TWI304067B - Novel quinuclidine carbamate derivatives and medicinal compositions containing the same - Google Patents

Description

1304067 A7 B7 OBJECT DESCRIPTION OF THE INVENTION (The present invention relates to a novel method for the preparation of a quinuclidinic acid formic acid derivative having therapeutic use and a pharmaceutical composition containing the same. The novel structural formula according to the present invention has a strong long-term A long-lasting anti-toxic base agent. In particular, these compounds show a high affinity for the muscarinic M3 receptor. This muscarinic receptor subtype is present in the glands and smooth muscles, and the mediator's sensory nervous system is on the gland. Excitatory effects of body secretion and visceral smooth muscle contraction (Chapter 6, Cholinergic transmission, Η·Ρ·Rang et al., Pharmacology, Churchill Livingstone, New York, 1995). M3 antagonists can be used to treat diseases characterized by increased parasympathetic tone, excessive glandular secretion, or smooth muscle contraction (R M. Egien & SS Hegde, (1997), New Drug Prospects, i〇(8): 462-469 Such diseases include, for example, respiratory conditions such as chronic obstructive pulmonary disease (C〇PD), bronchitis, bronchial allergy, asthma, cough and rhinitis; urinary disorders such as urinary incontinence, Urine, neurogenic bladder or unstable bladder, bladder spasm and k-type cystitis, gastrointestinal disorders such as irritable bowel syndrome, spastic colitis, diverticulitis and peptic ulcer; and cardiovascular disorders such as vagus nerve-induced sinus Pulses (Chapter 7, muscarinic receptor agonists and antagonists, Goodman and Gilman V Pharmacological Foundations, 10th Edition, McIlroth Books, Inc., 2001, 2001). Compounds of the Invention It can be used alone or in combination with other drugs which are generally considered to be effective in treating such conditions. For example, it can be combined with a point 2 agonist, a steroid drug, an antiallergic drug, a phosphodiesterase IV inhibitor and/or a white three.埽D4 (LTD4) antagonists are administered for simultaneous, separate or sequential treatment of respiratory diseases. Compounds can be combined without 2_ agonist, steroid, anti-allergic paper & Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 1304067 A7 B7 V. INSTRUCTIONS (2) Drugs or phosphodiesterase IV inhibitors are used to treat respiratory diseases. Compounds of the relevant structural formula have been described for use in Patient as biliary antispasmodic and anti-shock test agent. For example in the patent application ΕΡ 747 · 355, allophanate described amine derivative represented by the following general formula

Wherein each symbol is defined as a ring of benzene or a pyridine ring, and the ring of (J) is a nitrogen-containing saturated heterocyclic ring which may have a substitution based on a nitrogen atom and cross-linking, and R1 is a phenyl group which may have a substituent. a cycloalkyl group having 3 to 8 carbon atoms or a cyclic group ' or a 5 or 6 membered nitrogen-containing heterocyclic group, X being a single bond or a methylene group, Y being a single bond 'carbonyl group, and a methylene group thereof The base or the formula d(0)r represents a base substitution, and 1 is an integer of 0-2. The structural properties of these compounds are distinct from those of the present invention, which often have a hydrogen-urethane-bonded nitrogen. Further, another patent application EP 8 〇 1.067 discloses a compound represented by the following formula

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1304067 A7 B7 V. Description of invention (3 where aryl, cycloalkyl, cycloalkenyl or heteroaryl X is a single bond or methylene , 1 is 0 or 1, and η is an integer of 1 or 2. These compounds are also different from the compounds claimed in the present invention because the nitrogen group of the urethane group is included in the cyclic structure. WO 01/04118 Describe a compound of the formula

Where Β is the basis of formula (1) or (ii):

A, (^), Rl, R2, R3, m, η, p, X-, Q, R8, R9 & R1 〇 are defined as the first item in the scope of the patent application. The present invention provides a novel compound which is a quinine base carbamate derivative having potent antagonistic activity at a muscarinic M3 receptor, and which has a chemical structural formula represented by the formula (1) or which comprises a salt of the formula (II) Pharmaceutically acceptable salts. Formula (I) represents a urethane of the general formula:

-9 - The paper is long-term applicable to China National Standard (CNS) A4 specification (210X 297 mm) 130^6^31867 Patent application Chinese manual replacement page (94 years 12 as. V. Invention description (4) $ ρ which can be quaternized to obtain a pharmaceutically acceptable salt of a urethane of the formula (I), in particular a salt of the formula (II)

(II) where:

R 1 Table 7F

Wherein R3 represents hydrogen or hydrazine+ or a linear or > low-carbon alkyl or amino group; R2 represents benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, hydrazine- 2-ylmethyl or thiophen-3-ylmethyl, or a linear or branched alkyl group having 3 to 8 carbon atoms, a linear or branched alkyl group having 3 to 8 carbon atoms, or 3 a cycloalkyl group of up to 6 carbon atoms;

The substitution of Mi or 2 and the bicyclic ring may include all possible asymmetric carbon configurations at the 2, (4) position; m is an integer from 0 to 8; 10- 1304067 A7 B7 5. Inventive Note (5) A represents -CH2 -, -CH = CR4-, -CR4 = CH-, -CO-, -0-, -S-, -S(O)-, -S02-, -NR4- or -CR4R5-group, where R4 and R5 Each represents a hydrogen atom, a linear or branched lower alkyl group, or R4 and R5 together form a cycloaliphatic ring; η is an integer from 0 to 4; Β represents a hydrogen atom, an alkoxy group, a cycloalkyl group, -COOR4 Or -OOCR4 wherein R4 is as defined above or cyano, fluorenyl, 5,6,7,8-tetrahydronaphthyl, biphenyl or a group of formula (1) or (ii)

Wherein Z represents Ο, N or S; R3 is as defined above; and R6, R7 and R8 each represent hydrogen or a halogen atom or a hydroxyl group, respectively, phenyl, -OR4, -SR4, -NR4R5, -NHCOR4, -CONR4R5, -CN , -N〇2, -COOR4 or -CF3 group or a straight or branched substituted or unsubstituted lower alkyl group; wherein R4 and each of 4 represent a hydrogen atom, a straight or branched low carbon tiger base, or R4 and R5 together form a cycloaliphatic ring; or R6 and R7 together form an aromatic, cycloaliphatic or heterocyclic ring; and 乂_ represents a pharmaceutically acceptable anion of a monovalent or polyvalent acid. The fourth ammonium compound of the present invention includes a compound represented by the formula (II), and the anion equivalent (X·) combines a positive charge of a nitrogen atom. 1 can be used for a variety of inorganic acid negative paper standards China National Standard (CNS) A4 specifications (210 X 297 mm) 1304067 A7 B7 V. Description of invention (6) ions such as chloride anion, bromine anion, cesium anion, sulfate , nitrate, phosphate, or organic acid anions such as acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate , methanesulfonate, and p-toluene cross-acid. X' is preferably an anion selected from the group consisting of a chloride anion, a bromine anion, an anthraquinone ion, a sulfate, a nitrate, an acetate, a cis-sebacate, an oxalate or a succinate. More preferably, τ is a chloride anion, a bromine anion, a trifluoroacetate, or a methanesulfonate. Unless otherwise specified, the lower alkyl and lower alkyl moieties described herein are straight or branched alkyl groups having from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms. Preferred lower alkyl and moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, second and third. The alkyl group having 3 to 8 carbon atoms as used herein, for example, the alkyl group present in the R 2 group includes n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, pentyl, hexyl, Heptyl and octyl. The optionally substituted lower alkyl group as used herein includes the aforementioned straight or branched alkyl group having 1 to 6 preferably 1 to 4 carbon atoms which may be unsubstituted or may be subjected to one or more at any position. Substituents such as 1, 2 or 3 substituents are substituted. When two or more substituents are present, the respective substituents may be the same or different. The substituent is typically a hydroxy or alkoxy group. The fluorenyl group having 3 to 8 carbon atoms as described herein, for example, the alkenyl group present in the R 2 group is a straight-chain or branched group such as a linear or branched propylene group, a butenyl group, a pentenyl group, a hexyl group, a gem group. Mercapto or octenyl. The double bond can be located at any position of the alkenyl group, for example, at the end of the terminal relative to the urethane group. The alkoxy group described herein, for example, is present in the B group, and the alkoxy group is typically a lower alkane-12 - the paper scale is suitable for @S家鲜(CNS) A4 specification (21GX 297 public I) 1304067 A7 B7 V. Invention It is indicated that the (7) oxy group, that is, the alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, is branched or linear. Preferred alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, second butoxy and tert-butoxy. Unless otherwise specified, the cycloalkyl and cycloaliphatic groups described herein typically contain from 3 to 8, and preferably from 3 to 6, carbon atoms. The cycloalkyl and cycloaliphatic ring having 3 to 6 carbon atoms includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. The aromatic ring described for R6 and R7 typically contains 5 to 4, preferably 5 to 1 carbon atoms. The aromatic group includes, for example, a cyclopentadienyl group, a phenyl group, and a naphthyl group. The heterocyclic ring of R6 and R7 is typically a 3 to 1 member ring such as 5 or 6 members which contains one or more heteroatoms selected from the group consisting of N, S and oxime. Typically there are 1, 2, 3 or 4 heteroatoms and preferably there are deuterium or 2 heteroatoms. The heterocyclic ring includes, for example, piperidinyl, pyrrolidinyl, azetidinyl, aziridine, piperylene, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl, imidazolidinyl, pyrazolinyl, Porphyrin, iso-porphyrinyl, pyridyl, pyridinyl, pyrimidinyl, haring, argon, isodecyl, fluorenyl, carbazolyl, fluorenyl, porphyrin , isoquinolyl, quinolyl, hydrazine, acridinyl, quinolinyl, quinazolinyl, porphyrin, acridinyl, quinuclidinyl, triazolyl, pyrazolyl, three Junki, tetrazolyl and far phenyl. The halogen atom here includes a fluorine, chlorine, bromine or iodine atom, typically a fluorine, chlorine or bromine atom. The compound of the present invention represented by the formula (1) and a salt thereof, for example, the salt represented by the formula (π) contain = one or more asymmetric carbons, including all possible stereoisomers. Both single constructs and mixture of isomers are within the scope of the invention.

Binding

13 - 1304067 A7 __ B7 V. INSTRUCTIONS (8) 杈 式 (I) urethanes are those in which R1 is phenyl, ρ-phene-2-ylmethyl, 4 phenyl or fluoren-2- The methyl group is an unsubstituted compound (ie, R3 is hydrogen). However, if R1 is substituted with an R3 group other than hydrogen, the substituent may be at the 2' 3 '4' 5 position or may be at the 6 position if R1 is a phenyl group. When R1 is phenyl, the substituent is preferably located at the 4 position of the ring. The substituent base 3 is preferably hydrogen, a halogen atom or a lower alkyl group, preferably hydrogen, fluorine, chlorine, methyl or ethyl and particularly preferably hydrogen, fluorine or methyl. The substituted R1 group includes, for example, halophenyl, halo-porphin-2-ylmethyl, halosulfonyl, halo-furan-2-ylmethyl, *alkyl)-phenyl, (Cm-alkane) - thiophen-2-ylmethyl, (Ci4 alkyl exeso or (Ci 4 alkyl)-furan-2-ylmethyl. Specific examples thereof include 'fluorophenyl, 'methylphenyl, 4 ·Chlorophenyl, 4·ethylphenyl, 3-methylphenyl, % fluorophenyl, chlorophenyl, 3-ethylphenyl, fluorophene-2-ylmethyl, fluoro-p-phene And fluorofuran·2-ylmethyl. The particularly preferred R1 group includes phenyl, 'fluorophenyl, 'methylphenyl, thiophen-2-ylmethyl, P-secenyl and bromomethyl. Preferred R2 groups include + group, p-sequenylmethyl, phenanthrylmethyl, furan-2-ylmethyl, phenethyl, pent-4-phenyl, pentyl, butyl, propyl or cyclo The NR1R2 group of the formula (I) includes the following groups: fluorenyl (phenyl); -N(fluorenyl)(4-fluorophenyl); -N(fluorenyl) (pair) Tolylphenyl); Ν (butyl) (phenyl); - fluorene (phenyl) (thiophen-2-ylmethyl); - fluorene (phenethyl) (phenyl); - pentyl) (phenyl), -Ν (pent-4- (phenyl); (phenyl) (thiophen-3-ylmethyl), - oxime (butyl) (thiophen-2-ylmethyl); - fluorene-purine, 2-ylmethyl; _Ν(furan-2-ylmethyl)bucephen-2-ylmethyl); Ν(propyl)(sulfonyl-2-ylmethyl), -oxime (cyclopentyl) (soul phen-2) -ylmethyl);(furan-2-ylmethyl)(phenyl) -14 - This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 1304^)^131867 Patent Application A7 B7 Chinese manual replacement page (December 94) V. Description of the invention (9) and -Ν-贰furan-2-ylmethyl. ρ is preferably 2. The substitution of the azabicyclo[2·2·2]octane is preferably at the 3-position. The substituted carbon atom may have a (R) or (s) configuration, preferably a (R) configuration. The following compounds of the general formula (I) are intended to illustrate, but not limit, the scope of the invention. Nonylphenylaminocarbamic acid 1-azabicyclo[2.2 2]octyl-3-(hypusyl ester decyl (4-fluorophenyl)carbamic acid 1-azabicyclo[2.2 2] xin_3_ (magic Base oxime (p-tolyl) carbamic acid 1 · azabicyclo[2 2 2] octyl_3_(11) fluorene: butylphenylaminocarbamate 1-azabicyclo[2·2·2] Oct-3-(R)-based phenyl thiophene-2-ylhydrazinocarbazate 氮 azabicyclo[2 2 2]octyl_3_(phanyl phenylethylphenylaminocarboxylic acid 1·nitrogen Heterobicyclo[2]2]xin_3_(phanyl 35 pentylphenylaminocarbamic acid 1_azabicyclo[2.2.2] xin_3_(foot) base 1 pent-4-enylphenylamino group 1-Azabicyclo[2 2 2]octyl-3^ phenylpyrimidin-3-ylmethylcarbazate formate 丨-azabicyclo[2·2·2]octyl_3_(曰幻基酯butyl Bismuthene-2-ylmethylaminocarbazide oxalate azabicyclo[222]octyl-3-yl ester oxime-pyridin-2-ylmethylcarbamic acid 1-azabicyclo[2.2 oxiran-2-yl Mercapto-2-violet-2-ylmethylaminocarboxylic acid / = [2.2.2] oct-3-(R) yl ester 虱 ice double * propyl propyl p-secen-2-ylmethylamino Formic acid ι_gas cone s basal vinegar with double %U.2.2] xin_3_(R) cyclopentyl p-secen-2-ylmethylcarbamic acid 1-azaindole $ gnach-2 base Amino-based decanoic acid 1-azaindole r 挪 衣 [2.2·2] 辛_3-(R) 酉 日 C - 吱 -2- -2-ylmethylphenyl amide phthalic acid 1-aza Bicyclo, L · 2 2] oct-3-(R) -15- ^ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm:) ------ 1304067 A7 ____ B7 ____ Five , invention description (1〇) acetal phenylphenylaminocarbamate 1-azabicyclo[2,2,1]hept-4-yl ester benzylphenylaminocarbamate 1-azabicyclo[2.2.2 An octyl-4-ester and a pharmaceutically acceptable salt thereof. The preferred salt of the formula (II) is a preferred definition of R1, R2, -NR1R2 and p as described above for the formula (1) and a fluorenylbicyclic ring. The substituent has the same position and configuration of the compound. Further, preferably B represents a hydrogen atom or a substituted or unsubstituted phenyl, pyrrolyl, thienyl or furyl group, or a biphenyl group, a fluorenyl group, 5, 6 , 7,8-tetrahydroindenyl or benzo[1,3]dioxoindolyl, especially substituted or unsubstituted phenyl or 4 phenyl, such as 2 - p-septenyl or 3 - π-septenyl , especially 2 - p thiophenyl. Thienyl, pyrrolyl or furyl may be unsubstituted or taken as R3 as defined above The substituent may be at the 2, 3, 4 or 5 position of the ring. The phenyl group may be unsubstituted or substituted with one, two or three groups (R6 to R8) which may be substituted at any position of the ring. Substituting for, for example, substitution with a base, for example, at position 2, 3 or 4. Preferred substituents R6, R7 and R8 each represent hydrogen or a halogen atom, respectively, or hydroxy, methyl, tert-butyl, -CH2OH, 3-hydroxypropyl, -OMe, -NMe2, -NHCOMe, -CONH2, - CN, -N02, -COOMe, or -CF3 groups, or R6 and R7 together form a 5- or 6-membered ring such as a phenyl ring or a thiazolyl ring. More preferably, R6, R7 and R8 represent hydrogen or a halogen atom or a thin group, a methyl group, a -CH2OH, -OMe, -NMe2, -NHCOMe, <ΟΝΗ2, -CN, -N02, -COOMe, or -CF3 group, particularly A hydrogen atom, a meridine or an _ atom, wherein the atom is preferably fluorine. Indicates that the substituted phenyl group of 8 is, for example, a tolyl group including o-, m- and p-tolyl, 3 • cyanophenyl-16 - the paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇x 297 public) PCT) 1304067 A7 _____ B7 V. Description of the invention (^ ' —, 2-, 3- and 4-hydroxyphenyl, 2-, 3- and 4-fluorophenyl and benzothiazolyl. β is particularly preferred as phenyl , 4-fluorophenyl or 3-hydroxyphenyl. Typical η = 0 or 1; m is an integer from 1 to 6 in particular i, 2 or 3; and a represents -CH2-, -CH=CH-, -CO -, -NMe-, -〇- or -s- group, especially -CH2-, -CH=CH- or -Ο-yl. Suitable examples of -(CH2)mA-(CH2)n- group include Base, ethyl, allylic, propyl, isopropyl, butyl, 4-methyl-3-pentyl, heptanoyl, ethyloxy, propyloxy , butyloxy, sulfonyl propyl, methylamino phenyl and 4 oxy butyl, preferably methylene, ethyl, propyl, n-propyl, heptyl Further, an ethyloxy group or a propyloxy group is preferred. The salt of the formula (II) is a compound in which a knee-based bicyclic ring is substituted with a nitrogen atom via a group selected from the group consisting of the following: 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 4-phenylene, 3-phenylpropyl, 3-[2-hydroxyphenoxy]propane '3-[4-Fluorophenoxy]propyl, 2-benzyloxyethyl, 3-pyrrol-1-ylpropyl, 2-thiophen-2-ylethyl, 3-thiophen-2-ylpropyl , 3-phenylaminopropyl ' 3-(methylphenylamino)propyl, 3-phenylsulfanylpropyl, 3-o-tolyloxypropyl, 3-(2,4,6 -trimethylphenoxy)propyl, 3-(2-tributyl-6-methylphenoxy)propyl 3-(biphenyl-4-yloxy)propyl, 3-(5,6 ,7,8-tetrahydronaphthalen-2-yloxy)-propyl' 3-(naphthalen-2-yloxy)propyl, 3-(indol-1-yloxy)propyl, 3-(2-gas Phenoxy)propyl 3-(2,4-difluorophenoxy)propyl, 3-(3-trifluoromethylphenoxy)propyl, 3-(3-cyanophenoxy)propyl, 3 -(4-cyanophenoxy)propyl, 3-(3-methoxyphenoxy)propyl, 3-(4-methoxyphenoxy)propyl, 3-(benzo[1,3]dioxo Wuqi-5-yloxy)propyl ' 3-(2-aminomethylphenyloxy)propyl, 3-(3-dimethylaminophenoxy)propyl, 3-(4-nitro Phenoxyl)propyl, 3-(3-nitrophenoxy)propyl, 3- -17 - This paper scale applies to China Household Standard (CNS) A4 Specification (210X297 Gongdong) 1304067 A7 ____B7 V. Description of Invention (12) (4-Ethylaminophenoxyphenoxy)propyl, 3-(3-methoxycarbonylphenoxy)propyl, 3-[4-(3-hydroxypropyl)phenoxy]propyl, 3-(2-hydroxymethylphenoxy)propyl, 3-(3-hydroxymethylphenoxy)propyl, 3-(4 -hydroxymethylphenoxy)propyl, 3-(2-hydroxyphenoxy)propyl, 3-(4-hydroxyphenoxy)propyl, 3-(3-hydroxyphenoxy)propyl, 'oxygen Benzyl-2-butyl, 3-(1-methyl-[1Η]-imidazol-2-ylsulfanyl)propyl, benzothiazol-2-yloxy)propyl, 3-decyloxypropyl , 6·(4-phenylbutoxy)hexyl, 'phenoxybutyl or 2-decyloxyethyl. Particularly preferred salts are those wherein the indenylbicyclic ring is based on a nitrogen atom via 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, phenethyl, 3-phenylpropyl, 3-( 3-Hydroxyphenoxy)propyl, 3-gas 4-fluorophenoxy)propyl, 3-pyridin-2-ylpropyl, 1-propylidene or fluorenyl-heptyl. The following general formula (II) salts are intended to illustrate but not to limit the scope of the invention. 3-(R)(benzylphenylaminomercaptooxy)-1-(3-phenylallyl)-dibenzylbicyclo[2.2.2] succinimide; bromide 1-allyl-3- (R) (benzylphenylaminomethionyloxy) indenylbicyclo[2.2.2] octane, >Smell 3-(R)(benzylphenylaminocarbazyloxy-μ-phenethyl _^Zongjibicyclo[2 2 2] octane; bromide 3-(R)(nonylphenylaminomethyl fluorenyloxy) thiophene 2 yl propyl bromobicyclo[2·2·2] octyl Alkane; bromide 3-(R)(nonylphenylaminocarbazolyloxy)_W3_phenylpropylbubumidylbicyclo[2·2·2]octane; bromide 3-(R)(benzyl Phenylaminomethylmercaptooxy)·phenoxyethyl)·indolylbicyclo[2.2.2]octane; bromide 3-(R)(butylphenylaminocarbamidooxyphenyl)晞propyl)·^腙基双-18 - This paper scale is applicable to China National Α4 specifications (2iGxNokonghuang)~一~ ---- 1304067

