound of the present invention on the M3 sputum receptor is determined by the following binding assay: 蕈 验 验 艘 艘 放射性 放射性 放射性 放射性 放射性 放射性 放射性 放射性 放射性 放射性 放射性 放射性 放射性 放射性 艘 艘 艘 艘 艘N-methylpurine ([3h]-NMS) and radioligand binding assays for commercially available cell membranes exhibiting human scorpion venom (M2 and M3) to study the antagonism of antagonists against M2 and M3 receptors Affinity. Membranes in tris buffer were cultured for 3 hours in 96-well plates with various concentrations of [3H]_NMS &amp; M3 antagonists. The membranes were then collected by filtration and bound radioligands. The cells were allowed to dry overnight. Subsequently, scintillation fluid was added and the bound radioligand was counted using a Canberra Packard Topcoimt scintillation counter. The alternative radioligand [3 Η ] - QNB and the modification of the affinity assay described above were used for the measurement. The half-life of the antagonist on each muscarinic receptor. As determined by the [3η]_QNB ligand, the antagonist exhibits human 蕈 at a concentration 10 times higher than its illusion with 121575.doc •95-200848416 The membrane of the muscarinic receptor was incubated for 3 hours. At the end of this time, [3H]-QNB was added to a concentration 25 times higher than the Kd of the receptor under study and incubation was continued for various periods of 15 minutes to 180 minutes. The membrane was then collected by filtration and bound to the radioligand and allowed to dry overnight. The scintillation fluid was then added and the bound radioligand was counted using a Canberra Packard Topcount flash counter. The detected [3H]-QNB and scorpion venom The rate of base receptor binding is related to the rate at which the antagonist dissociates from the receptor, i.e., the half-life of the antagonist on the receptor. Alternatively, the recombinant human M3 receptor is expressed in CHO-K1 cells. Film and by scintillation proximity method (scintillation proximity assay; SPA) analysis of [3H] -N- K-methyl scopolamine ([3H] -NMS) in combination with the compound. Incubate for 16 hours at room temperature in the presence of 1% (v/v) DMSO. The assay was performed in a white 96-well bottom transparent NBS plate (Corning). Prior to the assay, a CHO cell membrane containing the M3 receptor was coated on SPA WGA (wheat germ agglutinin) beads (GE Healthcare). Non-specific binding was determined in the presence of 1 μΜ Atropine. Radioactivity was measured on a Microbeta scintillation counter (PerkinElmer) using a 3H protocol with a reading time of 2 minutes per well. The [3H]-NMS bound compound inhibition is typically determined using concentrations in the range of n. 〇 3 nM to 1 μΜ and is expressed as percent inhibition of plate-specific radioligand binding relative to the plate. The concentration-dependent inhibition of the compound to [3H]-NMS binding is expressed as pIC50. All of the example compounds tested in the assays exhibited less than 10 nM of 121575.doc-96-200848416 19 and 28 exhibited less than 100. Example 8 exhibited a binding affinity Ki value of 0·1 nM, with the exception of Example 6, nM Ki value. As another illustration of the invention, the Ki value and Example 22 exhibit a Ki value of 0.4 nM. Example M3 Binding (NMS) M3 Binding (SPA) 1 ++ NT 2 +++ NT 3 +++ NT 4 ++ NT 5 +++ NT 6 + NT 7 +++ NT 8 +++ NT 9 ++ + NT 10 +++ NT 11 +++ NT 12 +++ NT 13 ++ NT 14 +++ NT 15 ++ NT 16 +++ NT 17 ++ NT 18 +++ NT 19 + NT 20 ++ NT 21 NT NT 22 NT +++ 23 NT NT 24 NT ++ 25 NT NT 26 NT NT 27 NT NT 28 +++ NT 29 NT NT 30 NT ++ 31 NT NT 32 NT +++ 121575.doc -97 - 200848416

