TW200300673A - Azabicyclic-phenyl-fused-heterocyclic compounds for treatement of disease - Google Patents

Abstract

The invention provides compounds of formula I: wherein Azabicycio is any of: These compounds may be in the form of pharmaceutical salts or compositions, and racemic mixtures or pure enantiomers thereof. The compounds of formula I are useful in pharmaceuticals in which α7 is known to be involved.

Description

200300673 0) 说明, Po Ming description of the implementation and schematic brief description of the system (CNS) activity involves cognition, learning from acid test acetic acid showed different role activities. Unfortunately, the least desirable and low safety of nicotine are other large acting molecules of the receptor family. Target of sex drug molecules. nAChR contains a large family of ion channels, this gene family is assembled together, and acetylcholine is the majority of breastfeeding that selectively activates all difficult-to-test targets (the description of the invention should state: the technical field to which the invention belongs (Previous technology, content, and description) Technical Field The nicotinic acid acetylcholine receptor (nAChR) plays a major role in the central nervous system. In particular, its habits, moods, feelings, and neuroprotection are known. There are several types of base receptors, and each is significant in regulating CNS function. Nicotine affects all such receptors, and has multiple, not all activities are expected. In fact, one of its properties is its addictive nature, and its proportion in efficacy. The present invention relates to a7 nAChR when compared to members closely related to the gating of this large ligand. Therefore, the present invention provides actives with fewer side effects. Prior art Cell surface receptors are often superior and effective drugs: ligand gating groups that control neuronal activity and brain function. These receptors have a pentameric structure. The lactation group is composed of nine alpha and four subunits. It forms multiple subtypes of receptors and has unique pharmacology. These subtypes are endogenous modulators, and the nicotine non-selected nAChR 〇 a7 nAChR is a receptor system that has been proven to be. Natural a7 nAChR cannot routinely stabilize surface animal cell lines (Cooper and Millar, J. Neurochem., 1997, 68 (5): 2140-51) 0 makes the functional testing of α7 nAChR challenging another The characteristic is, 0 continuation pages (when the description page of the invention is insufficient, please note and use the continuation page) 200300673

Description of the invention IfM (2)---This receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation is greatly limited by the functional assays that can be used to measure channel activity.

Recently, Eisele et al. Have indicated that the N-terminal ligand binding functional site of a7 nAChR (Eisele et al., Nature, 366 (6454), 479-83, 1993) forms C- with the pores of 5-HT3 receptor Chimeric receptors formed between the terminal functional sites are well expressed in Xenopus egg cells, while maintaining nicotinic acid sensitizer sensitivity. Eisele et al. Used the a-nAChR receptor N-terminus in birds (chicken) and the C-terminus in mouse form of the 5-HT3 gene. However, under physiological conditions, a7nAChR is a calcium channel and 5-HT3R is a sodium and potassium channel. In fact, Eisele et al. Stated that a7nAChR / mouse 5-HT3R behaves very differently from natural α7 nAChR, in which the pore structure does not conduct calcium, but is actually blocked by calcium ions. WO 00/73431 A2 reports on the conditions under which 5-HT3R can conduct calcium. This test can be used to screen for activator activity at this receptor. U.S. patent application 2002/0016334 discloses a pharmaceutical composition for treating a disorder of hyperattention. U.S. Patent 6,441,049 B2 discloses a method for treating neurodegenerative disorders by inhibiting amyloid cold peptide binding. U.S. Patent No. 6,054,464 discloses amine-methylacid bicyclic esters, as well as intermediates, and the synthetic use of intermediates that can be used in therapy, particularly for the treatment or prevention of mental disorders and mental impairment. U.S. Patent No. 5,977,144 discloses compositions of benzylidene- and cinnamyl-neonicotinoid, and the use of these compositions to treat symptoms associated with defects or dysfunctions of nicotinic acid subtype brain receptors method. These compositions are treated as α7 by 200300673.

(3) The body subtype is the target, showing the ancient 4T I> _L 'Λ- ^ ^ Ί has little or no α402 or other effects. Activation of Dou Yali U.S. Patent No. 5,830,902 discloses a tricyclic heterocondensation product, oral, awakening, and / or with another activity 1 for nasal administration. At first glance, 5 tryptaminergic 5-HT3 These compounds have been revealed to have strong horny shark association? It can be used as a cholesterol-lowering agent without causing parabens j activity. US Patent No. 5,576,434 discloses a method for preparing fluorene ... 2,3,3 \ 4,5,6-hexahydro.-benzo [(1 Division Isoquinoline Small Ketone, its medicinal effect [2'2'2] oct-3-yl)-a novel method, the compound is a pentamidine 3 receptor antagonist, = can be connected to the double salt U.S. Patent 5,561,149 discloses mono- or bicyclic carbocyclic family two intermediates. Or amidine or imidazocarbazole in the manufacture of pharmaceuticals, 5 carboxylic acid esters for the treatment of stress-related psychiatric disorders, use: thumb medicine is suitable for the treatment of rhinitis or serotonin-induced diseases For example, co-administration of a police agent to increase its bioavailability U.S. Patent No. 5,434,161 discloses a melamine and p-pyridine antagonist. U.S. Patent No. 5,362,74 ° discloses dihydrobenzofurancarboxamides for treating CNS disorders, as well as motility disorders, and / or breastfeeding 'which can be used to treat and / or pain and / or migraine. Uterine in animals U.S. Patent No. 5,185,333 discloses τι Taolin compounds which can prevent, treat or treat various digestive diseases, vomiting and central nervous system = 4 drugs for pre-U.S. Patent No. 5,175,173 disclosed as antiemetic drugs Disturbances on the Latin American system etc. ^ Carboxamide. & U.S. Patent No. 5,122,528 for the use of sperm arsenic agents discloses the use of bicyclic cyclamidine, and U.S. Patent No. 5,114,947 for the use of benzobicyclic cyanine. Prolonged amines to reduce anxiety 200300673 (4) Invented a method for m. U.S. Patent No. 5,039,680 discloses 5-HT3 antagonists for preventing or reducing dependence on agents that cause dependence. U.S. Patent 4,983,600 discloses heterocyclic compounds useful as 5-HT3 antagonists. U.S. Patent No. 4,935,511 discloses benzohumine and benzoxazepine carboxamide 5-HT3 antagonists, which have properties including CNS, antiemetic and pregastric motility, and do not have any significant D2 receptor binding affinity . U.S. Patent 4,933,445 discloses heteroazabenzobicyclic carboxamide 5-HT3 antagonists which have properties including CNS, antiemetic and progastric motility. U.S. Patent 4,924,010 discloses benzoxamidine as an intermediate of a 5-HT3 antagonist which has CNS and progastric motility without any significant receptor-binding properties. U.S. Patent 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-polyacid, which can be used as an intermediate for 5-HT3 antagonists. U.S. Patent No. 4,920,227 discloses benzobicyclic carboxamide 5-HT3 antagonists. U.S. Patent 4,920,219 discloses substituted saturated and unsaturated indolequinines and benzodiazepine carboxamide, and their valuable uses as 5-ht3 antagonists with CNS and progastric motility, Without any significant 02 receptor binding properties. / U.S. Patent 4,910,193 discloses the treatment of gastrointestinal disorders. U.S. Patent No. 4,892,872 discloses benzohumine compounds which exhibit 5-HT3 receptor antagonistic activity and can be used as antiemetics and the like. U.S. Patent 4,863,921 discloses dibenzofurancarboxamide and its use as 5-HT3 -10- 200300673 ⑸ Description of the invention An antagonist, which has unique CNS, antiemetic and pregastric motility, without any significant D2 exposure体 Binding properties. U.S. Patent No. 4,857,517 discloses certain specific substituted y-bicyclic _ [2 · 2 · 2] octan-3-yl) fluorenamino-2,3,4,5-tetrahydro- small benzoxadenine, And its valuable use as a pentamidine 3 antagonist, it has CNS and progastric motility activity 'without any significant D2 receptor binding properties. U.S. Patent No. 4,835,162 discloses nicotine as an activator and antagonist of smoking inhibitors. U.S. Patent No. 4,803,199 discloses pharmacologically useful heterocyclic acid esters and fluorene amines or sub-fe-based bridging anhydropyridines as fluorescein melamine antagonists. U.S. Patent No. 4,797,406 discloses amines and esters containing bridging hexahydroe, and uses as 5- # tryptamine M antagonists. U.S. Patent 4,721,720 discloses a method for treating vomiting, anxiety, and / or irritating bowel symptoms. U.S. Patent No. 4,612,319 discloses bridging pyridinamides, compositions containing them, and methods of using the same. U.S. Patent 4,605,652 discloses the use of arylamidoamino (and arylthioamido). Yabihuan 'and its pharmaceutically acceptable acid addition salts, hydrates and alcoholates to strengthen memory or correct memory defects. WO01 / 76576A2 discloses a pharmaceutical composition for treating acute, chronic pain and / or neuropathic pain and migraine. W001 / 60821 Α1 reveals novel biarylcarboxamides, human liters for therapeutic use 'especially for the treatment or prevention of mental illness and intellectual impairment symptoms WO 01/36417 Α1 reveals novel N-acyl bicyclic ring. Neck Hopper 1 Jujube and organisms, and their use in the treatment of -11-200300673, especially for the treatment or prevention of mental disorders and mental impairment.

WO 00/73431 A2 reveals two binding assays to directly measure the affinity and selectivity of compounds for a7nAChR and 5-HT3R. The combined use of these functionalities and binding assays can be used to identify a7 nAChR compounds as selective activators. WO 96/33186 discloses substituted dihydrobenzofuran derivatives as 5-HT4 activators. WO 93/06108 discloses pyrrobenzobenzoin derivatives as 5-HT activators and antagonists. WO 92/10494 discloses novel compounds which are 5-HT3 receptor antagonists. WO 91/09593 discloses 5-HT3 antagonists for the treatment of myocardial instability associated with nausea, bradycardia or hypotension. EP 496 064 A1 discloses a method for preparing substituted benzofuran derivatives. These compounds have been revealed as useful 5-HT3 receptor antagonists. In Bioorg. &Amp; Med. Chem · Let · 11 (2001) 319-321, the 5-HT3 antagonist tropisetron (ICS 205-930) is discussed as an effective and selective α7 nicotinic acid Receptor partial activator. In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that α7 nicotinic acid receptors in the brain can be an important target of treatment. DMXBA called GTS-21 is used to treat Alzheimer's disease. . SUMMARY OF THE INVENTION The present invention discloses compounds of formula I: -12- 200300673 Description of the invention _ page ⑺-

Where the azine ring is any of the following groups:

X is 0 or S;

W is CH or N; Y is 0, CRY or C (RY) 2, provided that when Y is CRY, one R6 is a bond to CRY, and further provided that at least one of Y or Z is 0; each RY is independently fluorene, F, Br, Cl, CN, alkyl, halogenated alkyl, substituted alkyl, bulk, cycloalkyl, -ORi 1 or -Nd 丨) 2, provided that when Y is C (RY) 2, and the further condition is that when one RY is F, Br, Cl, CN, -ORi i or -NCRi i) 2, the other RY is Η; Z is 0, CRZ or C (RZ) 2. The condition is that when Z is CRZ, one R4 is a bond to CRZ, and the further condition is that at least one of Y or Z is 0; each Rz is independently Η, F, Br, Cl, CN, alkyl , Halogenated alkyl, alkyl substituted with -13-200300673 (3), alkynyl, cycloalkyl, -ORi i or l) 2, provided that when Z is C (RZ) 2, and further conditions are When 1 ^ is f, Br, Cl, CN, · 〇 & i or -N (Rn) 2, the other center is η; R0 is Η, a low-carbon group, a substituted low-carbon group or ii is a low-carbon radical; R! is independently fluorene, alkyl, cycloalkyl, self-alkylated, or aryl; each R2 is independently F, Cl, Br, I, alkyl, halogen Alkenyl, substituted alkyl, cycloalkyl, aryl, or R2 does not exist, provided that k2, k5, or kg is 0; I12 · 3 is fluorene, F, Cl, Br ,; [, alkyl , Halogenated alkyl, substituted alkyl, cycloalkyl or aryl, ki is 0 or 1; k: 2 is 0 or 1; k5 is 0, 1 or 2 independently of the heart system; R3 is fluorene, alkyl , Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocyclic alkyl, substituted alkyl, substituted Alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, R7, R9, -OR8, -015, -SRg, -SR ^ 7, F, Cl, Br, I, -NR8 R8, -NRg Ri 6,, -NRi 6 Ri 6, -c (o) r8, -cn '-c (o) m8R8, -NR8C (0) R8, -S (0) R8, -S (0) R17, -0S (0) 2R8, -NR8S (0) 2R8, -N02, or -n (h) c (o) n (h) r8; each R4 is independently H, alkyl, Substituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl 'or a bond to Z, provided that Z is CRZ; R5 is fluorene, alkyl, substituted alkyl, cycloalkyl, Alkyl, heterocycloalkyl, substituted heterocycloalkyl, The substituted phenyl or substituted naphthyl -14- of (9) Buy $ invention is described on page

base

The Han 6 series is independently fluorene, alkyl, fluorenyl, substituted alkane; or the bond to Y, its rules, 3 ', and heterocyclic aromatic monocyclic partial groups. ί is selected from the group consisting of = N ·, -N (R14)-, -0-, and ^ α, B n is selected from R18, and further has 0-3 substitutions C, 7 is 9_member temple together The ring part of the group 0 soil 5-members, including the following formula ^, self-chemical alkyl, ring Y Y is CRy, I contains 1-3 heterogen 丨-, and has 0-1 radicals, Independently selected from F,, which has a 6-membered ring, where ^ is 0

Gan ψ, ', G are c (Ri 8) or N, and each G2 and G3 are independent i 0, S, N, and N (Ri 8), provided that g2 and g3 are not 3 or not 0 and S, or [from 8] 2, C (Ri 8) are 0 at the same time, not at the same time

Where G is C (Rls) or N, and each 02 and G3 are independently transported, 0, S, N, and N (R! 4), each 9-membered fused ring moiety is selected from Ri 8, and Further has 0-3 substitutions: from c (R18) 2, c (r18) groups have 0-1 radicals, independently selected from F, -15- 200300673

(10) C1, Br or I 'wherein the R7 moiety is connected to other substituents as defined in formula I and is at any position on any ring when a valence bond allows;

Each Rs is independently fluorene, alkyl, functional alkyl, substituted alkyl, cyclic dry group, #cyclocycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyclic group, Substituted heterocycloalkyl, r7, r9 ′ phenyl, or a phenyl group having 1 substituent selected from R2 0 and further having 0 to 3 substituents independently selected from F, C1, Br, or I, or substituted benzene R9 is a & member heteroaromatic monocyclic partial group, which contains 1-3 heteroatoms in the ring, and has 0-1 substituents, selected from r20, and 0-3 Substituents are selected from the group consisting of F, Cl, Br or I, or R9 is a 10-membered heteroaromatic bicyclic moiety. The group contains 1-3 heteroatoms in one or two rings, and is selected from = N-, including, but not limited to, 4- or iso-4: linyl, each 10-membered fused ring moiety, having 0-1 substituents, selected from Ris, and 0-3 substituents, Independently selected from F, Br, or I, and where a valence bond permits, has a connection point at any position on the above 'each 0 is independently Η, alkyl, cycloalkyl, heterocycloalkyl, 1 selected from & A substituted group of 3, a ring substituted by a substituent selected from R1 3 Alkyl, heterocyclyl substituted with 1 substituent selected from Ri3, halogenated alkyl, halogenated cycloalkyl, self-heterocyclic alkyl, phenyl or substituted phenyl; each Ri is Independently fluorene, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, cycloalkyl, or functional heterocycloalkyl; ^ 2 is -ORn, -S & i, alkyl, cycloalkyl , Heterocycloalkyl, halogenated alkyl, functionalized cycloalkyl, dented heterocycloalkyl, substituted alkyl, substituted ring · pit group, substituted heterocycloalkyl, -NR " Ri 1 , I, -N02, -16- 200300673 Description of the Invention _ Stomach (11) -----CCCONRi ii, -CN, -N & i aCORi i, -S (0) 2 NRi i Ri i or -NRi i S (0) 2 Ri !;

Ri 3 is -〇Ri 1, -SR ", -NRi i Ri i, -C (0) Ri i, -QC ^ NRi! &Amp; i, -CN, -CF3, -N〇2, -NR! I C (0) Ri i, -S (0) 2 NRi i Ri i, -NR ^ i S (0) 2 Ri i 'or phenyl, optionally substituted by up to 3 functional atoms, and further optionally by 1 substituent selected from Ri 2;

Ri 4 is independently an alkyl group, a halogenated alkyl group, a substituted alkyl group, a cycloalkyl group, a halogenated cycloalkyl group, a substituted cyclofluorenyl group, a heterocycloalkyl group, a self-heterocyclic heteroalkyl group, or a substituted group. Heterocyclyl,

Ri 5 is fluorene, i-alkyl, substituted alkyl, cycloalkyl, self-cyclized cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyclic halogeno, substituted heterocyclic Alkyl, r7, r9, phenyl or substituted phenyl; each Ri 6 is independently alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkane Group, heterocycloalkyl group, dentified heterocycloalkyl group, substituted heterocycloalkyl group, R7, R9, phenyl group, or a substituent selected from the group consisting of F, C1 Βγ or a phenyl group of 1; each 1117 is independently H, a functional alkyl group, a substituted alkyl group, a cycloalkyl group, a halogenated cycloalkyl group, a substituted cycloalkyl group, a heterocycloalkyl group, a Heterocycloalkyl, substituted heterocycloalkyl, R7 or R9, each R18 is independently fluorene, F, ci: Br, I, alkyl, alkyl, heterocycloalkyl, haloalkyl Group, i-cycloalkyl, haloheteroalkyl, substituted fluorenyl, substituted cyclyl, substituted heterocyclic ^ I CN _N〇2, -〇 \ i, now i, see iii ... Chat ~ 1, Τ (0) ΝΚι 1 Rl 1, as 11 C (〇) Rl 1 , S (0) 2NRuRu, -NRuS (0) 2Rn, or directly or indirectly connected to the core-17- 200300673 Description of the invention Lii knife bond, the condition is that there is only one Xi n bond to the core molecule at 9 -In the condensed ring part of the group, further ^, provided that where the valence bond allows, the fused ring part of the group has 0-1 substituents, where A ^, #, and # 丞 is selected from alkyl , Cycloalkyl, heterocyclic alkyl, halogenated alkyl, halogenated alkyl, halogenated, jt fluorene, alkylated, heterocyclic alkyl, substituted alkyl, substituted cycloalkyl, substituted Heterocycloalkyl, _〇Rn, _Sh

, -NRllR ", -C⑼Rll, .N〇2, _c (0) nr " Rii, CN, and whichever is selected) -S (O) 2 NRi i Ri 丨 or -NRi i S (O) 2 h 丨 'and A further condition is that the fused ring moiety has 0 to 3 substituents, and is selected from f, α, or alkyl; ho is alkyl, cycloalkyl, heterocycloalkyl, alkylated, or functionalized ring Alkyl, halogenated heterocycloalkyl, i, -S &!, I [[-C (〇) Ri 工, -C (〇) NRi) 心 工 -CN ^ -NRnC (0) Rn > -S (0) 2NR11ru .-NR !! S (0) 2 Rt! ≫ -N02 ^ alkyl substituted with M substituents independently selected from F, C1, Br, and "Ru"

(12) Cyclopentyl substituted by M substituents independently selected from F, Cl, Br, I, or Rl 3, or by 1-4 substituents independently selected from F, Cl, Br, I, or 3 Substituted heterocycloalkyl; or a pharmaceutical composition, a pharmaceutically acceptable salt, a racemic mixture, or a pure paraisomer thereof. Specific embodiments of the present invention may include one or more or a combination thereof. A specific embodiment of the present invention provides the use of a compound of formula I for the treatment of a disease or condition, wherein the disease, condition and / or condition is any one or more or a combination of the following: Alzheimer's cognition Neurodegeneration associated with symptoms of attention deficit, such as Alzheimer's disease, senile dementia (mild cognitive decline), Alzheimer's disease, schizophrenia, mental illness, attention deficit disorder, Insufficient activity -18- 200300673 Description of the invention continued (13)-degree of illness, depression, anxiety, general anxiety disorder, post-traumatic stress disorder, mood and emotional disorder, amyotrophic lateral sclerosis, borderline personality disorder, Traumatic brain injury, general and brain cancer-related behaviors and cognitive problems, AIDS dementia relapse, dementia associated with Down's syndrome, dementia associated with Lewy body, Hunting Dayton's disease, Parkinson's disease, tardive dyskinesia, Pick's disease, dysregulation of food intake, including bulimia and anorexia, and stopping smoking And stopping drug dependence has associated symptoms of withdrawal, Gilles de la Tourette's symptoms error, associated with the aging of the spots denatured 'glaucoma, neurodegeneration associated with glaucoma, the pain or symptoms associated with a sum. In another aspect, the invention includes treating mammals with schizophrenia or psychosis by administering a compound of formula I with an antipsychotic drug (also known as an antipsychotic). The compounds of the invention and the antipsychotics can be administered simultaneously or at separate intervals. When administered at the same time, the compound of the present invention, human psychiatric psychiatric drugs, can be incorporated into a single pharmaceutical composition. Alternatively, two separate compositions, i.e. one containing a compound of the invention and the other containing an antipsychotic drug, may be administered simultaneously. The compound of formula 1 (acyl bicyclic and I) has an optically active center on the pyridine ring. The compounds of the present invention include those having a 3R configuration, a 3R, 2S configuration, and quinidine, and also include racemic mixtures, individual stereoisomers, and different stereochemical purity (compositions. For example, without limitation, compounds of formula I Includes compounds that have stereospecificity comprising any of the following:

-19- 200300673 (14) Description of the invention Ifi compound of formula I (acyl bicyclic and Π) has an optically active center on C3 and C4 of [2.2.1] acyl bicyclic. The scope of the present invention includes different stereochemical purity racemic mixtures' individual stereoisomers, and compositions of different stereochemical purity of formula I are inward-4S, inward-4R, outward-4S, and outward-4R:

Inward-4R Outward-4S Inward isomers are the isomers in which the non-hydrogen substituent at C3 of the [2 · 2 · 1] acyl bicyclic compound is protruding toward the larger of the two remaining bridge groups. An exoisomer is an isomer in which the non-hydrogen substituent at C3 of the [2.2.1] azine bicyclic compound projects toward the smaller of the two remaining bridge groups. Therefore, there can be four individual isomers, Extrovert-4 (R), Extrovert-4 (R), Intro-Dipper, and Intro-4 (S). The compound of formula I (leaf bicyclic ring II) has an optically active center at [2.2.1]. A bicyclic Cl, C4 and C5. The scope of the present invention includes racemic mixtures of different stereochemical purity, individual stereoisomers, and compositions of different stereochemical purity of formula I, which are (1R, 4R, 5S)., (1R, 4R, 5R), (1S, 4S, 5R), (1S, 4S, 5S):

V 〇

Outgoing -1 R, 4R, 5S Outgoing -1 S, 4S, 5R The inward isomer is where the non-hydrogen substituent at C5 of the [2 · 2.1] ργ bicyclic compound is larger toward the two remaining bridge groups Those protruding isomers. Exoisomerism-20- 200300673 (15) Description of the invention The continuation is an isomerism in which the non-hydrogen substituent at C5 of the [2.2.1] azine bicyclic compound projects toward the smaller of the two remaining bridge groups Thing. Therefore, there can be four individual isomers: outward- (1R, 4R, 5S), outward_ (is, 4S, 5R), inward- (1S, 4S, 5S), inward- (1R, 4R, 5R) . The compound of formula I (azepine bicyclic IV) has an optically active center on Cl, C4 and C6 of [2.2.1] azabicyclo. The scope of the present invention includes racemic mixtures of different stereochemical purity, individual stereoisomers, and compositions of different stereochemical purity of formula I, which are exo- (1S, 4R, 6S), exo- (1R, 4S, 6R), inward- (1S, 4R, 6R) and inward- (1R, 4S, 6S): 〇

, R〇

Inward-1R, 4S, 6S

Inward-1S, 4R, 6R outward-lMSAR outward-1S wind 6S

Introisomers are the isomers in which the non-hydrogen substituent at C6 of the bicyclic compound [2 · 2 · 1K "is protruding toward the larger of the two remaining bridge groups. Exoisomers are those in which the [ 2.2.1 The non-hydrogen substituent of the KΓ bicyclic compound is an isomer that protrudes toward the smaller of the two remaining bridge groups. Therefore, there can be four individual isomers: outward- (1S, 4R, 6S ), Outward- (1R, 4S, 6R), inward-oriented, 4R, 6R) and inward- (1R, 4S, 6S). The compound of formula I (4 bicyclic and v-system) has an optically active center at [3 21] C3 and C5 of the outer bicyclic ring. The scope of the present invention includes racemic mixtures of different stereochemical purity, individual stereoisomers, and compositions of different stereochemical purity of the formula 'which are inward-oriented-3S, 5R, inward-oriented _3R, 5S, outbound_3R, 5R 'Outbound -3S, 5S: -21-200300673 Description of the invention continued (16)-

Inward-3S, 5R Inward-3R, 5S Outward-3R, 5R Outward-3S, 5S

The compound of formula I (acyl bicyclic and system VI) has an optically active center on the [3.2.2] acyl bicyclic ring, and when R2 is absent, it has a center at C3. The scope of the present invention includes racemic mixtures of different stereochemical purity, individual stereoisomers, and compositions of different stereochemical purity of formula I, which are 3 (S) and 3 (R):

Η, 〇3 (S) 3 (R) Compounds of the present invention with specific stereochemistry, have different degrees of activity, and in the specific sense of a group of variable substituents, one isomer may be superior to other isomers Thing. Although stereochemical purity is generally expected to be as high as possible, absolute purity is not required. The present invention relates to racemic mixtures and compositions of varying stereochemical purity for the entire molecule comprising an azine bicyclic moiety and a bicyclic fused ring moiety. The present invention relates to racemic mixtures and compositions of different stereochemical purity. When referring to racemic mixtures and compositions, it is meant that racemic mixtures and compositions of different stereochemical purity in the stomach. Preferably, stereoselective synthesis is performed and / or the reaction product is subjected to appropriate purification steps to produce a substantially para-isomerically pure substance. Appropriate stereoselective synthetic procedures for the production of paraisomeric pure substances are known in the art, such as for making racemic mixtures pure -22- 200300673 Description of the invention Procedure for pure dissolving fraction. Selective synthesis of carcass and / or the reaction to produce substantially paraisomerically pure substances: Substances undergo appropriate purification steps, and appropriate stereoselective synthetic procedures of high quality to produce isomerically pure isomeric substances such as Purification of the racemic mixture into two is known in the art '

1 # 士 & Hand isomerization on pure dissolving procedure. Regarding all the compounds that have been explicitly referred to, the non-PE is a special name for the isomers, and. ^ Is used as an example. The denomination of a specific palm isomer includes its racemic mixture such as N-[(2S, 3R) -2-methyl--ortho-coated and [.2.2] octyl] _2,3- Dihydrogenates hydrazone from benzodioxolane, and within the scope of the present invention includes methyl groups with bicyclic fluorene [fluorene. Octyl] -2,3-dihydro-: l, 4-benzodioxolidine · 6 • carboxamide. Furthermore, 'refers to (3s) | [(3R) -W double mounting and [2 · 2.2] oct-3-yl] each (phenoxymethyl hydrogen. Amines, including aceto [(3R) -1 · azinebicyclo [2 2 · 2] octane · 3 • yl] -3- (phenoxymethyl) -2 > Oxytetrapine and carboxamide, (3S) _

N- [Mγbicyclo [2 · 2 · 2] oct-3-yl] -3- (phenoxymethyl) -2,3-dihydro · M • benzodioxolane · 6- Chitosamine and N- [l-azinebi [2 · 2 · 2] octyl] -3- (phenoxymethyl) -2,3 · dihydro'M ** benzodioxo晞 -6-Falconamide. Another specific embodiment of the compound of formula I includes any one or more or a combination of the following compound configurations:

Where (i) this compound has S stereochemistry at C-2 and r stereochemistry at 03 'and & has any meaning as discussed herein; -23- 200300673 Description of the Invention I Selling Stomach (18 ) ----- (ii) this compound is a racemic mixture and R2 is at C-6, and R2 has any meaning as discussed herein; or (iii) this compound has R stereochemistry at C- 3, as discussed herein, and stereochemistry is not specified at C-6, and R2 has any meaning as discussed herein.

Another specific embodiment of the compound of formula I includes any one or more or a combination of the following compound configurations:

Where (!) 1 ^ is 0 (R2 does not exist); (ii) R2 is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl; (iii) R2 is alkyl, halogenated alkyl , Substituted alkyl, cycloalkyl, or aryl: or

(iv) 2.2.1 Some groups have an outward-4 (S) stereochemistry as discussed herein. Another specific embodiment of the compound of formula I includes any one or more or a combination of the following compound configurations:

(0 (ii) (iii) where (i) R2_3 is Η; (ii) R2-3 is F, Cl, Br, I, alkyl, halogenated alkyl 'substituted alkane-24- 200300673 Description of the invention Page (19) ^-group, cycloalkyl or aryl; or (iii) R2_3 is alkyl, haloalkyl, substituted alkyl, cycloalkyl or aryl. Another particularity of compounds of formula I Embodiments, including any one or more or a combination of the following compound configurations:

Wherein (i) R2-3 is H; (ii) R2-3 is F, C1, Bi, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl; or (iii) R2-3 is alkyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl.

Another specific example compound of formula I includes any one or more or a combination of the following compound configurations:

Where (i) k5 is 0 (R2 is absent); (ii) R2 is absent, and the stereochemistry of the bicyclo ring has 3R, 5R; (iii) k5 is 2, where R2_a is an alkyl group, a halogenated alkyl group, Substituted alkyl, cycloalkyl or aryl, and wherein R2-b is F, Cl, Br, I, alkyl, halogenated-25- 200300673 Description of the Invention (20)-alkyl, substituted alkyl, Cycloalkyl or aryl; (iv) k5 is 1, where R2 is fluorenyl, halogenated alkyl, substituted alkyl, cycloalkyl or aryl; or (v) k5 is 1, where R2 is F, Cl, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl.