Cyclo [2_2,2]octane; bromide 1-mercaptopropyl '3)) (Germanyl phenylaminomethyl octyl octane; bromide fluorenylbicyclo[2.2.2] 3-(R)笨 基 胺 胺 胺 [ [ 2 [2·2·2] octane; bromide gas ethyl)-1-mercaptobicyclo 3-(R) (butylphenylaminomethyl fluorenyl) Oxygen)_〗·[ 3 base bicyclo [2.2.2] octyl; desert october propyl] propyl] hydrazine 3-(R) (butylphenylaminomethyl decyloxy)·ι·[3 Bicyclo[2.2.2]octane; desert oxy) propyl] hydrazine 3-(R)(butylphenylaminomethyl hydrazino-oxime-(a) 喽bicyclo[2.2_2] octyl; Bromide, 2-ylpropyl)]-kneepropyl)-1-indenylbicyclo-3-(R)(butylphenylaminocarbamimidyloxy)·ι_(3 •phenyl[2 · 2 · 2 ] 辛:) 3⁄4 ; sulphate 3-(R) (phenyl phenyl phenylmethylaminomethyl hydrazino. gan, n, hexathiophen-2-ylpropyl)-1-indenyl double ring [2.2.2] Octane; bromide% phenoxyethyl)·3 Fu (phenyl-4-phenenyl-2-ylmethylaminomethylthioxanthene-(3-indol-2-ylpropane) H-fluorenylbicyclo[2 2 2]xin; desert compound propyl _3_(R) (phenyl 4 phen-2-ylmethylaminomethyl aryloxy) small gland double Ring [2 · 2 · 2 ] octyl; bromide 3-(R) (stupyl ethyl phenylaminomethyl hydrazino) 4-(1 phenoxyethyl fluorenylbicyclo[2.2.2] octane Trifluoroacetate 1-heptyl-3-(R)(indol-4-alkenylaminocarbamoyloxy)nonylbicyclo[2·2·2]octane; trifluoroacetate 1- Mercaptopropyl-3-(R)(phenylthiophen-3-ylmethylaminomethionyloxy)-1·mercapto-19 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 Male t) 1304067 A7 ______B7____ V. Description of the invention (14) Bicyclo[2·2·2]octane; trifluoroacetate 3-(R)(phenylthiophen-3-ylmethylaminomethylcarbonyl) 1-(3-phen-2-ylpropyl)-1-indenylbicyclo[2.2.2]octane; bromide 1-(2-phenoxyethyl)-3-(R)(phenyl Thiophen-3-ylmethylaminomethionyloxy)-didecylbicyclo[2·2.2]octane; bromide 3-(R)(贰-phen-2-ylmethylaminomethionyloxy)-1 -(3-phenylpropyl)-didecylbicyclo[2·2·2]octane; bromide 3-(R)(贰-phen-2-ylmethylaminomethionyloxy)-1-(3) -Umimiphen-2-ylpropyl)-1-ylbicyclo[2·2·2]octane; bromide 1-mercapto-3-(R) (propyl propyl thiophene-2-yl) Methylamino group Oxy-oxy)-1-indenylbicyclo[2.2.2]octane; trifluoroacetate 3-(R)(cyclopentylthiophen-2-ylmethylaminocarbamimidyloxy)-1-(3- Phenylpropyl)-1-indenylbicyclo[2·2·2]octane; trifluoroacetate 3-(R)(furan-2-ylmethylphenylaminocarboxyloxy)_ΐ-( 3-phenylpropyl)-1-indenylbicyclo[2·2·2]octane; trifluoroacetate 1-allyl-3-(R)(di-furan-2-ylmethylamino) Mercaptooxy)-1-indolylbicyclo[2·2·2]octane; Trifluoroacetate The present invention also provides a process for the preparation of compounds of formula (1) and (11). The compound of the formula (I) can be produced by the method (a) shown in the following reaction scheme and described in detail in the experimental section. -20 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public dream) 1304067 A7 B7 V. Invention description (15)

In the formulae (I), (III) and (IV), R1, R2 and p are as defined above. The compound of formula (III) can be prepared from the corresponding second order amine according to standard method (b) as described in the references. /R1 ΗΝζ R2 Triphos — — —> Method (b) (V)

Commercially available amines of the general formula (V) can be synthesized according to standard methods. For example, an amine wherein R1 is thiophen-2-ylmethyl and R2 is as defined above is obtained by a reductive alkylation process. The corresponding aldehyde is treated with a corresponding first-stage amine to form an imine, and the imine is reduced with sodium borohydride to obtain a second-order amine. The urethane of formula (I) can be converted to a pharmaceutically acceptable salt by methods known in the art. The typical (I) urethane is treated with an inorganic or organic acid such as fumaric acid, tartaric acid, succinic acid or hydrochloric acid. The fourth ammonium derivative of the formula (II) can be produced by reacting an alkylating agent of the formula (VI) with a compound of the formula (1). In the formulae (I), (II) and (VI), R1, R2, A, B, X, n, m and ρ are defined before the mouth. -21 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1304 笫oQom867 Fuli application 蚩 Chinese manual replacement (heat miscellaneous 3 % correction A7 B7

V. Description of invention (W NC(CH2);

(CH2)n_A —(CH^vv (1)

Method, (¢) and (sentence (VI) /R1

0\/NC γ where 'w' in the formula (VI) denotes any suitable leaving group such as the thiol group as defined above. Preferably W represents an X group. This alkylation reaction can be carried out by two different experimental procedures (4) and (d), as explained below. Special method (d) provides a novel experimental method that allows the preparation of multiple compounds in parallel using solid phase extraction. If w represents a group other than X, the fourth ammonium salt of the formula (11) is produced by the method (4) or (4) by performing an exchange reaction according to a standard method using a predetermined anion χ_substituted anion W-. Methods (C) and (d) are described in the experimental section. Non-commercially available compounds can be prepared synthetically according to standard methods. For example, wherein (4) and Α=·0·, -S- or -NR4, wherein R4 is as defined above, the corresponding compound is via a corresponding aromatic derivative or "A phoenix conversion formula Y-(CH2)mx burning agent, wherein X It is obtained by reacting a halogen atom and ruthenium as a β atom or a ruthenium. In other examples, the compound of the general formula (W) is in the form of tens of thousands and tens of thousands; and the first method is obtained by a known method from the corresponding alcohol derivative of the formula (^): 297 PCT -22- 1304067 A7 B7 V. Description of invention (17) Cheng.

B-(CH2)nA-(CH2)m-OH (VII) The compound of formula (VI) can be: 4-hydroxy-1-azabicyclo[2.2.1]heptane, described in W0 93/15080 4-hydroxyl 1-azabicyclo[2.2.2]octane, described in Grob, CA et.al· Helv·

Chim. Acta (1958), 41, 1184-1190 3(R)-hydroxy-1-azabicyclo[2.2.2]octane or 3(S)-hydroxy-1-azabicyclo[2·2·2 ] Xin Shao, described in Ringdahl, R. Acta Pharm Suec (1979), 16, 281-283 and commercially available CU Chemical Industries. The structural formula of the prepared compound was confirmed by W-NMR and MS. NMR was recorded using a Varian 300 megahertz instrument and the chemical shift was expressed in parts per million (5) of the internal standard tetramethyl decane. The purity was determined by HPLC using a reversed phase chromatography on a Waters instrument and obtained values above 95%. Molecular ions were obtained from HP Instruments by electrospray ionization mass spectrometry. The HPLC-MS experiment was performed on a Gilson instrument equipped with a binary pump (Gilson Piston Pump 321); a vacuum degasser (Gilson 864) injector part collector (Gilson Liquid Processor) 215); two injection modes including analysis and preparation (Gilson 819) valve (Gilson valve 7000); 1/1000 shunt (Acurate manufactured by LC packing company); supplementary pump (Gilson) 307); Diode Array Detector (Gilson 170) and MS Detector (Thermoquest Finnigan aQa, quadrupole mass spectrometer with ES APCI free mode). The HPLC-MS instrument was controlled by an IBM personal computer. -23 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 B7 V. INSTRUCTIONS (18 Methods (a) Example 54 - butyl phenyl phenylcarbamate _ aza bicyclo [222] Preparation of oct-3-(11)-ester. 0.65 g (28.50 mmol) of sodium was added to 7 ml of anhydrous toluene. The suspension was refluxed with vigorous stirring. When all the sodium was melted, 3.6 g was added. (28.3 〇 mmol) (R)-3-Hydroxy-1-azabicyclo[2.2.2]octane, stirring was continued for 2 hours, at which time all of the nanoparticles were reacted to form an alkoxide. Then 6 〇〇 was added. The gram (28.303⁄4 mol) phenylbutylaminomethyl hydrazine gas was dissolved in 3 ml of toluene. The mixture was refluxed for 1 hour, then the reaction was stirred at room temperature overnight. The suspension was filtered and the filtrate was evaporated. The mixture was stirred for a few minutes, the suspension was filtered, and the filtrate was concentrated in vacuo to afford 718 g of brown oil. The product was purified by column chromatography (EtOAc, chloroform/ethanol/ammonium 14:8:1). Millol) (22%) pure product, the structure was confirmed by lH-NMR. 300MHz, CDC13: <5 0,9 (m,3H),1,3 (m,4H) 1,5 (m,4H),1,9 (s,1H),2,7 (m,5H),3,2 (m,1H),3,7 (m,2H),4,7 (m , 1H), 7,2-7,4 (m,5H); MS [M+l]+: 303. Example 150 _cyclopentylthiophene-2-ylmethylcarbamic acid diazabicyclo[2 ·2·2] Preparation of octyl-(R)-based vinegar 0.57 g (24.59 mmol) of sodium was added to 7 ml of anhydrous toluene. The suspension was refluxed with vigorous stirring. When all the sodium was melted, 311 g was added. (24 42 mmol) (R)-3-hydroxy-1-azabicyclo[2·2·2]octane and stirred for 2 hours, at which time sodium has reacted to form an alkoxide. Then slowly add 4.96 g. (2〇35 mmol) cyclopentylthiophen-2-ylmethylaminopyridinium chloride was dissolved in 3 mL of toluene. The mixture was refluxed for 5 hours, then the reaction was stirred at room temperature overnight. 1304067 A7 ______B7 _ V. Description of the invention (19) Filtration and washing of the filtrate with water. The organic layer was extracted with 20% hydrochloric acid, the aqueous layer was basified with 8N sodium hydroxide and extracted with ethyl acetate. Dehydration and evaporation of sodium anhydrate. Obtained oil (4.50 g) by column chromatography (Jumin, chloroform/ethanol/ammonia 2 25:8:1) Obtained 2.25 g (6.73 mmol) (33%) of pure product. The structure was confirmed by 1H-NMR. 300 MHz, (DMSO-d6): 5 l, 2 (M, 40 (m, 1H) ), 1, 45-1, 72 (m, 11H), 1, 89 (bs, 1H), 2, 45-2, 62 (m, 5H), 3, 03-3, 10 (m, 1H), 4,22 (Bs,1H),4,50-4,63 (m,3H),6,93-6,99 (m,2H),7,38 (m, 1H); MS [M+l] +: 335 〇 Example 159 - Preparation of hydrazinyl hydroxy-amino-bicyclo[221]hept-4-yl ester. Under a nitrogen atmosphere in a two-necked flask, 3 ml of THF and 150 mg (1.33 mmol) of 4-hydroxy-1-azabicyclo[2·2·1]heptane were placed. The suspension was cooled to -60 ° C and 7 mL (1.46 mmol) of LDA was added dropwise. After the addition, the temperature was raised to 0 ° C and maintained for 2 hours. 295 mg (1·20 mmol) of nonylphenylaminocarbamidine in 2 ml of thf was added over 30 minutes. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 h. The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with dichloromethane and water. The organic layer was extracted with 2% aqueous hydrochloric acid. The organic layer was dehydrated and evaporated with sodium sulfate anhydrate. The oil obtained (162 mg) was purified by HPLC-MS to yield 4.86 g (0.015 mmol) of 1.3% of pure product as the formate. The structure was confirmed by 1H-NMR. 300MHz, (DMSO-D6): δ 1,86 (m, 4Η), 2,65 (s, 2Η), 2,77 (bs, 2H), 3,03 (bs, 2H), 4,84 (s ,2H),7,14-7,32 (m,10H),8,19 (s, ___ - 25 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 public) 1304067 A7 B7 , invention description (20 1H); MS [M-HCOO] +: 323. Method (b)