33 NT NT 34 NT +++ 35 NT NT 36 +++ NT 37 NT NT 38 NT +++ 39 NT NT 40 NT +++ 41 NT NT 42 NT +++ 43 NT NT 44 NT +++ 45 NT NT 46 NT +++ 47 NT NT 48 NT +++ 49 NT NT 50 NT +++ 51 NT NT 52 NT +++ 53 NT NT 54 NT +++ 55 NT NT 56 NT +++ 57 NT NT 58 NT + 59 NT NT 60 NT +++ 61 NT NT 62 NT +++ 63 NT NT 64 NT NT 65 NT NT 66 NT NT 67 NT NT 68 NT +++ 69 NT NT 70 NT ++ -98 - 121575. Doc 200848416 M3 Binding (NMS)Ki&lt; 2 nM,, +++,,; Ki 2-10 ηΜ η++π ; Ki &gt; 10 nM ” + &quot;; NT-not tested. M3 binding (SPA) IC5〇&lt; 2 nM,, +++"; IC5〇2-10 nM π++π ; IC5〇&gt; 10 nM ” + ”; NT-not tested. Analysis of inhibition of M3 receptor activation via calcium mobilization

In an alternative M3 receptor binding assay, CHO cells expressing human M3 receptor were seeded and plated in 96-well collagen coated plates (black plate, bottom transparent) in 30,000 sera of 50,000/75 pL medium. Density culture overnight. f The next day, Ma Sencular Devices (catalog number R8041) was prepared in HBSS buffer supplemented with 5 mM probenecid (pH 7.4). An equal volume of dye solution (75 pL) was added to the cells and incubated for 45 minutes, followed by the addition of 50 μL muscarinic antagonist or vehicle. After another 15 minutes, the plate was read on a FLEXstationTM (excitation at 488 nm, emission at 525 nm) for 15 seconds to determine baseline fluorescence. Subsequently, the muscarinic agonist Carbachol was added at an EC8G concentration and the fluorescence was measured again for 60 seconds. The signal was calculated by subtracting the peak response from the mean I of the baseline fluorescence in the control well in the absence of the antagonist. Subsequently, the percentage of the maximum response in the presence of the antagonist was calculated to generate an IC5G curve. The inhibitory effect of the compounds of the invention on the M3 muscarinic receptor can be assessed in the following 'in vitro and in vivo assays: For example, the compound of Example 3 exhibits an IC50 value of less than 10 nM in this assay. Methacholine-induced in vivo bronchoconstriction Individual identification of 5 groups of male guinea pigs (Guinea 121575.doc -99- 200848416 pig) (Dunkin Hartley) weighing 500-600 g. Allow animals to adapt to the environment in which they live for at least 5 days. Animals were allowed access to water and food at random throughout the period and during the study period. The guinea pigs were anesthetized with an inhaled anesthetic Halothane (5 ° / 〇). The test compound or vehicle (0.25-0.50 mL/kg) was administered intranasally. The animals were placed on a heated pad and allowed to recover, then returned to the living cage for up to 24 hours after administration, and the guinea pigs were anesthetized with haloethane (250 pg/mL, 2 mL/kg). . In surgical anesthesia, a portex intravenous cannula filled with heparinized phosphate buffered saline (hPBS) (10 U/mL) was inserted into the jugular vein for intravenous administration of methacholine. The trachea was exposed and inserted into a rigid portex cannula and inserted into the esophagus via a flexible protex infant feeding tube. Subsequently, the spontaneously breathing animals were connected to a lung measurement system (EMMS, Hants, UK) consisting of a flow pneumotach and a pressure sensor. Connect the tracheal cannula to the pulmonary flow meter and connect the esophageal cannula to the pressure sensor. The esophageal cannula was placed to produce a baseline resistance between 0.1 cm H2 〇/mL/s and 0.2 cm H20/mL/s. Baseline readings were recorded for 2 minutes, followed by intravenous administration of methacholine (up to 30 pg/kg, 