Another specific embodiment of the compound of formula I includes any one or more or a combination of the following compound configurations:

Wherein (the company 6 is 0 (R2 does not exist); F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl; (iii) k6 is 1, where R2 is alkyl, halogenated alkyl, substituted alkyl Or (iv) k6 is 1, where R2 is F, Cl, Br, 1, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl. Formula I Another specific embodiment of the compound includes any one or more of the following configurations, wherein R3, R4, R6, RY, Rz, and W all have any of the definitions discussed herein, and wherein the bicyclic fused ring The groups are: -26- 200300673 Description of the invention ϋΜ (21)-

Another specific embodiment includes compounds of formula i, where x is 0 or where x is s. Another embodiment includes a compound of formula I, wherein R0 is fluorene, a lower alkyl group, a substituted lower alkyl group, or a halogenated lower alkyl group. Another embodiment includes a compound of formula I, wherein R0 is hydrazone. Another specific embodiment includes a compound of formula I, wherein R0 is a lower alkyl group, a substituted lower alkyl group, or a halogenated lower alkyl group. Another embodiment includes a compound of formula I, wherein R1 is any one or more of: fluorene, alkyl, cycloalkyl, haloalkyl, or aryl. Another specific embodiment includes a compound of formula I, wherein R0 is hydrazone. Another specific embodiment includes a compound of formula I, wherein R0 is any one of: hydrazone, alkyl, or cycloalkyl. Another specific embodiment includes a compound of formula I, wherein the azine ring is any one or more of I, Π, III, Γ /, V, or VI. Another specific embodiment includes a compound of formula I, wherein each R2 is independently F, Cl, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, aryl, or R2 is absent, The condition is that lq, k2, k5, or k6 is 0. Another specific embodiment includes a compound of formula I in which each R2 is absent (ki, k2, k5, or k6 each is 0). Another specific embodiment includes a compound of formula I in which there is only one R2 and which is methyl. Another specific embodiment includes compounds of formula I-27-200300673. Description of the invention m (22)-, wherein R2 is lower alkyl, lower alkyl halide or lower alkyl substituted fluorene, k2, k5 or k6 Each is 1). Another specific embodiment includes a compound of formula I, wherein R2-3 is independently any of the following: hydrazone, F, Cl, Br, I, alkyl, haloalkyl, substituted alkyl, cycloalkyl, or Aryl. Another embodiment includes a compound of formula I, wherein R2_3 is fluorene. Another specific embodiment includes a compound of formula I, wherein R2_3 is alkyl, haloalkyl, substituted alkyl, cycloalkyl, or aryl. Another specific embodiment includes a compound of formula I, wherein W is N. Another embodiment includes a compound of formula I, wherein W is CH. Another specific embodiment includes a compound of formula I, wherein Z and Y are each 0. Another embodiment includes a compound of formula I, wherein only one of Z and Y is 0. Another specific embodiment includes a compound of formula I, wherein Z is 0 and Y is -C (RY) =. Another embodiment includes a compound of formula I, wherein Z is 0 and Y is C (Ry) 2. Another specific embodiment includes a compound of formula I, wherein Z is 0 and Y is -CH (RY)-. Another specific embodiment includes a compound of formula I, wherein Y is 0 and Z is -C (RZ) =. Another specific embodiment includes a compound of formula I, wherein Y is 0 and Z is C (RZ) 2. Another specific embodiment includes a compound of formula I, wherein Y is 0 and Z is -CH (RZ)-. Another specific embodiment includes a compound of formula I, wherein Y is 0, CRY or C (RY) 2, provided that when Y is CRY, one R6 is a bond to CRY, and further conditions are Y or Z At least one of them is 0. Another specific embodiment includes a compound of formula I, wherein Z is 0, CRZ or C (RZ) 2, provided that when Z is CRZ, one R4 is a bond to CRZ, and further conditions are Y or Z At least -28- 200300673 Invention description $ Selling page (23) ---- one is 0. Another specific embodiment includes compounds of formula I, wherein each RY is independently Η, F, Br, Cl, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -OR! i or 丨) 2, the condition is when Y is C (RY) 2, and further conditions are when one RY is F, Br, Cl, CN, -0% i or -N (Ri) 2 One RY is H. Another specific embodiment includes compounds of formula I, wherein each Rz is independently fluorene, F, Br, Cl, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -ORi i Or: N (Ri 丨) 2, if Z is C (RZ) 2, and further if Rz is F, Br, Cl, CN, -0R! 丨 or -N (Ri!) 2 And the other Rz is Η. Another specific embodiment includes a compound of formula I, wherein R3 has any of the definitions discussed herein, only one of Z and Y is 0, and the other is CRZ or CRY, and one R4 or R6 is each bonded, And the other R4 and R6 have any definition as described herein. Another specific embodiment includes a compound of formula I, wherein Rz or RY is independently any of the following: fluorene, F, Br, Cl, CN, alkyl, haloalkyl, substituted alkyl, alkyl, cycloalkyl Group, -0R11 or -N (Ri!) 2. Another specific embodiment includes a compound of formula I, wherein each of RY and Rz is fluorene. Another specific embodiment includes a compound of formula I, wherein R3 is any one or more of: fluorene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, halide Group, functionalized alkynyl, sulfonated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkane Group, aryl group, R7, R9, -0¾, -〇R! 5, -SRg, 7, F, Cl, Br, I, _NRg Rg, _NRg Ri 6, -NRj 6 Ri 6 -29- 200300673 * 1, 1 Description of an Invention Continued (24) ------^ (C (0) R8 > -CN > -C (0) NR8R8 > -NR8C (0) R8 ^ -S (0) R8 ^ -S (0) Ri7 > -OS (0) 2R8, -NR8S (0) 2R8, -N02 or -n (h) c (o) n (h) r8. Another specific embodiment includes a compound of formula I, wherein R3 is H. Another specific embodiment includes compounds of formula I, wherein R3 is fluorene, lower alkyl, lower substituted alkyl, cycloalkyl, heterocycloalkyl, lower substituted alkynyl, substituted hetero Cycloalkyl, -OR8, -ORi 5, -SR8, -SRi 7, F, Cl, Br, I, -NR8 R8, -NR8R! 6 > -NR! ERl6 > -C (0) R8 ^ -CN ^ -C (0) NR8R8 > -NR8C (0) R8 '-S (〇) R8, -S (0) R17, -OS (〇) 2R8, -NR8S (0) 2R8 or -N (H) C (0) N (H) R8, where R8 is H, lower alkyl, lower carbon alkyl, lower substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, Heterocycloalkyl, halogenated heterocycloalkyl or substituted heterocycloalkyl; wherein Ri 5 and Ri 7 are independently fluorene, low-carbon pit group, low-carbon alkynyl group, low-carbon substituted alkyl group, Cycloalkyl, iS-cycloalkyl, substituted cycloalkyl, heterocycle, j: end group, functional heterocycloalkyl or substituted heterocycloalkyl; and R! 6 is a lower alkyl group , Low-carbon halogenated alkyl, low-carbon substituted alkyl, cycloalkyl, dented cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocyclic alkyl, or substituted Burning soil base. Another specific embodiment includes a compound of formula I, wherein one R4 and one R6 are fluorene, and the other R4 and the other R6 are each independently fluorene, alkyl, substituted tiger, odontyl, cycloalkyl or Heterocycloalkyl. Another embodiment of the compound of formula I includes one in which & is Η, and the other R6 is not Η, and has an S configuration on a bicyclic fused ring moiety. Another specific embodiment of the compound of formula I includes wherein each & is hydrazone. Another specific embodiment includes a compound of formula I, wherein each & and each R6 is fluorene. -30 · 200300673 (25) Description of the invention Another specific embodiment on the next page includes a compound of formula I, wherein at least one & and at least one & are each Η, and the other & and r6 are each independently H, Alkyl, substituted alkyl, haloalkyl, cycloalkyl or heterocycloalkyl, wherein each R10 in the definition of substituted alkyl is independently fluorene, lower alkyl, lower alkyl haloalkyl , Cycloalkyl, heterocycloalkyl or lower alkyl substituted with i substituents selected from ^ 3. A compound of formula I, wherein the compound is any one or more or a combination of the following, is a free state base, or a pharmaceutically acceptable salt thereof, is its pure paraisomer or racemic mixture: N-((3R) -l- < Bicyclo [[2.2.2] oct-3-yl) -2,3-dihydro-1,4-benzodioxolene chinospinamine; N-[(2S, 3R)- 2-methyl-1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2,3-dihydro-1,4-benzodioxolidine-6-rejuvenated amine; N -[(3R) -1 』Yarabicyclo [2.2.2] octyl] -2-ethyl-2,3-dihydro-1,4-benzodioxolidine-7-rejuvenated amine ; 2 (R) Zan [(3R) -W bicyclo [2 · 2 · 2] octyl | yl] -2-[(Wordoxy) methyl] _2,3-dihydro · 1,4-benzo Dioxolene-6-carboxamide; 2⑸-N-[(3R) _W bicyclo [2.2 · 2] octylnor [(fluorenyl) methyl] · 2,3 · dichloro · 1,2 -Benzodioxolene-6-carboxamide; N-[(3R) -ie bicyclo [2.2.2] octylpyrene, pyrene (benzyloxy) methyl] _2,3 · dihydro · 丨, 4_benzodioxolene · 6-carboxamide; Luzhou hydrazone-Buya bicyclo [2.2.2] octyl | yl] _3 · [(benzyloxy) methyl> 2, 3_diazepine, 1,4-private dioxolidine-6-rejuvenated amine, pyrene-Keping)-;!-. Ya bicyclo [2.2.2] oct-3_yl] · 3 _ [(fluorenyloxy) methyl] _2,3_diazine_ ~ 31-200300673

(26) 1,4-benzodioxolane-6-fluorenamine; N_H (3R > 1-azabicyclo [2 2.2] oct-3-yl] _3 · (Isomethyl p, 3_ Dihydro · Benoxydioxolene-6-benzamine; (3S) -N- [⑽ΚBicyclo [2 · 2.2] oct_3_yl] _3_ (Styroxymethylfluorene dihydrogen Benzodioxolane-6-complex g fishamine;

N-[(3R) -M-Ya bicyclo [2 · 2 · 2] octyl] -2,3-dihydro · 丨, winter dioxolane association and [2,3 ^ pyridine-7-carboxyfluorene Amine; N-[(3R) -W bicyclo [2.2 · 2] octyl] κene · 6-carboxamide; N- [〇3R) -W bicyclo [2.2 · 2] octyl Ji Kejiu each produced N-[(; 3R) -1-acyl bicyclic and [2 · 2,2] Xin! Group] πg-6-benzamine; N-[(3R) -lp bicyclo [2 · 2 · 2] oct-3-yl] bit-7-carboxamide; group [2,3-c ] Tonidine · 6 · N-[(3R) -1-acylbicyclo [2.2 · 2] oct-3-yl] -3,4-dihydro-2Hf soil & South Guinea SI amine; outward -4 (S) N- (1-Acridinebicyclo [HI] heptyl_2,3_dihydro, Benzene, 晞 -6-carboxamide; or I-oxophenylamine N-[(3R, 5R) -1-Acridinebicyclo [3 · 2 · 1] oct-3-yl] -2,3-dihydro, benzene, and carbamidine. 'Lydroxydioxolene compounds of formula I, in which The compound is any of the following ~ Yuhe or more # 2, is a free state test 'or a pharmaceutically acceptable salt thereof, or is a pure I $ substance or a racemic mixture:', dry isomer N -[(3R)-; l · Acridinebicyclo [2.2.2] oct-3-yl] -2-methyl-2,3, diazepine, 丨, 4, benzyl-1-pinene-7- Carboxamide; ^ (1) (211) 1 ((311) -1-17) Bicyclo [2 · 2 · 2] oct-3-yl] -2-methyl, 2 ~~ ksr oxygen -7-carboxamide; oxybenzidine-32- 200300673

Description of the invention liM (27)-(2S) -N-[(3R) -P-A bicyclo [2.2.2] oct-3-yl] -2-methyl-2,3-dihydro-1,4- Benzodioxolene-7-carboxamide; (2R) -N-[(3R) -1-. Y-Bicyclo [2.2.2] oct-3-yl] -2-ethyl-2,3-dihydro-1,4-benzodioxolulene-7-fluorenamine; (2S) -N -[(3R) Xiaokouya bicyclo [2 · 2 · 2] oct-3-yl] -2-ethyl-2,3-dihydro-1,4-benzodioxolidine-7- complex B amine, N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-methyl-2,3-dihydro-1,4-benzodioxolane Hydrazone-6-carboxamide; (2S) -N-[(3R) -le bicyclo [2.2.2] oct-3-yl] -2-methyl-2,3-dihydro-1,4- Benzodioxolene-6-pyrimidine; (2R> N-[(3R) Smallazine [2.2.2] oct-3-yl] -2-methyl-2,3-dihydro -1,4-benzodioxolene-6-carboxamide; N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-ethyl-2, 3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S) -N-[(3R) -1-azabicyclo [2 · 2 · 2] oct-3- Phenyl] -2-ethyl-2,3-dihydro-1,4-benzodioxolene-6-¾amidamine; (2R) -N-[(3R) -1 " 2.2.2] oct-3-yl] -2-ethyl-2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S, 3S) -N- [ (3R) -1-Acridinebicyclo [2.2.2] oct-3-yl] -2,3-dimethyl-2,3-dihydro-1,4-benzodioxy "Lu Yingxi *- 6-fermenting amine, (2R, 3R) -N-[(3R) -1- Bicyclo [2.2.2] oct-3-yl] -2,3-dimethyl-2,3-dihydro-1,4-benzodioxolane-6-SS amine; (2S, 3S) -N-[(3R) -1-acylbicyclo [2.2.2] octyl-3.yl] -2,3-diethyl-2,3-dihydro-1,4-benzodioxy陆 圜 协 -6- complex S: amine, -33- 200300673 (28) Description of the invention _ stomach (2R, 3R) -N-[(3R) small acridine bicyclo [2 · 2.2] octyl] -2, 3-diethyl-2,3_dihydro ", 4-benzodioxolane-6-carboxamide; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] Oct-3-yl] -2-[[(4-fluorobenzyl) oxy] methyl] _ 2.3-Diazide-1,4-benzodioxopropanyl-6-plex SS Amine; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[[(3-fluoromethylfluorenyl) oxy] methyl >; 2.3- Dichloro-1,4-private dioxofuran-6-rejuvenated amine; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] xin-3 -Yl] -2-[[(2-fluorobenzyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolane-6-respermine; (2S)- N-[(3R) -1-. Yabicyclo [2 · 2 · 2] oct-3-yl] -2-[[(4-chloro; yl) oxy] fluorenyl] dihydro-1,4-benzodioxolidine-6 -Rejuvenated amines; (2S) -N-[(3R) -1-l-f-bicyclo [2 · 2 · 2] oct-3-yl] -2-[[(4-methylmethyl) oxy] Methyl] -2,3 · dihydro-1,4-benzodioxofluorene · 6-carboxamide; (2S) -N-[(3R) -1-azabicyclo [2,2 · 2] oct-3-yl] -2-[[(4-hydroxy; yl) oxy] methyl R3_diazine-1,4-benzodioxofluorene-6-stilbylamine; (2S ) -N-[(3R) -1-leaf bicyclo [2 · 2.2] oct-3-yl] -2-[[(4-methoxymethyl) oxy] methyl] -2,3- Diazo-1,4-winter dioxolan-6-jimonamine; (2S) shan [(3R) -1-acylbicyclo [2 · 2 · 2] octyl] -2- [ [(4-cyanobenzyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolane-6-carboxamidine; (2R) Xian [(3R) + azepine Benzo [2 · 2.2] oct-3-yl] -2-[[(4-fluoromethylfluorenyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolene-6 -Carboxamide; (2R) -N-[(3R) -1-leaf bicyclo [2 · 2 · 2] oct-3-yl] · 2-[[(3-aminohexyl) oxy] Methyl] · 2.3-dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R) -1-leafbicyclo [2 · 2 · 2] Oct-3-yl] -2- [ [(2-Fluoromethyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolane-6-amino SS amine; -34- 200300673 Description of the invention !: (29 ) (2R) -N-[(3R) Small acryl bicyclo [2.2.2] octyl] -2-[[(4-chlorofluorenyl) oxy] methyl] -2,3-dihydro- 1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R) -1-azinecyclo [2 · 2 · 2] oct-3-yl] -2- [[(4-fluorenzylbenzyl) oxy] methyl] -2,3 · dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R ) -1-acylbicyclo [2 · 2 · 2] octyl] -2-[[(4-hydroxyfluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzo Dioxolane-6-carboxamidine; (2R) Xian [(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[[(4-methoxy Fluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R) -1-acylbicyclo Benzo [2.2.2] octyl] -2-[[(4-cyanofluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolane-6 -Carboxamide; N-[(3R) -1-acylbicyclo [2,2.2] oct-3-yl] -2- (hydroxymethyl) -2,3-dihydro-1,4-benzo Dioxotriol-6-fermenting amine; (2R) -N-[(3R) Small acridine bicyclo [2 · 2 · 2] oct-3-yl] -2- (hydroxymethyl) -2, 3-dihydro-1 4-Benzodioxolene-6-carboxamide; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2- (hydroxyl (Methyl) -2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (2S) -N- [C3R) -W bicyclo [2 · 2 · 2] octyl Each group] _2-[(4 · Fluorophenoxy) fluorenyl] -2,3-diaza-1,4-dongno-oxyl Luyuanlian-6-pyramidamine, (2S) -N -[(3R) Small acryl bicyclo [2 · 2 · 2] octyl] -2-[(3-fluorophenylphenoxy) fluorenyl] -2,3-dihydro-1,4-benzo Dioxolene-6-carboxylamine; (2S) -N-[(3R) -1-Xia bicyclo [2.2.2] oct-3-yl] -2-[(2 · fluoro group (Phenoxy) methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S) -N-[(3R) small acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-chlorophenoxy) methyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxyfluorene Amine; -35- 200300673

Description of the invention liM (30) -—- (2S) Zhen [(3R) Small acryl bicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-methylphenoxy) methyl] · 2,3-Dimurine-1,4-benzodioxopropan-6-chitosamine, (2S) -N-[(3R) -1-acylbicyclo [2.2.2] octyl ] -2-[(4-hydroxyphenoxy) fluorenyl] · 2,3_dihydro-1,4-benzodioxoroxine-6-stilbeneamine; (2S) -N-[( 3R) small acylbicyclo [2 · 2 · 2] octyl] -2-[(4-methoxyphenoxy) methyl] · 2.3-dihydro-1,4-benzodioxolane Hydrazone-6-carboxamide; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-cyanophenoxy) Methyl] -2,3 · dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R) -1-azabicyclo [2.2.2] Octyl-3-yl] -2-[(4-fluorophenylphenoxy) methyl R3-dihydro-1,4-benzodioxolane-6-carboxamide; (2R) -N- [(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(3-fluorophenylphenoxy) methyl] _2,3_ dihydro-1,4-benzene Benzodioxol-6-carboxamidine; (2R) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-[(2-fluoroylbenzene (Oxy) methyl] · 2 >dihydro-1,4-benzodioxolane-6-carboxamidine; (2R) -N-[(3R) -1 · azinebicyclo [2.2.2 ] -3-yl] -2-[(4-chlorophenoxy) methyl] · 2 >dihydro-1,4-benzodioxolane-6-carboxamide; (2R) -N -[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-methylphenoxy) fluorenyl] · 2,3 · dihydro-1, 4-benzodioxolene-6-carboxamide; (2R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[( 4-hydroxybenzyloxy) methyl R3_dihydro-1,4-benzodioxolene-6-carboxy'pyramine; (2R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-methoxyphenoxy) methyl] · 2.3-dihydro-1,4-benzodioxolane-6-carboxyfluorene Amine; (2R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-cyanophenoxy) methyl] · 2, 3. · Dihydro-1,4-benzodioxolane-6-carboxamidine; -36- 200300673 (31) Description of the Invention Continued on page (3S) -N-[(3R) -1-Acridine [2 · 2.2] oct-3-yl] each [[(4-fluorobenzyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolene, each carboxamidine; (3S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -3-[[(3-fluorobenzyl) oxy] methyl] _ 2.3 -Dihydro-1,4-benzodioxolene carboxamide; (3S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oxinyl ] Each [[(2-fluoromethylfluorenyl) oxy] methyl 2.3-dihydro-1,4-benzodioxolene carboxamide; (3S) -N-[(3R) -1 -Azepine bicyclo [2.2.2] oct-3-yl] -3-[[(4-chlorobenzyl) oxy] methyl] -2,3 · dihydro-1,4-benzodioxane Allyl-6-carboxamide; (3S) -N-[(3R) -1-acylbicyclo [2 · 2.2] octyl] each [[(4-methylamidino) oxy] methyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (3S) -N-[(3R) -1-azabicyclo [2 · 2 · 2] octyl -3-yl] -3-[[(4-hydroxyfluorenyl) oxy] methyl R3-dihydro-1,4-benzodioxolene-6-carboxamide; (3S) -N -[(3R)-; l-azinebicyclo [2 · 2 · 2] oct-3-yl] -3-[[(4-fluorenyloxy) oxy] methyl] -2,3- Dihydro-1,4-benzodioxolane-6-rejuvenated amines; (3S) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] each [ [(4-cyanobenzyl) oxy] methyl] -2.3-dihydro-1,4-dongodioxorane-6-polyfluorenamine; (3R) -N-[(3R)- W Bicyclo [2 · 2 · 2] oct-3-yl] -3-[[(4- · fluorobenzyl) oxy] methyl] · 2.3-monorat-I, 4-Medioxyl Lu Xie-6-Futanamide, (3R) -N-[(3R) Small acryl bicyclo [2 · 2 · 2] octyl] -3-[[(3-fluoroyl; yl) oxy ] A ] _, 2.3-Dihydro-1,4-benzodioxolene, each carboxyamidamine; * (3R) -N-[(3R) -1-acylbicyclo [2,2 · 2] xinge [] [[(2-Fluorofluorenyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolidine, each compound amine; (3R) -N-[(3R ) Small acryl bicyclo [2.2,2] octyl] [[(4-chlorofluorenyl) oxy] methyl] -2,3 ·· Fermented amine; -37- 200300673 Description of the invention continued (32) ----- (3R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -3- [[(4-methylamido) oxy] methyl] -2,3-di-iL -1,4-Mercaptolactam-6-chitinamine, (3R) -N-[(3R ) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] each [[(4-hydroxybenzyl) oxy] methyl] -2,3-dihydro-1,4-benzo Dioxolene-6-carboxamide; (3R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] each [[(4-methoxy Benzyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxopropan-6-carboxamide; (3R) -N-[(3R) small acyl bicyclic benzo [ 2 · 2 · 2] oct-3-yl] -3-[[(4-cyanofluorenyl) oxy] methyl > 2,3-dihydro-1,4-benzodioxolene -6-Carboxamidamine; (3R) -N-[(3R) lobular bicyclo [2 · 2.2] oct-3-yl] -3- (¾methyl) -2 , 3-dihydro-1,4-benzodioxolene-6-carboxamide; (3S) -N-[(3R) -1-leafbicyclo [2 · 2 · 2] ocin-3 -Yl] -3- (via methyl) -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (3§) with [(311) -1-leaf Bicyclic ac [2.2.2] oct-3-yl] -3-[(4-fluorophenylphenoxy) methyl] -2,3-dihydro-1,4-benzodilactulene-6 -Rejuvenated amines; (3S) -N-[(3R) -lp bicyclo [2 · 2 · 2] oct-3-yl] -3-[(3-fluorophenoxy) fluorenyl] _2 , 3_ dihydro-1,4-benzodioxolane-6-chia ¾amine; (3S) -N-[(3R) leaflet bicyclo [2 · 2 · 2] oct-3-yl]- 3-[(2-Fluorophenoxy) methyl] _2,3 · dihydro-1,4-epidioxolan-6-succinic amine; (3S) -N-[(3R ) Leaflet bicyclo [2 · 2 · 2] oct-3-yl] -3-[(4-chlorophenoxy) methyl] · 2,3 · dihydro-1,4-benzodioxane Pyrene-6-carboxamide; (3S) -N-[(3R) -1-leaf bicyclo [2.2.2] oct-3-yl] -3-[(4-methylphenoxy) methyl Base] _2,3_ dihydro-1,4-dihydrodioxolan-6-chitosamine; (3S) -N-[(3R) -1-leaf dicyclo [2 · 2 · 2] xin -3-yl] -3-[(4-merylbenzyloxy) methyl] dihydro-1,4-benzodioxolane-6-compound: amine; -38- 200300673 (33) invention Ming continued (3S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] each [(4-methoxy2,3-diaza-1,4- Benzodioxolane-6-rejuvenated amine,

Phenylphenoxy) methyl] -phenoxy) methyl] -2,3-phenoxy) methyl] -2,3-phenoxy) methyl] -2,3- (3S) (3R) -1-acylbicyclo [2 · 2 · 2] octyl] -3-[(4-cyanodihydro-1,4-benzodioxolane-6-carboxamide); (3R) -N-[(3R) -1-acylbicyclo [2.2 · 2] oct-3-yl] each [(4-fluorodihydro-M-benzodioxolene-6-carboxyl Hydrazine; (3R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -3-[(3-fluorodihydro · 1,4-benzo Dioxolene-6-carboxamide; (3R) -N-[(3R) small acridine bicyclo [2 · 2 · 2] oct-3-yl] -3-[(2-fluorobenzyloxy (Meth) methyl] _23 · diazepine-diphenyldiamine-6-rejuvenated amine; (3R) -N-[(3R) small acylbicyclo [2 · 2 · 2] oct-3-yl] -3-[(4-chlorophenoxy) methyl] · 23 dihydrobenzodioxolane-6-rejuvenated amine; (3R) -N-[(3R) -1-acylbicyclic [2.2.2] oct-3-yl] each [(4-fluorenylphenoxy) methyl> 2,3 dihydro-1,4-benzodioxolane-6-carboxamidine;

(3R) -N-[(3R) -1-azabicyclo [2.2.2] oct-3-yl] -3-[(4-hydroxybenzyloxy) methyl R3 · dihydro-1A · private Dioxolan dilute -6-6-fermented amine; (3R) -N-[(3R) Small acryl bicyclo [2 · 2 · 2] oct-3-yl] each [(4-methoxyphenoxy Group) fluorenyl group> 2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (3R) -N-[(3R) -W bicyclic benzo [2.2.2] Octyl-3-yl] -3-[(4-cyanophenoxy) fluorenyl] · 2,3 ·, dihydro-1,4-benzodioxolene-6-sodiumamine; i N- (l- (2-methyl) -azinecyclo [2 · 2 · 2] oct-3-yl) -2,3-dihydro-1,4-benzodioxolene-6- Carboxamide; _ N- (l- (6-methyl) -leafbicyclo [2.2 · 2] oct-3-yl) -2,3-dihydro-1,4-benzodioxolene Each Carboxamide; -39- 200300673 Description of the Invention Continued (34) L ———- N- [l- (2S, 3R) -2-methyl-azinebicyclo [2.2 · 2] oct-3-yl ] -2,3-dihydro-M-dioxolene [2,3-c] pyridine-7-carboxamide; N- [l- (2-methyl) -azepine bicyclo [2.2. 2] oct-3-yl] -2,3-dihydro-i, 4-dioxolurino [2,3-c] pyridine-7-chipinamine; N- [l- (6-methyl ) -Acridinebicyclo [2 · 2 · 2] oct-3-yl] -2,3-dihydro-i, 4-dioxalo [2,3-c] pyridine -7-Falbinamine; N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -4-fluorenyl-2H-bene-6-carboxamide; N -[(3R) -1-acylbicyclo [2,2.2] oct-3-yl] -4-ethyl-2ti-bitan-6-carboxamide; N-[(3R) -1-leafbi 5 Tsukamoto [2.2,2] oct-3-yl] -4-airyl-2H-17 grams of association-6-Tibetanamine, N-[(3R) small acylbicyclo [2.2.2] xin · 3 -Yl] -4-chloro-2H-bendene · 6-carboxamide; N-[(3R) -1-azinebicyclo [2 · 2 · 2] oct-3-yl] -4-bromo -2fluorene-bene-6-carboxyfluorenamine; N-[(3R) small acrylbicyclo [2 · 2 · 2] oct-3-yl] -4-cyano · 2fluorene-pinene-6-carboxyfluorene Amine; N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -4-ethynyl-2fluorene-carboxamide; N-[(3R) -1 -Acridine bicyclo [2 · 2 · 2] oct-3-yl] -4-methyl-2fluorene-pinene-7-carboxamidine; N-[(3R) small acridine bicyclo [2 · 2 · 2 ] Oct-3-yl] -4-ethyl-2fluorene-pinene-7-carboxyfluorenamine; N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl]- 4-Fluoro-2H-bite 晞 > Scopolamine, N-[(3R) -1 · Acridinebicyclo [2.2.2] octyl] -4-chloro-2H- 咣 女 -7- Carboxylamine; Ν-[(3ΙΙ) · 1-azinebicyclo [2.2 · 2] oct-3-yl] -4-bromo-2H-pinene-7-carboxydonylamine; N-[(3R) Small acridine bicyclo [2.2.2] oct-3-yl] ascyano-2fluorene- Ene) carboxymethylamine; N-[(3R) -1-acylbicyclo [2,2.2] octyl_3_yl] · 4-ethynyl-2ί-pinene-71 donkey amine; N- (l- ( 2S, 3R) -2-methyl-αγbicyclo [2 · 2 · 2] octodecyl carboxy total amines; Ν- (fluorene 2-methyl) -acylbicyclo [2 · 2 · 2] Octyl-3-yl) -fluorenylcarboxamidine; N- (l- (6-fluorenyl) -azabicyclo [2.2.2] oct-3-ylhug-6-carboxamidine, N- ( l- (2S, 3R) -2-methylif bicyclic benzo [2.2 · 2] octyl ketone carboxymethylamine -40- 200300673