Aminomethine of the general formula (III) is prepared according to the procedure described in the following references: M. Saraswati et al., Drug Development Research (1994), 31, 142-146; GM·Shutske et al., Journal of Heterocyclic Chemistry (1990), 27, 1617; GB 1246606; US 2762796. Example 1-1 - Preparation of cyanophenylaminocarbazide. 6.72 g (45 mmol) of butylphenylamine in 5 ml of methylene chloride was cooled to 10 ° (: solution was slowly added with stirring 6.67 g (22.5 mmol) of triphosgene in 40 ml of methylene The reaction was allowed to continue at room temperature for 27 h. The solvent was evaporated and the residue was purified eluted with EtOAc EtOAc EtOAc (EtOAc) CDCh;): 5 0.9 (m,3H),1,3 (m,2H),1,6 (m,2H),3,7 (m,2H),7,2-7,4 (m, 5H Example 1-2 - Preparation of cyclopentyl sulfenophen-2-ylmethylaminopyridinium chloride. 5.0 g (27.58 mmol) of cyclopentylthiophen-2-ylmethylamine in 40 ml Methyl chloride was cooled to a solution of 10 ° C to slowly add 4.09 g (13.79 mmol) of triphosgene to 35 ml of methylene chloride. The reaction was allowed to continue at room temperature for 64 hours, refluxed for 4 hours and again in the chamber. After stirring for 25 hours, the solvent was removed by evaporation and the residue was purified eluting with EtOAc EtOAc. m,8H),4,2 (bs,1H),4,5 (m,2H),6,8 -7,3 (m,3H). Method (c) Example 146 - (R)-3-(anthracene-thiophen-2-ylmethylaminomethionyloxy)-1-(3-4 -26 - This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm) 1304067 A7 ___— B7 V. Description of invention (21) phen-2-ylpropyl)-1-glycosylbicyclo[2.2.2 Preparation of octane, bromide. 0.54 g (1.5 mmol) of oxenophen-2-ylmethylcarbamic acid-i-azabicyclo[2.2.2]oct-3-(11)-ester, 7.5 ml of tetrahydrofuran and 46.46 g (2.25 mmol) of 2-(3-bromopropyl)thiophene were mixed. The solution was refluxed for 4 hours and allowed to stir at room temperature for 1 16 hours. Add ether and suspension to stir 3 After a few minutes, the solvent was extracted and a larger amount of ether was added. This procedure was repeated several times to remove the alkylating agent. The final suspension was filtered and the residue was dehydrated in a vacuum oven. The yield was 0. 69 g (1,22 m Mohr) (81%). iH-NMRCDMSO-dJ: 1,78·2,1〇(m,6Η), 2,34 (bs,1Η), 2,82 (m,2Η),3,21- 3,46 (m,7Η),3,89 (m,lH),4,54(m,4H),5,06(m,lH),6,95-7,01(m,4H),7 ,07-7,11 (m,2H),7,38-7,49 (m,3H); MS [M -Br]+: 487; Melting point: 143 〇C 0 Method (d) Example 133 - 1-heptyl-3-(R)(phenylthiophen-3-ylmethylaminocarbamimidyloxy)-1- Preparation of fluorenylbicyclo[2.2.2]octane; trifluoroacetate salt. 30 mg (0.08 mmol) of phenyl-porphin-3-ylmethylaminocarbazide-1-azabicyclo[2·2·2]oct-3-(R) ester was dissolved in 1 ml of OMSO. To this solution was added 75 mg (0.40 mmol) of heptyl bromide. After stirring overnight at room temperature, the mixture was purified by solid phase extraction using a cation exchange Mega Bond Elut cassette, and the cassette was conditioned at pH = 7.5 using 0.1 Torr sodium dihydrogen phosphate buffer. The reaction mixture was applied to the carmine, first washed with 2 ml of DMSO and then washed three times with 5 ml of acetonitrile to wash all starting materials. The derivative was eluted with 5 ml of 0·03 M TFA solution in acetonitrile: gas (2:1). This solution was neutralized with 300 mg of poly(4-vinylpyridine), filtered and evaporated to dryness. -27 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1304067

The rate is 12 grams (34%) of the title compound. iH-NMR (D]vis〇-d6): 5 0 88 (m,3H),1,28 (m,8H),1,60-2,19 (m,7H),3,00-3,41 (m, 7H), 3.83 (m, lH), 4.88 (s, 2H), 5.99 (m, lH), 7.01 (m, lH), 7, 21-7'39 (m, 6H), 7,49 -7,52 (m,1H); MS [M-CF3COO]+: 441. Also included within the scope of the invention are pharmaceutical compositions comprising at least one quinuclidine derivative of the formula (1) or (II) as an active ingredient in combination with a pharmaceutically acceptable carrier or diluent. Preferred compositions are made to be suitable for oral administration. The pharmaceutically acceptable carrier or diluent is mixed with the active compound to form a composition of the present invention. A pharmaceutically acceptable carrier or diluent is known, and the excipients actually employed will be determined depending on factors such as the intended method of administration of the composition. The compositions of the invention are preferably suitable for oral administration. In this embodiment, the composition for oral administration may be in the form of a keying agent, a film-coated tablet, a liquid inhalant, a powder inhaler, and an inhalation aerosol; all of which contain one or more compounds of the present invention; such preparations may be utilized by the art world It is prepared by known methods. The diluents which can be used in the preparation of the compositions include liquid and solid diluents which are compatible with the active ingredient, if desired, in the presence of a coloring or flavoring agent. The lozenge or film coat is conveniently contained in an amount of from 0.1 mg to 500 mg, preferably from 0.5 to 2 mg. The inhalant composition contains from i micrograms to 1, micrograms, preferably from 1 to 800 micrograms of active ingredient. For human therapy, the dose of the compound of formula (1) or (π) will depend on the intended therapeutic effect and duration; adult doses are usually from 0.53⁄4 grams to 3 003⁄4 grams per tablet and from 1 microgram to 8 micrograms per day. Inhaler composition. The compound of the present invention or the pharmaceutical composition containing the same can be combined without the paper size of 2 -28 - j. Applicable to the Chinese National Standard (CNS) A4 specification (210 X 29 Ϋ mm) 1304067 A7 B7 V. Invention Description (23) The agents, steroids, antiallergic agents and/or phosphodiesterase IV inhibitors are used simultaneously, separately or sequentially for the treatment of respiratory diseases. Pharmacological effects The following examples demonstrate that the compounds of the invention have excellent pharmacological activities. The results of obtaining human muscarinic receptor binding and guinea pig bronchospasm test are as follows. Human muscarinic receptor research. The [3H]-NMS binding to human muscarinic receptor system was carried out as described by Waelbroek et al. (1990), Molecular Pharmacology, 38: 267-273. The assay was performed at 25 °C. A cell membrane preparation of a Chinese hamster ovary K1 cell (CHO) stably transfected with a human muscarinic M3 receptor gene was used. For the determination of IC5G, the membrane preparation was suspended in DPBS to a final concentration of 89 μg/ml for the M3 subtype. The membrane suspension was incubated with the gasification compound for 60 minutes. After the incubation, the membrane fraction was separated by filtration and assayed for binding radioactivity. Non-specific binding was determined by the addition of 1 (Τ4 a atropine). At least six concentrations were assayed repeatedly to generate individual displacement curves. The results obtained by the inventors (Table 1) show that the compounds of the invention are muscarinic M3 receptors. Preferably, the human muscarinic receptor has a high affinity. -29 - The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 B7 V. Description of the invention (24) Table 1 Example number combination To receptor M3 (IC5〇nM) Atropine 3.2 Ipratropium 1 5.0 5 11.1 6 18.0 31 8.0 32 8.0 58 8.0 79 14.0 82 4.5 90 9.2 91 6.8 92 11.5 104 19.0 126 8.6 136 9.0 142 17.8 146 14.4 153 6.0 156 18 -30 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067

Preferably, the compounds of the invention have an iC5G £nMi value for the M3 receptor of less than 35, preferably less than 25, 20 or 15 and more preferably less than 1 Torr. The guinea pig bronchospasm test was carried out according to H. Konzett and F. R6ssler (1940), Arch. Exp Path. Pharmacol. 195, 71-74. The aqueous solution of the agent to be tested was aspirated and inhaled by an anesthetized and artificially ventilated male guinea pig (Dunkin-Hartley). The response of the bronchi to intravenous choline was measured before and after administration, and the change in lung resistance at several time points was expressed as a percentage of bronchial fistula inhibition. The compounds of the present invention exhibit bronchodilator activity with high strength and long-term action time. From the foregoing results, those skilled in the art will readily appreciate that the compounds of the present invention have excellent antimuscarinic activity (M3) and are therefore useful in the treatment of diseases involving the muscarinic %3 receptor, including respiratory diseases such as chronic obstructive pulmonary disease, bronchi. Inflammation, planting * W, bronchial allergy and rhinitis; urinary diseases such as urinary incontinence, frequent urination, neurogenic bladder, nocturia, unstable bladder, bladder spasm and chronic cystitis; gastrointestinal diseases such as irritable bowel syndrome, sputum Crohn's colitis, vaginitis and peptic ulcer; and cardiovascular disorders such as vagus nerve-induced Bao Fu Xumai. For example, the compounds of the present invention are useful for the treatment of respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; urological diseases such as urinary incontinence, (neuropathic penile urinary), neurogenic bladder, nocturia, unstable bladder , bladder spasm and chronic cystitis; and gastrointestinal diseases such as irritable bowel syndrome, spastic colitis and diverticulitis. The present invention further provides a compound of the formula (1) or (π) or a pharmaceutical acceptable composition comprising the formula (1) or (i)-31 - 1304067 A7 _____ B7_____ 5. The invention (26) is for treating a human or animal body The method 'is especially used to treat respiratory, urinary or gastrointestinal diseases. The invention further provides the use of a pharmaceutical composition of formula (1) or (II) or a pharmaceutical composition comprising a compound of formula (1) or (II) for the manufacture of a medicament for the treatment of respiratory, urinary or gastrointestinal disorders. Further, a compound of the formula (I) or (11) and a pharmaceutical composition comprising the compound of the formula (I) or (11) can be used for a method for treating respiratory, urinary or gastrointestinal diseases. The method comprises a human or a human in need of such treatment or An animal subject is administered an effective amount of a compound of formula (I) or (11) or a pharmaceutical composition comprising a compound of formula (I) or (11). Further, the compound of the formula (I) and the pharmaceutical composition comprising the compound of the formula (I) can be used in combination with other drugs which are effective for treating such diseases. For example, a combination of 2 agonists, steroids, antiallergic agents, phosphodiesterase I V inhibitors and/or leukotriene D4 (LTD4) inhibitors are used for simultaneous, separate or sequential treatment of respiratory diseases. The invention therefore further provides a combination product comprising (i) a compound according to the invention; and (ii) another compound effective for treating a respiratory, urinary or gastrointestinal disease or condition for simultaneous, separate or sequential use. Compounds (ii) which are effective for the treatment of respiratory, urinary or gastrointestinal diseases or conditions, may be yS2 agonists, steroids, antiallergic agents, phosphodiesterase IV inhibitors and/or leukotriene D4 (LTD4) antagonists, The product is for simultaneous, separate or sequential use in the treatment of respiratory diseases. In addition, compound (ii) may be a non- 2 agonist, steroid, anti-allergic and/or citrate diesterase IV inhibitor, and -32 - this paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm > 1304067 V. INSTRUCTIONS (27 A7 B7 for simultaneous, separate or sequential treatment of respiratory diseases. This January will be further illustrated by the following examples. The examples are for illustrative purposes only and are not limiting. Example 1 Section 1 phenylphenylcarbamic acid i-azabicyclo[2·22]octyl j(8) benzyl ester The title compound was synthesized according to Method a. The final step yield was 1000 mg 18 / 〇H*NMR (CDC13) : δ 1,3-1,7 (m, 4H), 1,9 (s, 1H), 2,5- 2'8 (m,5H),3,2 (m,1H),4,8 ( m,1H),4,9 (s,2H), 7,l-7,4 (m, 10H); MS [M+l]'· 337. Example 2 3-(R)(nonylphenylamine) Methyl fluorenyloxy)·1βmethyl 4·indenylbicyclo[2.22]octane, trifluoroacetate salt: The more compound was synthesized according to method d. The final step yield was 2 〇 mg ' 34%. h-NMR (DMSO-d6): 5 1,54-1,90 (m,4H), 2,17 (s, 1H), 2.95 (s,3H), 3.22-3.52 (m,5H), 3.84 (m, 1H), 4.92 (s, 2H), 4, 99 (m, 1H), 7, 12-7, 37 (m, 10H); MS [M-CF3COO] + : 351. Example 3 3-(R)( <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;丨8 mg, 25% 〇MS [M-CF3COO] + : 419. Example 4 3-(R)(indolyl-phenylaminomethylmercaptooxy)-1-(3-phenoxypropyl)_丨- Mercaptobicyclo[2·2·2]octane; Trifluoroacetate ____ - 33 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210χ 297 mm) 1304067 A7 ___ B7___ V. Description of invention (28 The title compound was synthesized according to Method d. The final step yield was 21 mg, 26%. i-NMR (DMSO-d6): 5 l, 56-l, 9i (m, 4H), 2, 11-2, 20 (m,3H),3,12 (m,1H),3,34-3,51 O,6H),3,86 (m,1H),4,06 (m,2H),4,93 ( s,2H),5,02 (m,1H),6,97 (m,3H),7,20-7,38 (m,12H); MS [M-CF3COO]+: 471 0 Example 5 3- (R)(Germanylaminomethylglycosyloxy)-1-(3-tallowylpropyl)-1-kentylbicyclo[2·2·2]octane; bromide title compound The system was synthesized according to method c. The final step yield was 220 mg, 70%. i-NMR (DMSO-d6): 5 1,55-1,92 (m,4Η), 2,21 (s, 1H), 3,15 (m,1H),3,34-3,50 (m ,5H),3,90 (m,1H),4,1 (m, 2H),4,02 (s,2H),5,05 (m,1H),6,49 (m,1H),6 , 85-6,90 (d, 1H), 7,20-7,59 (m,12H),7,59-7,61 (m,2H); MS [M-Br]+:453: melting point 129 °C β Example 6 1-Allyl-3-(R)(nonylphenylaminocarbazyloxyindenylbicyclo[2.2.2] octane, brook compound title compound was synthesized according to method c. Final step Yield 230 mg, 85%. i-NMR (DMSO-d6): 5 1,58-1,91 (m, 4H), 2,20 (s, 1H), 3,10 (m,1H), 3,27-3,41 (m,4H),3,79-3,90 (m,3H),4,92 (s,2H),5,03 (m,1H),5,61 (m, 2H), 5, 98 (m, 1H), 7, 20-7, 38 (m, 10); MS [M-Br], 377; melting point: 7 〇 ° C. Example 7 3-(R)(芊Phenylaminomethylmercaptooxyethyl)-1-indenylbicyclo-34 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 ____ B7 V. Description of invention (29 [2.2.2] octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 12 mg '19%. MS [M-CF3COO]+: 381. Example 8 3-(R)(T-phenylphenylaminocarbamidooxy)-1-isopropyl-1-indenylbicyclo[2.2.2]octane, trifluoro The title compound of the acetate was synthesized according to Method d. The yield of the final step was 17 mg '26%. iNMR (DMSO-d6): 5 1,24 (m, 6H), 1,64-1,89 (m, 4H) , 2,20 (s,1H),2,78 (m,1H),3,23-3,32 (m,4H),3,50 (m, 1H),3,76 (m,1H), 4,92 (s, 2H), 5,06 (m,1H), 7,20-7,38 (m, l〇H); MS [M-CF3COO]+: 379. Example 9 Phenylamino group甲 基 oxy)-1-propyl-1-tylbicyclo[2.2.2] zeozone; trifluoroacetate title compound was synthesized according to method d. The final step yield was 16 mg, 25%. </ RTI> <RTIgt; 2,99-3,14 (m,3H),3,26-3,40 (m,4H),3,83 (m,1H),4,92 (s,2H),5,01 (m, 1H), 7, 20-7, 37 (m, 10H); MS [M-CF3COO]+: 379. Example 10-Phenylaminomethylglycosyloxy)-1-(3-cyanopropyl)-1-indenylbicyclo[2·2·2]octane; trifluoroacetate title compound was synthesized according to method d . The final step yield is 13 mg, 19% 〇lH-NMR (DMSO-d6): 5 1,67_2, 07 (m, 6H), 2,19 (s, -35 - This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) 1304067 A7 B7 V. Description of invention (3〇) 1H), 2,60 (m, 2H), 3,07 (m, 1H), 3, 21_3, 48 (m, 6H),3,85 (m, 1H),4,92 (s,2H),5,01 (m,1H),7,20-7,37 (m,10); MS [M-CF3COO]+ : 404 〇 Example 11 3-(11)(+Phenylaminomethylglycosyloxy)-1-cyclopropylmethyl-1 -fluorenylbicyclo[2.2.2] Octane, trifluoroacetate title compound It is synthesized according to method d. The final step yield was 9 mg, 14% ° MS [M-CF3COO] +; 391 ° Example 12 3-(R)(benzylphenylaminocarbazinyloxy)-1-(2-ethoxyethyl) ) 丨 腙 腙 双 双 [2.2.2] octyl, trifluoroacetate title compound was synthesized according to method d. The final step yield was 22 mg, 32%. iH-NMR (DMSO-d6): 5 1,12 (m,3H), 1,58-1,90 (m, 4H), 2,19 (s,1H),3,12-3,15 (m ,1H),3,28-3,53 (m,8H),3,75 (m,2H),3,90 (m,1H),4,91 (s,2H),5,02 (m, 1H), 7, 20-7, 37 (m, 10H); MS [M-CF3COO]+: 409. Example 13 3-(R)(nonylphenylaminomethionyloxy)-1-(4-ethoxycarbonylbutyl)-didecylbicyclo[2.2.2]octane; trifluoroacetate title compound Method d synthesis. The final step yield was 14 mg, 18%. iH-NMR (DMSO-d6): 5 1,19 (m, 3H), 1,5 (M, 67 (m, 4H), 1,85-1,88 (m, 2H), 2,18 (s ,1H),2,38 (m,2H),3,99 (m,1H),3,16·3,42 (m,8H),3,82 (m,1H),4,06 (m, 2H),4,92 (s, 2H),5,02 (m,1H),7,19-7,37 (m,10H); MS [M-CF3COO]+: -36 - This paper size applies to China National Standard (CNS) A4 Specification (210 x 297 mm) 1304067 A7 B7