0.5 mL/kg). A 2-minute recording of induced contraction was initiated starting from intravenous administration. The bronchial protection effect of the test compound was tested using a soft body analysis of the area under the curve (AUC) of the peak resistance and resistance during each 2 minute recording period. As an illustrative example, Figure 1 shows that the compound of Example 3, 121575.doc - 100 · 200848416, has bronchial protection 1 hour after administration. Example 3 (3 pg/kg, intranasal) effect on methamphetamine-induced bronchoconstriction in guinea pigs

I I - 4 3 2 (sioCNIHEO)SMSI ρ&lt;0·001

ρ&lt;0_05

Baseline vehicle Example 3 121575.doc -101 -

Claims (1)

200848416 X. Patent application scope: A compound of formula (I): R is C^c: 6 alkyl or hydrogen atom; and R2 is a hydrogen atom or a group -R5 or a group -Z-Y_R5 or a group Z-NR9Ri〇 or a group _z_n(r9)c(〇) R11; and R3 is a lone pair, or a Cl-C6 alkyl group, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and is positively charged; r4 is selected from the formula (a), (b), One of c) or (d) a group; 2 is (^-(:16 alkylene, (:2-(:16) or C2-Ci6 alkynyl; γ is a bond or an oxygen atom; &amp; is (^-(:6 alkyl, Aryl, arylalkyl, aryl fused cycloalkyl, aryl fused heterocycloalkyl, heteroaryl, aryl (Cl_C8-alkyl)-, heteroaryl (C^Cr alkyl)- , cycloalkyl or heterocycloalkyl; ... is 匚 ^ ^ alkyl or hydrogen atom; R7aA R7b is independently Cl-C6 alkyl or halogen; η and m are independently 〇, 1, 2 or 3; RSa and RSb is independently selected from the group consisting of aryl, aryl fused heterocycloalkyl, 121575.doc 200848416 heteroaryl, c^c:6 alkyl, cycloalkyl and hydrogen; '--OH, CVQ alkane a group, a hydroxy group -Ci_C6 alkyl group or a hydrogen atom; the human R and R1 ❶ are independently a hydrogen atom, a Ci_C6 alkyl group, an aryl group, an aryl fused heterocycloalkyl group, an aryl fused cycloalkyl group, a heteroaryl group, an aromatic group. a group (Ci_c6 alkane: group &gt; or heteroarylalkyl)- group; or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring containing 4 to 8 atoms of another nitrogen or oxygen atom, as the case may be Ring; only C i · C6 alkyl or hydrogen atom; f ' 1 Ar is aryl, heteroaryl or An alkyl group; Ar is independently an aryl group, a heteroaryl group or a cycloalkyl group; and Q is an oxygen atom, a rhyme 2, a pectin 2- or a bond; or a pharmaceutically acceptable salt or solvate thereof; An oxide or a prodrug. The compound of claim 1, wherein R ac^c: 6 alkyl or a hydrogen atom, and R 2 is a ci-C 6 alkyl group, a hydrogen atom (or a group -ZY-R 5 or a group) _z_nr9r10 or a group _z_n(r9)c(〇)r11; R is a lone pair; or a Ci-C0 alkyl group, in which case the nitrogen atom to which it is attached is a quaternary nitrogen and is positively charged; R4 Or one of the groups of formula (a) or (b) or (C): z is C^c8 alkylene; 121575.doc 200848416 γ is a bond or an oxygen atom; R is an aryl or aryl (Ci-Cs alkyl) group; R is a ^-^ group or a hydrogen atom; R7a&amp;R7b is independently alkyl or halo; η and m are independently 〇, 1, 2 or 3; R8a&amp; R8b are independently selected from aryl, heteroaryl, Ci_c6 alkyl, cycloalkyl and hydrogen. a group; R8&lt;^-OH, CVC6 alkyl, hydroxy-Ci_C6 alkyl or a hydrogen atom. R9 and Rle are independently a hydrogen atom, a Ci_Ce alkyl group, an aryl group, a heteroaryl group, an aryl group (Cl-C6 alkane) a group of - or a heteroaryl (Ci_c0 alkyl) group; or R9 and R1. The nitrogen atom to which it is attached forms a heterocyclic ring containing, as the case may be, another 4 to 8 atoms of a nitrogen or oxygen atom; R is a ^-alkyl group or a hydrogen atom. 3. A compound of claim 2 or 2, wherein is a decyl or ethyl or a chloro atom, and R2 is a methyl or ethyl group, a hydrogen atom or a group _Z_Y_R group -z-NR9R10. 