(35) N- (l- (2-methyl) -azabicyclo [2.2.2] oct-3-yl) -fluorene-7-carboxamide; N- (l- (6-methyl)- Azabicyclo [2.2.2] oct-3-yl) -fluorene-7-fluorenamine; N-[(3R, 5R) Xiakoubicyclo [3 · 2 · 1] oct-3-yl] -2 -Fluorenyl-2,3-dihydro-1,4-benzodioxolane-7-carboxamidine; (2R) -N-[(3R, 5R) small acyl bicyclo [3.2.1] Octyl-3-yl] -2-methyl-2,3-dihydro-1,4-benzodioxolene-7-carboxamide; (2S) -N-[(3R, 5R) small Azabicyclo [3.2.1] octyl] -2-methyl-2,3-dihydro-1,4-benzodioxolene-7-carboxamide; N-[(3R, 5R ) -1-acylbicyclo [3.2.1] oct-3-yl] -2-ethyl-2,3-dihydro-1,4-benzodioxolane-7-fermenting amine; ( 2R) -N-[(3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] -2-ethyl-2,3-dihydro-1,4-benzodioxolene -7-carboxamide; (2S) -N-[(3R, 5R) -1-acylbicyclo [3.2.1] oct-3-yl] -2-ethyl-2,3-dihydro-1 , 4-Benzodioxolene-7-carboxamidine; N-[(3R, 5R) -1-l-f [2.2.1] oct-3-yl] ** 2-methyl -2,3-diwind-1,4-dongodioxolene-6-carboxamide; (2S) -N-[(3R, 5R) -1-acylbicyclo [3.2.1] octyl -3-yl] -2-fluorenyl-2,3-di -1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R, 5R) -1 ^ γbicyclo [3.2.1] oct-3-yl] -2 -Methyl-2,3-dihydro-1,4-benzodioxolan-6-polysiamine; — N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1 ] Oct-3-yl] -2-ethyl-2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S) -N-[(3R, 5R) Small acylbicyclo [3.2.1] oct-3-yl] -2-ethyl-2,3-dihydro-1,4-benzodioxolene-6-carboxamide; -41-200300673 (36) Description of the invention Continued on (2R) -N-[(3R, 5R) Small acryl bicyclo [3 · 2 · 1] octyl] -2 · ethyl · 2,3 · dihydroa head benzodioxy Terpinene-6-carboxamide; (2S, 3S) -N-[(3R, 5R) small acridine bicyclo [3 · 2 · 1] octyl] · 2,3_dimethyl · 2, 3-dihydro], 4-benzodioxolane-6-carboxamide; (2R, 3R) -N-[(3R, 5R) -1-azabicyclo [3.2.1] octyl] · 2,3dimethyl-2,3_dihydro], Benzodioxo-6-carboxamidine; (2S, 3S) -N-[(3R, 5R) -1-azabicyclo Benzo [3 · 2 · 1] oct-3-yl] -2,3-diethyl · 2,3 · dihydroκ benzodioxolene-6-carboxamide; (2R, 3R)- N-[(3R, 5R) Small acryl bicyclo [3.2.1] octyl] · 2,3-diethyl-2,3 di Benzodioxolene Carboxamides; (2R) -N-[(3R, 5R) Small acridine [3 · 2 · 1] oct-3-yl] -2- (hydroxymethyl >2,3_dihydro-1,4-benzodioxolane-6-carboxamide; (2S) -N-[(3R, 5R) -1-azabicyclo [3 · 2 · 1] Octyl-3-yl] -2- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R, 5R) -l · azinebicyclo [3.2.1] oct-3-yl] -2-[(fluorenyloxymethyl) -2,3-dihydro-1,4-benzodioxolene -6-Carboxamidamine; (2S) -N-[(3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] -2-[(fluorenyloxy) methyl] -2,3 -Dihydro-1,4-benzodioxolene-6-carboxamide; (2R) xian [(3R, 5R) small acylbicyclo [3.2.1] oct-3-yl] -2- [[(4-Fluorofluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolan-6-carboxamide; (2S) -N-[( 3R, 5R) -14 bicyclo [3.2.1] octyl] -2-[[(4-fluoroylyl) oxy] methyl] -2,3-diwind-1,4-benzyl ^ Dioxolidine-6-quinolamine; (2R) -N-[(3R, 5R) Small acridine bicyclo [3 · 2 · 1] oct-3-yl] -2-[[((4- (Methylbenzyl) oxy] methyl] 2,3-dihydro-1,4-benzodioxolane-6-carboxamidine; -42- 200300673 (37) Description of the invention Continued on page (2SHsH (3R, 5R) -l-azinebicyclo [3 · 2.1; ^ groups] · 2-[[(4-methylamido) oxy] methyl] _ 2.3-dihydro-1, 4-Benzodioxolene Carboxamides; (2R) -N-[(3R, 5R) -1-acylbicyclino]] octyl] _2-[[(4-methoxybenzyl (Yl) oxy] fluorenyl] -2,3-dihydro-l, 4-benzodioxolane-6-carboxamidine; (2S) -N-[(3R, 5R) -lu-Ya bicyclo And the peaks of each base [[(4-foxymethyl) oxy] methyl] -2,3- ^ one-mouse-1,4-winter oxophenylalanine-6-suptilamine; ( 2R) -N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1] octyl] -2- (phenoxymethyl) -2,3 · dichloro-1,4- Benzodioxolene-6-carboxamide; (2S) -N-[(3R, 5R) -lp bispyrido [3.2.1] oct-3-yl] -2- (phenoxy Methyl >23-digas-1,4-epidioxolene-6-chitosamine; (2R) -N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1] oct-3-yl] -2-[(4-fluorobenzyloxy) methyl] · 2.3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S ) -N-[(3R, 5R) -W Bicyclo [3.2.1] octyl] -2-[(4-fluorophenoxy) methyl] · 2.3- Dirat-1,4-benzene Benzodioxin-6-fermenting amine; (2R) -N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1] oct-3-yl] -2-[(4-methylphenoxy) methyl 2.3-digas-1,4-epibenzoyloxy] "Lu Yuan Dian-6-BeiSheng Sheng Amine; (2S) -N-[(3R, 5R) -P bicyclo [3 · 2 · 1] oct-3-yl] -2-[(4-methylbenzyloxy) methyl] · 2.3- di Rat-1,4-Winter and Dioxin "Lu Yihoo-6-Bacteramine, (2R) -N-[(3R, 5R) Small acryl bicyclo [3 · 2 · 1] oct-3-yl] -2-[(4-methoxyphenoxy) methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S) -N- [ (3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] -2-[(4-methoxybenzyloxy) methyl] -2,3-dihydro-1,4-benzene Benzodioxolene-6-carboxamide; (3R) -N-[(3R, 5R) Small acridine bicyclo [3 · 2 · 1] oct-3-yl] (hydroxymethyl) -2 , 3-dihydrobenzodioxolane carboxylic acid amines; -43- 200300673 (38) Description of the invention I sell; 1; (3S) -N-[(3R, 5R) small acyl bicyclic benzo [3 · 2 · 1] oct-3-yl] -3- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (3R) -N- [(3R, 5R) -1-azabicyclo [3.2.1] oct-3-yl] each [(benzyloxy) methyl] -2,3-dihydro. 1,4-benzodioxo Limonene-6-carboxamide; (3S) -N-[(3R, 5R) small acridine bicyclo [3 · 2 · 1] oct-3-yl] -3-[(芊(Methyl) -2,3-dihydro. 1,4-benzodioxofluorene-6-g g of amine; (3R) -N-[(3R, 5R) -1-acylbicyclic [3 · 2.1] oct-3-yl] -3-[[(4-fluorobenzyl) oxy] methyl] -2,3-dirat-1,4-dong and qi -Reconstituted amines; (3S) -N-[(3R, 5R) -1-acylbicyclop · 2.1] oct-3-yl] -3-[[(4-fluoromethylfluorenyl) oxy] methyl Group] -2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (3R) -N-[(3R, 5R) -1-azabicyclo [3 · 2 1] oct-3-yl] each [[(4-methylfluorenyl) oxy] fluorenyl] 2.3-dihydro-1,4-benzodioxolene 6-carboxamide; ( 3S) -N-[(3R, 5R) -l-4 bicyclo [3.2.1] octyl] each [[(4-fluoranyl) oxy] fluorenyl] · 2.3-dihydro-1, 4-Benzodioxolene-6-chipinamine; (3R) -N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1] oct-3-yl] -3- [[(4-methoxyfluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (3S) -N- [ (3R, 5R) small azine bicyclic p.2.1] oct-3-yl] each [[(4-methoxybenzyl) oxy] methyl] -2,3-dihydro-1,4-benzene Benzodioxol-6-carboxamidine; (3R) -N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1] octyl] each (phenoxymethyl) ) · 2,3-Dihydro-1,4-Benzodioxolene Carboxamide] (3S) -N-[(3R, 5R) -1-Acecylcyclo [3.2.1] octyl- 3-yl] each (phenoxymethyl) -2,3-dihydro. 1,4-benzodioxolene-6-carboxamide; (3R) -N-[(3R, 5R) Small acridine bicyclo [3 · 2 · 1] oct-3-yl] each [(4-fluorophenoxy) methyl] · 2.3-dihydro-1,4-benzodioxolane-6 -Carboxamide; -44-200300673 Description of the Invention, Continued (39) L ---- (3S) -N-[(3R, 5R) -1-acylbicyclo [3 · 2.1] oct-3-yl ] -3-[(4-Fluorophenoxy) methyl] _ 2.3-dihydro-1,4-benzodioxolane-6-polyamidamine; (3R) -N-[(3R , 5R) -1-acylbicyclo [3.2.1] oct-3-yl] Each [(4-methylphenoxy) methyl] · 2.3-dihydro-1,4-benzodioxolane Feminine SS amine; (3S) -N-[(3R, 5R) -1-acylbicyclo [3 · 2.ηoctyl] -3-[(4-methylphenoxy) methyl] _ 2.3-Dihydro-1,4-benzodioxolene-6-carboxamide; (3R) -N-[(3R, 5R) small acylbicyclo [3.2.1] octyl] each [(4-methoxyphenoxy) methyl] -2,3-dihydro-1,4-benzodioxolane, each compound fluorenamine; (3S) -N-[(3R, 5R) -1-Acridinebicyclo [3.2 · ΐ] oct-3-yl] · 3-[(4-methoxy Phenylphenoxy) methyl] -2,3-dihydro-1,4-benzodioxotriamine amines; N-[(3R, 5R) -1-azabicyclo [3 · 2 · 1] octyl] -4-fluorenyl-2fluorene-bene-6-carboxamide; Ke (311,511) small acylbicyclo [3.2.1] oct-3-yl] -4-ethyl -21 ^ ene-6-carboxamide; N-[(3R, 5R) -1-acylbicyclic hydrazone [3.2.1] octyl fluorenyl-fluoro-2 fluorene-in-law-6-carboxamine; N-[(3R, 5R) small acylbicyclo [3.2.1] octyl] -4-chloro-2H-bene-6-carboxamide; N-[(3R, 5R) small acylbicyclic [3.2.1] Octyl] Homobromo-2H-benzene carboxamide; N-[(3R, 5R) Small acryl bicyclo [3 · 2 · 1] octyl] -4-cyano -2H-Bentene-6-carboxamide; N-[(3R, 5R) Small acridine bicyclo [3.2.1] octyl] asethynyl-2fluorene-beneten-6-carboxamide; N- [(3R, 5R) Small acryl bicyclo [3.2.1] octyl] Hydroxy-2H · bita-7-carboxamide; N-[(3R, 5R) Small acryl bicyclo [3 · 2 · 1] octyl H-ethyl-2H-biten-7-carboxamidine; N-[(3R, 5R) small acylbicyclo [3.2.1] octyl] -4-fluoroyl-2Η ^ Cerene-7-carboxamidine; N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1] oct-3-yl] -4-chloro-2fluorene-fluorene-7- Carboxamide; N-[(3R, 5R) -W bicyclic benzo [3 · 2 · 1] ocin-3 -Yl] bromo-2Η · bite-7-carboxamidine; N-[(3R, 5R) -l-4bicyclo [3 · 2 · 1] oct-3-yl] -4-cyano -2Η-biten-7-carboxamide; N-[(3R, 5R) -1-acylbicyclo [3 · 2.1] octylpyridine-ethynyl-2Η-bitene A carboxamide; -45 -200300673 Description of invention $ Selling stomach (40)---N-[(3R) -1-leaf double soil and [3.2.2] non-3-yl] -2,3-dirat-1,4-winter Pyridoxine-6-pyridamine; N- (2-azinebicyclo [2.2.1] hept-5-yl) -2,3-dihydro-1,4-benzodioxolidine En-6-carboxamidine; N- (2- (2-methyl) -azinebicyclo [2.2.1] hept-5-yl) -2,3-dihydro-1,4-benzodioxy Lu Xun's various benzamines; N- (2-azinebicyclo [2.2.1] heptan-6-yl) -2,3-dihydro-1,4-benzodioxolene-6-carboxyl Fluorene; N- (2- (2-methyl) -azepine bicyclo [2.2.1] heptan-6-yl) -2,3-dihydro-1,4-benzodioxolane-6 -Pro-amines; N- (2 ^ γbicyclo [2.2.1] hept-5-yl) -2,3-dihydro-1,4-dioxolan [2,3-c] pyridine -7-carboxamidine; N- (2- (2-methyl) -leaf bis [2.2.1] hept-5-yl) -2,3-diaza-1,4-dioxolane Fuco [2,3-c] pyridine-7-carboxamidine; N- (2-leaf bis [2.2.1] heptan-6-yl) -2,3- Chloro-1,4-dioxotriamidine [2,3-c] p ratio reading · fermented amine, N- (2- (2-methyl) -azabicyclo [2.2.1] heptan-6- ) -2,3-dihydro-1,4-dioxolene [2,3-(: > specific bite-7-decanolamine]; N- (2-mouth bicyclic benzo [2 · 2 · 1] hept-5-yl) -bite-6-benzidine; Ν- (2- (2-methyl) -azepine bicyclo [2.2.1] hept-5-yl) -bite-6 -Carboxamide; Ν- (2-mouth bicyclo [2 · 2 · 1] hept-5-yl) -bite-7- # complexamine; N- (2- (2-methyl > acryl) Bicyclo [2.2.1] hept-5-yl) -bite-7-carboxamide; N- (2-azinebicyclo [2.2.1] heptan-6-yl) -bite-6-carboxamide; N- (2- (2-methyl) -azinebicyclo [2.2.1] heptan-6-yl) -fluorene-6-carboxamide; -46- 200300673 Description of the invention continued; (41)-N -(2-azinebicyclo [2.2.1] heptan-6-yl) -bite-7-fluorenamine; or N- (2- (2-methyl) -azinebicyclo [2.2.1] heptan- 6-yl) -fluorene-7-carboxamide. For those skilled in the art, other aspects and specific embodiments of the present invention can be read from the detailed description below, and used in conjunction with the application examples and the scope of patents attached to the article, to make it clear. Although the present invention is susceptible to specific embodiments in various forms, the following is a special embodiment of the present invention, and it should be understood that the disclosure of the present invention is intended as an illustrative example, and is not intended to limit the present invention to the present invention. Specific specific embodiments described in. Detailed description of the invention Surprisingly, we have found compounds of formula I:

-47- 200300673 (42) Description of the invention $ Selling page X is 0 or s; W is CH or N; Y is 0, CRy or C (Ry) 2, the condition is that when γ is CRY, one r6 is for CRY And a further condition that at least one of γ or z is 0; each Ry is independently fluorene, F, Br, Cl, CN, fluorenyl, halogenated alkyl, substituted alkyl, alkyl, naphthene Base, -ORi i or -N (Rq i) 2, when Y is C (RY) 2, and further if one Ry is ρ, Br, C1, CN, -〇Rn or -N ( R! 1) 2, the other RY is Η; Z is 0, CRZ or C (RZ) 2, provided that when Z is CRZ, 'a r4 is a bond to CRZ, and further conditions are γ or z At least one of them is 0; each Rz is independently fluorene, F, Br, Cl, CN, alkyl, halogenated alkyl, substituted alkyl, alkynyl, cycloalkyl, -ORi i or!) 2 which Provided that when Z is C (RZ) 2, and further conditions are when rz is f, Br, Cl, CN, -0 & 丨 or _n (Rii) 2, the other RZ is Η; alkyl is Linear and branched chain partial groups, with 1-6 carbon atoms; haloalkyl groups are alkyl partial groups, with 1-6 carbon atoms, and have! To (2n + 1) substituents, independently selected from F, Cl, Br or I, where η is the highest number of carbon atoms in this group; substituted alkyl is 1-6 carbon atoms Alkyl moiety with 0 to 3 substituents, independently selected from F, Cl, Br or I, and further having 1 substituent, selected from -CN, -N02, -OR10, -SR10, -NR10R10, -C (O) R10, -C (O) OR10 ... (: ⑸ 心 〇, -qCONd 0) 2, -N ^ 0 匸 ⑼ 风 心 〇) 2, -NR! 〇QO)! ^ 〇 , 4 (0) 1 0, -S (O) 2R10, -〇S (O) 2R10, -S (O) 2NR10R10, -NR10S (O) 2R1 (), phenyl, or have one selected from R2. Substituents, and further having 0-3 independently selected -48- 200300673 Description of the Invention Continued (43) ~-Phenyl with substituents from F, Cl, Br or I; Cycloalkyl has 3-6 Carbon atom cyclic alkyl moiety; R0 is fluorene, lower alkyl, substituted lower alkyl or iS-lower alkyl; low-end alkyl is one having 4 carbon atoms Partial groups of linear and branched chains; low-functionalized radicals are low-carbonated radicals with 1 to (2n + 1) substituents, independently selected from F, Cl, Br, or I, where η is at This part of the group The highest number of carbon atoms; the substituted lower alkyl group is a lower alkyl group, which has one substituent, and is independently selected from F, C1, BΓ, or I, and further has one substituent, selected from -CN, -N 〇2, -OR ^ 〇, -SRi 〇, -NR! 〇0, -QO)! ^ 〇,-(^ (0) 01 ^ 〇, -C⑸ 心 〇, -CXCON ^ 〇) 2, 〇CXC ^ Nd 〇) 2, -NR! 〇0 (0) 1 ^ 〇, 4 (0) 1 ^ 〇, -S (0) 2 Ri 〇, -OS (0) 2 0, -S (0) 2 NRi 〇 Ri 〇, -NRi 〇S (0) 2 R! 〇, phenyl, or having 1 to 3 substituents selected from ho, and further having 0 to 3 substituents independently selected from F, Cl, Br or I Phenyl

Ri is unique. JL is fluorene, alkyl, cycloalkyl, functional alkyl, or aryl; aryl is phenyl, substituted phenyl, fluorenyl, or substituted fluorenyl; Phenyl, whether it has 1-4 substituents, is independently selected from F, C1, Br or I, or has 1 substituent, selected from Rl2, and 0-3 substituents' are independently selected from F, Cl, Br or I; Substituted tbonyl is a hydrazone moiety, which has 1-4 substituents independently selected from F, Cl, Br or I, or has 1 substituent selected from Heart 2 'and 0-3 substituents are independently selected from ρ, ci, or I, wherein the substitution may be JL on only one ring or two rings of the 1 group group; each R2 is independently F, Cl, Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, aryl, or & does not exist, provided that it is Xin, k2, Xin-49-200300673 Description of the invention _ page (44)-or k6 is 0; R2_3 is fluorene, F, Cl, Br, I, alkyl, halo, substituted alkyl, cycloalkyl, or aryl; lq is 0 or 1; k2 0 or 1; k5 and k6 are independently 0, 1 or 2; R3 is fluorene, alkyl, alkenyl, alkyne Radical, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkynyl, halide alkynyl, 1S-substituted cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted alkyl, Substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, R7, R9, -0R8, -ORi 5, -SRg, -SRi 7, F, C ^ l, Br, I , -NRg, -NRg Rj 6, 6 Ri 6, .C (0) R8, -CN, -C (0) NR8R8, -NR8C (0) R8, -s (o) r8, -s (o) r17 , -Os (o) 2r8, -nr8s (o) 2r8, -no2, or -n (h) c (o) n (h) r8; fluorenyl is a linear and branched chain partial group, with 2- 6 carbon atoms and having at least one carbon-carbon double bond; halogenated alkenyl is an unsaturated alkenyl moiety, having 2-6 carbon atoms, and having 1 to (2n-1) substituents, independently selected From ρ, Cl, Br or I, where η is the highest number of carbon atoms in this group; the substituted alkenyl group is an unsaturated fluorenyl group group, has 2-6 carbon atoms' and has 0- 3 substituents independently selected from C1, and further having 1 substituent selected from -CN, -N02, -〇r10, -SR10, -NR10R10, -C (〇) R10, -0 (0) 0 ^ 〇 > -C (S) R10 > -C (O) N (R10) 2 > -NR10C (O) N (R10) 2 > -NR10C (O) R10, -S (O) R10… S (0) 2R1〇, · 08 (〇) 2 1 1〇 , -S (〇) 2NRi〇Ri〇, -NRi〇s (〇) 2; Ri0, phenyl, or having 1 substituent selected from R2〇, and further having 0-3-50-200300673 invention Explanation _ stomach (45) --- --- a phenyl group independently selected from the substituents of F, Cl, Br or I; alkynyl is a straight chain and branched chain partial group, having 2-6 carbon atoms, and Has at least one carbon-carbon reference bond; Halogenated alkynyl is an unsaturated alkynyl moiety, has 3-6 carbon atoms, and has 1 to (2n-3) substituents, independently selected from F, Cl, Br or I, where η is the highest number of carbon atoms in this group; the substituted alkynyl group is an unsaturated alkynyl group with 3-6 carbon atoms and 0-3 substitutions Group, independently selected from C1, and further has 1 substituent, selected from -CN, -NO2, -OR10, -SR10, -NR10R1 (), -C (O) R10, -C (O) OR10 ^ -C (S) R10 > -C (O) N (R10) 2 > -NR10C (O) N (R10) 2 ^ .NR10C (O) R10 > -S (O) R10 ^ -S (O) 2R10 > -OS (O) 2R10 ^ -S (O) 2NR10R10 ^ -NR10S (O) 2R10, phenyl, or 1 substituent selected from R2O, and phenyl further having 0-3 substituents independently selected from F, C1, Bi * or I; a halogenated cycloalkyl group is a cyclic moiety having 3 6 carbon atoms, with M substituents, independently selected from C1; substituted cyclic alkyl groups are cyclic moiety groups, with 3-6 carbon atoms, and 0-3 substituents, independently selected From C1, and further having 1 substituent, selected from -CN, -NO2, -OR10, -SR10, -NR1〇R1〇, · 〇ρ) ΙΙΟ, -C (〇) 〇Ri〇, -C⑸Ri 〇 ,-. (.Members ~ 〇) 2, -ah 〇 namely wind ~ 0) 2, depending on 1 〇qo)! ^ 〇, 4 (0) 1 ^ 〇, -S (O) 2R10, -〇S (O) 2R10, -S (O) 2NR10R10, jnr10S (O) 2R10, phenyl, or one having a substituent selected from R20, and further having 0 to 3 substituents independently selected from F, Cl, Bι: or I Phenyl; heterocycloalkyl is a cyclic moiety with 4-7 atoms, of which 1-2 atoms in this ring are -S-, -N (Ri or -0; -51- 200300673 Description of the invention Continuation page Halogenated heterocycloalkyl is a cyclic moiety fluorene, having 4 · 7 of which 1-2 atoms in each ring are each, π >, /, neutral or -〇-, and With M-generation group, independently selected from C1;

The substituted heterocycloalkyl group is a cyclic partial group, having 4-7 atoms, and the U2 atoms in the ring are each, ah, or · α, and have _3 substituents' independent Is selected from C1, and further has i substituents, selected from -CN, -N02, and even. , -SRl. , View 1gRig 'gang Rig, -c (〇) 〇Ri. _C⑸ ~ ^ -C (0) N (R1 〇) 2 > -NR! 〇〇) 2 ^ -NR! 〇α〇) Κλ 〇 ^ .S (0) R1 〇. .S (0) 2 R 〇, -os (o) 2r1 (), -s (o) 2nr10r1q, -NR10s (0) 2R1Q, phenyl, or has i substituents selected from & 〇, and further has 〇-3 A phenyl group independently selected from the substituents F, α, Br or I; each R4 is independently fluorene, alkyl, substituted alkyl, halogenated alkyl, cycloalkyl, heterocycloalkyl or p-Z Bond, the condition is that Z is CRZ;

(46) R5 is fluorene, alkyl, substituted alkyl, cycloalkyl, functional alkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted phenyl, or substituted naphthyl; Each R6 is independently fluorenyl, fluorenyl, substituted alkynyl, autofluorinated, cycloalkyl, heterocycloalkyl, or para-fluorine, provided that fluorene is CRY; R7 is 5-membered heteroaryl Group monocyclic partial group, containing 1-3 heteroatoms in the ring, independently selected from = N-, -N (R14)-, -0-, and -S-, and having 0-1 substitutions Group, selected from Ri 8, and further having 0-3 substituents, independently selected from F, Cl, Br or I, or R7 is a 9-membered fused ring moiety, having 6-membered ring, Close to 5-member ring 'which includes the following formula -52- 200300673

(47)

DESCRIPTION OF THE INVENTION_Page Φ ρ »» ”u is C (Ri 8) or N, and each & and & are independently selected from c (Ri 8) 2 '8), 0,, S, n and N (Ri §), provided that 〇2 and g3 are not 0 at the same time, S at the same time, or 0 and s at the same time, or

Where G is C (Ri 8) or N, and each of g2 and G3 is independently selected from C (Ri 8) 2, (: (& 8), 0, S, N, and N (R14), each 9-member The fused ring moiety has (M substituents selected from Heart 8, and further has 0-3 substituents, independently selected from F, Cl, Br or I, where the r7 moiety is Other substituents as defined in formula I, at any position on any ring, when valence bonds allow; each Rs is independently fluorene, alkyl, functional alkyl, substituted alkyl, cycloalkyl, functional Cycloalkyl, substituted cycloalkyl, heterocycloalkyl, functionalized heterocyclyl, substituted heterocycloalkyl, R //, 9, phenyl 'or having one selected from R20 A substituent, and a phenyl group further having 0 to 3 substituents independently selected from F, Cl, Br, or I, or a substituted phenyl group, R9 is a 6-membered heteroaromatic monocyclic partial group, Contains 丨 -3 heteroatoms in the ring, selected from = N-, and has (M substituents, selected from R2 ◦, and 0.3 substitutions -53-200300673

(48) Description of the invention_Stomach group, independently selected from F, Cl, Br or I, or & is a heteroaromatic bicyclic part of the melon member, containing one to two rings Atom, selected from = N-, including but not limited to. Kui 17 linyl or isoρ quelinyl, each 10-membered fused ring moiety, has 0-1 substituents 'selected from R 1 8 and 0-3 substituents' independently selected from F, Cl , Br or I, and any position of the connection point on R9 'position is allowed by the valence bond; each Ri 〇 is independently fluorene, alkyl, cyclofe, heterocyclic group is selected from one of Ri 3 An alkyl group substituted with a substituent, a cycloalkyl group substituted with a substituent selected from Ri 3, a heterocyclic alkyl group substituted with a substituent selected from Ri 13, a self-chemical alkyl group, a halogenated cycloalkyl group, Halogenated heterocycloalkyl, phenyl or substituted phenyl; each i is independently halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halogenated cyclohexyl or halogenated heterocycle Alkyl; R12 is -ORii, ~ SRu, alkyl, cycloalkyl 'heterocyclic tiger group, Hanhuayuan group, halogenated cycloalkyl group, self-generated heterocycloalkyl group, substituted alkyl group, substituted ring Alkyl, substituted heterocycloalkyl, -NRi 丨 i, -C (〇) Ri 1, -N02, -CCCONRi ii, -CN, -Nh i C (0) Ru, -S (0) 2 NI ^ i Ri l or -NR11 S (0) 2 Rn '

~ 3 is -OR! 1, -SRU, -NR ^ i, heart i, -C (0) Rn,-[(CONI ^ ii, -CN, -CF3, -N〇2, -NRn (: (0) 11 ^, -SPhNRnRu, * nriis (〇) 2Rii 'or phenyl, optionally substituted with up to 3 dent atoms, and further optionally substituted with 1 substituent selected from Ri 2;

Rl 4 is independently H, alkyl, functional alkyl 'substituted alkyl, cyclohexyl, self-cyclized cycloalkyl, substituted cycloalkyl, heterocycloalkyl, self-heterocycloalkyl or Substituted heterocycloalkyl; Heart 5 is fluorene, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated ring tiger -54- 200300673 Description of the invention $ 卖 Μ (49) group, substituted cycloalkyl , Heterocycloalkyl, dendritic, heteroheterocycloalkyl, h, R9, phenyl or substituted benzene; each Ri6 is independently alkyl, haloalkyl, boat substituted, halocycloalkyl, substituted A cycloalkyl group, a heterocyclic alkyl group, a substituted heterocycloalkyl group, R7, R9, phenyl 'or a substituent thereof, and further having 0-3 phenyl groups independently selected from the F-substituted group; each R17 series Independently fluorene, halogenated alkyl 'substituted halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl' substituted heterocycloalkyl, R7 or; each Ri 8 is independently H, F, C1 , ΒΓ, 1, alkynyl, i-alkynyl, halogenated cycloalkynyl, self-heterocyclic heterocyclyl, substituted cycloalkyl, substituted heterocyclyl 0 &!, -SR !!, See 11 Ri 1, -C (0) Rii, smoke i, -S ( 0) 2 NRi l Rl 1, -NRi 1 S (〇) 2 Ri 1 'or direct or I molecular bond, provided that there is only one group of the fused ring part of the core member, further conditions are The valence ring moiety has 0-i substituents' selected from the group consisting of alkyl, alkyl, haloalkyl, self-heterocycloalkyl, substituted cycloalkyl, substituted cycloalkyl Cyclopeptane '-NR!! ~ 1, -C (〇) Ri 1, · N02, _C (〇) NRl 1 i,., -S (0) 2 NRi 1 Ri1 or -Deta S (〇) 2 Ri 1 ′ and further cyclic groups have 0-3 substituents, selected from F, Cl, R! 9 is fluorene, alkyl, haloalkyl, substituted cycloalkyl, substituted t; alkyl, cycloalkyl, halogenated heterocyclic ring has one selected from R20, Cl, B1: or I alkyl, cycloalkyl, halogenated heterocycloalkyl, cycloalkyl, hetero Cycloalkyl, substituted radicals, -CN, -N02, Rn ^ -NRnC ^ Rn are tangentially connected to the core molecule where the 9-bond is allowed. This thick, cycloalkyl, heterocycloalkyl, Substituted groups, -ORi 1,, SRI 1 .CN, Na 1 C (0) Ru, provided that this condensed Br or I; group, cyclic group, -55-200300673 (50) of cycloalkyl, substituted cycloalkyl of oysters, phenyl, 4 having substituents selected from i r2. And a phenyl group further having 0 to 3 substituents independently selected from F, Cl, Br or I;

R20 is an alkyl group, a cycloalkyl group, a heterocyclic alkyl group, a self-chemical alkyl group, a self-chemical cycloalkyl group, a heterocyclic alkyl group, -ORi il, _NRi i], (⑼ R < Rl i, N 1々0) 1111, 2) 2NRnRn, depending on where! ^, -N〇2, have been independently written by 1.4, p, ci, b L., The director selected u 选, I or R! 3 Substituent substituted alkyl, Br, I, or Ri 3 substituted F, Cl, Br, I, or h 3 substituted by 'M independently selected from F, C1 cycloalkyl, or by 1- 4 independently selected g-substituted heterocycloalkyl groups; or a pharmaceutical composition, a pharmaceutically acceptable salt thereof, a racemic mixture or a pure palmar isomer, which can be used to treat any one or a combination of the following diseases , Alzheimer's disease symptoms of cognitive and attention deficit, neurodegeneration associated with the disease, such as Alzheimer's disease, senile dementia (temperature and cognitive impairment), Alzheimer's Disease, schizophrenia, psychiatry, > Wang Yili disorder, inadequate attention disorder, mood and affective disorder, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury Damage, behaviors and cognitive problems associated with brain tumors, AIDS dementia relapse, dementia associated with Down's syndrome, dementia associated with Lewy body, Huntington's disease, depression, general Anxiety disorders, spot degeneration associated with aging, Parkinson's disease, tardive dyskinesia, pick's disease, post-traumatic stress disorder, dysfunction in regulating food intake, bulimia and anorexia, and stopping smoking and stopping Symptoms of drug dependence associated with withdrawal, Gilles de la Tourette's symptoms are misidentified as' glaucoma, and glaucoma -56- 200300673

Description of the invention IfM (51)-associated neurodegeneration, or symptoms associated with pain. The invention also includes pharmaceutical compositions containing active compounds, and methods of treating the identified diseases. In another aspect, the invention includes a method of treating a mammal suffering from schizophrenia or psychosis by administering a compound of formula I with an antipsychotic drug, also known as an antipsychotic agent. Compounds of formula I and antipsychotics can be administered simultaneously or at separate intervals. When administered simultaneously, a compound of formula I and an antipsychotic can be incorporated into a single pharmaceutical composition. Alternatively, two separate compositions can be administered simultaneously, meaning that one contains a compound of formula I and the other contains an antipsychotic drug. You can use the abbreviations commonly known to the artist (for example, nPh '' is phenyl, " Me '' is fluorenyl, 'ΈΓ is ethyl, nh " or one or more hours, " min' 'is one Minutes or minutes, and nrt "or nRTf 'is room temperature). All temperatures are expressed in degrees Celsius. Room temperature is in the range of 15-25 degrees Celsius. AChR refers to the acetylcholine receptor. NAChR refers to Acetylcholine receptors of nicotinic acid. 5HT3R refers to serotonin type 3 receptors. `` Presenile dementia and " mild cognitive impairment " refers to the same disease state. Alpha-btx refers to alpha-cobra toxin. ‘FLIPR is a device marketed by Molecular Device Corporation, designed to accurately measure cell fluorescence in high-throughput whole-cell detection. (Schroeder et al., J. Biomolecular Screening, 1 (2), pp. 75-80, 1996). TLC refers to thin layer chromatography. -57- 200300673 Description of the invention (52) ----- HPLC means high pressure liquid chromatography.