V. INSTRUCTIONS INSTRUCTION (31) 465 ° Example 14 3-(R)(^-Phenylaminocarbamoyloxy)-1-(4-phenylbutyl)-1 -indolylbicyclo[2·2· 2] 辛坑; trifluoroacetate title compound was synthesized according to method d. The final step yield was 14 mg' 18%. tNMR (DMSO-d6): (5 1,57_1,65 (m,6H), 1,88 (m, 2H), 2,18 (s,1H), 2,63 (m, 2H), 3,00 (m,1H),3,18-3,42 (m, 6H),3,79-3,86 (m,1H),4,94 (s,2H),5,00 (m,1H), 7,18-7,37 (m,15H); MS [M-CF3COO]+: 469 0 Example 1 5 3-(R)(nonylphenylaminomethionyloxy)-1-[3·( 4-fluorophenoxy)propyl]-1-indenylbicyclo[2·2.2]octane, trifluoroacetic acid salt The title compound was synthesized according to method d. The final step yield was 21 mg, 25%. W-NMR ( DMSO-d6): 5 1,55-1,91 (m,4H),2,10-2,20 (m,3H),3,10 (m,1H),3,28-3,50 (m ,6H),3,88 (m,1H),4,02 (m,2H),4,93(s,2H),5,02(m,lH),6,95-7,12(m, 2H),7,12-7,38 (m,12H); MS [M-CF3COO]+: 489 〇Example 16 3-(R)(nonylphenylaminocarbazyloxy)-1-(3) -Hydroxypropyl)-1-indenylbicyclo[2·2·2]octane, the title compound of the trifluoroacetic acid salt was synthesized according to procedure Cl. The final step yield was 12 mg, 18%. iH-NMR (DMSO- D6): 6 1,54-1,88 (m, 6H), 2,18 (s, 1H), 3,09 (m,1H),3,23-3,49 (m,8H),3, 85 (m, 1H), 4,84 (m, OH), 4,92 (s,2H),5,02 (m,1H),7,19-7,37 (m,10H); MS [Μ- -37 - This paper scale applies to Chinese National Standard (CNS) Α4 Specifications (210 x 297 mm) 1304067 A7 ___ B7 V. Inventive Note (32) CF3COO]+: 395. Example 1 7 N(4·Ethyloxybutyl)-3-(R)(nonylphenylamino) Mercaptooxy)-1-indenylbicyclo[2·2·2]octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 9 mg, 12%. iH-NMR (DMSO- D6): 5 1,4(M,70 (m,5H),1,81-1,91 (m,3H),2,〇2 (m,3H),2,19 (s,1H),3 ,03 (m,1H),3,19 (m, 2H),3,26-3,46 (m,4H),3,80-3,84 (m,1H),4,04 (m,2H ), 4,92 (s, 2H), 5, 〇l-5, 〇2 (m, 1H), 7, 19-7, 37 (m, 10H); MS [M-CF3COO]+: 451. Example 18 3-(R)(;Phenylphenylaminocarbamimidyloxy)4-(4-oxy-4-pyrephen-2-ylbutyl)·1-indenylbicyclo[2.2,2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 16 mg '19%. i-NMR (DMSO-d6): 5 1,55-1,69 (m,2H), 1,87-2,〇5 (m,4H),2,19 (s,1H),3,09 ( m,3H),3,22 (m,2H),3,29-3,46 (m,4H),3,88 (m,1H),4,93 (S,2H),5,02 (m , 1H), 7, 19-7, 38 (m, 11H), 7, 98-8, 06 (m, 2H); MS [M-CF3COO]+: 489. Example 19 3-(R)(^-Phenylaminocarbamoyloxyhydroxyphenoxy)propylsulfonylbicyclo[2.2.2]octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 丨7 mg '21%. ^-NMR (DMSO-d6): 5 1,57-1,68 (m,2H), 1,90 (m, 2H), 2,08-2,19 (m,3H),3,11 (m ,1H),3,28-3,50 (m,6H),3,88 -38 - I paper size national standard for financial institutions (CNS) A4 specifications (torn tears) 1304067 A7 _ B7____ V. Description of invention (33)

(〇1,1H),3,97 (m,2H),4,93 (s,2H),5,02 (m,1H),6,33-6,40 (m,3H),7,04 (m,1H),7,20-7,38 (m,10H),9,5 (s,OH); MS

[M-CF3COO]+: 487 〇 Example 20 3-(R)(nonylphenylaminocarbenyloxy)-1-heptyl-1-indenylbicyclo[2·2·2]octane; The fluoroacetate title compound was synthesized according to Method d. The final step yield was 17 grams, 23%. j-NMR (DMSO-d6): 5 0.88 (m, 3H), 1,28 (m,8H), 1,62 (m,4H), 1,85-1,88 (m,2H),2, 18 (s,1H),3,02 (m,1H), 3,15 (m,2H), 3,26-3,40 (m,4H),3,83 (m,1H),4,92 (s, 2H), 5, 〇l (m, 1H), 7, 20-7, 37 (m, 10H); MS [M-CF3COO]+: 435. Example 21 1-(2-Mercaptooxyethyl)-3-(R)(nonylphenylaminocarbazyloxy)-1-indenylbicyclo[2·2·2]octane; trifluoroacetic acid The salt title compound was synthesized according to method d. The final step yield was 20 mg, 25%. tNMR _SO-d6): 5 1,54-1,94 (m,4H),2,20 (s, 1H),3,17 (m,1H),3,28-3,55 (m,6H) ,3,85 (m,2H),9,92-3,99 (m,1H),4,53 (s,2H),4,91 (s,2H),5,02 (m,1H), 7,18-7,40 (m,15H); MS [M-CF3COO]+: 471. Example 22 Alkyl-(4-fluorophenyl)carbamic acid guanidine-azabicyclo[2 2 2]oct-3-(11)-yl ester The title compound was synthesized according to Method a. The final step yield was 111 mg, 13%. [H-NMR (DMSO-d6): 5 iw (m, 4H), 181 (s, 1H), 2, 42-2, 57 (m, 5H), 2, 99-3, 07 (m, lH ), 4,63 (m, 1H), 4,84 • 39 -

1304067 A7 B7 V. INSTRUCTIONS (34) (s, 2H), 7, 10-7, 32 (m, 9H); MS [M+1]: 355 〇 Example 23 1-allyl-3-(R [Benzyl-(4-fluorophenyl)aminocarbamidooxy]-1-indenylbicyclo[2·2·2]octane; the title compound of the trifluoroacetic acid salt was synthesized according to the procedure d. The final step yield is 1 mg, 23% 〇MS [M-CF3COO]+: 395 0 Example 24 3-(R)[Benzyl-(4-fluorophenyl)aminocarbamoyloxy]-1- (3-Phenylpropyl)-1-indenylbicyclo[2.2.2]octane; the title compound of the trifluoroacetate salt was synthesized according to Method d. The final step yield was 13 mg, 25%. MS [M-CF3COO] V473 0 Example 25 Benzyl-p-tolylamidocarboxylic acid 1-azabicyclo[2·2·2]oct-3-(R)-yl ester The title compound was synthesized according to Method a. The final step yield was 1 〇 70 mg, 11%. iH-NMR (DMSO-d6): 5 1,18-1,30 (m,2H), 1,45-1,55 (m,2H),1,83 (s,lH),2,25(s ,3H),2,43-2,59 (m,5H),3,01-3,10 (m,1H),4,64 (m,1H),4,85 (s,2H),7, 12-7,34 (m,9H); MS [M+l]+: 351. Example 26 1-allyl-3-(R)(benzyl-p-tolyl-aminocarbamidooxy)-fluorenyl-indenylbicyclo[2.2.2]octane; trifluoroacetate title compound Method d synthesis. The final step yield is 9 mg, 19% 〇 MS [M-CF3COO] +·· 39 b Example 27 -40 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067

3-(R)(fluorenyl-p-tolyl-aminomethylmercaptooxyl-(3-phenylpropyl)-1-fluorenylbis%[2·2·2]octane; trifluoroacetate The title compound was synthesized according to Method d. The yield of the final step was 13 mg &apos; 25%. MS [M-CF3COO]+: 469. Example 28 3-(R)(nonylphenylaminocarbazinyloxy M-[ 2-(2-methoxyethoxy)ethyl b 1-month-based bis-cyclo[2·2·2]octane; bromide title compound is synthesized according to method c-take, ry township is rarely a ν~~ , 84%. i-NMR (DMSO-d6): 5 1,55-1,75 (m,2H), 1,88 (m, 2H), 2,17 (s,1H),3,14 (m ,1H),3,22 (s,3H),3,29-3,55 (m, 10H),3,78 (m,2H),3,90 (m,1H),4,89 (s, 2H), 4,99 (m,1H), 7,17-7,35 (m,l〇H); MS [M-Br]+: 439. Example 29 3-(R)(benzylphenylamine苯 乙基 氧 氧 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; NMR (DMSO-d6): 5 1,55-1,75 (m,2H), 1,90 (m, 2H), 2,19 (s,1H),3,00 (m,2H),3, 10 (m, 1H), 3, 31-3, 51 (m, 6H), 3, 90 (m , 1H), 4, 91 (s, 2H), 5,04 (m, 1H), 7, 18-7, 37 (m, 15H). MS [M-Br]+: 441; Example 30 3-(R)(¥-Phenylaminocarbamoyloxy)-1-(3-pyrimenylpropyl) 4-indolylbicyclo[2.2.2]octane; bromide title compound is based on Method c synthesis. The final step yield is 970 mg-41 - This paper scale is applicable to China National Standard (CNS) A4 specification (21〇x297 mm) 1304067 A7 _ B7 V. Invention description (36), 82% 〇lH- NMR (DMSO-d6): 5 1,55-1,69 (m,2H), 1,85-2,04 (m, 4H), 2,18 (s, 1H), 2,83 (m, 2H) ), 3,01 (m, 1H), 3,20-3,44 (m,6H),3,85 (m,1H),4,92 (s, 2H), 5,00 (m,1H) , 6, 94-7, 00 (m, 2H), 7, 19-7, 40 (m, 11H). MS [M-Br]+: 461; Example 3 1 3-(R)(nonylphenylaminocarbazolyloxy)-1-(3-phenylpropyl)-1-indenylbicyclo[2 · 2.2 ] octane:): completion; bromide The title compound was synthesized according to Method c. The final step yield was 880 mg, 79%. W-NMR (DMSO-d6): (5 1,55-1,69 (m,2H), 1,85-2,00 (m,4H), 2,18 (s,1H),2,59 ( m,2H),3,04 (m,1H),3,23-3,44 (m,6H),3,85 (m,1H),4,92 (s,2H),5,02 (m ,1H),7,18-7,36 (m,15H); MS [M-Br]+: 455; mp 101 ° C. Example 32 3-(R)(benzylphenylaminocarbazinyloxy) 1-(2-phenoxyethyl)- hydrazinobicyclo[2 · 2 · 2 ] octone; bromide title compound was synthesized according to method c. The final step yield was 3 60 mg, 67%. -NMR (DMSO-d6): 5 1,5-1,73 (m,2H),1,89 (m, 2H), 2,20 (s,1H),3,23 (m,1H),3 ,46-3,72 (m,6H),4,〇2 (m, 1H),4,43 (m,2H),4,92 (s,2H),5,03 (m,1H),7 , 01 (m, 3H), 7, 17-7, 38 (m, 12H); MS [M-Br]+: 457; mp. i17 〇c. Example 33 3-(R) Mercapto oxycyanophenoxy propyl bromidylbicyclo [2.2.2] octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 16 mg-42 - I paper scale Guan Jia Xian (CNS) A4_21Gχ 297 public I) 1304067 A7 B7 V. Description of invention (37), 36%; MS [M-CF3COO] +: 496 〇 Example 34 3-(R)(Benzylphenylaminocarbamimidyloxy)-1-[3-(indol-1-yloxy)propyl]β1_indenylbicyclo[2.2.2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 1 〇 mg, 21%; MS [M-CF3COO]+: 521. Example 35 3-(R)(nonylphenylaminocarbazolyloxy)-1-[3-(methylphenylamino)propyl]-1-indenylbicyclo[2.2.2]octane; The title compound of the trifluoroacetate salt was synthesized according to method d. The final step yield was 12 mg, 28%; MS [M-CF3COO]+: 484 0 Example 36 3-(R)(nonylphenylaminocarbazinyloxy)-1-(3-phenylsulfane Propyl)-i-fluorenylbicyclo[2·2·2]octane; the title compound of trifluoroacetate is synthesized according to method d. The final step yield was 8 mg, 18%; lH-NMR (DMSO-d6): δ 1,45^2,00 (m, 6H), 2,17 (bs, 1H), 3,00 (m, 2H) ),3,28-3,41 (m, 7H), 3,83 (m,1H),4,91 (s, 2H),4,98 (m,1H),7,18-7,41 ( m, 15H); MS [M-CF3COO]+: 487. Example 37 3-(R)(^-Phenylaminocarbamoyloxy)· 1-(4-oxy-4-phenylbutyl)-1-indenylbicyclo[2·2·2]octane The title compound of the trifluoroacetate salt was synthesized according to Method d. The final step yield is 10 mg? 23%; lH-NMR (DMSO-d6): 5 1,50-2,06 (m, 6H), 2,20 (bs, -43 - this paper scale applies to Chinese national standards (CNS) A4 size (21〇x 297 mm) 1304067 A7 B7 V. Description of invention (38) 1H), 3,13-3,47 (m,9H),3,89 (m,1H),4, 93 (s,2H),5,02 (m, 1H),7,19-7,38 (m,10H),7,54-7,70 (m,3H),7,98-8,00 ( m, 2H); MS [M-CF3COO]+·· 483. Example 38 3-(R)(nonylphenylaminocarbazyloxy)-1-[3-(2,4,6-trimethylphenoxy)propyl)-1-indenylbicyclo[2· 2. 2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield is q 4 mg, 30%; lH-NMR (DMSO-d6): 6 1,50-2,20 (m,7H), 2,19 (s, 9H), 3,16-3, 52 (m,7H),3,73 (m,2H),3,92 (m, 1H),4,93 (s, 2H),5,03 (m,1H),6,83 (s,2H ), 7, 19-7, 38 (m, 10H); MS [M-CF3COO]+: 513. Example 39 3-(R)(benzylphenylaminomercaptooxy)-l-[3-(2-chlorophenoxy)propyl]-indole-indenylbicyclo[2.2.2]octane; The fluoroacetate title compound was synthesized according to Method d. The final step yield was 14 mg, 31%; MS [M-CF3COO]+: 506. Example 40 3-(R)(nonylphenylaminocarbazolyloxy)-1-[3-(3-trifluoromethylphenoxy)propyl]-1-indenylbicyclo[2.2.2] octane The title compound of the trifluoroacetic acid salt was synthesized according to Method d. The final step yield was 14 mg^29%; lH-NMR (DMSO-d6): 5 1,50-2,00 (m, 4H), 2,08-2,20 (m,3H),3,12 -3,50 (m,7H),3,90 (m,1H),4,14 (m,2H),4,93 (s,2H),5,03 (m,1H),7,19- 7,38 (m,13H),7,54-7,59 (m,1H)· MS [M-CF3COO]+: 539 〇-44 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 B7 V. INSTRUCTIONS (39) EXAMPLE 4 1 MR) (Benzylphenylaminomethionyloxybiphenyl-4-yloxy)propyl]-buyendronbicyclo[2.2.2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 12 mg, 24%; iH-NMR (DMSO-d6): 5 1,50-2,20 (m,7H),3,14 (bs, 1H),3,28-3,52 (m,6H),3,91 (m,1H),4,10 (m,2H),4,93 (s, 2H),5,03 (m, 1H),7,03-7,08 ( m, 2H), 7, 18-7, 47 (m, 13H), 7, 61-7, 65 (m, 4H); MS [M-CF3COO]+: 547. Example 42 3-(R)(nonylphenylaminocarbazolyloxy)-1-[3-(2,4-dichlorophenoxy)propyl]-1-indenylbicyclo[2·2·2 ]octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 10 mg, 22%; i-NMR (DMSO-d6): &lt;5 1,50-2,19 (m,7H),3,10 (bs, 1H),3,28-3 , 51 (m, 6H), 3, 90 (m, 1H), 4, 10 (m, 2H), 4, 93 (s, 2H), 5, 02 (m, 1H), 7, 02-7, 09 (m, 1H), 7, 19-7, 37 (m, 12H); MS [M-CF3COO]+: 507. Example 43 3-(R)(Benzylphenylaminocarbamimidyloxy)-1-[3-(4-methoxyphenoxy)propyl]-1-indenylbicyclo[2·2·2] octane The title compound of the trifluoroacetic acid salt was synthesized according to Method d. The yield of the final step was 10 mg 5 22%; lH-NMR (DMSO-d6): (5 1,50-2,19 (m, 7H), 3,11 (bs, 1H), 3, 28-3, 51 (m,6H),3,70 (s,3H),3,89 (m,1H),3,94-3,99 (m,2H),4,93(s,2H),5,02 (m,lH),6,85-6,92 (m,4H),7,19-7,38 (m,10H); MS [M-CF3COO]+: 501. -45 - This paper size applies to China National Standard (CNS) A4 Specification (210X297 mm) 1304067 A7

Example 44 3-(11)(nonylphenylaminomethionyloxy)_1-[3_(5,6,7,8-tetrahydroindol-2-yloxy)propyl]-1-indenylbicyclo [2.2.2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The yield of the final step is 丨〇mg, 21%; iH-NMR (DMSO-d6): 5 1,50-1,71 (m,6H), 1,87-2,19 (m,5H), 2, 63-2,68 (m,4H),3,10 (bs,1H),3,28-3,50 (m,6H), 3,88(m,lH),3,98(m,2H) , 4,93(s,2H),5,02(m,lH),6,63-6,70 (m,2H),6,95-6,98 (d,1H),7,19-7 , 38 (m, 10H); MS [Μ- CF3COO]+: 525. Example 45 l-[3-(Benzo[1,3]dioxoindol-5-yloxy)propyl-3-(R)(nonylphenylaminocarbazyloxy)-1-indenylbicyclo [2.2.2] Octane; Trifluoroacetate salt-labeled compound was synthesized according to Method d. The final step yield was 12 mg, 26%; MS [M-CF3 C </ RTI> +: 515. Example 463-(R)(nonylphenylaminocarbazolyloxy)-i _[3-(2-aminomethylguanidinophenoxy)propyl]-1-kentylbicyclo[2.2.2] octane The alkane; trifluoroacetate salt &gt; € compound was synthesized according to method d. The final step yield was 1 〇 mg 22%; H-NMR (DMSO-d6): 5 1,50-2,27 (m, 7H), 3,09 (bs, 1H), 3,28-3,48 (m,6H),3,88 (m,1H),4,14 (m,2H), 4,93 (s, 2H),5,04 (m,1H),7,02-7,15 ( m, 2H), 7, 19-7, 38 (m, 10H), 7, 44-7, 50 (m, 1H), 7, 55 (bs, NH2), 7, 69-7, 72 (dd, 1H); MS [M-CF3COO]+: 514. Example 47 -46 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