4. The compound of claim 3, wherein R3 is methyl such that the nitrogen atom to which it is attached is a quaternary nitrogen and has a positive charge. 5. A compound as claimed in the claims, wherein in any of the groups _r5, _y_r5, _z_y-R5, -Z-nr9r10: H2^'16 is optionally substituted with methyl at up to two carbons in the chain; Is a bond or; R is the following group substituted as appropriate: 121575.doc 200848416 Phenyl, 3,4-methylenedioxyphenyl, 3,4-extended ethyldioxyphenyl, two Hydroquinone, naphthyl; or pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzoxazole, benzoxazolyl, thiazolyl, benzothiazolyl, Quinolinyl, thienyl, benzoquinone, furyl, azathiofuryl, imidazolyl, benzalkonium, isoindole t-sitting, benzoquinone-isosyl, s-hydrazyl, isothiazole a triazole group, a benzotriazolyl group, a thiadiazolyl group, an oxadiazolyl group, a pyridazinyl group, a pyridazinyl group, a triazinyl group, a fluorenyl group or a carbazolyl group; or an arylalkyl group, wherein The aryl moiety is phenyl, 3,4-decylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrophenylfuranyl or naphthyl' and the alkyl moiety is - CH2· or -CH2CH2_; or a heteroarylalkyl group, wherein The heteroaryl moiety is σ-pyridyl, fluorenyl, pyrimidinyl, oxazolyl, isoxazolyl, benzoxazole, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl , thiophenyl, phenylhydrazino, furyl, benzofuranyl, imidazolyl, benzimidazolyl, isothiazolyl, phenylisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benzoquinone An oxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, fluorenyl or oxazolyl group, and the alkyl moiety is _Ch2_4_CH2CH2_; or a fluorenyl or 1, 2,3,4-tetrahydronaphthyl; or heteroalkyl (C^C: 6 alkyl)-, wherein the heterocycloalkyl moiety is azetidinyl, piperidinyl, piperazinyl, such as methylpiper N-substituted piperazinyl or tetrahydropyrrolyl, and the alkyl moiety is _CH2_4_CH2CH2_, or % propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl 121575.doc -4- 200848416 base; and R and R are independently hydrogen 'methyl, ethyl or n-propyl or isopropyl; phenyl, 3,4-methylenedioxyphenyl, 3, 'extension Ethyldioxybenzene group, two Hydroquinonefuranyl, naphthyl; 0 sigma group, each group, η-decyl, fluorenyl, iso-sigmatyl, benzoxazole, benzoxazolyl, thiazolyl, benzothiazole , quinolyl, thienyl, benzoquinenyl, furyl, azathiofuryl, imidazolium, benzoimidazolyl, isothiazolyl, phenylisothiazolyl, pyrazolyl, isodecyl, three. a pendant group, a benzoquinone, a fluorenyl group, a fluorenyl group, a sigmazinyl group, a pyridazinyl group, a triazinyl group, a fluorenyl group or a carbazolyl group; or an arylalkyl group, wherein the aryl group Partially phenyl, 3,4-decylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrophenylfuranyl or naphthyl' and the alkyl moiety is -CH2- Or -CH2CH2_; or R9 and R10 together with the nitrogen atom to which they are attached form a butyl group, a sigma group, a sulfhydryl group, an N-methyl benzyl group, a fluorenyl group, a morpholinyl group or a thiomorpholinyl group. ring. 6. The compound of claim 1 or 2, wherein in the group -NRiR^R3, R1 is methyl or ethyl, R2 is a group -ZY-R5, and R3 is methyl such that the nitrogen to which it is attached It is quaternized and positively charged. 7. A compound according to claim 6 wherein R5 is optionally substituted phenyl, γ is a bond or -〇-, and Ζ is a chain of up to 12 or up to 9 carbon atoms and nitrogen and -YR5 A straight or branched chain of alkyl groups is attached. 