MeOH means methanol.

EtOH means ethanol. IPA means isopropanol. THF refers to tetrahydrofuran.

DMSO refers to Dimethylarsine. DMF means dimethylformamide.

EtOAc refers to ethyl acetate. TMS refers to tetramethylsilane. TEA means triethylamine. DIEA refers to diisopropylethylamine.

Na2S〇4 refers to the bowl of copper acid. K2C03 refers to potassium carbonate.

MgS04 refers to magnesium sulfate. When Na2S04, K2C03 or MgS04 is used as the desiccant, it is anhydrous. MLA means methyl taurine. The mystery is acetic acid. HATU refers to 0- (7-azabenzotriazole small group of hexafluorophosphate :) Zhao Fan 乂 ^ tetramethyl fluorene. 50% saturated 1: 1 NaCl / NaHC〇3 means 1: 1 saturation

NaCl / NaHC03 solution, and a solution made by adding an equal volume of water. Halo is halogen. Halogen is F, Cl, Br or I. The content of carbon atoms in various hydrocarbon-containing parts is indicated by the prefix. The lowest and highest number of specified carbon atoms in the group of the part, that is, the prefix Ci_j represents an integer with an integer T carbon atoms (inside Including) part of the group. -58- 200300673 Description of the invention $ Selling page (53) ----- For example, Cu alkyl means an alkyl group of one to six carbon atoms. Non-exclusive examples of heteroaryl compounds falling within the definitions of R7 and R9, including, but not limited to, P-secenyl, benzo-P-secenyl, P-bitenyl, Yuanjun, Jun4, Ye b 17 Base, p-pentyl, midazolyl, sulfanyl, benzocranyl, benzoxazolyl, isoxazolyl, benzoisoxazolyl, benzoisozazolyl, benzimidazolyl Sitting base, 丨 base, benzoσ base, p ratio σ base, three turkey, four base, iso p base, 4 base, ρ bihyl, isoρ ΤΤ 林基, Itchy 11 forest base, Η 峻 基, indura 基, blown 基, ta 基 基, 耕 耕, 啕 啕 基, 基 基 基, 呤 基 基 基Acetylthio, benzo-4pyridyl, p-quinothyl, 0-quinylpyridyl, 4-pyridyl, pyranopyridyl, pyrrolopyridyl or fluorenopyryl. All isomer forms of non-exclusive reference groups are included, such as benzofuranyl, including 1-benzoxan-2-yl, 1-benzoxan-3-yl, 1 -Pyreno-4-an, 1-dongfuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 2-benzofuran-1-yl, 2-Mulino-ran-2-yl, 2-private-ran-3-yl, 2-fauren-4-an or 2-benzofuran-5-yl. Non-exclusive examples of R7 and R9 may be replaced when the price key permits, in the manner permitted in the individual definitions of R7 and R9. Generally familiar with this art, the artist can confirm the permissible substitution by comparing non-exclusive examples with the individual definitions of R7 and R9. Non-exhaustive examples of heterocyclic alkyl include, but are not limited to, tetrahydropyranyl, tetrahydrocitaranyl, morpholinyl, tetrahydrop-bihalyl, hexahydrop-pyridyl, and hexahydrop-pyridyl. Well-based, monoaza-tetramethyl, monoaza-tetramethyl, trioxo, tetrahydropyridyl, tetrahydropyrrolyl, or isodihydro-7 azole. The core molecule is acridine bicyclo-fengxin) -c (= x)-: -59- 200300673 Description of the invention (54)-

Indirect bonding to a core molecule includes bonding to a bicyclic fused ring moiety group directly connected to the core molecule. One of the most commonly accepted naming methods:

The system is N-((3R) -1-acylbicyclo [2.2.2] octyl) -2,3-dihydro-1,4-benzodioxolane-6-scopolamine, but For those skilled in the art, this same compound can be referred to as N-((3R) -1-acylbicyclo [2.2.2] oct-3-yl) -1,4-benzodioxolane -6-carboxamide. These two can be used interchangeably in this article. In addition, N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-ethyl-2,3-two-star ^ -1,4-winter-oxoluyuan association -7-Fermented Amine and N-[(3R) Small acryl [2.2.2] oct-3-yl] -3-ethyl-2,3-dihydro-1,4-benzodioxo Pinene-6-carboxamide refers to the same compound:

Some of the amines described herein require the use of amine protecting groups to ensure the functionalization of the desired nitrogen. The artist is generally familiar with where to use this protecting group in synthetic systems. The protective group of the amine group includes, but is not limited to, oxocarbonyl-60-200300673 Description of the Invention _ stomach (55) group (CBz), tertiary-butoxycarbonyl (BOC) and the like. Other suitable examples are known to those skilled in the art and can be referred to the "protective group π in organic synthesis" by Peter Wuts. The third mammal refers to humans and other mammals. Saline refers to a saturated aqueous solution of chlorinated # 3.

Equ means Morse equivalent. IR refers to infrared spectroscopy.

Lv refers to the release group in the molecule, including Cl, OH or Parr refers to the name of the company, which is a jar for sale for pressurization. PSI means pounds per square inch. NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical 6 ppm ((5) for low magnetic field for reporting. MS refers to mass spectrometry, in m / e or mass / charge single refers to high-resolution mass spectrometry, with m / e or mass / charge] refers to the positive ion of the parent plus the hydrogen atom. M-ΗΓ refers to the negative ion of the parent. M + Na— refers to the positive ion of the parent plus the sodium atom and the positive ion of the potassium plus potassium EI means electron ionization ionization. CI means chemical ionization. FAB means strike. — The compound of the present invention may be in the form of a pharmaceutically acceptable salt ^ The term "accepted salt" refers to a pharmaceutically acceptable salt Salts of inorganic bases and organic bases, and salts made from inorganic acids and organic bases, including aluminum, ammonium, calcium, iron, and ferrous amine-based protecting groups. Theodora Greene Edition 0 gf. The i-shift system is represented by the distance from TMS. The HRMS is represented by the Wu position. The M + H + body minus the hydrogen atom ions. The M + K + system is collided. The ESI refers to the electric finger rapid atom collision C. The f 'is pharmacologically non-toxic, including acid Salt. Derivative, Wei, Iron, Potassium -61-

200300673 (56), sodium, zinc, etc. Derived from pharmaceutically acceptable, including primary, secondary and tertiary amines, substituted amines generated from substituted amines, cyclic amines, such as arginine, choline, N, N- Dimethylethylenediamine, diethylamine, alcohol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, NN-ethylhexahydropyridine, glucosamine, glucosamine, amine, isopropylamine, lysine , Methyl glucosamine, morphine, hexahydropyridine, polyamine resin, procaine, purine, amine, trimethylamine, tripropylamine, etc. Derived from inorganic acid, hydrobromic acid, hydrolytic acid, sulfuric acid, phosphoric acid, and linoleic acid. Salts of pharmaceutically acceptable organic non-toxic acids, including Cl-6 dicarboxylic acids and tricarboxylic acids such as acetic acid, propionic acid, Transperbulic acid, tartaric acid, maleic acid, adipic acid, and citric alkylsulfonic acids, such as toluenesulfonic acid salts. The so-called "effective amount of compound" is the term, when used herein as a non-toxic but sufficient amount of compound to provide what is indicated, the exact amount required varies with the patient's species, age, and general condition, The severity of the disease to be treated depends on the compound, the mode of administration, etc. Therefore, there is no net effect. " However, an appropriate effective amount can be determined by routine experimentation. The compound of formula I has an optically active center in the azine ring and although it is generally desirable that the stereochemical purity should be as high as possible, the purity is as high as possible. The present invention relates to non-organic non-toxic salts of different stereochemical purity, including natural, beet test, Rakkou 2-diethylaminoethylethylmorpholine, histidine, hyprine, and hexahydrogen. Salts of theobromine, triethyl, including salts. Derivatives of alkyl carboxylic acids, butenedioic acid, succinic acid, and aryl are intended for use when provided. As described below, depending on the patient's property, the special L used is designated to be an artist, and only some groups are used. There is no need for an absolute racemic mixture with -62- 200300673 Description of the Invention # 卖 Μ (57) -—- Composition. Preferably, stereoselective synthesis is performed and / or the reaction product is subjected to appropriate purification steps to produce a substantially optically pure substance. Appropriate stereoselective synthetic procedures for generating optically pure substances are known in the art, such as procedures for purifying racemic mixtures into optically soluble fractions.

The amount of the therapeutically effective compound administered and the dosage regimen of the compound and / or composition of the present invention for the treatment of a disease state depend on a variety of factors, including the age, weight, sex, and medical symptoms of the patient, The severity, route and frequency of administration, and the particular compound employed, can therefore vary widely. These compositions contain conventional carriers and excipients in addition to a therapeutically effective amount of a compound of formula I. These pharmaceutical compositions may contain active ingredients in the range of about 0.001 to 100 mg / kg / day for adults, and preferably in the range of about 0.1 to 50 mg / kg / day for adults. The total daily dose of about 1-1000 mg of active ingredient is suitable for adults. The daily dose can be administered one to four times a day. In addition to the compound of formula I, the composition for therapeutic use may also contain one or more non-toxic, pharmaceutically acceptable carrier substances or excipients. As used herein, the term `` carrier π substance or π excipient '' means any substance that is not itself a therapeutic agent and is used as a carrier and / or diluent and / or adjuvant or vehicle to deliver the treatment Agent to a patient or added to a pharmaceutical composition to improve its handling or storage properties, or to allow or assist in forming a dosage unit of the composition into discrete objects, such as capsules or tablets suitable for oral administration. Excipients The following can be used as illustrations, without limitation, including diluents, disintegrating agents, adhesives, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or neutralize unpleasant tastes or odors, Bridge flavor, dye -63- 200300673 Description of the invention _ stomach (58)---

, Fragrances and substances added to improve the appearance of the composition. Acceptable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sulfuric acid. Salt, gelatin, gum arabic, sodium alginate, polyethylenetetrahydropyrrolidone and / or polyvinyl alcohol, and then tabletted or encapsulated for easy administration. Such capsules or tablets may contain a controlled release formulation, which may be provided as a dispersion of the active compound in hydroxypropyl methylcellulose, or other methods known to those skilled in the art. For oral administration, these pharmaceutical compositions may be in the form of, for example, tablets, capsules, suspensions or liquids. If desired, other active ingredients can be added to the composition. In addition to the oral administration indicated above, the composition of the present invention may be administered by any appropriate route, in the form of a pharmaceutical composition suitable for such a route, and in a dose effective for the intended treatment. For example, these compositions can be administered parenterally, such as intravascularly, intraperitoneally, subcutaneously, or intramuscularly. For parenteral administration, saline solution, dextrose solution or water may be used as a suitable carrier. Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules with one or more of the carriers or diluents mentioned for use in oral dosage formulations. These compounds can be dissolved in water, polyethylene glycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil, sesame oil, alcohol, sodium chloride and / or various buffering agents. Other adjuvants and modes of administration are well and widely known in the medical arts. The serotonin type 3 receptor (5HT3R) is a member of the ligand-gated ion channel superfamily, which includes muscle and neuron nAChR, glycine receptors and [-64- 200300673. ) ----

Aminobutyric acid type A receptor. Like other members of this receptor superfamily, 5HT3R shows a large degree of sequential similarity to a7nAChR, but functionally, these two ligand-gated ion channel systems are very different. For example, α7 nAChR is rapidly inactivated, highly permeable to calcium, and activated by acetylcholine and nicotine. On the other hand, 5HT3R is slowly inactivated, is relatively impermeable to calcium, and is activated by serotonin. These experiments indicate that a7 nAChR and 5HT3R proteins have some degree of similarity, but have very different functions. In fact, the pharmacology of these channels is very different. For example, Ondansetron is a highly selective 5HT3R antagonist with very little activity for a7nAChR. The opposite is also true. For example, GTS-21 is a highly selective α 7 nAChR activator and has very little activity against 5HT3R. a7 nAChR is a ligand-gated Ca ++ channel formed by a homopentamer of the α7 subunit. Previous studies have established that α-cobra toxin (α-btx) selectively binds to this homopentameric a7 nAChR isoform, and that a7 nAChR has a high affinity binding site for a-btx and methyl taurotonin (MLA) . α7 nAChR is expressed to a high degree in the hippocampal peritoneal region and the ascending cholinergic protrusions from the base nucleus to the thalamus and cortex. a7 nAChR activators increase neurotransmitter release and increase cognition, arousal, attention, learning and memory. Data from human and animal pharmacological studies establish that the nicotinic cholinergic neuron pathway controls many important aspects of cognitive function, including attention, learning, and memory (Levin, ED., Psychopharmacology, 108: 417-31, 1992; Levin, ED · and Simon Β · Β, Psychopharmacology, 138: 217-30, 1998). For example, learning the If test increases cognitive and attention in humans. ABT-418, a compound that activates α4 / 32 and a7 nAChR, improves Alzheimer's disease and attention-65- 200300673 Description of the Invention, (60)-Clinical trials of deficient conditions that improve cognition and Attention (Potter A. et al., Psychopharmacology, (Berl) "142 (4): 334-42, March 1999; Wilens, T.E. et al., Am. J. Psychiatry, 156 (12) ·· 1931-7, December 1999). It is also clear that nicotine and the selective but weak a7 nAChR activator increase cognition and attention in rodents and non-human primates. Spirit Schizophrenia is a complex multifactorial disease caused by genetic and non-genetic risk factors. The risk factors can produce positive and negative symptoms. Positive symptoms include delusions and hallucinations, while negative symptoms include emotion, attention, and cognition. And inadequate information processing. In this disease, no single biological element has emerged as a dominant pathogenic factor. In fact, schizophrenia may be a symptom cluster generated by a combination of many risk factors with low genetic trait performance frequency. Pharmacology Studies have established that dopamine receptor antagonists are effective in treating the obvious psychotic features (positive signs) of schizophrenia, such as hallucinations and delusions. Clozapine, an f'atypical 'antipsychotic, is novel because It is effective in treating both positive and some negative signs of this disease. The use of clozapine as a drug is greatly restricted, and continuous use will increase the risk of agranulocytosis and sudden onset. No other antipsychotic drug is effective in treating the negative signs of schizophrenia. This is important because the repair of cognitive function is the best predictor of the successful clinical and functional evolution of schizophrenia (Green, M.F., Am J Psychiatry, 153: 321-30, 1996). By extension, it is clear that better drugs are needed to treat cognitive disorders of schizophrenia, so that patients with this disorder can return to a better state of mental health. One aspect of cognitive deficits in schizophrenia, the use of sensory gating -66- 200300673

Description of the invention IfM (61) -II-

Audit event-related potential (P50) test measurement. In this experiment, an electroencephalogram (EEG) record of hippocampal neuron activity was used to measure the patient's response to a series of auditory hallucinations (Adler · LE et al., Biol · Psychiatry, 46 8-18, 1999). Normal people respond more to the first click than to the second click. In general, schizophrenics and schizophrenic patients respond almost identically to two clicks (Cullum, C.M. et al., Schizophr. Res., 10: 131-41, 1993). This information reflects that schizophrenics cannot “filter” or ignore unimportant messages. Insufficient sensory gating appears to be one of the key pathological features of the disease (Cadenhead, K.S. et al., Am. J. Psychiatry, 157 55 55-9, 2000). Multiple studies have shown that nicotine normalizes hyposensory schizophrenia (Adler, L.E. et al., Am J. Psychiatry, 150: 1856-61, 1993). Pharmacological studies have shown the effect of nicotine on sensory gating via a7nAChR (Adler, L.E. et al., Schizophr. Bull., 24 · 189-202, 1998). In fact, biochemical data show that schizophrenics have less than 50% of the a7 nAChR receptors in the hippocampus, thus gaining a theoretical basis for a partial loss of a7 nAChR functionality (Freedman, R. et al., Biol. Psychiatry, 38: 22-33, 1995). Interestingly, genetic data show that polymorphism in the promoter region of the a7 nAChR gene is strongly associated with insufficient sensory gating in schizophrenia (Freedman, R. et al., Proc. Nafl Acad. Sci. USA, 94 (2): 587-92, 1997; Myles-Worsley M. et al.,

Am. J. Med. Genet, 88 (5) · 544-50, 1999). To date, mutations in the coding region of a7 nAChR have not been confirmed. As a result, schizophrenics will perform the same nAChR as non-schizophrenics. Selective a7 nAChR activators can be found on FLiPR using functional tests (see WO 00/73431 A2). FLIPR is designed to read fluorescence signals from wells of 96 or 384 -67- 200300673 (62) Description of the invention. This test can be used to accurately measure the functional pharmacology of a7nAChR and 5HT3R. To perform this test, we used a cell line expressing W Xin functional form, a α7 / 5-ΗΤ3 channel as a drug target, and a functional 5HT3R cell line. In both cases, the ligand-gated ion

The channel system appears in SH-EP1 cells. Both of them are early and related ... Ali ion force can produce strong signals in FLIPR detection. The compounds of the present invention are a7nAChR activators and can be used to treat a wide variety of diseases. For example, it can be used to treat schizophrenia or psychosis. Schizophrenia is a disease with multiple aspects called I-Chronic. The drugs that Muli can use are generally for the purpose of controlling the positive aspects of schizophrenia, such as delusion. A drug, clozapine, is designed for the poorer I | perimeter < sensitivity to schizophrenia #. The drug JL You Er Jia Jiao and Zong M Yi have many side effects, so it is not suitable for many sick hearts. Therefore, bismuth is still needed, associated cognitive and attention deficit = treatment of cognitive dysfunction associated with schizophrenia and schizoaffective disorder, tone: Needs medicine to treat similar diseases found in relatives of schizophrenia : "Not 'footed' or a mental illness in mental illness, and the sign is a general weakening of the patient's physical perception. Patients may have paranoid spots See above <-, hook, and may be left coherent. Its behavior may be radical,-No, I, Shang,-, * ’workers are ignorant of their surroundings. In the past, the term mental illness has been ridden ^. Therefore-a ,, ... is used for many of the more stringent ones that do not satisfy the above, and I am fierce. For example, #,, 工 所, and mental illness are referred to as mental illness. There are many antipsychotic drugs. Conventional rhodium psychiatric medicines include chloropropanol • 68-200300673 Description of the invention _ stomach (63)-(-) (Chlorpromazine), fluphenazine, Haloperidol, Xexepin ( Loxapine), Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine, and Amine. Thiothixene and Trifluoperazine. These drugs all have an affinity for the dopamine 2 receptor. These conventional antipsychotics have several side effects, including sedation, weight gain, tremor, increased prolactin levels, inability to sit still (motor nervous disturbances), insufficient muscle tone, and muscle stiffness. These drugs can also cause difficulty with delayed movement. Unfortunately, only about 70% of patients with schizophrenia respond to conventional antipsychotic drugs. For these patients, atypical antipsychotics can be used. Atypical antipsychotics usually reduce the positive symptoms of psychosis, and also improve the negative symptoms of psychosis, to a greater extent than conventional antipsychotics. These drugs can improve neurocognitive deficits. Extrapyramidal (motor nerve) side effects are not likely to accompany atypical antipsychotics, and therefore, these atypical antipsychotics have a lower risk of developing delayed motor difficulties. Finally, these atypical antipsychotics cause little or no rise in prolactin. Unfortunately, these drugs are not without side effects. Although each of these drugs has different side effects, overall these side effects include: Granulocytic Deficiency, Increased Risk of Burst, Weight Gain, Drowsiness, Dizziness, Tachycardia, Decreased Ejaculatory Volume and QTc Interval Gentle extension. In combination therapies for the treatment of multiple symptoms of diseases such as schizophrenia, compounds of formula I and antipsychotics can be administered simultaneously or at separate intervals -69- 200300673 Description of the invention, f sell stomach (64) -----

. When administered simultaneously, a compound of formula I and an antipsychotic can be incorporated into a single pharmaceutical composition, such as a pharmaceutical combination therapeutic composition. Alternatively, two separate compositions may be administered at the same time, meaning that one contains a compound of formula I and the other contains an antipsychotic drug. Examples of antipsychotic drugs, in addition to those listed above, include, but are not limited to, chloropropane 1, Mellaril, Trilafon, amine peptone, trifluoro Lawei, Permitil, Prolixin, Risperdal, Zyprexa, Seroquel, ZELDOX, Ethylphenazine ( Acetophenazine, Carphenazine, Chlorprothixene, Droperidol, Xeroxine, Mesoridazine, Molindone, Ondancy From (Ondansetron), Pimozide, Prochlorperazine and Promazine. A pharmaceutical combination therapeutic composition may comprise a therapeutically effective amount of a compound of formula I indicated above, and a therapeutically effective amount of an antipsychotic drug. These compositions can be formulated with commonly used excipients, diluents or carriers, and compressed into tablets, or formulated as tinctures or solutions for convenient oral administration, or administered by intramuscular intravenous route. These compounds can be administered rectally, topically, orally, sublingually or parenterally, and can be formulated in a sustained-releasing dosage form and the like. When administered individually, a therapeutically effective amount of a composition containing a compound of formula I and an antipsychotic is administered at different schedules. One can be administered before the other, as long as the time between administrations falls within the therapeutically effective interval. The therapeutically effective interval is a period of time that begins when either the compound of formula I or (b) one of the antipsychotic drugs is administered to humans, and -70- 200300673 invention description f sells M (65)-between ⑻ and (b ) The combination of schizophrenia or psychiatric treatment terminates below the limit of beneficial effects. The method of administering a compound of formula I and an antipsychotic can be changed. Therefore, either or both agents can be administered rectally, topically, orally, sublingually, or parenterally.

As discussed, the compounds of the invention are a7 nAChR activators. Therefore, as another aspect of the present invention, the compounds of the present invention can be used to treat a variety of diseases, including Alzheimer's cognitive and attention deficit symptoms, and neurodegeneration associated with the disease, such as Alzheimer's Disease, senile dementia (also known as mild cognitive impairment), and senile dementia. There are many aspects of Alzheimer's disease, including cognitive and attention deficits. Currently, these are not adequately treated with cholinesterase inhibitors. These inhibitors slow the degradation of acetylcholine and accordingly provide a generally non-specific increase in cholinergic nervous system activity. Since these drugs are non-specific, they have a wide variety of side effects. Therefore, there is still a need for a drug that stimulates a part of the cholinergic pathway and thereby provides an improvement in cognitive and attention deficits associated with Alzheimer's disease without the use of non-cholinergic pathways. Side effects from specific stimuli. Neurodegeneration is a common problem associated with diseases such as Alzheimer's disease. Although current medications treat some symptoms of this disease, it does not control the underlying pathology of this disease. Therefore, it is generally desirable to provide drugs that can slow the progression of Alzheimer's disease. Presenile dementia (mild cognitive decline) is about memory loss rather than attention deficit problems and other non-impaired cognitive functions. The difference between mild cognitive decline and Alzheimer's is that the mild cognitive decline is -71-200300673 Description of the invention m (66)---- It involves the problem of memory loss that is more durable and difficult to handle as the patient ages. There are currently no drugs specifically identified for the treatment of mild cognitive impairment, which is a result of confirming the novelty of the disease. Therefore, a drug is still needed to treat memory problems associated with mild cognitive decline. Dementia is not a single disease state. However, symptoms classified under this name often include cognitive and attention deficits. In general, these deficiencies have not been treated. Therefore, a drug is still needed to provide improvement in cognitive and attention deficits associated with Alzheimer's. As discussed, the compounds of the invention are nAChR activators. Accordingly, yet other diseases to be treated with the compounds of the present invention include the treatment of cognitive and attention deficits, and neurodegeneration associated with any one or more or a combination of: attention deficit disorders, attention deficit hyperactivity disorders , Depression, anxiety, general anxiety disorder, post-traumatic stress disorder, mood and affective disorder, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, behavioral and cognitive problems associated with brain tumors, aids dementia Relapse, dementia associated with Down's syndrome, dementia associated with Lewy body, Huntington's disease, Parkinson's disease, dyskinesia, Pick's disease, and regulation of food intake Disorders, including bulimia and anorexia, neurological symptoms associated with cessation of smoking and dependence on drugs, errors in Gilles de la Tourette's syndrome, speckle degeneration associated with aging, glaucoma, neurodegeneration associated with glaucoma, or Symptoms associated with pain. Attention deficit disorders are usually treated with fenamic acid 曱 S, which is a amphetamine-like molecule with several possibilities of abuse. Therefore, General -72- 200300673 Description of the Invention ®M (67) ----- It is desirable to provide a drug for the treatment of attention deficit disorders while having fewer side effects than currently used drugs. Attention deficit hyperactivity disorder, also known as ADHD, is a neurobehavioral disorder affecting 3-5% of all children in the United States. ADHD is about cognitive effects alone or both cognitive and behavioral effects by interfering with individuals' ability to stay in work and exercise their age-inhibiting effects. There are several types of ADHD: one is mainly the inattentive subtype, the other is the hyperactive impulsive subtype, and one is the combined subtype. Treatment may include medications such as methylphenylate, dextroamphetamine, or phenytoin, which are used to reduce impulsivity and hyperactivity, and to increase attention. There are currently no "curatives" to cure f'ADHD. Children with this condition rarely get rid of them due to older age; therefore, appropriate medications are still needed. Depression is a mood disorder with varying lengths of time, usually from months to more than two years , And have varying degrees of feeling, involving depression, despair, and depression. Heterocyclic antidepressants (HCA) are currently the largest class of antidepressants, but monoamine oxidase inhibitors (MAOI) are used for specific types of depression. From HCA Common side effects are sedation and weight gain. In elderly patients with organic brain disease, side effects from HCA can also include sudden and behavioral symptoms. The main side effects from the use of MAOI are due to diet and drug interactions Effects occur. Therefore, 'medicines with fewer side effects are useful. Anxiety disorders (conditions with significant anxiety or horror avoidance) represent areas where the treatment of psychiatric disorders does not meet medical needs. See also Diagnostic & Statistical Manual, IV (1994), pp. 393-394, Notes on Anxiety-73-200300673, Invention Description, (68) ----a form of disease. / General anxiety disorder (GAD) occurs when people worry about things, such as family, health or work 'when there is no reason to worry and can not help but worry. During a year, about 3 to 4% of the US population has GAD. GAD most often hits people during childhood or musical years, but it can also start in adulthood. It affects women more often than men. Currently, the treatment system involves cognitive behavioral therapy. , Relaxation techniques and biofeedback to control muscle tension, as well as medicinal therapies, such as benazepines, imipramines, and buspirone. These drugs are effective 'but all have a tendency to side effects. Therefore, Agents with fewer side effects are still needed to find solutions to these symptoms. Anxiety also includes post-traumatic stress disorder (PTSD), which is a form of anxiety triggered by the memory of a traumatic event, which directly affects the patient, Or the patient may have witnessed the event. This condition usually infects survivors of trauma events, including sexual assault, physical assault, war, torture, natural disaster, car accident, airplane crash , Hostage status or death row. This condition may also affect rescue workers at the scene of an airplane crash or mass shooting, witnessing a tragedy or someone who has accidentally lost a lover. Treatment of pTSD includes cognitive behavioral therapy, group psychotherapy and medicine Therapies, such as clonazepam, Lomzepaxn ', and selective serotonin reuptake inhibitors, such as Fluoxetine, Sertralme, and Paroxetine paroxetme), Ckalopram and Fluvoxamine. These medicines are effective for anxiety and depression. Various forms of exposure therapy (such as system warming 2 and imagination) All have been used in patients with PTSD. PTSD, Luye Therapy Department involves repeatedly experiencing the wound under controlled conditions, and its purpose is to help deal with the wound. Therefore, there is still a need for better agents to treat post-traumatic stress disorders.