装

▲ 1304067 A7 B7

V. INSTRUCTION DESCRIPTION (41) 3-(R)(Benzylphenylaminocarbazyloxy)-1-[3-(3-dimethylaminophenoxy)propyl]-1-indenylbicyclo [2.2.2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 12 mg, 26%; MS [M-CF3COO]+: 514. Example 48 1-[3-(4-Ethylaminophenoxy)propyl]_3_(R)(nonylphenylaminocarbazyloxy)-1-indenylbicyclo[2·2·2] octane Alkane; trifluoroacetate; ί: the compound is synthesized according to method d. The final step yield was 12 mg, 25%; W-NMR (DMSO-d6): (5 1,5 (M, 92 (m, 4H), 2,01 (s, 3H), 2,04-2, 20 (m,3H),3,12 (bs,1H),3,28-3,51 (m,6H),3,89 (m,1H),4,00 (m,2H),4,93 (s,2H),5,02 (m,1H),6,86-6,91 (m,2H),7,19-7,38 (m,10H),7,48-7,53 (m , 2H), 9, 85 (s, NH); MS [M-CF3COO]+: 528. Example 49 3-(R)(nonylphenylaminocarbamoyloxy)-143-(4-methoxy Carbonylphenoxy)propyl]-1-indenylbicyclo[2·2·2]octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 12 mg^25%; 'H-NMR (DMSO-d6): 5 1,50-2,20 (m, 7H), 3,12 (bs, 1H), 3,29-3,51 (m,6H),3,82 (s, 3H) ,3,87-3,93 (m,1H),4,14 (m,2H),4,93(s,2H),5,03(m,lH),7,04-7,09 (m , 2H), 7, 19-7, 38 (m, 10H), 7, 92-7, 96 (m, 2H); MS [M-CF3COO] +·· 529. Example 50 3-(R)(^ Phenylaminomethylmercaptooxy)-i-[3-(4-nitrophenoxy)propyl]-didecylbicyclo[2.2.2]octane; trifluoroacetate-47 - paper scale for China National Standard (CNS) A4 Specification (210 X 297 mm) 1304067 A7 __ B7 invention description (42) ~ - The title compound was synthesized according to method d. The final step yield was 12 mg, 26%; ^-NMR (DMSO-d6): 5 1,50·2,27 (m,7H) ),3,12 (bs 1H),3,29-3,5i (m,6H),3,87-3,94 (m,1H),4,21 (m,2H),4,93 (s , 2H), 5, 03 (m, 1H), 7, 14-7, 38 (m, 12H), 8, 22-8, 28 (m, 2H); MS [M-CF3COO]+: 516. 5 1 3-(R)(^-Phenylaminocarbamoyloxy)-1-[3-(4·monomethylphenoxy)propyl]- 1-indenylbicyclo[2·2·2] Octane; the title compound of the trifluoroacetate salt was synthesized according to Method d. The yield of the final step was </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 52 1-Azabicyclo[2·2·2]oct-3-(S)-based decylphenylcarbamic acid The title compound was synthesized according to Method d. The yield of the final step is 1000 gram ^ 23%; !H.NMR (DMSO-d6): 5 1,14-1,57 (m, 4H), 1,83 (bs, 1H), 2,43-2 ,61 (m,5H),2,61-3,01 (m,1H),4,64 (m,1H),4,89 (s,2H),7,16-7,35 (m,10H ). MS [M+l]+: 337. Example 53 3-(S)(nonylphenylaminocarbamoyloxy)-1-(3-phenylpropyl)·indolyl-bicyclobicyclo[2 · 2 · 2 ]octane; bromide title compound It is synthesized according to method c. The final step yield was 660 mg » 83%; lH-NMR (DMSO-d6): 5 1,40-2,00 (m, 6H), 2,18 (bs, 1H), 2,59 (m, 2H) ), 2, 95-3, 44 (m, 7H), 3, 84 (m, 1H), 4, 92 (s, 2H), 5,00 (m, 1H), 7, 19-7, 36 ( m, 15H)· MS [M-Br], 455. -48 - This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1304067 A7 ____ B7 V. Inventive Note (43) Example 54 1-Phenylphenylcarbamic acid 1-azabicyclo[2· 2·2] oct-3-(R)-ester; ί: the compound is synthesized according to method a. The yield of the final step is 1 88 mg, 22%; (CDC13): 5 0.9 (m, 3H), 1, 3 (m, 4H), 1, 5 (m, 4H), 1, 9 (s, 1H ), 2,7 (m,5H),3,2 (m,1H),3,7 (m,2H),4,7 (m,1H),7,2-7,4 (m,5H) ; MS [Μ+ΐΓ: 303. Example 55 3-(R)(butylphenylaminocarbamidooxymethyl-1β-decylbicyclo[22.2]octane; trifluoroacetic acid salt title compound was synthesized according to procedure cl. Mg, 30%; MS [M-CF3COO]+: 317 0 Example 56 3-(R)(butylphenylaminocarbamidooxy)-1-(4-methyl-pent-3-enyl) -i-fluorenylbicyclo[2·2·2]octane; the title compound of the trifluoroacetate salt was synthesized according to method d. The final step yield was 18 mg, 27%; MS [M-CF3COO]+: 385 〇 57 3-(R)(butylphenylaminomethionyloxy)-1-(3-phenoxypropyl-terminated bicyclo[2.2.2]octane; trifluoroacetate title compound was synthesized according to method d The final step yield was 21 mg, 28%; MS [M-CF3COO]+: 437. Example 58 3-(R)(butylphenylaminocarbazinyloxy)-1-(3-phenylindole) Propyl)-fluorene-fluorenylbicyclo[2.2.2]octane; bromide-49 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X '297 mm) 13〇4〇67 A7 _ B7 V. Inventive Note (44) The title compound was synthesized according to Method c. The final step yield was 1 82 mg, 48%; lH-NMR (DMSO-d6): (5 0.84 (m? 3H), 1,25 (m, 2H), 1,40 (m,2H), 1,70-1,91 (m,4H),2,20 (s,1H),3,2-3,4 (m, 6H),3,64 (m,2H),3,88 (m,1H),3,88-4,07 (d,2H),4,97 (m, 1H),6,45 (m,1H) ),6,83-6,88 (d,1H),7,23-7,45 (m,7H),7,60 (m,2H); MS [M-Br]+: 419; Melting point: 144 Example C. 1-Subpin-3-(R)(butylphenylaminocarbamidooxy)-1-indenylbicyclo[2.2.2] 辛健; bromide title compound according to method c Synthesis. The final step yield is 200 mg? 72%; lH-NMR (DMSO-d6): 5 0.85 (m, 3H), 1,21-1,34 (m? 3H), 1,40-1,45 (m, 2H), 1, 70-2, 18 (m, 4H), 3, 15_3, 40 (m, 5H), 3, 61-3, 67 (m, 2H), 3, 82 (m, 1H ),3,92-3,94 (m,2H),4,95 (m, 1H), 5,62 (m, 2H), 5,97-6,01 (m, 1H), 7,26^ 7,44 (m, 5H); MS [M-Br]+: 343; mp. Example 60 3-(R)(butylphenylaminomercaptooxy)-1-(2-hydroxyethyl)-didecylbicyclo[2·2·2]octane; trifluoroacetate title compound Method d synthesis. The final step yield was 13 mg, 19%; MS [M-CF3COO]+: 347. Example 6 1 3-(R)(butylphenylaminocarbamimidyloxy)-1-isopropyl-1.glycosylbicyclo[22.2]octane; trifluoroacetate The title compound was synthesized according to procedure d. The final step yield is 2 〇mg-50 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 B7 V. Description of the invention (45), 29%; MS [M-CF3COO] +: 345. Example 62 3-(R)(butylphenyl phenylmercaptooxypropyl-1-indenylbicyclo[2.2.2]octane; trifluoroacetic acid salt title compound was synthesized according to procedure d. 16 mg, 23%; MS [M-CF3COO]+: 345. Example 63 3-(R)(butylphenylaminocarbamoyloxy)-1-(3-cyanopropyl)-1- Indolebicyclo[2.2.2]octane; the title compound of the trifluoroacetate salt was synthesized according to method d. The final step yield was 15 mg, 20%; MS [M-CF3COO]+: 370. Example 64 3-(R (butyl butylaminomethionyloxy)-1-cyclopropylmethyl-1-indenylbicyclo[2.2.2] octane; trifluoroacetate salt title compound is synthesized according to method d. The rate is 2 mg, 3%; MS [M-CF3COO]+: 357. Example 65 3-(R)(butylphenylaminocarbamoyloxy)-1-(2-ethoxyethyl)-1 - mercaptobicyclo[2.2.2]octane; trifluoroacetic acid salt title compound was synthesized according to method d. The final step yield was 19 mg ' 25%; MS [M-CF3COO]+: 375. Example 66 3-( R) (butylphenylaminomethionyloxyethoxycarbonyl butyl)-1-fluorenylbicyclo[2·2·2]octane; trifluoroacetate-51 - suitable for this paper size National Standard (CNS) Α4 Specification (210 X 297 mm) 1304067 A7 ___B7_ V. Description of Invention (46) The title compound was synthesized according to Method d. The final step yield was 12 mg, 14%; MS [M-CF3COO]+ : 431 0 Example 67 3-(R)(butylphenylaminocarbamimidyloxy)-1-(3-propyl)-1-terbicyclobicyclo[2.2.2]octyl:trifluoroacetate title The compound was synthesized according to Method d. The yield of the next step was 12 mg, 17%; MS [M-CF3COO]+: 361. Example 68 3-(R)(butyl-whenylamino)f7-decyloxy)-1- (3 - ρ, bilo-1-ylpropyl)-1-keptytylbicyclo[2.2.2]octane; the title compound of the trifluoroacetic acid salt was synthesized according to method d. The final step yield was 19 mg, 23%; MS [M-CF3COO]+: 410. Example 69 1-(4-Ethyloxybutyl)-3-(R)(butylphenylaminocarbamidooxy)·!·腙-bisbicyclo[2 · 2·2]octane; the title compound of the trifluoroacetate salt was synthesized according to Method d. The final step yield was 10 mg, 12%; MS [M-CF3COO]+: 417. Example 70 3-(R) Alkylamino-based base milk)-1-(4-oxy-4-0-cephen-2-ylbutyl)· 1-indolylbicyclo[2·2.2]octane; trifluoroacetate title Chemical It was synthesized according to method d line. The final step yield was 17 mg, 19%; MS [M-CF3COO]+: 455. Example 7 1 3-(R)(butylphenylaminoglycolyloxy)-1-(4-phenylbutylbubuylbicyclo-52 - This paper scale applies to Chinese National Standard (CMS) A4 specification (210 X 297 浚) 1304067 A7 _____ B7 _ V. Description of the invention (47) [2.2.2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was Πmg, 20%; M-CF3COO]+: 435 0 Example 72 3-(R)(butylphenylaminomethionyloxy)-i-[3-(3-hydroxyphenoxy)propyl)-1-indenylbicyclo[ 2.2.2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 21 mg, 23%; MS [M-CF3COO]+: 453. Example 73 3-(R)(butylphenylaminocarbamimidyloxy)-1.heptyl-1-indenylbicyclo[2.2.2]octane; trifluoroacetate The title compound was synthesized according to procedure d. The final step yield was 17 mg, 21%; MS [M-CF3COO]+: 401. Example 74 1-(2-Benzyloxyethyl)-3-(R)(butylphenylaminocarbamidooxy)-1-indenylbicyclo[2.2.2] octyl; trifluoroacetate title compound It is synthesized according to method d. The final step yield was 22 mg ' 25%; MS [M-CF3CO〇]+: 437 〇 Example 75 3-(R)(butylphenylaminocarbazinyloxy)-1_phenethyl-1- Indenylbicyclo [2.2.2] octyl; bromide title compound was synthesized according to method c. The yield of the final step was 33 〇 mg ^ 82%; lH-NMR (DMSO-d6): (5 0.83 (m, 3H), 1,27-1,34 (m, 2H), 1,41-1,48 (m, 3H), 1,60-2,23 (m, 4H), 2,96-3,47 (m, 7H), -53 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304067 A7 _______ B7 V. Description of invention (48) 3,57-3,71 (m, 4H), 3,92 (m, 1H), 4,98 (m, 1H), 7,25- 7,45 (m, 10H); MS [M-Br]+: 407; melting point: 139 〇. Example 76 3-(R)(butylphenylaminocarbazinyloxy)_ι·[ 2- (2-methoxyethoxy)ethyl]-1-indenylbicyclo[2·2·2]octane; bromide title compound was synthesized according to method c. The final step yield was 520 mg, 81%; iH- NMR (DMSO-d6): 5 〇·82 (m, 3 Η), 1,24-1,31 (m, 2H), l, 39-l, 47 (m, 2H), 1, 70, 2, 20 (m,5H),3,26(s,3H),3,35-3,70 (m,13H),3,82-3,86 (m5 3H),4,94 (m,1H),7 , 26-7,44 (m, 5H); MS [M-Br]+: 405 ° Example 77 Butyl-(4-fluorophenyl)carbamic acid hydrazine-azabicyclo[2·2 2] sin The title compound of 3-(11)-ester was synthesized according to Method a. The yield of the final step was 165 mg / 24%; lH-NMR (DMSO «d6): 5 0.82 (m, 3H), 1,20-1,54 (m5

8H),1,83 (m,1H),2,49-2,70 (m,5H),3,02-3,09 (m,1H), 3,36-3,63 (m,2H) ,4,59 (m,1H),7,19-7,35 (m,4H); MS

[M+l]+: 321 〇Example 78 3-(R)(butyl phenylaminomethylmercapto oxime. gas 4_fluorophenyl) propyl bromidyl double ring [2·2·2] Octane; the chloride title compound was synthesized according to Method c. The final step yield was 39 〇 mg^75%; lH&lt;NMR (DMSO-d6): 5 0.82 (m, 3H), 1,26-1,31 (m? 2H), 1,4 (M,48 ( m,2H),1 is calculated as 2,17 (m,5H),3,2(M,7 (m,11H), 3,86 (m, 1H), 4,02 (m, 2H), 4,94 (m? 1H), 6,95-7,00 (m, 2H), -54 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1304067 A7 ___ B7 V. Description of invention ( 49) 7,12-7,18 (m,2H),7,26-7,44 (m,5H); MS [M-C1]+: 455; m.p.: 126° C. Example 79 3-(R (butyl butylaminomethionyloxy)-1-(2-phenoxyethyldipyridinium-fluorenylbicyclo[2,2·2]octane; bromide title compound was synthesized according to method c. The yield of the step is 260 mg J 53%; lH-NMR (DMSO-d6): (5 0.84 (m? 3H), 1,23-1,30 (m, 2H), 1,39-1,48 (m ,2H),l,70-2,20 (m,5H),3,20·3,72 (m, 9H), 3,99 (m, 1H), 4,44 (m, 2H), 4, 95 (m, 1H), 7,01 (m? 3H), 7,24-7,4〇(m,7H); MS [M-Br]+: 423; mp: 153 〇c. Example 80 3- (R)(butylphenylaminomercaptooxyl)·丨-(3-喽 ··2·ylpropyl)·didecylbicyclo[2.2.2]octane; bromide title compound It was synthesized according to the method. The final step yield was 11 mg, 62%; 4-NMR (DMSO-d6): 5 0.84 (m, 3H), 124], 31 (m, 2H), 1,42 ( m, 2H), 1,60-2,21 (m5 7H), 2^5 2H)5 3^.3^0 (m, 7H), 3,60-3,69 (m, 2H)3 3, 85 (m, 1H), 4,93 (m, 1H), 6,95- '〇〇(m, 2H), 7, 28-7, 43 (m, 6H); MS [M_Br]+: 427; Melting point: 127 ° C. Example 8 1 3-(R)(butylphenylaminoglycolyloxy)] ♦ phenyl propyl) fluorenylbicyclo[2·2·2]octane; bromide title The compound was synthesized according to Method C. The yield of the final step was 28 </ RTI> </ RTI> < 56 〇 / 〇; *H-NMR (DMSO-d6): 5 0.84 (m? 3H), ^23-1, 33 (m, -55) -

1304067 A7B? V. Description of invention (50) ^ —- 2H), 1,43 (m, 2H), 1,60-2,20 (m, 7H), 2,59 (m, 2H), 3,00 -3,78 (m,9H),3,84 (m,1H),4,92 (m,1H), 7 2〇7 42 (m, [M-Br]+: 421 ; melting point: 120 ° C Example 82 Phenyl phen-2-ylmethylaminocarbamate 1-azabicyclo[2 2 2]oct-3-yl (R) acrylate The title compound was synthesized according to Method a. The final step yield was 3 〇 〇 , 1〇%; i-NMR (DMSO-d6): &lt;5 4H), 187 (s, 1H), 2, 46-2, 63 (m, 5H), 3,04-3,33 (m, 1H), 4,66 (m, 1H), 5,01 (s,2H),6,87-6,94 (m,2H),7,20-7,43 (m,6h); MS [M +l]+: 343 ° Example 83 1-methyl-3-(R)(phenylthiophen-2-ylmethylaminocarbamoyloxyindenylbicyclo[2.2.2]octane; bromide title compound The product was synthesized according to the method c. The yield of the final step was ι 6 〇 mg » 80%; lH-NMR (DMSO-d6): 5 1,65-2,00 (m, 4H), 2,20 (s, lH), 2,98(s,3H),3,32-3,52(m,5H),3,85-3,92(m,lH),4,98-5,04 (m,3H),6, 94 (m,2H),7,24-7,45 (m,6H)·; MS [M-Br]+: 357 ° Example 84 1-(3-phenoxypropyl)-3-(R) ( Phenyl 4 phen-2-ylmethylaminopyridyloxy)-1-indenyl Ring [2·2·2]octane; trifluoroacetic acid salt title compound was synthesized according to method d. The final step yield was 16 mg, 42%; MS [M-CF3COO]+: 477 0 Example 85 -56 - Paper scale applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mil) 1304067 A7 B7 V. Description of invention (51) 1-(3-Phenylpropyl)-3-(R)(phenylthiophene-2 -methylaminoaminomethaneoxy&gt;i-decylbicyclo[2.2.2]octane; trifluoroacetate salt title compound was synthesized according to method d. The final step yield was 13 g &amp;35%; iH -NMR (DMSO-d6): 5 1,72·2,3 (m,7H), 2,58 (m 2H), 3,00-3,48 (m,7H),3,84 (m,1H ),5,04 (m,3H),6,92-6,9^ (m,2H),7,20-7,43 (m,11H); MS [M-CF3COO]+: 461 〇Example 86 1-(3-phenyl-propylpropyl)-3-(R)(phenylthiophen-2-ylmethylaminocarbamidooxy), 1-indenylbicyclo[2.2,2]octane; trifluoro The acetate title compound was synthesized according to method d. The final step yield was 4 mg, 1 1%; MS [M-CF3COO]+: 459. Example 87 4 1-(2-decyloxyethyl)-3-(R)(phenyl porphin-2-ylmethylaminomethionyloxy) sylvestre bicyclo[2·2·2] octane The title compound of the trifluoroacetic acid salt was synthesized according to Method d. The final step yield was 14 mg, 37%; MS [M-CF3COO]+: 477. Example 88 1-[3-(3-Phenoxy)propyl]-3-(R)(phenyl p-cephen-2-ylmethylaminomethyl methoxyl M-fluorenylbicyclo[2·2 2] octane; trifluoroacetate "pass compound was synthesized according to method d. The final step yield was 11 mg, 28%; MS [M-CF3COO]+: 493. Example 89 1-heptyl-3-( R)(Phenyl-α-phen-2-ylmethylaminomethylmercaptooxycarbonylbicyclo[2.2.2]octane; Trifluoroacetate-57 - This paper scale applies to Chinese National Standard (CNS) Α4 Specifications (210 X 297 mm) 1304067 A7