8. The compound of claim 1 or 2, wherein R4 is a group, R6 is a fluorenyl group or an ethyl or hydrogen atom; Ar1 is phenyl, thienyl, cyclohexyl, cyclopentyl, 121575.doc 200848416 cyclopropyl Or cyclobutyl; R7a&amp; R7b is independently methyl, ethyl, n-propyl or isopropyl, n-butyl, t-butyl or t-butyl, fluoro, chloro or bromo; And η are independently 〇, 1, 2 or 3. 9. The compound of claim 1 or 2, wherein R4 is a group, and RSb is independently selected from the group consisting of methyl, ethyl, n-propyl or isopropyl, n-butyl, second butyl And tributyl; phenyl, 3,4. methylene dioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrophenylfuranyl, naphthyl, σ ratio , Luo Luoji, mouth σ fixed base. The evil σ sits on the base and is different. Ester base, 幷 σ 嗤 嗤 、, benzoquinone, fluorenyl, phenyl fluorenyl, quinolyl, thienyl, benzoquinone, furyl, benzofuranyl, imidazolyl , phenylimidazolyl, isothiazolyl, phenylisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, dioxin, pyridazinyl, pyridazine , triazinyl, fluorenyl or carbazolyl-monohydroindenyl or 1,2,3,4-tetrahydronaphthyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl And cyclooctyl and hydrogen atoms; r8. It is _〇11, a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group. 10. The compound of claim 9, wherein the ulnar is -oh. 11. The compound of claim 9, wherein (i) R8a and each are optionally substituted acridinyl, oxazolyl, thiazolyl, furyl, thienyl or phenyl; or (ii) R8a&amp; R8b One of which is optionally substituted phenyl and the other is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or (iii) one of R8a and a ruthenium The pyridine group, thienyl group, oxazolyl group, thiazolyl group or furyl group which are optionally substituted and the other are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. 121575.doc -6- 200848416 • A compound of the formula 9, wherein _R8a and R8b are each 2-nonyl or phenyl; or R" and ^ are - phenyl and the other is 24 The compound of claim 1, which has the formula (IA) 〇 (CH2)S—Y-(CH2)t Χ' (ΙΑ) Wherein is a phenyl ring which is optionally substituted; R8a is phenyl, porphinyl, nucleopentyl or cyclohexyl; R8b is phenyl, porphinyl, cyclopentyl or cyclohexyl, s is 1, 2, 3 , 4, 5, 6 or 7 and t is 〇, 1, 2, 3, 4, 5, 6 or 7, with the constraint that s+t is not greater than 1〇; 丫 is a bond or 〇_, and X - a pharmaceutically acceptable anion. 14. The compound of claim 1 which has the formula (IB) Wherein ring B is a phenyl ring which is optionally substituted; s is 丨, 2, 3, $5, 6 or 7 and { is 〇, 1, 2, 3, 4, 5, 0 or 7, 1 illusion ^ The restriction condition is that S + t is not more than 10; Y is a bond or 〇 _; and 6 , Arl , ^ and ^ are defined by the above group (a); and χ · is pharmaceutically acceptable Anion,. 15. The compound of claim 1 having the formula (IC) 121575.doc 200848416 Wherein ring C is a phenyl ring which is optionally substituted; q is an oxygen atom, _cii2_, a CH2CH&quot; a one-key; 8 is! , 2, 3, 4, 5, 6 or 7 and Hongjun, 2 3, 4, 5, 6 or 7 ' is limited to s + t is not greater than 1 〇 and γ is a bond or X- is medicinal An acceptable anion. The compound of any one of claims 13, 14 or 15, wherein the ring or the optional substituent in C or C may optionally be selected from alkoxy; -yl, especially fluoro or chloro; a C1-C3 alkyl group; an amino-based Ci-Cs fluorenyl group; an amine group c "C3 alkyl group; and an aminosulfonyl group. 