Mood and emotional disorders fall into a large group of diseases, including unipolar depression # and bipolar mood disorders. These diseases are treated with three main types of compounds. The first group is heterocyclic antidepressants (HCA). This group includes conventional tricyclic antidepressants. The second group of compounds used to treat mood disorders is monoamine oxidase inhibitors (MAOI), which are used for specific types of diseases. The third drug is lithium. Common side effects from HCA are sedation and weight gain. In older patients with organic brain disease, the side effects of HCA can also include sudden and behavioral symptoms. The main side effect from the use of MAOI is due to the interaction between diet and drugs. The mild side effects of lithium use include, but are not limited to, weight gain, nausea, diarrhea, polyuria, thirst, and tremor. Toxic side effects from lithium can include persistent headaches, confusion, and bursts and arrhythmias. Therefore, agents that have fewer side effects or interactions with food or other drugs are useful. Borderline personality disorders, although not as familiar as bipolar disorders, are more common. People with borderline personality disorders are those who experience emotional regulation. Medicaments are used to treat specific symptoms, such as depression or mental disorders. Acquired immune deficiency syndrome (AIDS) is caused by infection with human immunodeficiency virus (HIV). The virus invades selected cells and impairs the proper functioning of the immune, nervous, and other systems. HIV infection can cause other problems, such as, but not limited to, difficulty thinking, otherwise known as AIDS dementia. Therefore, drugs are still needed to relieve the confusion and depression of people with AIDS. -75- 200300673 Amyotrophic lateral sclerosis, also known as Lou Gehrig's disease, belongs to a category of disorders known as motor neuron diseases, in which specific nerve cells in the brain and spinal cord gradually degenerate and negatively affect Control moving towards free will. There are currently no treatments for amyotrophic lateral sclerosis, but patients can be treated for some of their symptoms, and nonetheless, Riluzole has been shown to prolong patient survival. Therefore, agents are still needed to treat this disease. Traumatic brain injury occurs when the brain is injured when Li Kui physically attacks the head from m ^, u. The source of traumatic brain injury 6 ^, appeals include mental disorders and other cognitive problems. Therefore, there is still a need to seek solutions to the symptoms of Faraday and other cognitive problems. Brain tumors were found in the inside of the skull, and 田 ee was abnormally grown. Signs of brain tumors include behavioral and cognitive problems. Hand # f Α, used in surgery, radiation, and chemotherapy is used to treat this tumor, but other medicaments must be ΑΑ ^ ^ a shoulder to seek to resolve the related symptoms. Therefore, brothers still need to solve the symptoms of the problem of puppet & People with Down's syndrome have extra, important parts of chromosome 21 in all cells, or at least one portion of their cells. Adults with Down's syndrome are known to be at risk of Anetzheimer's punishment—a, 1, and dementia. Is there no evidence of Down's symptoms? Masashi Shiho \ therapy. Therefore, there is still a need to find solutions to diseases associated with Down's syndrome error

Neurons in some areas of the brain, with their Yin and Dou m, L_I due to 10,000-type programmed degeneration, will cause Huntington's disease. Huntington's disease #, Zhi # n, t, early symptoms of aunt, including

Mood swing, or learning new things or memories ~ pieces of mysterious ancient & A, 1 thousand things are always difficult. Most of the drugs used to treat the symptoms of Huntington's disease have female side effects such as fatigue, restlessness, or excessive excitement. At present, for% guding knot ☆, 0 r% to advance the disease of the Dayton * 76-200300673 ⑻ Description of the invention, page ¾ development or reversal, there is no therapeutic drug. Therefore, the agents are used to seek to resolve these symptoms.

Dementia with Lewy body is a neurodegenerative disorder involving an abnormal structure called Lewy body, which has been found in certain areas of the brain. Symptoms of dementia with Lewy's body include, but are not limited to, undulations of cognitive decline 'and occasional delusions. At present, the treatment department is about finding solutions to ^ Kingson's disease and psychiatric symptoms. But {, control of tremor or loss of muscle loss, "medicine, may actually aggravate the K-type disease with dementia with corpus corpus. Therefore, there is still a need for a medicament for the treatment of dementia. y 'Take it. Parkinson's disease is a neurological disorder characterized by tremors, hypokinesis, and muscle stiffness. There are currently no therapeutic drugs to stop the progression of this disease. Therefore, a drug is still needed to find a solution to Parkinson's disease.

There is still a need to have fewer secondary and delayed dyskinesias associated with the use of conventional antipsychotic drugs. The disease is also characterized by involuntary movement, most often evidenced by the curls of the lips and tongue and / or the pain of the arms or feet. The incidence of tardive dyskinesias, f Among patients taking conventional antipsychotic drugs, the annual drug exposure is ^. Among about 2% of people with this disease, tardive dyskinesias are severe and fugly. At present, there is no general cure for delayed movements. Furthermore, the removal of drugs that may cause effects may not be selective. This is due to dependent issues. Therefore, medicaments are still needed to address the symptoms of tardive dyskinesia.

Pick's disease is caused by the gradual degradation of social skills and personality changes. The symptoms formed are weakened intelligence, memory, and language: -77- 200300673 (72) Invention notes Common symptoms include memory loss, l 1; husband < spontaneity, difficulty thinking or concentration, and language dysfunction. Currently, there are no specific treatments or cures for Pan & Pharmacotherapy, but some symptoms can be treated with bilirubin and serotonin to accelerate antidepressant treatment. In addition, antipsychotics,

The therapy can alleviate the symptoms of FTD patients who have experienced delusions or hallucinations. Therefore, ‘still love.

To transform and change personality, and to find a solution to the problem of adolescents, but with fewer side effects. Houses linked to eating disorders. Take advantage of dysfunction, including bulimia, neuroticism and anorexia, neuropathy, gait and neurophysiological pathways. The lack of appetite and neuroticism is difficult to treat. This injury was recognized and the family did not enter or stay because of uncovering the disease after entering the plan. At present, 々 古 女 _ is / there are political treatments for people with severe anorexia and neuroticism. Two blades a, 丄,] will use the heart to know that the therapy has helped patients with bulimia nervosa "However, the response rate is only about 50%, and the current treatment does not seek to resolve emotional regulation. Because & Drugs are still needed to address the neurophysiological problems of the subordinate diseases of food intake regulation dysfunction. Smoking has been considered a major public health problem for a long time. However, despite public awareness of health hazards, smoking habits remain It persists abnormally and is difficult to cut off. There are many treatments available, and people continue to smoke. It is a common treatment in the body to be administered transdermally or in a gum base. However, nicotine is in the body. Has a large number of effects and therefore may have many side effects. Obviously there is a convenient and relatively easy method that is needed and requires long-term maintenance to help smokers reduce or eliminate cigarette consumption. It can selectively stimulate only some of the acid tests The recipient's drug can be used in a smoking cessation program. -78- 200300673 (73) Description of the invention The selected drug is taken orally. Dosage form. However, it is preferred to administer a daily dose when awake to a series of incremental doses throughout the day. This administration slowly dissolves sugar bonds, lozenges, or dispersed medicines therein Another medicine for cancer is Zyban. This substance is a colloid and a patch. More suitably, it is in other areas and its effectiveness is in the system of trying to quit. Nicotineism or ideas about cigarette use. Jibang is not an effective drug to help smokers who want to stop smoking use skin patches and transdermal administration. In some cases, it is administered by subcutaneous injection, especially if used Continuous release of drug use and drug dependence is a complex phenomenon, which is not within a single definition. Different drugs have different effects, so drug dependence. There are two basic reasons for drug drug dependence, which means drug dependence. When users must take a gradual comparison The effect achieved by a large dose is only a small dose, that is, there is drug resistance when a physiological adaptation state to the drug is developed, and when there are no symptoms of withdrawal (abolition), there is a body Existence of drug dependence can occur when the drug is discontinued or when the drug is replaced by a binding site on the antagonist receptor, so neutralizing its medicinal properties does not necessarily require physical drug dependence. In addition, drug dependence often involves psychological drug dependence. Drugs Feeling happy or contented. These feelings lead to experience of use, or to avoid the unpleasantness of being deprived of the drug. The drug can be produced in the amount of tablets, the preferred method is chewing gum. In the treatment is not a nicotine replacement effect People in the brain are very effective in helping control, so they are needed. When these drugs are available, they can be formulated. They can be included in different types of resistance and the body can produce them initially. When the user has taken the drug again Hours. The symptoms of withdrawal are when the drug is used in the cell. The drug relies on the body that repeats the strength of the drug when taking this drug. -79- 200300673 说明 Description of the invention; Gastric drugs, such as test, heroin, and, Jiu / Jingjing is often abused, and the drug-dependent form is difficult to remove. Lai Ling

A joyful drug can affect the CNS, and usually reduces anxiety and tension. It can produce excitement, euphoria, or other pleasant mood changes; provide users with support ^ 4,. ≪ 和加 心 和Of physical ability

Feel; or change the sensation in a pleasant way # A See 5 forbearance. Often abused

The drugs are ethanol, opioids, anxiolytics,   sleeping pills, cannabis (cannabis leaf), coca test, amphetamines and hallucinogenic drugs. #,, ， The current treatment of unpleasant addicts ’often involves a combination of therapy and medicine. Medications, such as methadone or LAAM (L-α-B_, I, methadol), are effective in suppressing symptoms of withdrawal, and are related to the mouth of narcotics addicts and related drugs Preferences, so reduce the use of darfa drugs, and improve personal & primary medical aids for narcotic addiction, and the opportunity in / oral therapy to produce comparable drugs with milder symptoms of withdrawal: &, It is to convert the patient to a partner M%-A, a person, a thing, and then gradually reduce this alternative fun thing. Take the foot medicine often used for beauty. The patient is to prevent more severe signs of withdrawal ’taken orally-once a day to reduce the dose slowly. #Can use alternatives to start at a low dose, and then switch the patient to long-acting sedatives, such as stupid, to get rid of self-sedatives. It can then be gradually reduced. Lymetriazine or phenobarbital,

Gilles de la Tourette's syndrome is a voice characterized by uncontrollable 浐 A 4 neurotransmission. The symptoms of this condition are convulsions that usually appear on the individual, where people do not move freely. The disease begins with pure convulsions and progresses to multiple complex ages. Movement disorders can be made by a single person. Vocal convulsions can be grunted, convulsions, including breathing and convulsions into forced vocalizations. Bad language (unfortunately, eruption, vocalization, or roaring noise begins, and development | thinking, wing learning vocalization) occurs in 50% of diseases * yr 4 4 \ ^ > -80- 200300673

(75) Description of invention] I °, severe convulsions and linguistic disorders may be physically and socially active, ... more complicated 'but less than choreographic movements, A minutes. ... suppress it with a free-will for a few seconds or

Compound eyes 1 two pure reduction to the regular line ^ stupid and diazepine treatment. For simple and ^. Clonidine can be used. Long-term use of cloninol: difficulty in linking ’its limited adverse effect is low blood I. In the case of chemotherapeutics, guess the psychiatric drugs, such as haloperidol, but worry about the side effects of Jinsheng's syndrome, inability to sit still, and difficulty with delayed movement: use of antipsychotic drugs. There is still a need for a safe and effective method: to treat this symptom cluster. Speckle degeneration (repeatedly) associated with aging is a common eye disease with spots / spots are tiny areas in the retina, helping to produce "just in front" and movement, "clear, central vision, including reading and driving Respectfully. With Ana = People will lose their bright _, medium (visual. The fine line takes two forms ...:, in the dry noodles with Ganji, ... the light in the king's point senses the slow drop of the cell T. Miri for Dry AMD has no therapeutic agent. In wet AMD, when dry AMD = turn, new and brittle blood vessels will grow under the spots, and these blood vessels will leak blood and fluid through suspension, causing rapid damage to the spots, quickly Causes loss of central vision. Laser surgery can treat some of the affection of wet AMD. Therefore, 'medicine is still needed to find a solution to AMD. ^ Glaucoma is a group of diseases that occur due to increased intraocular pressure and cause optic nerve disk Pathological changes in the brain and negatively affect the visual field. The medicine for treating glaucoma, whether it is to reduce the amount of fluid entering the eye, or to increase the flow -81-200300673 (76)

Problems shown in the eyes.

,. Edge out, and

The hemostatic phase in glaucoma can cause toxic amino acids, especially L. thorns ... irritable forms of nitric oxide synthase (iN0s), leading to nerve changes. Stimulating inhibitory amino acids such as GAgA release. Will reduce the over-excitation β α7 nicotinic acid activator is directly neuroprotective for neuronal cells. Therefore, α7 and alkaline acid activators really have the potential to become neuroprotective agents in glaucoma.

Exhaust from the eyes% to reduce intraocular pressure. But {, current drugs /, some disadvantages, such as the inability to work for a long time, or it will cause side effects: change the eyesight care professionals must be prescribed other medicines, the percentage of the use of drugs. There is still a need for a safe and effective method. Those who suffer from Taiwan's pain are often referred to as "the terrible three signs". Wen pain = square, causing sleeplessness and sadness, all of which are for tortured individuals. And his court is difficult. Pain can be found in various forms, including but not limited to all severe headaches, back pain, neuropathic pain, and foot pain from other diseases, such as arthritis, and cancer, from their presence or from radiation therapy. Pain can be chronic (persistent pain, over months or years) or acute (transient, immediate pain to inform people of possible harm and need treatment). People who experience pain respond differently to individual therapies, with varying degrees of success. There is still a need for safe and effective methods for treating pain. Finally, the compounds of the invention can be used in combination therapy with typical and atypical antipsychotics. All the compounds within the present invention can be used and can be used in combination with each other to prepare a pharmaceutical composition. This combination therapy will be -82-200300673

(77) Reduce the effective dose of antipsychotics, thus reducing the side effects of antipsychotics. Some typical antipsychotic drugs that can be used in the practice of the present invention include Haldol. Some atypical antipsychotics include Ziprasidone, Olanzapine, Resperidone and Quetiapine. Compounds of formula I can be prepared as shown in Figure 1. The key steps in the preparation of this type of compound are the acyl bicyclic moiety and the necessary fluorenyl chloride (Lv = Cl), mixed anhydride (for example, Lv = diphenylphosphonium, bis (2-keto) -3-tetrahydroindazolyl) phosphinic acid group or general formula 0-C (0) -RLvi 醯 oxy, where RLv includes phenyl or tertiary-butyl) or carboxylic acid (Lv = 0H), in Coupling in the presence of an activating reagent. Appropriate activating reagents are known in the art. For examples, see Kiso, Y., Yajima, H., Peptides, 丨, pp. 39-91, San Diego, CA, University Press (1995), It also includes, but is not limited to, medicaments such as carbodiimide, scales, and phosphonium salts (such as HATU). Embodiment 1 Scheme 1 Bicyclo-NH2 + Lv-C (= 0) -W〇-acylbicyclo-n (h) -c (= o > wg ′ where w〇 is:

In general, this acid is activated using HATU or converted to fluorenyl azide using DPPA. In the presence of excess DIEA, this suitable amine salt is added to a solution of an appropriate fiber or fluorenyl azide to obtain the desired final compound -83- 200300673 Invention Description m (78) --------- In some cases, this ester (Lv is 0 Me or OEt) can be directly reacted with a free state-based amine in refluxing methanol or ethanol to obtain a compound of formula I. The intermediate Lv-C (= 0) -Wg is known in the art, or can be obtained using a known procedure and performing insignificant changes. For example, the production of 1,4-benzodioxolane-6-acid is known. See, for example, Justus Liebigs Ann. Chem. 1873, 168, 99. Starting with an appropriate 5,7-disubstituted benzodioxolane intermediate, intermediate carboxylic acids in which R3 is not pyrene can be obtained. Such procedures are known in the art. It will be apparent to those skilled in the art that the necessary carboxylic acids can be obtained through literature procedures or with slight modifications and synthesis. For example, a compound of formula I in which W is N and Y and Z are 0 can be obtained as follows:

ν ^^ οη

Et02cAA〇H

Acid A can be prepared from ethyl 4,5-dihydroxy ppyzol-2-valerate (see Z. Naturfirsch, 34b, 1729-1736, 1979). By pyrolysis of 1,2-dibromoethane, B is obtained. B provides the necessary carboxylic acid A by saponification of NaOH aqueous solution. Using the conditions described herein, the formed acid is conjugated to the azine ring. Substituents can be introduced for R4 or R6, where W is CH and Z and Y are each 0, as described in Taniguchi, Eiji et al., Biosci. Biotech. Biochem., 56 (4), 630-635, 1992. See also Henning, R .; Lattrell, R .; Gerhards, H.J .; Leven M .; J. Med. Chem .; 30; 5; 1987; 814-819. This also applies to the production of the last compound where W is N, starting with ethyl 4,5-dihydroxypyridine-2-carboxylate to obtain an ester intermediate which can be saponified and then coupled with the appropriate acridine bicyclic and precursory coupling , And the obtained -84- 200300673 invention description m (79) compounds, such as:

Furthermore, where W is N and one of the compounds R4 is a bond to 012, or one of r6 is a bond to CRY, these compounds may use the method described herein with respect to W being CH, and the implementation is not critical. Change. Furthermore, where at least one R4 and / or at least one R6 is not fluorene and is not a bond, then these compounds can be obtained using the methods described herein with respect to wherein W is CH. Compounds in which W is N, Z, or 只有 are only 0, R3 is not Η, and one of R4 or 116 is bonded, can be obtained using the procedure in which W is CH as discussed herein. For example, 2-chloro-6- (hydroxymethyl) -4-vinylpyridin-3-ol can be converted to (8-chloro-2-methyl-2H- Piperano [2,3-porphyridin-6-yl) methanol. This alcohol can be oxidized to its corresponding carboxylic acid, which can then be coupled with the desired azine ring and precursor such as 3 (R) -aminopyridine to obtain:

Similarly, (8-chloro-2H-piperano [2,3 < Kidine-6-yl) methanol can be oxidized to obtain 8-chloro-2Η-piperano [2,3-c > Pyridine-6-carboxylic acid, which can then be combined with the desired acridine bicyclic precursor, such as 3 (R > aminopyridine coupling 'to obtain: -85- 200300673 Description of the invention continued (80)--

Cl

Those skilled in the art will understand that the method described for the reaction of unsubstituted 3-aminopyridine (where R2 is absent) is equally applicable to substituted compounds (where R2 is present). Certain 6-substituted- [2.2.2] -3-amines (azepine bicyclic I) are known in the art. Where R2 is a compound at C-6 of pyridine and is not a pyrene, its preparation is described in ActaPol. Pharm. 1981, 179. Certain 2-substituted- [2 · 2 · 2] -3-amines (azepine bicyclic fluorene I) are known in the art. Wherein R2 is at C-2 of pyridine and is not a compound of pyrene, its preparation is described in J. Med. Chem. 1975, 18, 587. Alternatively, there are several methods by which to obtain the amine precursor aziridinyl I in which R2 is present. Although the diagrams described below are for compounds in which R2 is at the C-6 position of pyridine, those skilled in the art can also obtain pyridines substituted at C-2. Substituted- [2.2.2] -3-amines can be prepared by the reduction of the corresponding substituted 3-pyrimidone oxime or imine by methods known to those skilled in the art (see J. Lablled Compds Radiopharm. 1995, 53; J. Med. Chem. 1998, 988; Synth. Commun. 1992, 1895; Synth. Commun. 1996, 2009). Alternatively, substituted- [2.2.2] -3 · amines can be prepared from substituted -3-mer groups by Mitsunobu reaction, followed by removal of protection, as described in Synth. Commun. 1995, 1895. Alternatively, substituted-[2 · 2.2] -3-amines can be obtained by converting each substituted hydroxypyridine to its corresponding methanesulfonate or tosylate, followed by replacement with sodium azide, and reduction. Made as described in J. Med. Chem. 1975, 587. -86- 200300673 Invention Description $ Selling stomach (81) -—-

2-substituted-3-pyridinone, in which R2 is a substituted alkyl or cycloalkyl, can be made by known procedures (see Tett · Lett · 1972, 1015; J · Am · Chem · Soc. 1994, 1278; J. Am. Chem. Soc. 1989, 4548; Tetrahedron, 2000, 1139). 2-substituted-3-p-quinone, in which R2 is an aryl group, can be arylated by palladium catalysis, according to J. Am. , As described in 1360. 6-substituted-3-orbital ketones can be made by known procedures (see J. Gen. Chem. Russia 1963, 3791, J. Chem. Soc. Perkin Trans. 11991, 409, J. Org. Chem. 2000 , 3982). Those skilled in the art will generally understand that the method described for the reaction of unsubstituted 3-amino-1-acylbicyclo [2.2.1] heptane (R2 is absent) is also applicable to substituted compounds. (R2 exists). For compounds in which the bicyclo ring is a bicyclocyclo ring II and the compound in which R2 is present, can be prepared from appropriately substituted nitro alcohols using the procedure described in Tetrahedron (1997), 53, p. 11121, as follows As shown. Methods for the synthesis of nitro alcohols are well known in the art (see J. Am. Chem. Soc. (1947), 69, p. 2608). The following diagram is a modification of the synthesis of the outward 3-amino small acylbicyclo [2.2.1] heptane, which is made into a bis (hydro-p-toluenesulfonic acid) salt, which is described in detail in this article to illustrate how These -87-200300673 inventions illustrate that f (M) (82) ---- amine precursors. The desired salt can be made using standard procedures. ΗΟ ^ .Ν09

Br.

Step A .no9 C〇2Et Step B / ^ — C02Et

02N Βζ〇κ

HN

Int 1

Int2

Step C -►

V ^ -Ph Int 3 C〇2Et \ nh2 R2 outwardly-directed [2.2.1] -3-amine with respect to acridine bicyclic π, in which R2 exists in the compound of C-6, but also through the outwardly-directed 3-amino group The small acyl bicyclo [2.2.1] heptane is modified from the intermediate described in the synthesis, which is made into a bis (hydro-p-toluenesulfonic acid) salt, which is described in detail herein. For example, Int 6 can be oxidized to an aldehyde and processed with an organometallic reagent to provide Int 20 using the procedure described in Tetrahedron (1999), 55, page 13899. Int 20 can be converted into an amine using the method described for the synthesis of outward 3-amino-1-acylbicyclo [2.2.1] heptane, which is made into a bis (hydrop-toluenesulfonic acid) salt. Once this amine is obtained, the desired salt can be made using standard procedures.

Int 20

Exo-6 · Asia [2.2.1] -3 · Amine -88- 200300673 (83) Description of the invention The pattern used is for the production of each outward amine group · p-ya bicyclo and [2 21] heptane. However, the modifications discussed also apply to the production of endomers. In a better case, for azine% and III and azinebicyclic IV, in the presence of TEA, using 0¾¾ or CHCI1 as a solvent, via bis (2 • ketotetrahydropyrazolyl) phosphine phosphine 醯Work up to convert the acid into a mixed anhydride. The resulting fiber solution was directly reacted with bubicyclo [1 · 2.1] octylamine, which was added without solvents or using DMF or DMF aqueous solution as the solvent. In some cases, the ester (Lv is OMe or OEt) can be reacted directly with an amine in refluxing methanol or ethanol to give a compound of formula I. N- (2-azinebicyclo [2 · 2 · 1] heptan) _5_amine and 6-amine:

> Arbicyclo [2.2.1] heptan-6-amine [2.2.1] -6-amine wherein Lv may be -CH2PH, -CH (Me) Ph, -OH, -OMe, or -0CH2Ph. The individual amine precursors of aziridinyl III and azridinyl IV can be reduced by the reduction of the corresponding N_2-acridinyl [2 · 2 · 1] -heptanone oxime or imine, and prepared by methods known to those skilled in the art Cheng (see J. Labelled Compds. Radiopharm., 53-60 (1995), J. Med. Chem. 988-995, (1998), Synth. Commun. 1895-1911 (1992), Synth. Commun. 2009-2015 (1996)). This oxime can be prepared in the presence of a base by treating N-2-azinebicyclo [2.2.1] heptanone with hydroxylamine hydrochloride. Imine can be dehydrated under the condition of -89-1 [2 · 2.1] -5-amine 2 · ργ bicyclo 幷 [2.2.1] hepta · 5-amine 200300673 Description of the invention, continued (84)-- -Primary amine is made by treating N-2-acylbicyclo [2.2.1] -heptanone. N-2-acylbicyclo [2.2.1] 'heptanone can be made by known procedures (see Tet. Lett. 1419-1422 (1999), J. Med., Chem. 2184-2191 (1992), J Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)). Extroversion and introversion-l, 17 ya bicyclic fused P · 2 · 1] octan-3-amines, according to, for example, in Lewin,

The general procedure discussed in AH et al., J. Med. Chem., 988-995 (1998), is made from 1-port "double soil-like [3.2.1] Xin-3- 酉 Tong (Thill, Β · P ·, Aaron, HS, J. Org. Chem., 4376-4380 (1968)). ^ Ν2Ν-φ Generally familiar with this artist will also understand, about the unsubstituted ya double ring and [3.2.1] Xin The method described in the reaction of -3-amine or 1-leaf bicyclo [3 · 2 · 2] non-3-amine (R2 is absent) is also applicable to the presence of substituted compounds (%).% Substituents may Introduced through standard alkylation in a way known to those skilled in the art. 1-Acridinebicyclo [3.2.1] octan-3 · one or Buyabicyclo [12 2] nononone is exposed to hindered base For example, LDA (lithium diisopropylamine), in a solvent such as THF or ether, between 0C and -78 ° C, and then add an alkylating agent (R2Lv, where Lv = a > ί '⑽, etc.) 'After warming it to about room temperature, then the water will provide the desired solution, and the desired compound will be provided as a mixture of isomers. Chromatographic analysis (flash, HPLC or palladium) ^) Provides the desired purified alkylated ketones. An oxime is formed therefrom, and then the stereoisomer is reduced. Thioamine m can be prepared from the necessary Thioamine by directly replacing the Thioamine with the amine_σΤ 胄 cyclic moiety as described herein. This sulfur brew can be made as described in the '90 -200300673 Invention Description, Continued (85)---J. Organometallic Chem., 95-98 (1987). Generally skilled artisans will quickly confirm these Compounds can also be prepared by directly using this reagent and Lawesson's reagent (see Lawesson et al., Bull. Soc. Chim. Belg., 229 (1978)) (scheme 2) or P4S10 (see Chem. Rev., 45 ( 1961)), and made directly from the brewed amines exemplified throughout this patent. N- (2S, 3R) -2-methyl-1-acylbicyclo [2.2.2] octylamine dihydrochloride Preparation: A mixture of 2-methylene-3-meridone dihydrate hydrochloride (27.18 g, 0.1296 mole, 1 equivalent) and K2CO3 (86.0 g, 0.6213 mole, 4.8 equivalent), Dissolve in 130 ml of water and 250 ml of CH2C12 and stir vigorously. After 3 days, separate the liquid layer and extract the aqueous layer with CH2C12. The combined organic layers were dried (MgS04), filtered and concentrated. 17.8 g (100%) of 2-methylenepyridin-3-one as a yellow oil. MS (ESI) m / zl38.1 (M +) for C8HnNO. In a Parr hydrogenation bottle, make 2-Amidinopyridin-3-one (17.8 g, 0.1296 mol, 1 equivalent) was dissolved in 40 ml of MeOH. 10% Pd / C (0.57 g) in THF slurry was added. The mixture was hydrogenated at 45 psi for 45 minutes and re-fed as needed. The mixture was filtered through celite. Wash the cherished soil with excess MeOH. The solution was concentrated to give a solid and a yellow oil. The mixture was dissolved in ether, filtered and concentrated to provide 16.2 g (90%) of 2-methylpyridin-3-one. MS (ESI) m / z 140.2 (M +) for C8H13NO. 'Make 2-amidinopyridin-3-one (39.59 g, -0.2844 mole, 1 equivalent) with hydroxylamine salt; acid salt (20.0 g, 0.2878) Moore, 1.01 equivalent) dissolved in 170 ml of anhydrous EtOH:. The mixture was heated at reflux until a clear solution developed (approximately 20 minutes), and immediately a white precipitate formed. The reaction was allowed to cool and allowed to stand overnight. Allow the mixture to cool in an ice bath 'Filter the solid and -91-200300673 Description of the invention, _page (86)-Dry (indoor vacuum), provide 46.4 g (3E / Z) -2-methyl small acryl bicyclic and [2 · 2 · 2] octan-3-one fatty hydrochloride. A second serving of 2.4 g of product was also obtained. The total yield is 48.8 grams (90%). The 2-fluorenyl small acylbicyclo [2.2 · 2] oct-3-one oxime hydrochloride is a 4: 1 mixture of oxime isomers. MS (ESI) m / zl54.8 (M +) for C8H14N20 Part 1 H NMR (400 MHz, DMSO) 5 4.39 (0.2H), 4.29 (0.8H), 1.57 (0.6H), 1.47 (2 · 4Η). A solution of sodium n-propoxide (made from 5.5 grams of sodium (0.24 mol) and 100 ml of n-propanol) was added dropwise to (3E / Z) -2-fluorenyl- A suspension of 1-mouth bicyclo [2.2.2] octan-3-one hydrochloride (45.8 g '0.24 mole, 1 equivalent) in 150 ml of n-propanol. After the addition was completed, 250 ml of n-propanol was added, and the mixture was heated under reflux. Sodium (55.2 g, 2.40 mil, 10 eq.) Was added to the mixture under reflux in portions. The mixture was heated at reflux overnight. After about 14 hours, the mixture was allowed to cool, water was added, and the layers were separated. The n-propanol layer was washed with brine and dried (MgS04). The combined aqueous layers were extracted with CHC13 'and dried (MgS04). The combined dehydrated organic layers were treated with about 70 ml of concentrated HC1. The solvent was removed in vacuo. Anhydrous EtOH was added and the solvent was removed. This sequence was repeated 2-3 times with new EtOH until a white solid formed. Anhydrous EtOH was added, and the solid was filtered and dried (vacuum oven, about 60 ° C) to provide 36.5 g of trans 3-amino-2-methylpyridine dihydrochloride. MS (ESI) m / zl41.3 (M +) for QHmN2. The other substances are obtained from the mother liquor: 78 g (the second product) and L5 g (the third product); this substance is trans Mixture with cis isomers. The 4-milk epidermis (26.3 g, 0.1681 moles, 1.1 equivalents) and Dingea (106 ml, 0.764 moles, 5 equivalents) were dissolved in 300 ml of THF. Diphenylphosphonium chloride (32.0 ml, 0.1681 mol, u equivalent) was added dropwise. After 1 hour, -92- 200300673 was added. Description of the invention: Stomach (87)-trans 2-methylpyridin-3-amine dihydrochloride (32.6 g, 0.1528 moles, 1 equivalent). The mixture was stirred at room temperature overnight. Add IN NaOH (about 100 ml) and adjust the pH to pH 11 with 50% NaOH and about 50 g of K2CO3. Separate the liquid layer. The aqueous layer was extracted with CHC13. The combined organic layers were dried (MgS04), filtered and concentrated. The residue was dissolved in heptane and concentrated to obtain 35.1 g (82%) of 4-chloro-N- (2-methyl-1-acylbicyclo [2 · 2 · 2] oct-3-yl) Phenyl-2-carboxamide, as a pale yellow solid. The palmar isomers were separated on a 5 X 50 cm Chiralcel OD column at 30 ° C with 15% IPA / heptane + 0.1% DEA at 90 ml / min to provide 17.4 g of 4- Chloro-N-[(2S, 3R) -2-methyl-1'bicyclo [2 · 2 · 2] octyl] benzamide, at about 97% ee. The p-TsOH salt was prepared and recrystallized from EtOH / EtOAc. [a] 25D = + 3o (c0.96, methanol). The calculated HRMS (FAB) for C15H19C1N20 + H is 279.1264, and the measured value is 2791.272. 4-Chloro-N-[(2S, 3R > 2-methyl-1-acylbicyclo [2 · 2 · 2] xin-3 -Yl] benzidine (17.2 g, 61.7 mmol) in anhydrous EtOH (70 ml) and concentrated HC1 (70 ml), heated at reflux for about 64 hours. By reverse phase HPLC (ZORBAX Eclipse XDB -C8, 4.6 mm X 15 cm, 80: 12: 8 H20 / CH3CN / IPA) monitor the initial acid amine of the reactant disappears. Remove the solvent in vacuum. Dissolve / suspend the residue in EtOH and remove Solvent (twice). Suspend the solid in boiling EtOH, filter and dry (vacuum oven, about 60 ° C) to provide 8.8 g (67%) of N- (2S, 3R) -2-methyl small acryl bicyclo And [2.2: 2] oct-3-amine dihydrochloride as a white solid. MS (EI) m / z 141.2 (M +). Preparation of 2 · 2 · 1 amines: Xibuxiang-3-amino Synthesis of small acridine bicyclo [2 · 2 · 1] heptane as bis (hydro-p-toluenesulfonic acid) salt: -93- 200300673 Description of the Invention

Et ho ^ v-no2 b 「a ^ c〇.