The chemotactic compound is synthesized according to method d. The yield of the final step was 13 mg, 37%; MS [M-CF3C〇〇]+: 44. Example 90 3-(R)(phenylthiophene-ylmethylaminomethylcarbonyl)_1-(3_ Thiophene-2-ylpropyl)-1-indenylbicyclo[2.2.2]octane; bromide title compound was synthesized according to the method. The yield of the final step was 14 〇 mg ^ 48%; lH-NMR (DMSO-d6): 5 1,40-2,30 (m3 7H), 2,83 (m, 2H), 3,00-3,60 (m,7H),3,88 (m,1H),5,04 (m,3H),6,93'99 (m,4H),7,28-7,43 (m,7H); MS [ M-Br] Ten: 467. Example 91 (2-phenoxyethyl)-3-(R)(phenylthiophen-2-ylmethylaminocarbamimidoxibylbicyclo[2·2·2]octane; bromide title compound Synthesis according to method c. The final step yield is 5 1 gram, 80%; h-NMR (DMSO-d6): 5 1,40-2,30 (m, 5 Η), 3, 20-3, 73 (m,7H),4,05 (m,1H),4,44 (bs,2H),5,04 (m,3H), 6,91-7,〇4 (m,5H),7,24 -7,41 (m,8H); MS [M-Br]+: 463; m.p.: i33 〇c. Example 92 1- propyl propyl-3-(R) (p-pyranylmethylamino)乙 基 氧 ) _ ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; :(5 1,40-2,30 (m, 5H), 3,00-4,41 (m, 5H), 3,81-3,92 (m, 3H), 5,04 (m, 3H) , 5,61 (m, 2H), 5,93. 6,05 (m, 1H), 6,93-6,96 (m, 2H), 7,24-7,46 (m, 6H); MS [M-Br] +: 383 ; melting point ii 〇 ° c. -58 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) 1304067

Example 93 1-Azabicyclo[2 2 2]octyl-3-(R)-based phenylethylphenylaminocarbamate The title compound was synthesized according to Method &amp; The yield of the final step is 〇〇4〇〇mg, Π%; (DMSO_d6): 5 11〇·16〇(m,4H), i 83 (s, 1H), 2,40-2,70 (m, 5H) , 2,78 (m, 2H), 3,00-3,08 (m, 1H), 3,87 (m, 2H), 4,58 (m, 1H), 7,16-7,40 (m , 10H); MS [M+l]+: 351 〇 Example 94 1-methyl-3-(R)(phenethylphenylaminocarbamoyloxy)el•indenylbicyclo[2 2·2] Octane; bromide The title compound was synthesized according to Method c. The final step yield was 14 mg, 73%; iH-NMR (DMSO-d6): 5 1,40-2,30 (m, 5H), 2,80 (m, 2H), 2,94 (s, 3H),3,10·3,50 (m,5H),3,78-3,95 (m,3H),4,89 (m,1H),7,16-7,41 (m,10H) MS [M-Br]+: 365; mp 203 ° C. Example 95 1-Mercaptopropyl-3-(R)(phenethylphenylaminocarbamimidyloxy)β1_fluorenylbicyclo[2.2.2]octane; trifluoroacetate title compound was synthesized according to method d . The final step yield was 11 mg, 35%; MS [M-CF3COO]+: 391. Example 96 3-(R)(Phenylethylphenylaminomethaneoxy)-1-(3-phenoxypropyl) 1-indenylbicyclo[2.2.2]octane; Trifluoroacetate title compound It is synthesized according to method d. The final step yield was 16 mg, 41%; MS [M-CF3COO]+: 485. Example 97 -59 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 B7 V. Description of invention (54) 3-(R)(Phenylethylphenylaminocarbamyl) Oxy)-1-(2-phenoxyethyl)-1-indenylbicyclo[2·2·2]octane; the title compound of the trifluoroacetate salt was synthesized according to Method d. The final step yield was 15 mg, 40%; fH-NMR (DMSO-d6): 5 1,45-2,18 (m,5H), 2,81 (m, 2H), 3,28-3,70 (m,7H),3,80-4,02 (m,3H),4,43 (m,2H),4,95 (m, 1H), 6,98-7,04 (m, 2H), 7,16-7,40 (m, 13H); MS [M-CF3C00]+: 471 〇Example 98 3-(R)(stupylethylphenylaminomethyl decyloxy)-1-(3-benzene Propyl)-i-fluorenylbicyclo[2·2·2]octane; the title compound of trifluoroacetate is synthesized according to method d. The final step yield was 14 mg, 37%; iH-NMR (DMSO-d6): 5 1,45-2,20 (m,7H), 2,59 (m, 2H), 2,81 (m, 2H) ), 3,05-3,5 (m,7H),3,78·3,89 (m,3H),4,91 (m,1H),7,17-7,42 (m,15H); MS [M-CF3COO]+: 469. Example 99 3-(R)(Winterethylphenylaminoglycolyloxy)-1-(3-phenyl-propyl)-indole-indenylbicyclo[2·2·2]octane; Trifluoro The acetate title compound was synthesized according to method d. The final step yield was 4 g, 11%; MS [M-CF3COO]+: 467 0 Example 100 1-(2-decyloxyethyl) 3-(R) (phenethylphenylaminocarbazinyl) Oxygen) β1•fluorenylbicyclo[2·2·2]octane; trifluoroacetate; fr pass compound is synthesized according to method d. The yield of the final step was 14 ' 36%; MS [M-CF3COO] +: 485. -60 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1304067 A7 B7 V. Description of invention (55) Example 1 0 1 1-[3-(3-Hydroxyphenoxy)propyl] _3-(R)(phenethylphenylaminocarbamimidyloxy)_" Knee-based bicyclo[2 · 2 · 2 ] octyl; trifluoroacetate title compound was synthesized according to method d. The final step yield was 14 mg J 35%; lH-NMR (DMSO-d6): 5 1,45-2,20 (m, 7H), 2,82 (m, 2H), 3,05-3,50 (m,7H) ,3,83-3,99 (m,5H),4,94 (m,1H), 6,33-6,39 (m,3H),7,04-7,09 (m,1H),7 , 18-7,44 (m,10H), 9,49 (s, OH); MS [M-CF3COO]+: 501. Example 102 1-heptyl-3-(R)(phenethylphenylamine)醯 氧 氧 氧 丨 丨 腙 腙 腙 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; D6): (5 0.88 (m, 3H), 1,28 (m, 8H), 1,55-2,20 (m, 7H), 2,82 (m, 2H), 3,00-3,50 (m, 7H), 3,68-3,89 (m,3H),4,92 (m,1H),7,18-7,43 (m,l〇H); MS [M-CF3COO]+ : 449. Example 103 3-( R)(phenethylphenylaminocarbamimidyloxy)-1-(3-p-sphenantylpropyl) -i-fluorenylbicyclo[2·2·2]octane; the title compound of trifluoroacetic acid salt was synthesized according to method d. The yield of the final step was 毫克5 mg, 3 9%; MS [M-CF3COO]+: 475 Example 104 Pentylphenyl-aminocarbamate 1-azabicyclo[2.2.2]oct-3-(R)-based hydrazine The title compound was synthesized according to Method a. The final step yield was 62 〇 s. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 _ B7 V. Invention description (56 ) &quot; ~ , 9%; ^-NMR (DMSO-d6): 5 0.83 (m , 3H), 1,22-1,30 (m, 5H),l,43-l,56(m,5H),l,83(s,lH),2,42-2,65 (m,5H ), 3,01-3,06 (m,1H), 3,59-3,65 (m,2H),4,49 (m,1H),7,22-7,41 (m, 5H); MS [M+l]+: 317 o Example 105 1-methyl-3-(R)(pentylphenylaminocarbamidooxy)-1-indolylbicyclo[2.2.2]octane; bromide The title compound was synthesized according to Method c. The yield of the final step was 130 mg^68%; lH-NMR (DMSO-d6): 0.81 (m, 3H), 1,21 (m, 5H), 1,45-2,20 (m,6H),2 ,93 (s,3H),3,10-3,70 (m,7H),3,80 (m, 1H),4,88 (m,1H),7,24-7,41 (m,5H ); MS [M-Br]+: 331. Example 106 1-allyl-3-(R)(pentylphenylaminocarbamidooxy)-1-indenylbicyclo[2.2.2]octane; trifluoroacetate title compound was synthesized according to method d . The yield of the final step is 10 mg^35%; lH-NMR (DMSO-d6): (5 0.83 (m, 3H), 1,21-1,28 (m, 4H), 1,46 (m,3H) ,1,54-1,91 (m,3H),2,30 (m,1H),3,28-3,41 (m,5H),3,78-3,92 (m,5H),4 ,94 (m,1H),5,54-5,64 (m,2H), 5,98 (m, 1H),7,26-7,43 (m,5H); MS [M-CF3COO]+ · 357. Example 107 3-(R)(pentylphenylaminocarbamidooxy)-1-(3-phenoxypropyl)-1-indenylbicyclo[2.2.2]octane; trifluoro The acetate title compound was synthesized according to Method d. The final step yield was 13 mg, 36%; MS [M-CF3COO]+: 451. - 62 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT 1304067 A7 B7 57 ) V. INSTRUCTIONS (Example 108 3-(R)(Pentylphenylaminocarbamimidyloxy)-1-(2-phenoxyethyl)-1 -indolylbicyclo[ 2.2.2] Octane; Trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 14 mg, 40%; lH-NMR (DMSO-d6): 5 〇·82 (m, 3H), 1 ,23 (m,4H), 1,46 (m, 3H), 1,54-1,91 (m, 3H), 2,25 (s, 1H), 3,28-3,70 (m, 9H ),3,98 (m,1H),4,43 (m,2H),4,95 (m,1H) 6,98-7,04 (m, 3H),7,23-7,4 (m,7H); MS [M-CF3COO]+: 437. Example 109 3-(R)(pentylphenylamino) Methyl methoxy)-1-(3-phenylpropyl)-1-indenylbicyclo[2.2.2]octane; the title compound of trifluoroacetate was synthesized according to Method d. The final step yield was 13 mg. 37%; lH-NMR (DMSO-d6): 5 0.82 (m, 3H), 1,20-1,25 (m, 5H), 1,44 (m,3H),1,68-2,13 ( m,7H),2,58 (m,2H),3,00-3,41 (m,5H),3,54-3,69 (m,2H),3,79-3,85 (m, 1H), 4,92 (m,1H), 7,20-7,42 (m,10H); MS [M-CF3COO]+: 435. Example 110 3-(R)(pentylphenylamino) Mercaptooxy)-1-(3-phenylindolyl)-1-indenylbicyclo[2·2·2]octane; trifluoroacetate salt title compound was synthesized according to method d. The final step yield was 4 mg, 12%; MS [M-CF3COO]+: 433. Example 111 1-(2-Benzyloxyethyl)-3-(R)(pentylphenylaminocarbamoyloxy)-1-indenylbicyclo[2.2.2]octane; Trifluoroacetate-63 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1304067 A7 ______B7 V. Description of the invention (58) The title compound was synthesized according to Method d. The final step yield was 15 mg, 42%; MS [M-CF3COO]+: 451. Example 1 12 1-[3-(3-Phenoxy)propyl]-3-(11)(pentylphenylaminocarbazyloxy)-didecylbicyclo[2.2.2]octane; Trifluoroacetic acid The salt title compound was synthesized according to method d. The final step yield was 丨2 mg, 32%; MS [M-CF3COO]+: 467. Example 113 1-Heptyl-3-(R)(pentylphenylaminocarbazyloxy-indenylbicyclo[2.2.2]octane; trifluoroacetic acid salt title compound was synthesized according to method d. The rate is 15 mg, 45%; MS [M-CF3COO]+: 415. Example 114 3-(R)(pentylphenylaminocarbhydryloxy)_1-(3·thienylpropyl)-; Indole-bicyclo[2.2.2]octane; the title compound of the trifluoroacetate salt was synthesized according to method d. The final step yield was 13 mg, 37%; 咕-NMR (DMSO-d6): 5 0.82 (m, 3H) , 1,22-1,26 (m, 5H),1,46 (m,3H),1,60-2,14 (m,7H),2,82 (m,2H),3,20-3 ,41 (m,5H),3,50-3,70 (m,2H),3,82(m,lH),4,92(m,lH),6,93-6,99 (m,2H ), 7,25-7,43 (m,6H); MS [M-CF3COO]+: 441. Example 1 1 5 pent-4-mercaptophenylcarbamic acid 1-azabicyclo[2·2· 2] Oct-3-(R)-ester ester The title compound was synthesized according to Method a. The yield of the final step was 690 mg, J 14%; &quot;H-NMR (DMSO-d6): 5 1,10-1,60 (m , 6H), 1,84 (bs, -64 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1304067 A7 _ B7 V. Invention description (59) lH), 1,9 7-2,04 (m, 2H), 2,45-2,65 (m, 5H), 3,02-3,10 (rri5 m)? 3,29-3,66 (m,2H),4 ,59 (m,1H),4,61-5,00 (m,2H),5,7 (M 84 (m,1H),7,22-7,42 (m, 5H); MS [M+ l]+: 315. Example 1 1 6 U晞propyl-3-(R)(pentyl-p-nonylphenylaminocarbamimidyloxy)nonylbicyclo[2.2.2]octane; trifluoroacetate The compound was synthesized according to the method d. The yield of the final step was 1 〇 mg, 35%; MS [M-CF3COO]+: 355. Example 117 3-(R)(pent-4-enylphenylamine Methylmercaptooxy)-1-(3-phenoxypropyl)_1β-mercaptobicyclo[2·2·2]octane; the title compound of trifluoroacetate is synthesized according to method d. The final step yield is 15 mg. , 42%; iH-NMR (DMSO-d6): 5 1,50-2,20 (m,11H),3,23-3,47 (m,7H),3,56-3,73 (m, 2H),3,87 (m,1H),4,03 (m,2H),4,92,4,95 (m,2H),5,00 (m,1H),5,70-5,82 (m, 1H), 6, 93-6, 99 (m, 2H), 7, 26-7, 44 (m, 8H); MS [M-CF3COO]+: 449. Example 118 3-(R)(pent-4-yl-phenylphenylaminomethyloxy)-1-(2-phenoxyethyl)-1-kentylbicyclo[2·2·2]octane; The title compound of the trifluoroacetate salt was synthesized according to method d. The final step yield was 13 g, 37%; i-NMR (DMSO-d6): (5 1,55 (m, 2H), 1, 65-2, 20 (m, 7H), 3, 28-3 ,75 (m,9H),3,98 (m,1H),4,43 (bs,2H),4,92-4,99 (m,3H),5,70-5,83 (m,1H ), 6,98-7,04 (m,3H),7,24·7,40 (m, 7H); MS [M-CF3COO]+: 435. -65 - This paper scale applies to Chinese national standards (CNS) A4 size (210X297 mm) 1304067 A7 B7 V. Description of the invention (6〇) Example 1 19 3-(R)(pent-4-mercaptophenylaminomethaneoxy)-1-(3-benzene Propyl)-1-fluorenylbicyclo[2.2.2]octane; the title compound was synthesized according to Method d. The final step yield was 13 mg, 37%; lH-NMR (DMSO-d6): 5 1,56 (m, 3H), 1,70-2,14 (m, 8H), 2,58 (m,2H),3,19-3,41 (m,7H),3,56-3 ,71 (m,2H),3,81 (m,1H),4,92-4,99 (m,3H),5,70-5,83 (m,1H),7,20-7,43 (m, 10H); MS [M-CF3COO]+: 433. Example 120 3-(R)(pent-4-mercaptophenylaminomethionyloxy)-1-(3-phenylpyranylpropyl) 1-(indolyl)bicyclo[2.2.2]octane; the title compound of the trifluoroacetate salt was synthesized according to method d. The final step yield was 4 mg, 12%; MS [M-CF3COO]+: 431 0 Example 12 1 1-(2-+Oxyethyl)-3-(R)(pent-4-phenylphenylaminomethyloxy)-1-l base Bicyclo[2.2.2]octane; the title compound of the trifluoroacetic acid salt was synthesized according to Method d. The final step yield was 16 mg, 44%; MS [M-CF3COO]+: 449. Example 122 1-[ 3-( 3-hydroxyphenoxy)propyl]_3-(R)(pent-4-enylphenylaminocarbazolyloxy)·1-indolylbicyclo[2·2·2]octane; trifluoroacetate The title compound was synthesized according to Method d. The final step yield was 12 mg, 32%; MS [M-CF3COO]'· 465. Example 123 - 66 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) 1304067 A7 B7 V. INSTRUCTIONS (61) 1-Heptyl-3-(R)(pent-4-phenylphenylaminocarbenyloxy)-1-indenylbicyclo[2.2.2 ]octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 3 mg, 9%; MS [M-CF3COO]+: 413 0 Example 1 24 1-Methyl-3-(R)(pent-4-enylphenylaminocarbazinyloxy) 1-nonylbicyclo[2·2·2]octane; trifluoroacetate title compound was synthesized according to method d. The yield of the final step was 13 mg, 49%; MS [M-CF3COO]+: 429 0 Example 125 3-(R)(pent-4-enylphenylaminopyridyloxy)-1-(3-喽-phen-2-ylpropyl)-1-indenylbicyclo[2.2.2]octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 15 mg '43%; ^H-NMR (DMSO-d6): (?l, 40-2,20 (m, 11H), 2,82 (m, 2H), 3,05-3 ,5 (m,7H),3,58-3,86 (m,3H),4,92-4,95 (m,2H), 5,00 (m,1H),5,70-5,84 (m,1H),6,93-7,0〇(m,2h),7,26-7,44 (m,6H); MS [M-CF3COO]+: 439. Example 126 Phenylthiophene-3 -Methylaminocarbamic acid 1-azabicyclo[2·2·2]oct-3-(R)-based title compound was synthesized according to Method a. The final step yield was 2 mg, 15%. ;丨H-NMR (DMSO-d6): 5 1,10-1,60 (m,4H),1,84 (bs, 1H), 2,46-2,62 (m,5H),3,02 -3,10 (m,1H),4,62-4,67 (m,1H), 4,84 (s,2H),6,99 (m,1H),7,18-7,36 (m ,6H),7,47-7,50 (m, 1H).; MS [M+l]+: 343 0 -67 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1304067 A7 B7) V. Description of the invention (62 Example 127 1-'-propyl-3-(R)(phenyl 4 phen-3-ylmethylaminocarbamimidyloxy)-1 -mercaptobicyclo[2.2.2 The title compound was synthesized according to Method d. The final step yield was 8 mg, 26%; lH-NMR (DMSO-d6): 5 45-2,00 (m, 4H), 2,21 (bs, 1H), 3,04-3,42 (m,5H),3,78-3,91 (m,3H),4,87 ( s,2H),5,02 (m,1H),5,54-5,64 (m,2H),5,91-6,02 (m,1H),7,00-7,02 (m, 1H),7,22-7,39 (m, 6H), 7,50-7,52 (m, 1H); MS [M-CF3COO]+: 383. Example 128 1-(3-phenoxypropyl) -3-(R)(phenylthiophen-3-ylmethylaminocarbamimidyloxy)-b fluorenylbicyclo[2·2·2]octane; the title compound of the trifluoroacetate salt was synthesized according to method d. The yield of the final step was 丨2 mg, 31%; MS [M-CF3COO]+: 477. Example 129 1-(3-phenylpropyl)-3-(R)(phenylthiophen-3-ylmethyl) Aminomethylmercaptooxybicyclobicyclo[2.2.2]octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 15 mg '41%; /H-NMR (DMSO-d6): 5 1,45-2,18 (m,7H), 2,59 (m, 2H), 3,02-3, 44 (m,7H),3,84 (m,1H),4,87 (s,2H),4,99 (m, 1H),7,00 (m,1H),7,21-7,38 (m, 11H), 7, 47-7, 50 (m, 1H); MS [M-CF3COO]+: 461. Example 130 1-(3-Winter-based propyl)-3-(R)(phenyl η-cephen-3-ylmethylaminomethyl aryloxy)_ -68 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1304067 A7 B7 V. Description of the invention (63) Ketyl bicyclo [2.2.2] octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 4 mg, 11%; MS [M-CF3C〇〇]+: 459 〇 Example 1 3 1 1-(2-lowoxyethyl)-3-(r) (phenyl P. 3-methylaminoaminomethyleneoxybicyclo[2.2.2]octane; trifluoroacetate title compound was synthesized according to method d. The final step yield was 丨6 mg '42%; MS [M, CF3COO ]+: 477. Example 132 i-[3-(3-Aminophenoxy)propyl]-3-(κ)(phenyl fluorenylmethylaminopyridyloxy)-1-indenylbicyclo[2.2 .2]octane; the title compound of the trifluoroacetate salt was synthesized according to Method d. The final step yield was 丨3 mg, 330 / 〇; MS [M-CF3COO]+: 493 0 Example 133 1-Heptyl-3- (R)(phenylthienylmethylaminomethylcarbazyloxyindenylbicyclo[2.2.2]octane; the title compound of the trifluoroacetate salt was synthesized according to Method d. The final step yield was 12 mg? 34%; ^-NMR (DMSO-d6): 5 0.88 (m, 3H), 1,28 (m, 8H), l,6〇-2,19 (m,7H),3,00-3,41 (m, 7H),3,83 (m, 1H),4,88 (s, 2H), 5,99 (m, 1H), 7,01 (m, 1H), 7,21-7,39 (m, 6H ), 7,49-7,52 (m, 1H); MS [M-CF3COO]+: 441 0 Example 134 1-methyl-3-(R)(phenylthiophen-3-ylmethylamino) Mercaptooxycarbonylbicyclo [2.2.2]octane; Trifluoroacetate -69 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) Binding