17. The compound of claim 1, which is selected from the group consisting of: Reverse S, 2S) [7-(2-hydroxy-2,2_di-thiophene-2-yl-ethenyloxy)·bicyclo[2·2·1]hept-2-yl]-didecyl _(3_phenoxy-propyl)-ammonium; inverse (IS, 2S) [7-(2-hydroxy-2,2-di-thiophen-2-yl-ethyloxy)-bicyclo[2.2. 1]hept-2-yl]-dimethyl-(4-phenyl-butyl)an; inverse (is, 2S)[7-(9-hydroxy-9Η-diphenylpyridinium-9-carbonyloxy) ))-bicyclo[2.2.1]hept-2-yl]-monomethyl-(4-phenyl-butyl); anti-(1S,2S)[3-(4-chloro-phenoxy) _propylbu [7_(2_hydroxy-2,2_di-thiophen-2-yl-ethenyloxy)-bicyclo[2·2·1]hept-2-yldimethylammonium; anti- (IS, 2S) [7-(9-Hydroxy-9Η-diphenylhydrazine-piperidinyloxybicyclo[2 ·2·1]hept-2-yl]-dimethyl-(3-phenoxy-propane Base)_ammonium; 121575.doc 200848416 anti-〇S, 2S )[7-(9-Hydroxy_9Η-diphenylhydrazone_9_weiΡ·1]heptyl]·: methyl group 4·phenyl·butyl·3趟bicyclic anti (IS, 2S) [4 -(4-Chloro-phenyl)·butyl]-[7-(2-Jingmei 7 八. 甘土二窠窠基乙ethoxy)_bicyclo[2.2.1]heptan-2-yl ]-Dimethylammonium·Reverse 2S)[7-(9-Hydroxy-9H-fluoren-9-carbonyloxy)_bicyclo 2-ami 1 Igata Ganyi·2·1]g-based l·monomethyl -(4-phenyl-butyl)-ammonium; ί anti-〇S, 2SH7-(2R_cyclohexyl_2_hydroxy_2_phenyl_, ethylbicyclo[...]histyl dimethyl ( Heart phenyl _ butyl group; milk base &gt; anti-(1 S, 2S) dimethyl * (9-methyl. diphenyl fluorene _ yl) _ double ring [2.2.1] g _2 ]]_(4-phenyl·butyl)_money; canine milk anti-Os, 2S) 7-(2-carbyl-2,2·di-nonyl-2-phenyl-ethoxylated ring [2] 2 11庵? m ^ 职^基)-double coat LU.1]heptyl; kib dimethyl | phenoxyethyl),; anti-(IS, 2S) [3-(4-chloro-phenyl) )_propyl]-[7_(2·经一v 〇公'5心二-11尽吻-2·基-乙醯oxy)_bicyclo[22hept-2-yl]_dimethylammonium ; anti-(IS,2S)[3-(2-Gasyl)-propyl Η7·(2_Μ _22 diphen-2-yl-acetamidine Oxy))bicyclo[2·2 dimethyl-records and ° anti-(1S,2S)[3-(3-gas-phenyl)-propyl H7_(2_trans-base_2,2_di·嗔-phen-2-yl-ethyloxy)-bicyclo[2 21]hept-2-yl]-dimethyl-methanol; medicinal or pharmaceutically acceptable salt, solvate, N-oxide thereof Or the first 18. If the compound of claim 2 or 2 is 'in the form of a main or reverse-in-loop bridging configuration. 19. The compound of claim ί or 2, for use in therapy. A pharmaceutical composition comprising, as claimed in the above-mentioned, all-in-one 121575.doc 200848416 compound and a pharmaceutically acceptable carrier or excipient. 21 • as claimed in claim 20 A pharmaceutical composition which is in a form suitable for inhalation. 22. Use of a compound according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment or prevention of a venom of the genus. Read-in vivo disease or condition 23. For the use of item 22, wherein the disease or condition is a respiratory condition. 22:. For example: !: Use of item 22 wherein the disease or condition is the gastrointestinal tract 25. The use of claim 22, wherein the disease is a cardiovascular condition. 26. The use of claim 22, wherein the disease is a chronic obstructive pulmonary disease, a chronic branch... , asthma, chronic respiratory obstruction, pulmonary fibrosis, emphysema or allergic rhinitis. Forklift s 27. The use of claim 22 'where the disease or disease: large intestine, spastic colitis, Gastric duodenal ulcer, sputum, sputum, gastrointestinal convulsion Diverticulitis, urinary tract disorders associated with painful gastrointestinal smooth muscle spasm, including neurological urinary dysuria, nocturnal enuresis, bladder dysfunction, = incontinence associated with cystitis, urgency or frequent urination; 7 Feng, and total heart disease , such as the vagus nerve-induced sinus rhythm depression. &amp; 28. The use of claim 22, wherein the disease or condition is a sinus rhythm depression. ^ Induction 121575.doc -10- 200848416 VII, designated representative map : (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 121,575.doc