Bz〇y

Step A. NO〇

Int 1 Step B CO〇Et

Int 2

Step C

Step D CO〇Et

OH

巳 〇CNH

Int 4

B〇CNjH / ^ C〇2Et h2N

Vph Step F Step E

Int 6, V-Ph

Int 5

Step G

, B〇C Int 7 H

Step H

H .NH,

Preparation of 2TsOH outward P.2.1] -amine Step 骡 Α · 2- (benzylideneoxy) small nitroethane (Int 1)

Add benzamidine chloride (14.9 ml, 128 mmol) to a stirred solution of nitroethanol (9.2 ml, 128 mmol) in anhydrous benzene (120 ml). The solution was refluxed for 24 hours and then concentrated in vacuo. The crude product was purified on SiO 2 by flash chromatography. Dissolve with hexane-Et〇Ac (80 ·· 20) to obtain Int 1 as a white solid (68% yield): iHNMRCCDClJ 5 8 · 0,7 · 6,7 · 4,4 · 9,4 · 8 · Step B. Preparation of E-4- (benzylamino) -2-butenoate (Int 2) E-4-bromo-2-butenoate (10 ml, 56 mmol) , Industrial grade) was added to a stirred solution of amidine (16 ml, 146 mmol) in CH2C12 (200 ml) at room temperature. The reaction mixture was stirred for 15 minutes and diluted with ether (1 liter). The mixture was washed with a saturated aqueous solution of NaHC03 (3x) and water, and dehydrated (Na2S04). Filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica. Dissolve with hexane-EtOAc (70:30) to obtain lnt 2 as a clear oil (62% yield): iHNMMCDCiy 5 7 · 4-7 · 2,7 · 0,6 · 0,4 · 2,3.8, 3.4, 2.1-1.8, 1.3. Step 骡 C. Preparation of trans-nitronitro (phenylmethyl) tetrahydropyrrole ethyl acetate (M3) Int 1 (6.81 g, 34.9 mmol) and M A solution of 2 (7.65 g, 34.9 mmol) in EtOH (70 ml) was stirred at room temperature for 15 hours and then concentrated in vacuo. The residue was diluted with ether (100 ml) and saturated aqueous NaHC03 (100 ml). The organic layer was separated and dried (Na2S04), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2. Dissolve with hexane · EtOAc (85:15) to obtain M3 as a clear oil (76% yield): iHNMR (CDC13) (5 7 · 4-7 · 3, 4 · 8-4 · 7, 4.1 · , 3 · 8-3 · 6, 3 · 3-3 · 0, 2.7-2.6, 2 · 4-2.3, 1.2 · Step D. Trans-amino-fluorenylmethyl) -3-tetrahydropyrrole acetic acid Preparation of ethyl ester (μ 4) A mixture of Int 3 (3.28 g '11.2 mmol) and RaNi (ι · 5 g) in EtOH (100 ml) was placed in a Parr bottle and exposed to hydrogen atmosphere ( 46 psi) and hydrogenation at room temperature for 4 hours. This mixture was filtered through a pad of diatomaceous earth and the solvent was removed in vacuo to obtain Int 4 as a clear oil (loo% yield): 1 η NMR (300 MHz, CDC13) § 7.3-7.2, 4.1, 3.6, 3.2, 3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2 2 1 2 Step 骡 · trans-4_ (U-dimethylethoxycarbonylamido) _ι_ (phenylmethyl Of Tetrahydropyrrole Ethyl Acetate (Int 5) Di-tertiary-butyl dicarbonate (3.67 g, 168 mmol) was added to Int4 (2.94 g, 11.2 mol) in CH2C12 (30 Milliliter), stirred in an ice bath -95- 200300673 Description of the Invention Continued (90) --------- The solution was stirred. The reaction was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo. The crude product was purified by flash chromatography on SiO 2. Dissolved with hexane-EtOAc (80:20) to obtain M 5 as a white solid (77% yield): 1 H NMR (300 MHz 5 CDC13) δ 7.4- 7.2, 5.1-4.9, 4.1, 4.0-3.8, 3.6, 3.2-3.0, 2.8-2.6, 2.5-2.4, 2.3-2.1, 1.4, 1.3. Step F · trans (third-butoxycarbonylamino ) -4- (2-hydroxyethyl) -1- (N-phenylmethyl) tetrahydropyrrole (Int 6) 4 powders (627 mg, 16.5 mmol) were added in small portions to Int 5 (3.0 g, 8.3 mmol) in anhydrous Thf (125 ml) and stirred in a -5 ° C bath Inside the solution. Stir the mixture in a -5 ° C bath for 20 minutes, and then add water (0.6 亳 L), 15% (w / v) aqueous NaOH solution (0.6ml), and water (1.8ml) successively. The reaction was quenched. An excess of anhydrous K2co3 was added and the mixture was stirred for 1 hour and then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on top. Dissolved in EtOAc to obtain Int 6 as White solid (94% yield): 111 Li {1 (€ 0 (: 13) 57.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3 · 7, 3 · 3 · 3 · 2, 2 · 8- 2 · 7, 2 · 3-2 · 1, 1.7, 1 · 5 ·

Int 6 is a racemic mixture that can be resolved by chromatography using a Diacel Chiral Pack AD official column. From the two para-isomers thus obtained, the ⑴-para-isomer U] 25D + 35 (c 1.0, MeOH) will result in its corresponding optically pure outward-looking final compound 'and the ㈠-para-isomer [a] 25D-34 (c0 98, Me0H), which results in an optically pure outgoing 4-R final compound. The method described herein uses the (+)-palladium isomer, Int6, to obtain the optically pure final compound. However, the method used is also applicable to Int 6 (+ palmar isomers, insignificant changes to the method provided herein, obtained optically -96- 200300673 (91) Description of the invention _ page pure outward- 4-R final compound. Step G. Preparation of outward M tertiary-butoxycarbonylamino) small acridine bicyclic and [2.2.1] heptyl (Int7) Preparation TEA (8.0 g '78.9 mmol) was added to Int 6 (2.5 g, 7.8 mmol) in a stirred solution of CH2C12 (50 ml), and the reaction was cooled in an ice-water bath. Then, CH3S02C1 (5.5 g, 47.8 mmol) was added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. The resulting yellow mixture was diluted with a saturated aqueous NaHC03 solution and extracted several times with CH2% until no product remained in the aqueous layer by TLC. The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in EtOH (85 mL) and heated to reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, transferred to a Parr flask, and treated with 10% pd / c catalyst (125 g). This bottle was placed under a hydrogen atmosphere (53 pSi) for 16 hours. The mixture was filtered through diatomaceous earth, and new catalyst (10% Pd / C, .25 g) was added. Continue hydrogenolysis overnight. This procedure was repeated three more times until the hydrogenolysis was complete. The final mixture was filtered through diatomaceous earth and concentrated in vacuo. The residue was purified by flash chromatography on SiO2. Dissolve with CHC13 -MeOH-NH4 OH (90 ·· 9.5: 0.5) to obtain Int7 as a white solid (46% yield): hNMRCCDC ^) 5 5 · 6-5 · 5, 3.8-3.7, 3.3-3.2, 2.8-2.7, 2.0-1.8, 1.7-1.5, 1.5. Step Η. Preparation of each outward amine group + acridine cyclic [2.2.1] heptane bis (hydrogen-p-toluenesulfonate) will be- Toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) was added to a stirred solution of Int 7 (770 mg, 3.63 mmol) in EtOH (50 ml). The reaction mixture was heated to reflux for 10 hours and then cooled to room temperature -97- 200300673

Description of the invention; ffM (92) -----

. The precipitate was collected by vacuum filtration and washed with cold EtOH to obtain the outward [2.2.1] -amine as a white solid (84% yield): 1HNMR (CD3OD) (5 7 · 7,7 · 3,3 · 9 -3, 7, 3.7-3.3, 3.2, 2.4, 2.3-2.2, 1.9-1.8. The corresponding amines can be obtained by using the resolved Int6, resulting in extraversion- (4R)-[2.2.1] -3 -Amine and outward- (4SH2.2.1) -3-amine. Synthesis of inward-3-amino-1ααbicyclo [2.2.1] heptane as bis (hydro-p-toluenesulfonic acid) salt ··

Int 14 Int 13

Step N

Int 15 lnt16

Step P · 2TsOH nh2 Inward [2.2.1] · amine Step I · Preparation of 5-hydroxy-6-keto-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl acetate (Int 10) Anhydrous EtOH (92.0 ml, 1.58 mol) was added to a suspension of mechanically stirred potassium ethoxide (33.2 g, 395 mmol) in anhydrous toluene (0.470 liter). When the mixture is homogeneous, add 2-tetrahydropyrrolidone (33.6 g, 395 mmol), and then add diethyl oxalate (53.1 mL, 390 mmol) in toluene (98 mL) via an addition funnel. Its solution. After the addition was completed, toluene (118 ml) and EtOH (78 ml) were added successively. The mixture was heated to reflux for 18 hours. The mixture was allowed to cool to room temperature, and an aqueous HC1 solution (150 -98- 200300673) was added to sell M (93)-ml, 6.0 M solution. The mixture was stirred mechanically for 15 minutes. The aqueous layer was extracted with CH2C12, and the combined organic layers were dried (MgS04), filtered, and concentrated in vacuo to a yellow residue. The residue was recrystallized from EtOAc to give Int 10 as a yellow solid (38% yield): iHNMR (CDCl3) 5 11.4, 7.4, 4.3, 3.4, 2.6, 1.3. Step J · cis-3-hydroxy- Preparation of 2-ketohexahydropyridine-4-carboxylic acid ethyl ester (Int 11) A mixture of Int 10 (15 g, 81 mmol) and 5% germanium / carbon (2.0 g) in glacial acetic acid was placed. Under a hydrogen atmosphere (52 psi). The mixture was shaken for 72 hours. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give

Int 1 is a white solid (98% yield) ... iHNMRiCDC ^) 5 6 · 3,4 · 2,4 · 0-3 · 8, 3.4, 3.3-3.2, 2.2, 1.3. Step K · cis- Preparation of 4- (hydroxymethyl) hexahydropyridine-3-ol (Int 12) Int 11 (3.7 g, 19.9 mmol) was added as a solid in small portions to UAIH4 in THF and on ice. The stirred solution (80 ml, ιOM solution) in a water bath. The mixture was allowed to warm to room temperature and the reaction was heated to reflux for 48 hours. The mixture was allowed to cool in an ice-water bath, and then water (3.0 ml, 170 μmol) was added dropwise, followed by NaOH (3.0 ml, 15% (w / v) solution) and water (9.0 ml, 500 mmol). Moore). An excess of K2co3 was added and the mixture was stirred vigorously for 15 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give Int 12, as a yellow powder (70% yield): iHNMr (DMSO-d6) δ 4.3, 4.1, 3.7, 3.5-3.2, 2.9-2.7, 2.5 -2.3, 1.5? 13. Step L · Preparation of each cis-hydroxy-4- (hydroxymethyl) hexahydropyridine sulfonium carboxylate (1M 13) N- (fluorenyloxycarbonyloxy) number Amine (3.04 g, 12.2 mmol), -99- 200300673 (94) Description of the invention continued on the main 'Phase' added to Int 12 (1.6 g, 12.2 mmol) in saturated NaHC 03 (15 L) in a stirred solution. The mixture was stirred at room temperature for an hour and the organic and aqueous layers were removed by knife. The aqueous layer was extracted with (3x). The combined organic layers were dried (^ 3), filtered, and concentrated in vacuo to obtain Intl3 as a yellow oil (99% yield). IHNMR (CDCl3) 3 7 7.3, 52, 43, 41, 38_37 , 3.0-2.8, 2.1, ι · 9 丄 7, i 4 Step M · cis-hydroxyl [(4-methylphenyl) continyloxymethyl] hexahydropyridine benzyl small carboxylic acid ester (Int 14 ) Preparation-p-toluenesulfonium chloride (1.0 g, 5.3 mol) was added to 朌 13 (3.6 g '5.3 pen mol) in the talk (10 ml) In the stirred solution in the bath. The mixture was stirred for 4 hours, then HC1 (4.5 mL, 6.0 μ solution) was added. Add CH2C12 (5 mL). The organic and aqueous layers were separated. Extract the aqueous layer with ch2C12. The combined organic layers were washed with brine, dried (MgS04), filtered, and concentrated in vacuo to give Int 14 as a colorless oil (78% yield): iHNMRfDCiy 5 7 · 8,7 · 4-7 · 2,5 · 1,4 · 3-4,2,4.1, 3 · 9-3 · 8,2 · 9-2 · 7,2 · 4, 1.9, 1 · 6-1 · 3. Step N · Preparation of Outward-W Bicyclo [2 · 2 · 1] Heptan-3-ol (Int 15) Int 14 (3.6 g, 8.6 mmol) and 10% Pd / C catalyst (500 g) The mixture in EtOH (50 ml) was placed under a hydrogen atmosphere. The mixture was shaken for 16 hours. This mixture was filtered through diatomaceous earth. To the filtrate was added solid NaHC03 (U g, 13 mmol) and the mixture was heated in an oil bath at 50 ° C for 5 hours. Remove the solvent in Shingen. The residue was dissolved in a saturated aqueous K2CO3 solution. Using a liquid-liquid extraction device, the aqueous layer was continuously extracted (18 hours), then the organic layer was dehydrated and dried over anhydrous K2CO3, and the solvent was removed in vacuo to obtain Int 15 'as a white solid (91% yield ): IHNMR 3 3.8, -100- 200300673 Description of the Invention Continued (95) L --- 3.0 · -2-2,8 · 2 · 6-2 · 5, 2 · 4-2 · 3, 1.7, 1.1 · Step 0 · Preparation of inward azido-l-p-bicyclo [2 · 2 · 1] heptane (Int 16) prepared in Intl5 (1.0 g, 8.9 mmol) and triphenylphosphine (3.0 g , 11.5 mol) in toluene-THF (50 ml, 3: 2), in a mixture in an ice water bath, successively add a solution of azido acid in toluene (15 ml, about 2 M solution) and, A solution of diethyl dicarboxylate (1.8 ml, 11.5 mmol) in toluene (20 ml). The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was extracted with a 1.0 M HC1 aqueous solution. The aqueous layer was extracted with EtOAc and the combined organic layers were discarded. The pH of the water layer was adjusted to 9 with a 50% NaOH aqueous solution. The aqueous layer was extracted with CH2a2 (: 3) Q, and the combined organic layers were washed with brine, dehydrated and dried (v ~ 30), filtered and concentrated in vacuo. The crude product was borrowed on Si02 by a flash layer. Analytical and purified. Dissolved with CHCl3-MeOH-NH4OH (92: 7: 1) to obtain Intl6 as a colorless oil (41% yield): 1 H NMR (CDC13) 5 4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5. Step P · Preparation of inwardly directed amine bicyclo [2.2 · 1] heptyl bis (hydrogen-p-toluene xanthanate)

A mixture of Int 16 (250 mg, 1.8 mmol) and 10% Pd / C catalyst (12 mg) in EtOH (10 liters) was placed under a hydrogen atmosphere (15 pSi). The mixture was stirred at room temperature for 1 hour. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was dissolved in EtOH (10 ml) and p-toluene acid monohydrate (690 mg, 3.7 mmol) was added. The mixture was stirred for 30 minutes 4 li 'and passed; The Shen Dian objects were successively cold-washed and pickled. The precipitate was dried in vacuo to give inward [^ catamine, as a white solid (85% yield) ... 1 Η R R (CD3 0D) 5 7.7, 7.3, 4 · 2, 3 · 9, 3 · 6.3 4, 3% 2, 2 4, 2 3, 2 丄 [3 · 2 · 1] _ Preparation of amines: -101-200300673 Description of the invention continued alfalfa (96) ~ ^ outward-1-acylbicyclic benzo [3 · 2 · 1] octan-3-amine dihydrochloride (outward [^ external amine): 1-acrylbicyclic P · 2 · 1] octan-3-one hydrochloride (2.80 g, 17.3 mmol) A mixture of ethanol, ethanol (25 ml) and hydroxylamine hydrochloride (1.56 g, 22.4 mmol) was treated with sodium acetate trihydrate (7.07 g, 51.2 mmol). The mixture was stirred for 3 hours and evaporated in vacuo. The residue was diluted with CH2%, treated with charcoal, filtered and evaporated. The formed material was dissolved in 1-propanol (45 liters) and heated in a 100 ° C oil bath. This solution was treated with sodium metal (6.4 g, divided into portions). Heating was continued for 3 hours and the mixture was allowed to cool to room temperature. Water was added carefully, and the organic layer was extracted, dried (MgS04), dried over water, acidified with MeOH / HCl (gas), and evaporated. 2-propanol was added, and the formed solid was filtered and dried in vacuo to obtain an outward [3 · 2 · 1] -amine with a yield of 49%. For C7 Η! 4 A · (HC1) 2 MS (ESI) (M + H) + m / z = 127 · inward -1 』bicyclo [3 · 2 · 1] oct-3-amine dihydrochloride Salts (inward [3 · 2 · 1 propylamine): 1-Acridinebicyclo [3.2.1] octan-3-one hydrochloride (2.80 g, 17.3 mmol), ethanol (25 ml) and hydroxylamine salt A mixture of acid salts (1.56 g, 22.4 mmol) was treated with sodium acetate trihydrate (7.07 g, 51.2 mmol). The mixture was stirred for 3 hours and evaporated in vacuo. The residue was diluted with ¢: ¾¾, treated with charcoal, filtered and evaporated. The oxime formed (3.1 mmol) was treated with acetic acid (30 mL) and hydrogenated at 50 psi over PtO2 (50 mg) for 12 hours. The mixture was then filtered and evaporated. The residue was dissolved in a minimal amount of water (6 mmol #) and the pH was adjusted to > 12 using solid NaOH. Then, the mixture was extracted with ethyl acetate (4 × 25 ml), dehydrated and dried with MgSO, filtered, treated with ether containing HC1, and evaporated to give an inward [3.2.1] -amine. Preparation of 3R, 5R- [3.2.1] -amine: -102- 200300673 Description of the Invention _ Stomach (97)---Outward-(3S) -1-[(S) Phenethyl] -5-one -3_tetrahydropyrrole-carboxylic acid: 〇

h〇H According to the literature procedure (Nielsen et al., J. Med. Chem. 1990, 70-77), aconitic acid (123.2 g, 946.7 mmol) will be decomposed with (122 ml, 946 t mole), (without solvent) was heated in an oil bath at 160 ° C for 4 hours. While cooling, MeOH (~ 200 ml) was added and the formed solid was collected by filtration. The The solid was treated with EtOH (~ 700 ml) and warmed using a steam bath until ~ 450 ml of solvent remained. After cooling to room temperature, the solid product was collected and dried to give 83.2 g as a crystalline solid: [a] 25D = -80 (c0.97, DMSO). iHNMR (400 MHz, DMSO-d6) 5 12.66, 7.20-7.40, 5.23, 3.40-3.55, 3.10 -3.25, 2.40-2.65, 1.45; MS (El ) m / z 233 (M +). (3S) -1-[(S) _1-phenethyl] -3-pentyl) tetrahydropyrene:

， 〇〇H 0 put (3S) -1- (XS) -1-epiethyl] -5-g isopropyl-3-tetrahydrop-biharic acid (82.3 g, 352.3 mmol) in The suspension in EtzO (200 ml) was added in small portions to a slurry of LiAlH4 (17.4 g, 459 mol) in Et20 (700 ml). During the addition, the mixture began to reflux; the addition funnel containing the suspension was rinsed with EhO (2x50 ml). The mixture was reheated for 2 hours in a 50 t oil bath. -103- 200300673 (98) Description of the invention continued on the next page 'and allowed to cool to room temperature, and further cooled using an ice bath. The mixture was carefully treated with Η Ο (62 ml). The formed precipitate was filtered by%.

Rinse and discard. The filtrate was concentrated to an oil. When EtoAc was added to the oil, a solid began to form. Hexane was added and the mixture was filtered and the solid was dried to give 43.3 g of the desired product. [a] 25D = _7i (c.94, CHCl3); 1H NMR (400 MHz, CDC13) 5 7.20-7.45, 3.60-3.70, 3.40-3.60, 3.19, 3.05-3.15,

2.35-2.55, 2.25-2.35, 1.95 · 2 · 10, 1.75-1.90, 1.42; calculated HRMS (FAB) for q 3% 9NO (MH +) 26.01545, found 206.1532. -[(S) -1_phenethyl] _3_ (cyanomethyl) tetrahydrott

Such as

A solution of (3S) -1- (XS) -1-phenethyl] -3- (¾fluorenyl) tetrahydropyrrole (42.75 g, 208.2 mmol) in chloroform (350 ml) under n2 Heat to reflux. This solution was treated dropwise with a solution of thionyl dichloride (41.8 ml, 573 mmol) in chloroform (40 ml) for 45 minutes. The mixture was stirred for another 30 minutes, cooled and concentrated. The residue was diluted with H20 (~ 200 ml) and 1 NNaOH was added until the pH was ~ 8 (pH paper). A small portion (~ 50 ml) of saturated NaHC03 was added, and the basic mixture was extracted with EtOAc (3 X 400 ml), washed with brine, dried (MgS04), filtered and concentrated to give 46.51 g (3S) -1-[(S) -1-phenethylKHchloromethyl) tetrahydropyrrole: Ms (ESI +) m / z 224.2 (MH +). This chloride (46.4 g '208 mol) was transferred to a flask, DMSO (200 ml) was added, and the solution was treated with NaCN (17.84 g, 363.9 mmol). Will -104- 200300673 ㈣ 丨 send Oh Ming Continued

The mixture was heated under a N2 in a loot: oil bath overnight and cooled. The brown mixture was poured into H20 (300 mL) and extracted with EtOAc (1000 mL, in portions). The combined organic layers were washed with H20 (6x ~ 50 ml), brine (~ 100 ml), dried (MgS04), filtered and concentrated to obtain 40.61 g of oil: iHNMR (400 MHz, CDC13) 57.20-7.40 , 3.26, 2.70-2.85, 2.40-2.60, 2.27, 2.10-2.20, 1.50-1.70, 1.41; MS (ESI +) m / z 215.2 (Μ + Η +) · (3R) _methyl1- [(SH-phenylethyl) tetrahydropyrrole-3-acetate ··

Acetyl chloride (270 ml, 3.8 mol) was carefully added to a flask containing cooled (0 ° C) methanol (1 100 ml). After the addition was completed, the acidic solution was stirred for 45 minutes (0 ° C), and then (3R) -1-[(S) -1-phenethyl] -3- (cyanomethyl) in methanol (200 ml) was added. Base) tetrahydropyrrole (40.50 g, 189.0 mmol). The ice bath was removed, and the mixture was stirred at room temperature for 100 hours. The resulting suspension was concentrated. Add water (~ 600 ml) and stir the mixture for 45 minutes, then adjust the pH (to make it sensible) by adding ~ 700 ml of saturated NaHC03 aqueous solution. The mixture was extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine, dried (MgS04), filtered through diatomaceous earth, and concentrated to obtain 36.9 g of oil: iHNMRGOOMHz 'CDCiySTJiVZjOJjASJOJjOJ.SS-2.95, 2.40-2.70, 2.00-2.20, U0-1.65; MS (ESI +) m / z 248.2 (M + H +). (5R) -1-acylbicyclic 丨 3 · 2 · 1] octan-3-one hydrochloride: -105- 200300673 Description of the invention ^ Selling stomach (100 ) ___

A solution of (3R) -H (SH-phenylethyl] tetrahydropyrrole methyl acetate (25.7 g, 104.0 mmol) in THF (265 ml) was added at a temperature of C02 / acetone. Cool in the bath. Next, add ICH2C1 (22 7 ml, 312.0 mmol) and stir the mixture for 30 minutes. Within 30 minutes, slowly add 2.0M IS diisopropylamine solution (heptane / THF / Ethylbenzene, 56 ml, 312 mmol). During this addition, the internal temperature reached a maximum of -40 ° C. After 1 hour, saturated NH ^ Cl (100 ml) was added and the mixture was allowed to warm to room temperature. Warm. The organic layer was separated, dried (MgS04), filtered and concentrated. The resulting foam was chromatographed (300 g Si02, CHCl3-MeOH-NH4OH (89: 10: 1), followed by CHCl3-MeOH (3: 1)). The product fractions were pooled and concentrated to obtain (5R) -3-keto-1-[(1S) -1-phenylethyl] -1-azoniacyclo [3.2 .1] Sintered (10.1 g) as a foam (MS (ESI +) m / z 230.1 (M + H +)). This foam (10.1 g, 38.0 mmol) was dissolved in MeOH (500 ml) 10% pd (C) (3.0 g) was added and the mixture was hydrogenated (45 psi) overnight. The mixture was filtered and allowed to undergo reducing conditions again (9.1 g, 10% Pd / C, 50 psi). After 5 hours, TLC showed (5R) chlorinated keto-H (1S) small phenyl Consumption of ethyl] small azonium bicyclo [3 · 2 · 1] octane. This mixture was filtered, concentrated and triturated (minimum iPrOH) to obtain 3.73 g of the product collected twice as a solid: [a] 25D = 33 (c0.97, DMSO); the calculated HRMS (FAB) of C7Hn (M + H +) is 126.0919, and the measured value is 126.0937 3-amine dihydrochloride: -106- 200300673 (101) Description of the invention

Η (Λ ^ ΝΗ2 #HCI HCi (jR, 5R)-[3.2.1] -amine

Containing (5R) -1-acylbicyclo [3.2.1] octane-3 · one hydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g, 29.4 mmol) ) And ethanol (no ml), sodium acetate trihydrate (9.23 g, 67.8 mmol) was added. The mixture was drained for 3 hours, filtered and concentrated. The formed solid was dissolved in n-propanol (100 strokes) and sodium (~ 13.6 g, 618 mmol) was added in 20-25 parts. The reaction spontaneously began to reflux, and the reaction was heated in an oil bath (loot :). The addition was completed in ~ 20 minutes, and the mixture was cured in ~ 40 minutes. Remove the oil bath and add n-propanol (2 X 25 mL) to dissolve residual sodium metal. The reaction was quenched carefully by adding H2O (100 mL) dropwise. A saturated aqueous NaCl solution (20 ml) was added and the layers were separated. The organic layer was dried (MgSO4), filtered, treated with freshly prepared MeOH / HCl, and concentrated. The formed solid was triturated with 30 ml of EtOH, filtered and dried in vacuo to obtain 3.51 g of (3R, 5R)-[3.2.1] -amine as a solid: 〇] 25D = -3 (c0.94, DMSO); 1 H NMR (400 MHz, DMSO-d6) 6 3.60-3.80, 2.95-3.10, 2.65-2.75, 1.90-2 · 15, 1.70-1.90; HRMS (FAB for C7H14N2 (M + H +)) ) Calculated value 127.1235, found value 127.1235. 3 · 2 · 2 Preparation of amines -107- 200300673

(102)

Description of the invention $ Stomach; 1;

Preparation of 4- (2-ketopropylidene) hexahydropyridine-1-carboxylic acid, dibutane 35 quot; teammate di-butyl ester (Int 101) · Sodium hydride (60% oil dispersion, 2.01 g,% 古-Fanzhou · 2 pen ears) was washed with pentane (3χ), and suspended in anhydrous THF (40 liters). Sixth, public, can be J Jia. Add (2-ketopropyl) dropwise