1304067 A7 _________ B7 V. INSTRUCTIONS (64) The title compound was synthesized according to method d. The final step yield was 丨2 mg, 42%; MS [M-CF3C 〇〇]+: 357. Example 135 3-(R)(phenylsoxin-3-ylmethylaminomethionyloxybu-(i)-thienylpropyl)-1-indenylbicyclo[2.2.2]octane; bromide The title compound was synthesized according to Method c. The final step yield was 5 〇 0 mg 78%; !H-NMR (DMSO-d6): 5 1,45-2,19 (m, 7H), 2,83 (m, 2H), 3,04-3 ,13 (m,1H),3,19-3,46 (m,6H),3,83-3,90 (m,1H), 4,88 (s,2H),4,99 (m,1H ), 6, 94 (m, 3H), 7, 20-7, 40 (m, 7H), 7, 49 (m, 1H); MS [M-Br]+: 467; melting point: li〇t:. Example 130 3-(R)(phenylindole-3-ylmethylaminomethionyloxyphenoxyethylindenylbicyclo[2.2.2]octane; bromide; ft 4 compound according to method c Synthesis. The final step yield was 3 5 〇 mg 63%; H-NMR (DMSO-d6): (5 1,45-2,20 (m, 5H), 3,27 (m, 1H), 3,40 -3,80 (m,6H),4,00-4,06 (m,1H),4,44 (bs 2H),4,87 (s,2H),5,02 (m,1H),6 , 99-7,04 (m,4H),7,20-7,38 (m,8H), 7,48 (m,1H); MS [M-Br]+: 463; melting point: 131. Example 137 1-Butyl 4-phen-2-ylmethylaminocarbamate 1-azabicyclo[22.2]oct-3-(R)-ester The title compound was synthesized according to Method a. 〇mg^ 29〇/〇; lH-NMR (DMS〇.d6): (? 0.85 (m, 3H), 1,19-1,68 (m, 8H)' 1,92 (m,1H),2 , 49-2, 64 (m, 5H), 3, 〇 5-3, 22 (m, 3H),

4,56-4,62 (m, 3H), 6,95-7,04 (m, 2H), 7,42-7,44 (rn 1H)* MS -70 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 x 297 mm) 1304067 A7 ____ Β7 _ V. Description of invention (65 ) [M+l]+: 323 〇Example 138 1-allyl-3-(R)(butyl, stopper Phen-2-ylmethylaminomethionyloxy)-1-indenylbicyclo[2.2.2]octane; trifluoroacetate salt title compound was synthesized according to method d. The final step yield was 10 mg, 23%; W-NMR (DMSO-d6): (5 0.86 (m, 3H), 1, 20-1, 26 (m, 2H), 1, 42-1, 49 ( m,2H),1,58-2,05 (m,4H),2,32 (bs,1H), 3,20-3,41 (m,7H),3,74-3,94 (m, 3H),4,51-4,72 (m,2H),4,99 (m,1H),5,55-5,64 (m,2H),5,87-6,10 (m,1H) ,6,99 (m,1H), 7,08 (m,1H),7,46 (m,1H); MS [M-CF3COO]+: 363. Example 139 3-(R)(butyl propyl phene -2-ylmethylaminomethionyloxy)-l-(3-phenylpropyl y. sulphonylbicyclo[2.2.2]octane; bromide title compound is synthesized according to method d. The rate is 13 mg^25%; lH-NMR (DMSO-d6): (5 0.85 (m, 3H)5 1,19-1,26 (m, 2H), 1,41-1,50 (m, 2H) ), 1, 75-2, 10 (m, 6H), 2, 30 (bs, 1H), 2, 59 (m, 2H), 3, 10-3, 50 (m, 9H), 3, 83 ( m,1H),4,5(M,74 (m,2H), 4,97 (m,1H),6,97 (m,1H),7,07 (m,1H),7,20-7 , 35 (m, 5H), 7,43 (m, 1H); MS [M-CF3COO]+: 441. Example 140 贰-4-phen-2-ylmethylcarbamic acid 1-azabicyclo[2· 2 2] octyl R) ester ester The title compound was synthesized according to method a. Final step The rate is 34 〇 mg, 7%; W-NMR (DMSO-d6): 5 1,28], 31 (m, 1 Η), ΜΗ ” (m, 3H), 1,94-1,97 (m, 1H) ), 2,49-2,71 (m,5H),3,〇6-3,14 (m, -71 - This paper size applies to Chinese National Standard (CNS) A4 size (210 x 297 mm) 1304067 A7 ______ B7 V. INSTRUCTIONS (66) 1H), 4, 50-4, 57 (m, 4H), 4, 62-4, 69 (m, 1H), 6, 96-7, 06 (m, 4H) , 7,44-7,46 (m, 2H); MS [M+l]+: 363. Example 14 1 1-Mercaptopropyl-3-(R)(贰-thiophen-2-ylmethylamino) Mercaptooxycarbonylbicyclo[2.2.2]octane; trifluoroacetate title compound was synthesized according to the method. The final step yield was 9 mg, 19%; ^-NMR (DMSO-d6): 5 1,70-2,06 (m? 4H), 2,35 (bs, 1H), 3,25-3,50 (m,5H),3,80-3,94 (m,3H),4,54-4,71 (m,4H), 5,l〇(m,1H),5,55-5,65 ( m, 2H), 5, 87-6, 10 (m, 1H), 6, 98-7, 01 (m, 2H), 7, 06-7, 10 (m, 2H), 7, 47-7, 48 (m, 2H); MS [M-CF3COO]+: 403. Example 142 3-(R)(贰-4-phen-2-ylmethylaminomethionyloxy)-1-(3-phenylpropyl)-i-fluorenylbicyclo[2.2.2]octane; The bromide title compound was synthesized according to Method c. The yield of the final step was 690 mg^82%; ^-NMR (DMSO-d6): (5 1,78-2,10 (m, 6H), 2,34 (bs, 1H), 2, 53-2, 63 (m, 2H), 3, 23-3, 48 (m, 7H), 3, 88 (m, 1H), 4, 53-4, 74 (m, 4H), 5, 05 (m, 1H) ,6,98-7,01 (m,2H),7,〇2-7,ll (m,2H),7,21-7,37 (m,5H),7,44-7,48 (m , 2H); MS [M-Br]+: 48b Example 143 吱-2-ylmethyl-2-peak phen-2-ylmethylcarbamic acid i-azabicyclo[2 2 2] s- The 3-(R)-based title compound is synthesized according to Method a. The final step yield is mg-72 - This paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm) 1304067 A7 __B7 V. Invention Description (67) ' 10%; j-NMR (DMSO-d6): 5 1,1〇-1,34 (m,1H),1,44-1,67 (m, 3H), 1,93 (bs , 1H), 2,50-2,70 (m, 5H), 3,05-3,12 (m, 1H), 3,37-4,40 (m,2H),4,57-4,66 (m,3H),6,26-6,42 (m,2H), 6,95-7,03 (m,2H),7,45 (m,1H),7,61 (m,1H); MS [M+l]+: 347 ° Example 144 1-Allyl-3-(R)(furan-2-ylmethylthiophen-2-ylmethylaminocarbamidooxy)-1-indenyl Bicyclo[2.2.2]octane; trifluoroacetate title compound Synthesis according to method d. The final step yield was 7 mg, 15%; MS [M-CF3COO]+: 387. Example 145 3-(R)(purpur-2-ylmethylpyrim-2-ylmethyl) Aminomethylmercaptooxyl) small (3-phenylpropyl)-1-kentylbicyclo[2·2·2] octyl; trifluoroacetate title compound was synthesized according to method d. The final step yield was 11 MG

, 20. /. ; tNMR (DMSO-d6): 5 1,70-2,10 (m,6H), 2,31 (bs, 1H), 2,59 (m,2H),3,15-3,50 (m, 7H),3,84 (m,1H),4,36-4,56 (m,4H),5,03 (m,1H),6,32-6,44 (m,2H),6,92 -7, 〇8 (m, 2Ή), 7, 20-7, 35 (m, 5H), 7, 41-7, 46 (m, 1H), 7, 59-7, 62 (m, 1H); MS

[M-CF3COO]+: 465. Example 146 3-(R)(贰-thiophen-2-ylmethylaminomethionyloxythiophene-2-ylpropyl)-1-indenylbicyclo[2·2·2]octane; bromide The title compound was synthesized according to Method c. The final step yield was 69 〇 mg, 81%; tNMR (DMSO-d6): 5 1,78-2,1 〇(m,6H), 2 34 (bs, -73 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 x 297 mm) 1304067 A7 B7 V. Description of invention (68) 1H), 2,82 (m, 2H), 3,21-3,46 (m, 7H), 3,89 ( m, 1H), 4,54 (m, 4H), 5,06 (m, iH), 6,95-7,01 (m, 4H)? 7,07-7,11 (m, 2H), 7 , 38-7,49 (m,3H); MS [M-Br]+: 487; mp. Example 147 1-Acethiophen-2-ylmethylaminocarbamate 1-azabicyclo[2.2.2]oct-3-(R)-based ester The title compound was synthesized according to Method a. The final step yield was 3220 mg &gt;30%; lH-NMR (DMSO-d6): 5 1,20-1,33 (m, 1H), 1,45-1,80 (m,3H), 1, 93 (bs,1H),2,49-2,72 (m,5H),3,05-3,09 (m,1H), 3,81-3,83 (m,2H),3,83- 4,55 (m,3H),5,14 (m,2H),5,70-5,82 (m,1H),6,96-7,04 (m,2H),7,44-7, 45 (m,1H); MS [M+l]+: 307 〇 Example 148 1-Allyl-3-(R)(allylsulfon-2-ylmethylaminomethylmethyloxy)- 1-Mercaptobicyclo[2.2.2]octane; trifluoroacetate salt title compound was synthesized according to method d. The final step yield was 10 mg '24%; lH-NMR (DMSO-d6): 5 1,80-2,10 (m, 4H), 2,32 (bs, 1H), 3,20-3,50 (m, 5H), 3,75-3,94 (m, 5H), 4,5-4,69 (m, 2H), 5,01 (m,1H),5,10-5,23 (m ,2H),5,51-5,65 (m,2H),5,70-5,85 (m,1H),5,90-6,08 (m,1H),6,95-7,10 (m, 2H), 7, 47 (m, 1H); MS [M-CF3COO]+: 347. Example 149 3-(R)(propyl thiophen-2-ylmethylaminomethionyloxy)-1-(3-phenylpropyl)-1-indenylbicyclo[2·2·2] octane Alkane; Trifluoroacetate-74 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1304067 A7 ______ B7, invention description (69) The title compound is synthesized according to method d. The yield of the final step was 11 mg '22%; lH-NMR (DMSO-d6): 5 1,74-2,1 〇(m,6H), 2,31 (bs, 1H), 2,59 (m ,2H), 3,16-3,56 (m,7H),3,76-3,90 (m,3H), 4,48-4,71 (m, 2H), 4,99 (m, 1H ), 5,11-5,23 (m, 2H), 5,72-5,83 (m,1H),6,98 (m,1H),7,06-7,07 (m,1H), 7,20-7,35 (m,5H), 7,44 (m,1H); MS [M-CF3COO]+: 425 〇 Example 150 cyclopentylthiophen-2-ylmethylcarbamic acid 1-nitrogen Heterobicyclo[2.2.2]oct-3-(R) Ester The title compound was synthesized according to Method a. The yield of the final step was 2250 mg, 33%; iH-NMR (DMSO-d6): 5 1,20·1,40 (m,1H), 1,45-1,72 (m,11H),1,89 (bs, 1H), 2, 45-2, 62 (m, 5H), 3, 03-3, 10 (m, 1H), 4, 22 (bs, 1H), 4, 50-4, 56 (m , 3H), 6, 93-6, 99 (m, 2H), 7, 38 (m, 1H); MS [M+l]+: 335. Example 15 1 Bulyl-3-(R)(cyclopentylthiophen-2-ylmethylaminocarbamoyloxyindenylbicyclo[2.2.2]octane; trifluoroacetate salt title compound according to method d. The final step yield is 丨〇mg^22%; lH-NMR (DMSO-d6): 5 1,40-2,05 (m5 12H), 2,27 (bs, lH), 3,03- 3,42 (m,5H),3,70-3,95 (m,3H),4,15-4,35 (m,1H), 5,58 (m,2H),4,99 (m, 1H),5,54-5,65 (m,2H),5,87-6,10 (m, lH), 6,97 (m, 1H), 7,03 (m, 1H), 7,41 -7,43 (m, 1H); MS [M-CF3COO]+: 375. Example 152 -75 - ^ Paper size applicable Medium National Standard (CNS) A4 size (210X297 mm) 1304067 A7 B7 V. Description of invention (70) 3-(R)(cyclopentyl-2-phenethylaminomethylmercaptooxy)-1-(3-phenylpropyl)-1-indenylbicyclo[2.2.2] octane The title compound was synthesized according to Method d. The final step yield was 13 mg^24%; ^-NMR (DMSO-d6): 5 1,40-2,10 (m, 14H), 2, 25 (bs, 1H), 2,58 (m,2H), 2,95-3,50 (m,7H),3,81 (m,1H),4,26 (m, 1H), 4,50 -4,70 (m,2H),4,97 (m,1H),6,93 (m,1H),7,03 (m, 1H),7,20-7,40 (m,6H MS [M-CF3COO]+: 453. Example 153 furan-2-ylmethylphenylcarbamic acid 1-azabicyclo[2·2·2]oct-3-(R)-based ester title compound Synthesis according to method a. The final step yield is 1400 mg? 18%; lH-NMR (DMSO-d6): 5 1,19-1,60 (m, 4H), 1,84 (bs, 1H), 2, 44-2,57 (m,5H),3,01-3,09 (m,1H),4,63 (m,1H),4,82 (s, 2H),6,21 (m,1H) , 6, 36 (m, 1H), 7, 20-7, 37 (m, 5H), 7, 59 (m, 1H); MS [M+l]+: 327. Example 154 1-propyl- 3-(R)(Indolyl-2-ylmethylphenylaminomethyloxy)-1-indenylbicyclo[2.2.2]octane; trifluoroacetic acid salt title compound was synthesized according to procedure d. The final step yield was 7 mg, 16%; !H-NMR (DMSO-d6): (5; MS [M-CF3COO]+: 367. Example 155 3-(R) (furan-2-ylmethylbenzene Aminoaminomercaptooxyl-1-(3-phenylpropyl)-i-fluorenylbicyclo[2·2·2]octane; the title compound of trifluoroacetate is synthesized according to method d. The rate is 11 mg ^ 21%; !H-NMR (DMSO-d6): (5 1,65-2,10 (m, 6H), 2,19 (bs, -76 - This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1304067 A7 _ B7 V. Description of invention (71) 1H), 2,59 (m, 2H), 3,10-3,50 (m, 7H), 3,83 (m, 1H), 4,85 (bs, 2H), 4,98 (m,ih),6,26 (m,1H),6,36 (m,1H),7,20-7,39 ( m, 10H), 7,59 (m,1H); MS [M-CF3CO〇]+: 445 〇 Example 156 贰-furan-2-ylmethylcarbamic acid 1-azabicyclo[2.2.2] octane The title compound of -3-(R)-ester was synthesized according to Method a. The yield of the final step was 2 100 mg.sup.22%; lH-NMR (DMSO-d6): 5 1,20-1,70 (m, 4H) , 1,89 (bs, 1H), 2,45-2,71 (m,5H),3,00-3,12 (m,1H),4,40 (m,4H),4,62 (m , 1H), 6, 22-6, 40 (m, 4H), 7, 59 (m, 2H); MS [M+l]+: 331. Example 157 1- Allyl-3-(R)(fluorene-furan-2-ylmethylaminocarbamimidyloxy)-1-indenyl bis-% [2.2.2] octyl: 3⁄4: trifluoroacetate title compound Method d. The final step yield was 7 mg, 16%; W-NMR (DMSO-d6): 5; MS [M-CF3COO]+: 371. Example 158 3-(R)(贰-furan-2- Methylaminoaminomethaneoxy)-1-(3-phenylpropyl)-1-indenylbicyclo[2·2·2]octyl; trifluoroacetate title compound is synthesized according to method d. The yield of the step is 11 mg, 20%; iH-NMR (DMSO-d6): 5; 1, 70-2, 10 (m, 6H), 2, 29 (bs, 1H), 2, 59 (m, 2H) ),3,10-3,50 (m,7H),3,82 (m,1H),4,32-4,54 (m,4H),5,01 (m,1H),6,29- 6,41 (m,4H),7,20-7,35 (m,5H), 7,57-7,61 (m,2H); MS [M-CF3COO]+: 449 0 Example 159 Benzylbenzene 1-Azabicyclo[2.2.2]heptan-4-yl ester-77 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1304067 A7 B7 V. Title of invention description The compounds were synthesized according to the method &amp; The final step W is formate; iH_NMR (DMSO_d6): 5 (s, 2H), 2, 77 (bs, 2H), 3, 03 (bs, 2H), 4, 84 (S, 2H), 7, 14 -7,32 (m, 10H), 8,19 (s, 1H); MS [M-HCOO]+: 323 〇 Example 16 0 1 phenylaminocarbamic acid 1-azabicyclo[2.2.2] octane -4-based