) Diethyl phosphonate (9.75 g, 50.2 mmol) before cooling the solution to hydrazone. After the addition was complete, the solution was warmed to room temperature and stirred for 30 minutes. Add tert-butyl 4-ketohexahydropyridinecarboxylic acid (50 g, 25.1 mol) in portions over 10 minutes, then stir at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added and then diluted with a bond. The organic layer was extracted with water. The organic layer was dried (MgS04) ', dried over and concentrated to a yellow oil. The crude product was purified by flash chromatography on. Dissolved with hexane: 1¾-acid (60:40) to obtain 4.5 g (75,%) Intl01 as a white solid: 1HNMR (CDC13) (56.2, 3.5, 3.4, 2.9, 2.3, 2.2, 1.5. '4- ( 2. Preparation of ketopropyl) hexahydropyridine-1-carboxylic acid tertiary-butyl ester (int 102) · Int 101 (4,5 g, 19 mmol) and 10% palladium A mixture of activated carbon (450 mg) in EtOH (150 ml), placed in a Parr bottle, and hydrogen-108- 200300673 at 50 pSi ———. ^ ______ Description of the invention continued (103) L- -5 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to obtain 4.3 g (94%) of Int 102 as a transparent oil: hNMRCCDCb) 5 4 ″, 2.8, 2.4, 2.2, 2.0, Preparation of 1.7, 1.5, U · 4- (3-bromo-2-fluorenylpropyl) hexahydroxide than 1-bite-l-three-butyric acid (plus 103): In lithium hexamethyldisilazane To the stirred solution in butyl HF (20.0 ml, 1.0 M) in a -78 ° C bath, chlorotrimethyllithium (110 ml, 86.4 mmol) was added dropwise. The mixture was stirred at -78 ° C for 20 minutes, and then a solution of Int 102 (3.21 g, 13.3 mmol) in THF (50 ml) was added dropwise. After the addition was complete, the mixture was stirred at -78 ° C for 30 minutes. The mixture was allowed to warm to 0 ° C in an ice-water bath, and phenyltribromotribromide (5.25 g, 14.0 mmol) was added. The mixture was stirred in an ice bath for 30 minutes, and then water and ether were added. The aqueous layer was washed with ether, and the combined organic layers were washed with a saturated aqueous sodium thiosulfate solution. The organic layer was dried (MgS04), dried and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography on SiO2. Dissolved with hexane-ether (60:40) to obtain 2.2 g (52%) of Im 103 as a yellow oil: iHNMR (CDCl3) 5 4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1-2.0 , 1 / ^. 5,12] Preparation of 1-bromo-3-hexahydropyridin-4-ylacetone trifluoroacetate (Im 104): In Int 103 (2.2 g, 6.9 mmol) ) In ml), to the stirred solution in an ice-water bath, trifluoroacetic acid (10 ml, 13.0 mol) was added. The mixture was stirred at 0 C for 30 minutes. The volatiles were removed in vacuo to give 2.0 g (87%) of Intl04 as a yellow residue: MS (ESI) [M + H] m / e 20.1 for Shen 0 20.1-acylbicyclo [3 · 2 · 2] Preparation of non-3-one (Int 105): -109- 200300673 (104) Description of the invention I sell; g

In a stirred solution of DIEA (13 mL) in acetonitrile (680 mL), M 104 (2.0 g, 6,0 mmol) in acetonitrile (125 mL) was added via a syringe pump at reflux temperature. Solution over 4 hours. The mixture was kept at reflux temperature overnight. The mixture was concentrated in vacuo and the remaining residue was partitioned between saturated K: 2CO3 aqueous solution and CHC13-MeOH (90:10). The aqueous layer was extracted with CHCVMeOH (90:10), and the combined organic layers were dried (MgSCU), filtered and concentrated in vacuo to a brown oil. The crude product was purified by flash chromatography on SiO2. 600 mg (72%) of Int 105 was obtained with CHapMeOH_NH4 OH (95: 4 5: 0.5) as a transparent solid: iHNMRCDCb) 5 3.7, 3 · 3-3 · 2, 3.1-3.0, 2 · 7, 2 · 3, 2.0-1.8. 1-mouth bicyclo [3 · 2 · 2] non-3-amine bis (4-benzenesulfonic acid methyl ester χ [3 · 2 · 2] -amine) Preparation: To a stirred mixture of Int 105 (330 Aike '2.4 mmol) and sodium acetate trihydrate (67 mg, 4.8 Amor) in EtOH (6.0 ml), add a hydroxyl group Amine hydrochloride (200 gram, 2.8 mmol). The mixture was stirred at room temperature for 10 hours. The mixture was filtered and the filtrate was concentrated in vacuo to a yellow solid. In a solution of a solid (350 mg, 2.3 mmol) in n-propanol (30 ml), sodium metal (20 g, phantommol) was added in small portions at reflux temperature. ), After 30 minutes. Heat under reflux for 2 hours. The solution was allowed to cool to room temperature and brine was added. The mixture was extracted with n-propanol and the combined organic layers were concentrated in vacuo. Dissolve the residue in ah. Consider residual solids. The mash was dehydrated and dried (MgS04), filtered and concentrated in vacuo to a transparent solid. To this solid (32 mmol, 2.3 mmol) was stirred in dirty (4 ml), and p-formamate monohydrate (875 mg, 4.6 mmol) was added. Cold, 4_-110-200300673 Description of the invention_Stomach (105) After 30 minutes, the solvent was concentrated to obtain 710 mg (62%) of P.2.2] -amine as a white solid: 1HNMR (CD3OD) (57 · 7,7 · 3,4 · ^ 3 · 9, 3.6-3 · 4, 2 · 6-2 · 5, 2 · 4, 2 · 2- 2.1, 2.1-2.0, 1.9. Resolution of stereoisomers: This amine can be coupled to form a suitable amine or thioxamine as a racemic mixture. The racemic mixture can then be chromatographed using a palm column or a palm that is widely known in the art. Analytical HPLC technology is provided to provide the necessary analytical paraffin isomers 3 (R) and 3 (S) of amidine or thiamidine. The following examples are provided by way of example and are not intended to limit the scope of the invention Limited to only the exemplified compounds. The amines used for the coupling are examples only and are not intended to limit the scope of the invention; any amine identified herein may be used to perform insignificant changes to the procedures identified herein to obtain The final compound. Moreover, the salts made in these examples are for illustration only and are not intended to limit the invention. Any pharmaceutically acceptable salt may be It is generally made by a person skilled in the art. Furthermore, the designation of a specific compound or stereoisomer is an example, and is not intended to limit the scope of the present invention in any way. The present invention includes the following examples and the compounds referred to as pure Stereoisomers or racemic mixtures. Example 1: N-(((3R)-: M-A bicyclo [2.2.2] octyl) -2,3-dihydro-1,4-benzodi Oxalipine-6-carboxamide fumarate:

-111-200300673 (106) Description of the invention Continued on -10 ° c methanol-ice bath at 0.59 g (3.3 mmol) benzodioxolane and arsenic acid in o ^ CN (30 ml ) In the stirred solution, DIEA (1.65 ml, 9.5 mmol), 3 (R > aminopyridine dihydrochloride (0 62 g, 3.11 mmol), and HATU ( U8 g, 3, n mmol). The mixture was stirred at ^ ° C for 1 hour, then warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo to a yellow residue. The crude product was dissolved in Si. It was purified by flash chromatography over 0.22% and dissolved in CHCVMeOH-Ni ^ OHpo: 9: 1) to obtain 634 mg (71%) of a pale yellow solid. MS (ESI) m / e289 [M + H]. Add solid solution (634 mg, 2.2 mmol) in acetone (2.0 ml) and stir out the bath. , 2.4 mmol) in hot bath in ιρΑ. The mixture was allowed to warm to 45 ° C on a water bath for 30 minutes and then cooled to room temperature. Filter the solid sinks, wash them with Cg and dry them in vacuum, and 550 Aike (61%) as in Example 1 is a white solid: Irnmr (CD3 OD) δ 7Α-7.3, 6.9, 6.8, 4.4 , 4.3, 3.9-3.8, 3.5-3.3, 2.4, 2.3-2.2, 2.1, 1.9 Examples_? 1- > [(2S, 3R) Hydroxymethyl acridine bicyclo [2 · 2.2] octyl]- 2,3-dihydro-1,4-benzodioxolene-6-carboxamide hydrochloride: make 2,3-dihydro-M-benzodioxolene-6-chinic acid (〇18 g, 104 mmol), HATU (0.47 g, 1.25 mmol) and (2S, 3R) -2-methyl-l-p-bicyclo [2.2.2] oct-3-amine The second salt (0.213 g '1.0 mmol) was dissolved in 5 ml j) MF. DIEA (1.4 mL, 8.0 mmol) was added dropwise. After 18 hours, remove the solvent in a vacuum. The residue was dissolved in CHC13, added in NaOH, and the mixture was extracted with CHC13 '. The combined organic layers were dried (MgS04), filtered and concentrated. The residue was purified by chromatography (Biotage 40S, 90: 9: 1 CHCl3 / MeOH / NH4OH). Its hydrochloride was made and recrystallized from MeOH / EtOAc to provide 0.225 g (64%) -112- 200300673 (107) Description of the Invention Example 2 continued. The calculated HRMS (FAB) for c ^ Hu ^ C ^ + H is 30.33π08, and the measured value is 303.1697. 4 (S) N- (1-acylbicyclo [2.2 · 1] heptyl-2 , 3-Dihydrobenzodioxoamidine-6-chitosamine: In a 5t acetone-ice bath at 0 · 160 mg (0.88 mmol) 丨, 4_benzodioxin In a stirred solution of -6-sided acid in DMF (8 ml), DIEA (470 μl, 2.77 mmol) was added successively, and outward 4⑸ · [2 · 21; ^ (400 mg, 〇88 Pen mole) and HATU (333 mg, 0.88 mmol). The mixture was stirred at -5 for 1 hour, then warmed to room temperature and stirred overnight. The mixture was concentrated to yellow in true 2. The residue. The crude product was purified by flash chromatography on SiO2. It was dissolved in CHCl3-MeOH-NH4OH (90: 9: 1) to obtain 240 mg (99%) of a pale yellow solid. MS (ESI) m / e 275 [M + H]. To a stirred solution of the above solid (240 mg, 2.2 mmol) in propyl I (2.0 ml) was added fumaric acid (101 mg, 0.87 MM) in isopropanol. Warm the mixture to 45 ° C on a water bath for 30 minutes, then cool To room temperature. The solid precipitate was filtered, washed with acetone, and dried in vacuo to give 150 mg (44%) of the title compound as a white solid: ^ NMR ^ OD) 5 7.4-7.3,6.9,6.7,4.3, 4.1, 3.3-3.2, 3.1-3.0, 2.9, 2.1-2.0, 1 · 8-1 · 7 · Example 4: Nf (3R, 5RH-mouth bicyclo [3.2.1] oct-3-yl] -2 , 3-Dihydro-1,4-benzodioxolene carboxamide hydrochloride: Example 4 was carried out in accordance with the procedure discussed in Example 1 and applied insignificant changes to obtain 78% yield of solids: 1HNMR (400MHz, CD3OD) 5 7 · 3 (K7 · 40, 6.92, 4.55-4.70, 4.25-4.35, 3.50-3.75, 3.30-3.40, 3.05-3.20, 2.80-2.95, 2.25-2 · 40 , 2.05-2.20, -113- 200300673

Description of the invention; MM (108)-1.80-1.95; MS (Cl) m / z 289 (MH +). -2,3-dihydro-1,4-benzodioxolene-7-carboxamide hydrochloride:

A suspension of calcium ethoxide (816 mg, 6.3 mmol), butylene oxide (5.2 ml, 93 mmol) and 2,4-diiodophenol (2.17 g, 6.3 mmol) was placed in The flask was sealed and heated at 80 ° C for 18 hours. The reaction mixture was allowed to cool, poured into IN HC1, and extracted three times with CH2C12. The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. The resulting material was purified by column chromatography (two column, 30-40-50% CH2C12 step gradient in hexane) to obtain 1- (2,4-diiodophenoxy) butan- 2-alcohol as a clear oil (1.73 g, 67%). iHNMRGOOMHACDCU) 5 8.04, 7.56, 6.57, 4.03, 3.9, 3.84, 2.42, 1.65, 1.04. The flask was repeatedly evacuated and then filled with N2 to make 1- (2,4-diiodophenoxy) butan- A solution of 2-alcohol (1.27 g, 3.0) in pyridine (12 ml) was degassed. Add sodium hydride (60% suspension, 153 mg, 3.8 mmol) and stir the resulting mixture for 15 minutes. Copper (1) chloride (15 mg, 0.15 mmol) was added and the resulting mixture was heated at 80 ° C for 2 hours. The reaction was allowed to cool, poured into 1M HC1, and extracted three times with CH2C12. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The formed substance was purified by column chromatography (10% CH2C12 in hexane) to obtain 2-ethyl-7-iodine-114- 200300673 (109) Inventive radical-2,3 · dihydro-i , 4-benzodioxolane, a clear oil (493 mg, 57%). 1 H NMR (400 MHz, CDC13) 5 7.20, 7.10, 6.61, 4.22, 4.01, 3.85, 1.7, 1.6, 1.06. The flask was evacuated repeatedly and filled with N2 to make 2-ethyl-7- A solution of iodo-2,3-dihydro-1,4-benzodioxolene (486 mg, 1.68 mmol) in DMF (3 ml) was degassed. Zn (CN) 2 (117 mg, 1.0 mmol) and Pd (PPh3) 4 (97 mg, 0.084 mmol) were added, and the resulting solution was degassed, and then heated to 80 ° C for 1 · 5 hours. The reaction was allowed to cool, poured into water, and extracted twice with ether. The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. The resulting material was purified by column chromatography (25-50% CH2C12 step gradient in hexane) to obtain 3-ethyl-2,3-dihydro-1,4-benzodioxolane. Ene-6-carbonitrile as a clear oil (296 mg, 92%). 1 H NMR (400 MHz, CDC13) δ 7.16, 7.13, 6.91, 431, 4.05, 3.93, L7, 1.6, 1.08. Added ΟΗ (218 mg, 3.9 mmol) to 3-ethyl-2, In a mixture of 3-dihydro-1,4-benzodioxanthine-6-carbonitrile (247 mg, 1.3 mmol), ethanol (3 ml) and water (1 ml). The resulting mixture was heated to 80 ° C for 24 hours. The reaction was allowed to cool, diluted with water (2 ml), and acidified to pH < 2 with concentrated HC1. The formed solid was filtered, washed with water, and dried under vacuum at 60 ° C to obtain 3-ethyl-2,3-dihydro-1,4-benzodioxolidine-6-carboxylic acid, As a white solid (249 mg, 92%). iHNMRGOOMHiDMSO- ^) 5 12 · 66,7 · 43, 7.37, 6.95, 4.38, 4.10, 3.95, 1.64, 1 · 01 · Add DMF (3 ml) to ⑻-3-aminopyridine dihydrochloride ( 143 mg, 0.72 mmoles), 3-ethyl-2,3-dihydro-1,4-benzodioxolene-6-polyacid (150 mg, 0.72 mmoles) and DIEA (376 microliters, 2.16 millimoles) in a solution in water (300 microliters). HATU (274 mg, 0.72 mmol) was added, and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was diluted with methanol (5 ml) and poured onto a column of AG50Wx2 resin (H + form). The column was washed with methanol; the product was dissolved with 5% TEA in methanol. The solvent was removed in vacuo and the material formed was evaporated twice from acetonitrile. The crude product was dissolved in 1M HC1 in methanol. The solvent was removed in vacuum at 80 ° C to obtain Example 5 as a tan solid (228 mg, 86%). iHNMRGOOMHADMSO-A) 5 10.46, 8.46, 7.49, 7.43, 6.94, 4.37, 4.3, 4.09, 3.92, 3.59, 3.3, 3.2, 2.1, 2.0, 1.9, 1.7, 1.02; t Example 6 (a) and Example 6 (b ): 2fRV and 2 (S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl > 2-[(fluorenyloxy) methyl] -2,3 -Dihydro-1,4-benzodioxo-6-carboxamide (2E) -butan-2-dicarboxylic acid:

HOOC " CI1 > xC〇〇H 6- > Sulfuryl-2,3-digas-1,4-wood-dioxolan-2-yl) methanol based on 6-fluoro-2,3 -Digas-Benzo-1,4-dioxolidine-2-yl) -methanol was prepared in the literature. See Henning, R .; Lattrell, R .; Gerhards, H.J .; Leven M .; J. Med. Chem .; 30; 5; 1987; 814-819. The intermediate was obtained in 70% yield as a solid: 1 H NMR (400 MHz, CDC13) δ 7.08, 7.00, 6.81, 4.25-4.40, 4.10-4.20, 3.85-4.00, 1.95; MS (El) m / z 244 (M +). (6- > Sulky-2,3-dihydro-1,4-benzodioxolane-2-yl) methanol (3.94 g, 16.1 mmol) and DMF ( 35 ml), and treated with a 60% dispersion of NaH in mineral oil (0.706 g, 17.7 mmol) at room temperature. After 15 minutes, the mixture was treated with bromide (2.10 ml, 17.7 mmol). After 2 hours, -116- 200300673 invention description, gastric renewal (111) ----- Pour the mixture into Η20 and extract with EtOAc (2 X 125 ml). The combined organic material was washed with H20 (3 X 100 ml), brine, dried (MgS04), dried and concentrated. The formed oil was adsorbed on SiO 2 and chromatographed (Biotage 40M + SIM, 5% EtOAc / hexane). The product fractions were pooled and concentrated to obtain an oil, which was solidified (at rest) to obtain 3.91 g (73%) of 2-[(fluorenyloxy) methyl] -6-bromo-2,3 · Dihydro-1,4-benzodioxolane: iHNMR (400 MHz, CDC13) δ 7 · 30-7 · 45, 7.06, 6.99, 6.81, 4.60-4.70, 4.30-4.40, 4.05-4.15, 3.65-3.85; MS (El) m / z 244 (M +). Make 2-[(fluorenyl) methyl] -6-bromo-2,3-dihydro-1,4-benzodioxo A mixture of limonene (3.63 g, 10.8 mmol) in THF (60 ml) was cooled in a CO 2 / acetone bath under N 2. A solution of tertiary-butylbell in pentamidine (1.3 M, 17.5 ml, 22.8 mmol) was added. After 5 minutes, C02 (gas) was bubbled through the mixture and the mixture was allowed to warm to room temperature. A solution of HC1 in methanol was added, and the mixture was concentrated. The residue was extracted between NaOH (1 N) and EtOAc. Discard the organic layer. The pH of the aqueous layer was adjusted to ~ 4 and extracted with EtOAc (2 X 100 mL). The combined organic material was washed with h20 (3 x 100 ml), brine, dried (MgS04), filtered and concentrated. The resulting oil was chromatographed (Biotage 40M, 2% MeOH / CH2Cl2). The product fractions were pooled and concentrated to obtain 1.66 g (51%) of 2- (phenoxymethyl) -2,3-dihydro-1,4-benzodioxolene-6-carboxylic acid as an oil. Make this acid (L59 g, 5.29 mmol), (R) -3-aminoamidine. Dihydrochloride (1.05 g, 5.27 mmol) in THF (60 mL), DMF (10 mL) ' : And the mixture in DIEA (2.90 ml, 16.6 mmol), cooled in an ice bath under n2. HATU (2.01 g, 5.29 mmol) was added and the mixture was stirred off and allowed to warm to room temperature overnight. The mixture was concentrated, and the crude product was chromatographed.

(Biotage 40M, (1: 142 * 1418) NH4OH-MeOH-CHCl]). The product fractions were pooled and concentrated to obtain a white foam. This foam was subjected to preparative palm HPLC (0.46x25 cm Chiralcel OD-H, 0.5 mL / min (50% isopropanol / 50% heptane (0.5% diethylamine)) and detected at 220 nm (10 microliters of injection). The fractions containing the first diastereoisomer dissolved were pooled and concentrated. The formed foam was dissolved in 95% EtOH and filtered through glass wool. Butenedioic acid (1.0 equivalent), and this material was set aside. The formed solid was collected by filtration and dried to obtain 0.086 g (3%) of Example 6 (a) as a monohydrate: 1HNMR (400 MHz, DMSO-d6) 5 8.25-8.30, 7.25-7.50, 6.97, 6.49, 4.47, 4.35-4.50, 4.05-4.20, 3.70, 3.30-3 · 50, 3.05-3.20, 2.90-3.05, 1.85-2.05 , 1.70-1.85, 1.45-1.60; MS (El) m / z 408 (M +). The fractions containing the second dissociated diastereomer were pooled and concentrated. The resulting foam was dissolved in 95% EtOH and filtered through glass wool. Fumaric acid (1.0 equivalent) was added and the material was set aside. The solid formed was collected by filtration and dried to give 0.096 g (3%). 6 (b ) Is a monohydrate: iHNMR (400 MHz, DMSOd6) (5 8.25-8.30, 7.25-7.50, 6.97, 6.49, 4.47, 4.35-4.50, 4.05-4.20, 3.70, 3.30-3.50, 3.05-3.20, 2.90- 3.05, 1.85-2.05, 1.70 -1.85, 1.45-1.60; MS (El) m / z 408 (M +). No analysis was performed to identify which diastereomers are examples 6 (a) and what This is Example 6 (b). Example 7: N-[(3R) Xiakoubicyclo [2 · 2 · 2] oct-3-yl] Each [(fluorenyloxy) methyl] -2,3-dihydro -1,4-Benzodioxolane-6-a few g of fishamine (2E) -butanedioic acid:

HOOC ^ VCOOH -118- 200300673 Description of the invention_Page (113) --- (R) and (S)-(7-bromo-2,3-dihydro-benzo-1,4-dioxolene -2-yl) -methanol is prepared according to literature examples. In addition, the racemic mixture was obtained by starting with racemic epichlorohydrin. See Aiba, Y .; Hasegawa et al., Bioorg. Med. Chem. Lett .; 11; 20; 2001; 2783-2786. A mixture of 7-bromo-2,3-dihydro-1,4-benzodioxolene-2-yl) methanol (2.73 g, 11.1 mmol) and DMF (25 ml) was added at Ot : Next, it was treated with a 60% dispersion of NaH in mineral oil (0.49 g, 12.3 mmol). After 15 minutes, the mixture was treated with scandium bromide (1.46 ml, 12.37 mmol). After 2 hours, the mixture was poured into Η20 and extracted with EtOAc (2 X 125 mL). The combined organic layers were washed with H20 (3 X 100 ml), brine, dried (MgSO4), filtered and concentrated. The formed oil was adsorbed on SiO 2 and chromatographed (Biotage 40M + SIM, 5% EtOAc / hexane). The product fractions were pooled and concentrated to provide an oil, which was solidified (when left to stand) to obtain 3.48 g (93%) of 2-[(fluorenyl) methyl] -7- > , 3-Diazepine-1,4-benzodioxin. Make 2-[(Ethyloxy) methyl] -7-bromo-2,3-dihydro-l, 4-benzodioxolene (3.35 g, 10.0 mmol) in THF (60 ml ) And cooled in a CO 2 / acetone bath under N 2. A solution of tertiary-butyl boat in pentagon (1.7 M'6.0 ml, 0.02 mmol) was added. After 5 minutes, CO 2 (gas) was bubbled through the mixture and the mixture was allowed to warm to room temperature. A solution of HC1 in methanol was added and the mixture was concentrated. The residue was chromatographed (Biotage 40M, 3% MeOH / CH2Cl2). The product fractions were pooled and concentrated to give ι · ΐ9 g (40%) of 3-[(fluorenyl) methyl] -2,3-dihydro-fluorene, 4-benzodioxolene-6. -Carboxylic acid as an oil. This acid (U2 g, 3.73 mmol), pyridine (0.765 g, 3.84 mmol) in THF (45 ml), DMF (10 ml), and DIEA (2.15 ml, 12.3 -119) -200300673 Description of the invention, the mixture in (114)-millimolar) was cooled in an ice bath under N2. HATU (1.425 g, 3.75 mmol) was added and the mixture was stirred and warmed to room temperature overnight. The mixture was concentrated, and the crude product was chromatographed (Biotage 40M (1: 142: 1418) ΝΗΟΟΙί-Ν ^ ΙΙ-αία3). The product fractions were pooled and concentrated to obtain 1.33 g (87%) of the product, For foam. A portion of the free state base (0.287 g, 0.70 mmol) was treated with fumaric acid (0.082 g, 0.71 mmol), acetone (~ 10 mL), and MeOH (~ 5 mL). The mixture was evaporated and the formed solid was filtered from Et20 and dried to obtain (0.288 g, 78%) of Example 7 as a solid: 1 H NMR (400 MHz, CD3 OD) 5 7.45, 7.41, 7.25-7.40, 6.94, 6.70, 4.61, 4.35-4 · 45, 4.35- 4.45, 4.10-4.20, 3.70-3.85, 3.15-3.50, 2.30-2.40, 2.15-2.30, 2.00-2.15, 1.85- 2.00; MS (El) m / z 408 (M +). Example 8: (3S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] each [( (Methoxy) methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide (2E) -but-2-carboxylic acid:

^ hooc ^ cVcooh Example 8 was carried out in accordance with the procedure discussed in Example 7, with insignificant changes, and [(2S) -7-bromo-2,3-dihydro-1,4-benzodioxolane Fluoren-2-yl] methanol was obtained as a solid: 1 H NMR (400 MHz, CD3 OD) 5 7.25-7.50, 6.94, 6.70, 4.61, · 4.35- 4.45, 4.10-4.20, 3.70-3.85, 3.20- 3.50, 2.30-2.40, 2.15-2.30, 2.00-2.15, L85-2.00; MS (El) m / z 408 (M +) ·: Example 9: (3R) -N-[(3R) Small acryl bicyclic and [2.2 .2] oct-3-yl] -3-[(fluorenyloxy) methyl] -2,3- [dihydro-1,4-benzodioxolene-6-carboxamide (2E) -But-2-enedioic acid: -120- 200300673 (115)

HO〇CXfVCOOH Example 9 was performed in accordance with the procedure discussed in Example 7, and performed insignificant changes' and (3R) -3-[(^ oxy) methyl] -2,3-dihydro-1,4-benzene Beginning with dioxolane-6-metanoic acid, it was obtained in 84% yield as a solid: 1H NMR (400MHz, OD) Description of the invention δ 7.25-7.50, 6.94, 6.70, 4.61, 4.35- 4.45, 4.10-4.20, 3 JO-3.85, 3.20-3.50, 2.30-2.40, 2.15-2.30, 2.00-2.15, 1.85-2.00; MS (El) m / z 408 (M +). Example 10: N-1- [(3R) -1-azabicyclo [2.2.2] oct-3-yl] -3- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxolene-6 -Carboxamide (2E) -but-2-enedioic acid:

Make N-[(3R) small acyl bicyclo [2 · 2 · 2] oct-3-yl] -3-[(fluorenyloxy) methyl] -2,3-dihydro-1,4-benzo A mixture of dioxolene-6-carboxamide (1.04 g, 2.54 mmol), 10% Pd / C (0.78 g) and MeOH (45 ml) was shaken under H2. After 90 hours, the mixture was passed through crushed soil and evaporated. The residue was chromatographed (Biotage 40S, 1: 10: 89-NH4OH: MeOH: CHC13), and the fractions containing the desired product were pooled and concentrated to obtain 0.684 g (85%) of the free base as a solid. This solid (0.284 g, 0.89 mmol) was treated with fumaric acid (1.0 equivalent), EtOH (~ 10 ml) and acetone (~ 10 ml). The mixture was dissolved and evaporated. The formed solid was filtered from Et2O and dried in vacuo to give 0.274 g (71%) of Example 10 as a solid: 1 H NMR (400 MHz, CD3 OD) 7.45, 7.40, 6.94, 6.71, 4.35 -4.45, 4.20-4.25, 4.05-4.15, 3.75-3.90, 3.20-3.50, 2.30-2.40, 2.15-2.30, 2.05-2.15, 1.85-2.00; MS (El) m / z 318 (Μ +) · -121 -200300673 Description of the invention (1) (116)-Example 11: (3S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] each (phenoxymethyl ) -2,3 · Dihydro-1,4-benzodioxolene (2E) -but-2-enedioic acid:

[(2S) -7-bromo-2,3-dihydro-1,4-benzodioxol-2-yl] fluorenol (2.26 g, 9.20 mmol), phenol (0.87 g , 9.2 mmoles), triphenylphosphine (2.42 g, 9.20 mmoles) and THF (80 ml), cooled in a 0 ° C bath under N2. Diethyl azodicarboxylate (1.50 ml, 9.5 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was adsorbed on SiO2 and separated (Biotage40S + SIM, (1:19) EtOAc: hexane). The product fractions were pooled and concentrated to obtain 1.45 g (49%) of (2S) -7-bromo-2- (phenoxymethyl) -2,3-dihydro-M-benzodioxolane. Alas, it is transparent oil. This oil (14, 0.472 g, 1.47 mmol), (R) -3-aminopyridine (0.557 g, 4.41 mmol), palladium acetate (0.083 g '0.37 mmol) A mixture of 1,3-bis (diphenylphosphino) propane (0.153 g, 0.370 mmol) and toluene (20 ml) was stirred in an oil bath at 97 ° C under CO (gas). The mixture was allowed to cool to room temperature, and after 1.5 hours, it was concentrated. The residue was partitioned between NaOH (aq.) And EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The residue was chromatographed (Biotage 40S, (1:10:19) NH4OH-MeOH-CHCl3). The product fractions were pooled and concentrated to obtain the product as a foam. This foam was dissolved in EtOH, treated with fumaric acid (1 · 0 equivalent) and water (1 drop), and partially concentrated. Et20 was added, and the solid formed was filtered and dried to provide 0.310 g (53%) of Example 11 as a monohydrate solid: 1 η NMR (400 MHz, -122- 200300673

(117) CD3 OD) δ 7.49, 7.43, 7.25-7.35, 6.90-7.05, 6.70, 4.55-4.65, 4.45-4.55, 4.35-4.45, 4.20-4.35, 3.75-3.85, 3.20-3.50, 2.30-2.40, 2.15 -2.30, 2.00-2.15, 1.85-2.00. Example 12: (3R) -N-[(3R) -1-azabicyclo [2 · 2 · 2] octyl] -3- (phenoxymethyl ) -2,3-dihydro-l, 4 · benzodioxolane-6-polyamine hydrochloride:

[(2R) -7-bromo-2,3-dihydro-1,4-benzodioxolene_2-yl] methanol (0.648 g, 2.64 mmol), phenol (0.248 g, 2.64 mmoles), triphenylphosphine (0.692 g, 2.64 mmoles) and THF (26 ml) at 0 ° C. In the bath, cool under n2. Diethyl azodicarboxylate (0.42 ml, 2.7 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was concentrated, and the solution was separated between EtoAc and H20. The organic layer was dried (MgS04), adsorbed on Si02, and chromatographed (Biotage40S + SIM, (1:19) EtOAc). : Hexane). The product fractions were pooled and concentrated to give 0.315 g (37%) of (2R) -7-bromo-2- (phenoxymethyl) -2,3-dihydro-1,4-benzodioxy Terpinene as an oil. A solution of this oil (0280 g'0.87 mole) and THF (30 ml) was cooled in a co2 (solid) / acetone bath 'under & To this was added a solution of tertiary · butyllithium in pentane (1.7 M '1.10 ml, 1.9 mmol). After stirring for 5 minutes, co2 (gas) was bubbled through the solution for another 10 minutes. The mixture was treated with MeOH / HC1 'and allowed to warm to room temperature. The mixture was concentrated and the residue was chromatographed (BiotageWS '(1: 4 ") MeOH:?%). The product fractions were collected and reduced to obtain 0.103 g (41%) of (3R) -3- (phenoxymethyl) · 2,3-dihydrod, 4-benzodioxolene carboxyl Acid as a solid. Following the procedure in Example i, apply -123- 200300673