The title compound was synthesized according to Method a. The final step yield was 2 56 mg, 1% was formate; 1H-NMR (DMSO-d6): 5 1,81 (m, 6H), 2,83 (m, 6H), 4,81 (s, 2H),7,14-7,32 (m,10H),8,24 (s,1H); MS

[M-HCOO]+: 337. Examples 16 1 to 165 illustrate pharmaceutical compositions and preparation procedures thereof in accordance with the present invention. Example 161 Preparation of a pharmaceutical composition: a lozenge

Formulation: V The compound of the invention .................5.0 mg lactose........................ ........113.6 mg, microcrystalline cellulose.....................28.4 mg salty light tannic acid anhydrate..... .........1.5 mg 丨 magnesium stearate........................1.5 mg^ Using a mixer, 15 g The compound of the invention was mixed with 340.8 grams of lactose and 85.2 grams of microcrystalline cellulose. The mixture was subjected to compression molding using a roll compactor to obtain a sheet-like compressed material. The flaky compressed material was pulverized using a hammer mill. The pulverized material was sieved through a No. 20 sieve. A 4.5 g light-weight acid anhydride anhydrate and -78 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) l3〇4〇67 A7 B7 V. Invention description (is) 4.5 g hard Magnesium citrate is added to the sieved material and mixed. The mixer product was placed in a dosing machine. The tablet was equipped with a 7.5 mm diameter die/punch system to obtain 3,000 spindles, each weighing 150 mg. Example 162 Preparation of Pharmaceutical Composition: Coated Ingot Formulation: Compound of the Invention ........................... 5.0 mg Lactose.... ..................................... 95.2 mg corn starch......... .........................40.8 mg of polyethylidene leaves (: Harbinone............. .......7 · 5 mg magnesium stearate....................................1.5 Mg of hydroxypropyl cellulose........................2.3 mg of polyethylene glycol........... .......................0.4 mg of titanium dioxide........................ ..........1.1 mg purified talc...............................0.7 mg Using a fluid bed granulator, 15 g of the compound of the invention was mixed with 285.6 g of lactose and 122.4 g of corn starch. In addition, 22.5 g of polyethenyl pyrrolidone was dissolved in 127.5 g of water to prepare a binding solution. The binder solution was sprayed over the foregoing mixture to form granules. A portion of 4.5 g of magnesium stearate was added to the granules thus obtained and mixed. The resulting mixture was placed in a tableting machine equipped with a die/punch double concave system having a diameter of 6.5 mm. Obtained Each weighing 150 mg 3,000 spindles. Secondly, the coating solution is prepared by 6.9 g of hydroxypropyl methylcellulose 2910, 1.2 g of polyethylene glycol 6000, 3.3 g of titanium dioxide and 2.1 g of pure talc suspension -79 - This paper size applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) binding

1304067 A7 B7 V. INSTRUCTIONS (74) Prepared in 72.6 grams of water. The above-prepared 3 was prepared using a high speed coating, and the ingot was coated with a coating solution to obtain a film ingot, each weighing 154.5 mg. Example 163 Preparation of Pharmaceutical Composition: Liquid Inhalant Formulation: Compound of the Invention.............400 micrograms of physiological saline solution................ .... 1 ml a 40 mg of the compound of the invention is dissolved in 9 ml of physiological saline, the solution is adjusted to a total volume of 1 ml with the same salt solution, and 1 ml of each volume is dispersed in a volume of 1 ml and then at 115 Sterilize for 30 minutes at °C to obtain a liquid inhaler. Example 164 Preparation of Pharmaceutical Composition: Powder Inhaler Formulation: Compound of the Invention ...........200 micrograms of lactose.................... ... 4,000 micrograms A 20 grams of the compound of the invention is uniformly mixed with 4 grams of lactose, and each 2 〇 0 gram mixture is filled in a powder filler for exclusive use in the manufacture of a powder inhaler. Example 165 Preparation of a pharmaceutical composition: an inhalation aerosol. Formulation: Compound of the invention..........................200 micrograms of dehydrated (absolute) ethanol USP..... .................. 8,400 μg-80 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public love) 1304067 A7 B7 V. Description of invention (75) 1,1,1,2-tetrafluoroethane (^^(:-1348).........46,810 micrograms of active ingredient concentrate by dissolving 0.0480 grams of the compound of the invention at 2.0 1 60 g of ethanol is prepared. The concentrate is added to a suitable filling device. The active ingredient concentrate is dispensed into an aerosol container, and the space above the container is purged with nitrogen or HFC-134A vapor (the sweeping component must not contain more than 1 ppm of oxygen) and The valve is sealed. Then fill in 1.2.344 g of HFC-134A propellant into the sealed container. -81 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Claims (1)

9? Ββ4£^δ〇131867 Patent Application g L Public Chinese Patent Application Substitution (1997) g | VI. Patent Application 1. A compound which is an amino decanoic acid of formula (I) ester: Where R1 represents R3 represents hydrogen or a halogen atom, or a linear or branched alkyl group; R2 represents a fluorenyl group, a phenethyl group, a furan-2-ylindenyl group, a porphin-2-ylmethyl group or a pyrimen-3-ylmethyl group, Or a linear or branched alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms; p is 1 or 2, and aza Substitution of the bicyclic ring may include all possible asymmetric carbon configurations at the 3 or 4 position; or a pharmaceutically acceptable salt thereof. 2. For the compound of claim 1 of the patent scope, it is expressed by formula (II): This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 8 8 8 8 AB c D , (CH2)n —A — (CH2)fiT 1304067 Patent Application B wherein R1, R2 and p are as defined in claim 1; m is an integer from 0 to 8; A represents -CH2-, -CH=CR4-, -CR4=CH-, -CO-, -0-, -S- or -CR4R5., wherein R4 and R5 each independently represent a hydrogen atom, a straight or branched C! to C6 alkyl group, or R4 and R5 together form a C3 to C6 cycloaliphatic group η is an integer from 0 to 4; Β represents a hydrogen atom, an alkoxy group, -COOR4 or -OOCR4 wherein R4 is as defined above or is cyano, 5,6,7,8-tetrahydroindenyl, biphenyl Or the base of formula (1) or (ii) R7 4tT^R3 (0 wherein Z represents S; R3 is as defined above; and R6, R7 and R 8 each represent hydrogen or a halogen atom or a hydroxyl group, phenyl, -OR4, -NHCOR4, -CONR4R5, -CN, -N02 , -COOR4 or -CF3 group or linear or branched substituted or unsubstituted Cl to c6 2- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1304067 A8 B8 1304067 A8 B8 C8 D8 VI. Patent application scope -CH2-, -CH=CH-, or -0-base. 11. A compound according to claim 2, wherein b_(ch^_a_(CH2)m- represents one selected from the group consisting of 3-phenoxypropyl, 2-phenoxyethyl, 3-phenylallyl, benzene Ethyl, 3-phenylpropyl, 3-(3-hydroxyphenoxy)propyl, 3-(4-fluorobenzoxy)propyl, 3-ττcephen-2-ylpropyl, 1-propanil And a group of 1 - heptyl group. 12. A compound according to claim 2, wherein χ- represents a chlorine, a desert or a trifluoroacetic acid anion. 13. A compound according to claim 1 or 2, wherein The bicyclic group is substituted at the 3 position. 14. The compound of claim 13 wherein the substituent at the 3 position has the (R) configuration. 15. The compound of claim 1 or 2, Is a single isomer. 16. The compound of claim 1, wherein: benzylphenylaminocarbamate 1-azabicyclo[2.2.2]oct-3-(!1) acetazinyl (4-fluorophenyl)carbamic acid 1-azabicyclo[222]octyl_3_(phanyl ester fluorenyl (p-tolyl)amine decanoic acid 1-azabicyclo[2.22] 辛_3- (phantom酉 旨 butyl phenyl phenyl carbamic acid 1 · azabicyclo[2.2.2] osin-3_(r) vinegar 1-Azabicyclo[2 2 2]octyl 3 -ethylbiphenyl-2-ylmethylcarbamate (R) 1-Azabicyclophene phenethylphenylaminocarbamate [2.2.2] Xin_3_(11) Metopentylphenylaminodecanoic acid 1-azabicyclo[2.2.2]octyl_3_(11) Fu 61曰pent-4-enylphenylaminodecanoic acid 1-nitrogen Heterobicyclic sulphate L2·2·2] oct-3-(R) phenyl phenyl pyrimidin-3-ylmethyl carbamic acid 1-aza bis-pyrene Ι 2·2·2] 辛-3 -(R) -4- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) ^~--------__ A8 B8 C8 1304067 bis-cyclo[2·2·2] octyl-3. (R) butyl porphin-2-yl decylamino decanoate-3. (R) 贰-Ρ 士 士 基Methylamino decanoic acid 1-azabicyclo[2.2.2]octyl ester cyclofloxacin 2 ylmethyl _2 violent phenanthyl-2-aminomethyl carbazate diazepam [2·2·2 ] Xin-3-(R)-based esters, propyl sulfonate-2 - fluorenyl-based faecal manure, 丞, 丞 丞 曱 曱 L 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Amino-methylaminocarbamic acid 1-azabicyclo[2.2.2]oct-3-(R)-based ester furan-2-ylmethylphenylaminocarbamate, azabicyclo[22.2] xin^ _ Base ester y 贰-nonan-2-ylmethylphenylaminocarbamic acid, azabicyclo[2 2 2]octyl (R) benzyl phenyl phenyl carboxylic acid, 1-azabicyclononyl decyl benzene 1-Azabicyclo[2·2·2]octyl thioglycolate or a pharmaceutically acceptable salt thereof. 17. The compound of claim 2, which is 3-(R)(nonylphenylaminomethylindenyloxy)phenylallyl&gt;didecylbicyclo[2.2.2]octane; Bromide 1 1 -l-propyl-3-(R)( +ylphenylaminocarbazyloxy)_ι_cholyl double [2.2.2]octane; bromide 3-(R) (benzyl) Phenylaminomethionyloxy)_:[-Phenylethyl-didecylbicyclo-5- This paper is used in Chinese Standards (CNS) A4 Specification (210X297). ABCD 1304067 VI. Patent Application Park [2] ·2·2]octane; bromide 3-(R)(benzylphenylaminocarbamidooxy)septene-2-yl-propyl)^-indenylbicyclo[2.2.2]octane; Bromide &amp;3-(R)(benzylphenylaminomercaptooxyl)_1-(3-phenylpropanyl[2.2.2]octane; brook compound $yl double 3-(R)(benzyl Phenylaminomethylmercaptooxy)_1-(2-phenoxyethylindenylbicyclo[2·2·2]octane; bromide 3-(R)(butylphenylaminocarbazyloxy) Phenylallyl bicyclo[2.2.2]octane; bromide $ &amp; 1-allyl-3-(R)(benzylphenylaminocarbazyloxybutylidene bicyclo[2 · 2 · 2 ] Xin Shao, &gt; Stinky 3-(R) (butylphenylamino group A) Oxygen)phenoxyethyl)-indole-hydrazinobicyclo[2.2.2]octane; bromide &amp; 3-(11)(butylphenylaminomercaptooxyl)-1_[3-(3 -hydroxyphenyloxy)propyl]_1_mercaptobicyclo[2·2·2]octane; bromide 3-(R)(butylphenylaminocarbamimidyloxy) small [W4·fluorophenoxy)propene Keb^ fluorenylbicyclo[2.2.2]octane; bromide 3-(R)(butylphenylaminocarbamimidyloxy)1(34 phen-2-ylpropyl)+ fluorenylbicyclo[2.2 .2] Octane; bromide 3-(R) (butyl-benzylaminocarbazyloxy)-1-(3-phenylpropyl) succinylbicyclo[2.2.2]octane; bromide 3- (R) (phenyl phenanthene-2-ylmethylaminomethionyloxy) 4-(3-sulfenophene-2-ylpropyl)-1-indenylbicyclo[2.2.2]octane; bromine 1-(2-Oxo-Ethyl)-3 -(R)(phenyl-p-cephen-2-ylmercaptoamine-based urethane-6- This paper scale applies to Chinese National Standard (CNS) A4 Specification (210X297 public) 1304067 A8 B8 C8 ______ D8 VI. Patent application range Oxygen)-1-mercaptobicyclo[2.2.2]octane; bromide 1-allyl-3-(R) (phenyl pyrimidine) Benz-2-ylmethylaminomethionyloxy)-1-indenylbicyclo[2·2·2]octane; bromide 3-(R)(phenethyl) Aminomethylmercaptooxyphenoxyethyl)nonylbicyclo[2.2.2]octane; trifluoroacetate 1-allyl-3_(R)(phenylindole-3-ylmethylamino) Mercaptooxy)-1-indenylbicyclo[2·2·2]octane; trifluoroacetate 3-(R)(phenyl-phenant-3-ylmercaptoaminocarbamoyloxy)-1 -(3-sulfenophen-2-ylpropyl)-1-indenylbicyclo[2·2·2]octane; bromide 1-(2-phenoxyethyl)-3-(R)(phenyl Ρ-cephen-2-ylmethylaminomethionyloxy)·1-kneebicyclo[2.2.2]octane; desertification 3-(R)(贰-thiophene-2-ylmethylamino) Mercaptooxyphenylpropyl)- 1 fluorenylbicyclo[2.2_2]octane; bromide 3-(R) (贰 吩-2-aminomethylaminomethyl hydrazide) ΐ-(3 ·Umtraphene-2-ylpropyl)-1-indenylbicyclo[2.2.2]octane; bromide 1-allyl-3-(R) (dilyl far phen-2-ylmethylamine) Methyl fluorenyloxy)_1_ fluorenylbicyclo[2·2·2]octane; trifluoroacetate 3-(R)(cyclopentyl sulfen-2-ylnonylamino fluorenyloxy)_1- (3-phenylpropyl)-1-kentylbicyclo[2·2·2]octyl; trifluoroacetate 3-(R)(indol-2-ylmethylphenylaminodecyloxy) )-1_(3_phenylpropyl)-1-indenylbicyclo[2.2.2]xin Alkane; trifluoroacetate. 18. A compound according to claim 2 or 2, characterized in that it has an IC50 value (nM) of less than 35 for the muscarinic M3 receptor. 19. A pharmaceutical composition as a muscarinic μ 3 receptor antagonist, comprising _ -7 - the paper size is applicable to the Chinese National Standard (CNS) Α 4 specification (210X297 mm) 1304067 A8 B8 For example, the patent application Sutu goods can be used to treat people who are treating diseases or diseases. Or a compound of 2 compounds. 2〇=:: Compound of the first or second range of the range, in the treatment of the system or animal body. For example, in the pharmaceutical composition of claim 19, the treatment method of the body or animal body. ,, 22. The compound of the patent application scope (4), which is used for treatment, ', system. m (4) urine or gastrointestinal 23 · For example, please (4) (4) screaming doctor (9), the drug is used to treat breathing, secretion, and is used to make medicine. , urine or gastrointestinal diseases or diseases -8-