(118) Insignificant changes, Example 12 was obtained in 45% yield as a monohydrate solid: 111 Li 11 (400% 1 ^, 0300) (5 7.40-7.55, 7.25-7.35, 6.90-7.05, 4.35-4.65, 4.20-4.35, 3.75-3.90, 3.25-3.55, 2.30-2.40, 2.15-2.30, 2.05-2.15, 1.85-2 · 00; MS (El) m / z394 (M +). F Example 13 : —N-[(3R) -1-Ouyabicyclo [2.2.2] oct-3-yl] -2,3-dihydro-1,4-dioxobenzopyrene [2,3-c ] Pyridine-7-carboxamide · Fumarate:

In 4,5-hydroxypyridine-2-carboxylic acid [see: Kenichi Mochida et al., J. Antibiot. 1987, 182] (800 mg, 4.18 mmol) in MeOH (30 mL) 'Add concentrated sulfuric acid (1 mL). The mixture was heated to reflux for 2 days. The mixture was allowed to cool to room temperature, and then solid sodium bicarbonate was added. The mixture was diluted with water and the precipitate was filtered and dried to obtain 527 mg (75%) of methyl 4,5-dihydroxypyridine-2-carboxylate: 1 H NMR (400 MHz, MeOH-d4) 5 7.68, 7.24, 3.97 · To a stirred solution of 4,5-dihydroxypyridine-2.-chiral acid phosphonate (348 mg, 2.06 mmol) in DMF (20 ml), add solid K2c〇3 (31 g, 22 mmol) and 1,2-dibromoethane (386 µl, 4.5 mmol). The mixture was heated at 115 ° C for 2 hours. The DMF was removed in vacuo and the residue was partitioned between water and EtOAc. The aqueous layer was extracted once more with EtoAc. The combined organic layers were dried (MgS04) and concentrated in vacuo to obtain a yellow solid, which was 2,3 · dihydro-1,4 · dioxolane and [2,3-c > pyridine-7- Methyl carboxylate (348 mg, 86-124- 200300673 /, Description of the invention; _ stomach (119) ____%): 1H NMR (400 MHz, CDC13) 6 8.29, 7.71, 4.39, 3.99. At 2,3 -Dihydro-1,4-dioxobenzopyrene [2,3-c] p ratio of pyrene-7-chitoic acid methyl g (300 mg '1.54 mmol) in MeOH (10 liters) Discard the solution and add NaOH (10 liters of 5% water drop solution). The mixture was heated to reflux for 3 hours and then cooled to room temperature. The methanol was removed in vacuo and the residual aqueous layer was acidified to pH = 5 with 1N HC1 and extracted continuously with CH2C12 for 2 days. The organic layer was concentrated to a white solid (245 mg, 88%), which was 2,3-dihydro-1,4-dioxolane, and [2,3-c] orbital-7-chinic acid: iHNMR (400MHz, DMSO-d) 5 13-12, 8.21, 7.52, 4.39. At 2,3-dihydro-1,4-dioxolurene [2,3-c] pyridine- In a stirred solution of 7-carboxylic acid (130 mg, 0.72 mmol) in anhydrous DMF (10 ml), DIEA (381 µl, 2.19 mmol), 3⑻- Aminopyridine dihydrochloride (143 mg, 0.72 mmol) and HATU (273 mg, 0.72 mmol). The mixture was stirred at 0 ° C for 30 minutes, then warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo to a yellow residue. The residue was partitioned between CHCVMeOH (90:10) and a half-saturated & C03 aqueous solution. 'The aqueous layer was extracted with CHCVMeOH (90:10), and the combined organic layers were washed with water, dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on SiO2. CHC1 ^ MeOH NH4OH: $ 1) Fall off 'to obtain 130 mg (62%) of a white foam. To the solution of the above-mentioned amidine (128 mg, 0.44 mmol) in MeOH (10 ml) was added fumaric acid (51 mg, 0.44 mmol). The mixture was allowed to warm to 40 ° C on a water bath for 30 minutes, then the solvent was removed in vacuo. Adding acetone and two drops of water to the residue will produce white -125- 200300673 Description of the invention _ stomach (120)-sediment. The solid precipitate was filtered, washed with acetone, and dried in vacuo to give 116 mg (65%) of Example 13 as a white solid ... NMRMOOMHz, MeOH-d4) 6 8.17, 7.59, 6.70, 4.41-4.40, 3.78, 3.47-3.29, 2.33, 2.20, 2.11-2.07, 1.93. Example 14: N4 (3RV1-Bia bicyclo [2.2.2] oct-3-yl] bite-6-carboxamide • transbutazone Acid salt:

〇 Will bite (see: Chatteijea, J. Indian Chem. Soc. 1959, 35, 78.) (5.00 g, 37.8 mmol) with 10% palladium / activated carbon (250 mg) in glacial acetic acid (100 ml) The mixture was placed in a Parr bottle. The mixture was shaken at room temperature for 3 hours under hydrogen atmosphere (45 psi). The mixture was filtered through crushed earth, and the filtrate was concentrated in vacuo to give 5.00 g (98%) of the bite as a pale yellow oil: 1 H NMR (400 MHz, CDC13) 5 7.15-7.05, 6.89, 6.80, 4.23 , 2.84, 2.08-2.02. In a stirred solution of acetamidine chloride (4.78 ml, 67.1 mmol) in anhydrous CH2C12 (20 ml) in a -10 ° C bath, Add trichloromine (4.76 g, 35.7 mmol) in small portions. The mixture was allowed to fall for 15 minutes until the solution became homogeneous. This solution was added via a cannula to individual solutions of bites (4,79 g, 35.7 mmol) in CH2C12 (30 ml), all at -UTC. After adding the redundancy, this dropping liquid is good at -10 C; drop for 30 minutes. The solution was poured onto a mixture of crushed ice and concentrated HC1. The mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The remaining residue was purified by crystallizing from itself to obtain -126- 200300673 (121) Description of the invention, 4.0 g (64 /) 1- (3,4-a mouse-2Η-associated-6-yl) B continued Alas, as a white solid. 1 η NMR (400 MHz, CDC13) (5 7.76-7.73, 6.75, 4.27, 2.86, 2.57, 2.09-2.03. 1- (3,4-dihydro-2H-pinene-6-yl) ethanone ( 3.80 g, 22.0 mmol) and sodium hypochlorite [150 ml of 6.0% aqueous solution (Clorox brand bleach)], stirred in a 55 C oil bath for 2 hours. Allow the mixture (currently homogeneous) to cool to At room temperature, and solid sodium bisulfite was added until clear color persisted. HC1 (approximately 15 ml of 6.0 M aqueous solution) was added, followed by extraction with EtOAc. The organic layer was washed with brine, dried (MgS04), filtered and under vacuum. And concentrated to obtain 3.10 g (82%) of bitan-6-edge acid as a white solid. 1HNMR (400MHz, DMSO-d6) 5 12 · 55, 7.67, 7.6, 6.79, 4.20, 2.77, 1.96-1.90. Example I4 was obtained in the manner discussed in Example 1, with insignificant changes, using coupling procedures, and salt production. This free-state base was obtained in 93% yield as a white solid. MS ( ESI) m / e 287 [M + Η]. The salt of Example 14 was obtained in 75% yield as a white solid. 1 HNMR (400 MHz, MeOD-d4) δ 7.63-7.60, 6.80, 6.70, 4.46-4.40, 4.23, 3.85-3.79, 3.50-3.32, 3.30-3.23, 2.85, 2.37-2.34, 2.27-2.19, 2.12-2.05, 2.05-1.99, 1.98-1.89. Example 15: N-[(3R) -1- 口 丫 双环 合[2.2.2] Oct-3-yl] Hepta-7-carboxamidine · Fumarate:

In 4-methyl brewyl-3- # 垔 phenylbenzenesulfonic acid 旨 @ 旨 [Ref: Harayama, Chem · Pharm · Bull · 1994, 2170] (0.8 g, 4.1 mmol) and anhydrous K2C03 ( 1.1 grams, 8.0 millimoles) -127- 200300673 (122) Description of the invention Continuation sheet In a stirred solution of propylene chloride (12 liters), 3-bromopropionamine (0.7 ml, 8.1 mol) was added. ear). The mixture was heated in a 48 ° C oil bath for 2 hours. The reaction mixture was cooled to mains and filtered. The mother liquor was concentrated in vacuo to a brown oil. The crude product was purified by flash chromatography on SiO2. Dissolve in hexane_EtOAc (85:15) to obtain 0.85 g (49%) of methyl 3- (fluorenyloxy) benzylbenzoate as a transparent solid: iHNMRGOOMHiCDCiy 5 10.6, 7.9, 7.7, 6.1, 5.5, 5.4, 4.8, 4.0. Sodium hydride [220 mg (60% oil dispersion), 5.4 mmoles] was washed with pentane (3χ), and at 0 C. Ice bath, suspended in THF (12 mL). Methyltriphenylbromide scale (1.7 g ' 4.7 mmol) was added. This suspension was allowed to warm to room temperature and stirred for 30 minutes. A solution of methyl 3- (allyloxy) -4-methylfluorenylbenzoate (0.85 g, 3.8 mmol) in THF (5 ml) was added via a cannula. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc and the bars were washed with brine. The organic layer was dried over MgS04, filtered and concentrated in vacuo to a yellow residue. The crude product was triturated with hexane, filtered, and dried in vacuo to a clear oil, which was methyl 3- (allyloxy) -4-ethynylbenzoate (680 mg, 81%): 1 H NMR (400 MHz, CDC13) 5 7 · 65-7 · 54, 7.13, 6.13, 5.88, 5.49-5.29, 4.65, 3.93. For methyl 3- (allyloxy) -4-acetamidobenzoate (0 : 67 grams, 3.1 millimoles) in a stirred solution of CH2C12 (20 ml), at room temperature, benzylbis (tricyclohexylphosphine) dichlororuthenium (63 mg, 0.076 mmol) Moore). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to a dark residue. The crude product was purified by flash chromatography on SiO2. Dissolve with hexane-EtOAc (95: 5) to obtain 372 mg (64%) of 2H-pinene-7-carboxylic acid methyl ester as a transparent oil: iHNMRWOOMHACDCb) 5 7 · 56, 7.46, 7.01, 6. · 46, 5.91, 4.89, -128- 200300673 (123) Description of the invention, continued page 3.91.

A mixture of methyl 2H-nortenyl carboxylate (372 mg, 1.96 mmol) and 10% pd / c (25 mg) in methanol (15 ml) was stirred under 1 atmosphere of hydrogen at room temperature. 3 hours. The mixture was filtered through celite and the mash was concentrated to a yellow residue. The crude product was purified by flash chromatography on Si02. Dissolve in hexane-EtOAc (95 ·· 5) to obtain 140 mg (37%) of methyl-7-carboxylate as a transparent oil: iHNMRGOOMHiCDCb) 5 7.51, 7.47, 7.10, 4.23, 3.91, 2.85, 2.04. To a stirred solution of methyl-7-carboxylate (140 mg, 0.73 mmol) in MeOH (5 mL) was added NaOH (5 mL of 5% aqueous solution). The mixture was heated in an oil bath at 85 ° C for 3 hours, and then cooled to room temperature. The methanol was removed in vacuo and the remaining aqueous layer was acidified to pH = 1 with concentrated HC1 and extracted with EtOAc (3X). The combined organic layers were dried (MgS04) and concentrated to a white solid, which was ， -7-carboxylic acid (130 mg, 100%): iHNMRGOOMHiDMSOA) 5 13-12, 7.37, 7.24, 7.16, 4.16, 2.79, 1.92. Example 15 was prepared using the procedure discussed in Example 13. The free state base of Example 15 was obtained via coupling of 3 (R) -aminopyridine dihydrochloride with bite-7-carboxylic acid in 98% yield. Then, the fumarate salt of Example 15 was obtained as a white solid in 65% yield. IHNMR ^ OOMHAMeOHO 5 7.32, 7.26, 7.16, 6.70, 4.30, 4.21, 3.80, 3.42-3.19, 2.85, 2.34, 2.22 , 2.11-2.06, 2.04-1.99, 1.92. Example 16: N-[(3R) Xiakoubicyclo [2 · 2 · 2] oct-3-yl] -2H-crene, each carboxyamidamine · transbutene Diacid

-129- 200300673 (124) Description of the invention in 3-methyl 4-¾methylmethylethyl ester [see · skattebol, Acta. Chemica. ^ SCandmaviCa 1999,53,258] (1.9 g, 10.0 mmol) and anhydrous To a stirred solution of K2c03 (2.7 g ·, 19.5 mmol) in acetone (30 ml) was added > xi propyl hydrazone (1.7 ml, 19.8 mmol). The mixture was heated in a 6 (rc) oil bath for 2 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo to give 2.1 g (92%) of 4- (allyloxy) -3-methylamylbenzene Ethyl formate, as a white solid · iHNMRGOOMHz'CDCb) 5l0 · 5,8 · 5,8 · 2,7 · l, 6 · l, 5 · 5,5.4,4 · 8,4.4, l · 4 · Sodium hydride [588 mg (60% oil dispersion) '15 millimoles] was washed with pentane (3x) in THF (30 mL) at 0. O To the stirred suspension in an ice bath, methyltriphenyl bromide scale (4.6 g, 13 mmol) was added. This suspension was allowed to warm to room temperature and stirred for 30 minutes. A bath of allyloxy) methylmethylbenzoate (23 g, 9.8 mmol) in THF (100 ml) was added via a cannula. The mixture was stirred at room temperature for 2 hours. The mixture was diluted 'with EtoAc and washed with brine. The organic layer was dried over MgS04, filtered, and concentrated in true 2 to a yellow residue. The crude product was purified by flash chromatography on SiO2. Dissolve with hexane-EtoAc (95: 5) to obtain 18 g (79%) of ethyl 4- (allyloxy) -3-vinylbenzoate as a transparent oil: 1 H NMR (400 MHz) , CDC13) 5 8 · 2,7 · 9,7 · 1,6 · 9,6.1, 5 · 9,5 · 5,5 · 3,4.7,4 · 4, 1 · 4 · in 4- (association (Oxy)) Each ethyl benzoate (1.8 g, 7.7 mmol) was stirred in * CH2 0¾ (40 pens) and the solution was added at room temperature. (Monocyclohexylphosphine) ruthenium dichloride (27 mg, 5 mmol). The mixture was stirred for 2.5 hours at star temperature. The reaction mixture was concentrated in vacuo to a dark, residue. The crude product was purified by flash chromatography on SiO2. Hexane-EtOAc (95 · 5) was dropped to obtain u g (80%) of 2Η · bene · 6 · carboxylic acid ethyl ester, which was -130- 200300673.

Description of the invention

(125) Clear oil: 1 H NMR (400 MHz, CDC13) δ 7.8, 7.7, 6.8, 6.4, 5.8, 4.9, 4.4, 1A in 2Η-Bitum-6-carboxylic acid ethyl ester MeOH stirred solution (80 mL) was added NaOH (40 mL of 5% aqueous solution). Place the mixture at 60. 〇 Heat in an oil bath for 30 minutes, then cool to room temperature. The methanol was removed in vacuo, and the remaining aqueous layer was acidified to pH = 1 with concentrated HC1. Filter the solid sinks and wash with water to obtain 130 mg (13%) of 2H-H-6-carboxylic acid as a white solid: βΝΜΙΙ (400 MHz, CDC13) 5 12-11, 7.9, 7.7 , 6.8, 6.5, 5.8, 5.0. Example 16 was obtained using the coupling and salt formation procedures discussed in Example 13 with trivial changes. The free state base was obtained as a brown oil in 88% yield. Example 16 was obtained in 86% yield as a white solid: 1H NMR (400 MHz, CDC13) 5 7.7, 7.5, 6.8, 6.7, 6.5, 5.9, 4.4, 3.8, 3.5-3 · 2, 2 · 4, 2 · 3, 2 · 1, 1.9.

Example 17: _N-[(3RH-Bia bicyclo [2 · 2 · 2] oct-3-yl] -2-methyl-2H ”kemene carboxymethylamine · fumarate:

In a stirred solution of lithium bis (trimethylsilyl) amine (1.0M solution in tetrahydrofuran) (8 ml), in an acryl ice bath, add methyl bromide triphenyl rust = 92 g, 5.38 mmol Moore warmed the mixture to room temperature and stirred for a few minutes. A solution of methyl 3-formamyl-4-hydroxybenzoate (200 mg-THFA A, 丄 1 · Π penmor) in THF (3 gross liters) was added to the above solution. Place the compound in the chamber for 5 hours under π. The reaction mixture was acidified to 1N HC1 and extracted with acid (3x). The combined organic layers were washed with brine, pH ~ 5 'and dried with water (MgS04) -131-200300673

Description of the invention, MM (126) ---, filtered and concentrated to a yellow oil. The crude product was purified by chromatography on SiO2. Dissolve with hexane-EtOAc (80:20) to obtain 130 mg (66%) of 4-methyl methyl acetobenzoate as a white solid: iHNMR (400 MHz, CDaj 5 8.12, 7.86, 6.93, 6.85, 5.84, 5.50, 5.46, 3.92 · for methyl 4-hydroxy-3-vinylbenzoate (41 mg, 2.3 mmol), triphenylphosphine (787 mg, 3.0 mmol), 3- Butyl-2-ol (260 μl, 3.0 mmol) in a stirred solution in THF (15 mL) was added diethyl adicarboxylate (472 μl, 3.0 mL) Mol) in THF (5 ml). The mixture was heated to the main and stirred; left overnight. The mixture was concentrated in vacuo and the residue was purified by chromatography on SiO. Ethane_EtAc (95: 5) was dissolved to obtain 371 mg (69%) of methyl 3-fluorenyl-4-[(l-methylprop-2-enyl) oxy] benzoate, which was transparent Oil: iHNMR (400MHz, CDCl3) 5 8 · 18,7 · 89,7 · 08,6 · 90, 5.94, 5.86, 5.36-5.30, 4.93, 3.91, 1.51 · for the 3-acetic acid group- Methyl 4- [〇methylprop-2-enyl) oxy] benzoate (370 mg, 1.59 Emole) in a stirred solution of CH2% (8 ml) in Was added at a temperature benzylidene - bis (tricyclohexylphosphine) dichlororuthenium (56 mg, square 〇68 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to a dark residue. The crude product was purified by flash chromatography on SiO2. Dissolve in hexane-EtOAc (95: 5) to obtain 225 mg (69%) of methyl 2-methyl-2H-bene-6-carboxylate as a clear oil: 1 η NMR (400 MHz, CDC13) δ 7.82, 7.68, 6.79, 6.41, 5.71, 5.11, 3,89, 1.48, methyl 2-methyl-2,2-pinene carboxylate (225 mg, U〇mmol) in MeOH ( To the stirred solution in 5 ml), NaOH (5 ml of a 5% aqueous solution) was added. The mixture was heated in a 60 C oil bath for 40 minutes and then cooled to room temperature. At -132- 200300673

DESCRIPTION OF THE INVENTION MM ㈣ -—- Remove methanol in vacuum and acidify the remaining aqueous layer to pH = 5 with IN HC1. This solution was extracted with EtOAc (2X), washed with brine, dried (MgS04), and concentrated in vacuo to give 209 mg (100%) of each 2-methyl-2H-pinene carboxylic acid as Yellow oil: iHNMR (400 MHz, DMS0-d6) 5 13-12, 7.68, 7.65, 6.80, 6.53, 5.85, 5.10, 1.37.

Example 17 was obtained using the coupling and salt formation procedures discussed in Example 13 with trivial changes. The free base was obtained in 25% yield as a white foam. Example Π was obtained in 71% yield as a white solid NMR (400 MHz, MeOH-d4) δ 7.66, 7.55, 6.81, 6.70, 6.48, 5.83, 4.40, 3.81, 3.45-3.20, 2.35, 2.23, 2.11 -2.06, 1.92, 1.44. Chamber Example 18 ······················ Benzo [2,3-c] pyridine-6-adrenaline • fumarate:

2-Chloro-3 ^ pyridinol (20.0 g, 0.154 mol) and NaHC03 (19.5 g, 0.232 mol, 1.5 equivalents) were dissolved in 150 ml of water. The reaction mixture was placed in an oil bath at 90 ° C, and after 5 minutes, it was treated with a 37% aqueous formaldehyde solution (40.5 ml, 0.541 mol, 3.5 equivalents), which was added in six unequal doses; the first was 12 ml, 3 X 8 ml, followed by 1 X 2.2 ml, all at 90 minute intervals, and kept at 90 ° C overnight (15 hours), and finally added 2.3 ml. After stirring for an additional 4 hours in a 90 ° C bath, the flask was placed in an ice bath, and the contents were treated with 100 ml of crushed ice and acidified to 39 with 6 ml of 6 N HC1, 133- 200300673 / Description of the Invention I Selling page (128) _ and stirring the precipitated material in an ice bath for 1.5 hours. Unwanted solids were removed by filtration, and the filtrate was extracted seven times with EtOAc. The combined organic extracts were concentrated under reduced pressure, treated with toluene, and reconcentrated on a rotary evaporator to make most of the water azeotropic, suspended in CH2C12, and concentrated again under reduced pressure to obtain 19.9 g (81%) of 2-chloro-6- (methyl) -3-pyridinol is a pale yellow solid, pure enough for subsequent reactions. For C6H6ClN02i MS: m / z: 159 (M) +. In a flask, combine 2-chloro-6- (hydroxymethyl) -3-pyridinol (1L6 g, 72.7 mmol) with NaHC03 (18.3 g , 218 mmol) in 200 ml of water. The mixture was stirred until homogeneous, cooled in an ice bath, treated with iodine (19.4 g, 76.3 mmol), and stirred at room temperature for 60 hours when the cooling bath was terminated. The pH of the mixture was adjusted to 3 with 2N NaHS04, and the mixture was extracted with 4 X 50 mL of EtOAc. The combined organic layers were dried (MgSO.sub.4) and concentrated in vacuo to a yellow solid. The crude solid was washed with EtOAc to provide 12.9 g (62%) of 2-muryl-6- (¾methyl) -4-transyl-3-r-pyridanol 'as an off-white solid. The filtrate was concentrated to a small volume and chromatographed on 250 g of SiO 2 (230-400 mesh) and dissolved with EtOAc / CH 2 Cl 2 / hexane / acetic acid 2.5 ·· 4.5: 4 ·· 0.1. The appropriate fractions were combined and concentrated to give another 2.4 g (12%) of pure 2-chloro-6- (methyl) · 4-iodopyridinol. MSm / z for C6H5C1N02 · 285 (M) + · Under nitrogen, the ratio of 2-chloro-6- (light methyl) -4-mothyl ρ to 3-ol (5 · 7 g, 20亳 mol) and bis (triphenylphosphine) palladium dichloride (1.12 g, 1.6 mmol) were combined in 50 亳 DMF. The mixture was treated with tetraethyltin and warmed to 60. 〇 Over 6 hours, followed by 18 hours at 50 ° C, and 72 hours at room temperature. The mixture was diluted with 250 ml of EtOAc, and extracted with 4 X 100 ml of 2: 1: 1 water / saturated NaC1-134- 200300673 (129) Description of the invention continued on page / $ and NaHC03. The organic layer was dried, dried, and concentrated in vacuo to a yellow oil. The crude material was chromatographed on 200 g of SiO 2 (23 (m OO net L at 37 ° EtAC / hexane). The appropriate fractions were combined and concentrated to give 1.45 g (39%). 2-Chloro-methyl acetofluorenyl) methyl vinylpyridine, as a pale color solid. MS (EI) m / z for C8H8C1N02: 185 (M) +. In a dry flask under nitrogen, make 2 _Chloroquinone methyl) _4_Ethylpyridin-3-ol (1.35. G, 7.8 mol) is dissolved in 12 ml of DMF. This yellow solution was treated with 60% hydrogenated steel (312 mg, 78 mmol), stirred for 30 minutes' and treated with 3-bromopropene (744 µl, 8.6 mmol). The reaction was stirred at room temperature for 6 hours 'diluted with 50 ml leg c and washed with "25 ml 2: 1: 1 water / saturated NaCl / saturated NaHC0. The organic layer was dried (MgS〇4)' It was concentrated in vacuo to a yellow oil. The crude material was chromatographed on Skogel 102 (230-400 mesh) and dissolved at 30% EtoAc / hexane. The appropriate fractions were combined and concentrated to obtain h43 g (81%) of [5_ (fluorenylpropoxy) each chlorobenzylvinylpyridin-2-yl] fluorenol as a white solid. MS (El) mJz to CiiHi2CiNO2: 225 (M) +. Adding > (fluorenyloxy) -6-chloro-4-vinylpyridinyl] methanol (225 mg, 10 mmol) to bis (dicyclohexylphosphine) benzylidene monochloride Ruthenium (Ιν) (16.5 mg, 0.02 mmol) was combined in 5 ml of CH2%, and the reaction was stirred at room temperature for 4 hours. The volatiles were removed in Shingen and the The residue was chromatographed on SiO2 (230-400 mesh) and dissolved in 40% EtoAc / hexane. The appropriate fractions were combined and concentrated to give 175 mg (89%) (8 • chloro Benzyl-2H-pyrano [2,3-cKpyridin-6-yl) methanol, as a tan solid. ^ Η8αΝ〇2 < Hall (India ▲: 197 (M) +. -135- 200300673 (130) Description of the invention f sales page in a 250 ml Parr shaker bottle, the (8_chloro group_2 [2,3_Kobito-6-yl) methanol (988 g of '5.0 mmol) and 100 mg of 10% pd / c were combined in a 25% solution containing 3¾ liters (6 mmol) of 2N NaOH in water. Ml of EtOH. The reaction was hydrogenated at 50 pS1 for 48 hours, the catalyst was removed by filtration, and the filtrate was concentrated to dry wine. The mixture was made up in 1 x 10 ml of n 1 saturated NaC1 / concentrated NH4 0 h φ and 4 x 10 Separate the solution between CH 2 and CH 2 and dehydrate and dry the combined organic layers (K: 2 CO 3). The mixture was concentrated in vacuo to obtain 730 mg (89%) of 3,4-dihydro- 2H · piperano [2,3-c] pyridine-6-ylmethanol, as an off-white solid. HRMS (FAB) calculated for C9HnNO2 + H: ι660868, found 166〇868 (M + H). Under nitrogen and -78 ° C, dissolve chloramphenicol (452 μl, 5.1 mmol) in 15 ml of CH2 C2. This solution was mixed with 5 ml of DMSO (729 μl in CH2 Cl2) (10.3 millimoles) was treated dropwise, and the mixture was stirred at -78 ° C for 30 minutes. Bell. 3,4-Dihydro-2H-piperano [2,3-c] pyridine-6-ylmethanol (731 mg, 4.4 mmol φ ear) was added dropwise to the reaction mixture in 5 ml of CH2a2 And the reaction was stirred at -78 ° C for 30 minutes. The mixture was treated with τEA (308 ml, 221 mmol), stirred at -78 ° C for 30 minutes, and at 0 ° c for 2 hours. The mixture was washed with 1 X 10 mL of saturated NaHC03, dried (k2C03), and concentrated in vacuo. The crude intermediate was chromatographed on 25 g of SiO 2 (230-400 mesh) and isolated with 35% EtOAc / hexane. The appropriate fractions were combined and concentrated to give 685 mg (95%) as an off-white solid. Combine this aldehyde (685 mg '4.2 mmol) with NaciO2 (80%, 1.42 g, 12.6 mmol) and KHdO4 in 15 ml DHF / 7 ml t-Bu0H / 7 ml water, and The reaction was stirred under a stream of nitrogen overnight. The reaction was concentrated in vacuo -136-200300673 Description of the invention (131)-Shrinked to dryness and the residue was dissolved in 10 ml of water. The pH of the mixture was adjusted to 5 with 12 N HC1. The white solid was collected, washed with water, and dried under vacuum at 50 ° C to obtain 565 mg (82%) of 3,4-dihydro-2H-piranofluoride. [2,3-c] pyridine-6-carboxylic acid as a white solid. Calculated HRMS (FAB) for C9H9N03 + H: 180.0661, found 180.0652 (M + H) +. Example 18 was obtained using the coupling and salt formation procedures discussed in Example 13 and performing insignificant changes. The free base was obtained in 99% yield as a white foam. Example 18 was obtained in 80% yield as a white solid: 1 H NMR (400 MHz, MeOH-d4) (5 8.1, 7.8, 6.7, 4.5, 4.3, 3.8, 3.5-3.3, 2.9, 2.4-1.9 Materials and methods for measuring the activity of α7 nAChR activator to measure the ECS r > of a7 nAChR activator and the construction and performance of the detection receptor based on the micromoon package: it will make N- from human a7 nAChR The cDNA encoded by the 201 amino acid at the terminal end (containing the ligand binding functional site of the ion channel) is fused to the cDNA encoding the pore-forming region of the mouse 5HT3 receptor, such as Eisele JL et al., Chimeric nicotinic acid-5 -Serotonergic receptor binding to different ligand binding and channel specificity, as described in Nature (1993), December 2; 366 (6454) · 479-83, and modified by Groppi et al., WO 00/73431. The chimeric α7-5ΗΤ3 ion channel was inserted into pGS175 and pGS179, each of which contained resistance genes to G-418 and hygromycin B. The two plasmids were transferred to SH-EP1 cells at the same time and selected for G- 418 Cell line resistant to hygromycin B. Cell line expressing this chimeric ion channel is formed by binding on its cell surface The ability to combine fluorescent alpha-cobra toxin was confirmed. Cells with the highest fluorescent alpha-cobra toxin binding capacity were isolated using a fluorescence activated cell picker (FACS). Stably expressed chimeric α7- -137- 200300673 Invention Description Continued (132)-

The 5HT3 cell line is supplemented with 10% bovine fetal serum, L-glutamine, 100 units / ml penicillin / streptomycin, 250 nanograms / mg mycotoxine by making the cells contain non-essential amino acids. flmgizone), 400 μg / ml hygromycin B and 400 μg / ml G-418 in the minimum necessary medium at 37 ° C, using 6% C02 in a standard mammalian cell culture incubator, under continuous culture, After at least 4 weeks of growth, fluorescence alpha-cobra toxin binding was measured and confirmed. Detection of chimeric α7-5ΗΤ3 receptor activity is to detect the activity of the α7-5ΗΤ3 ion channel. Cells expressing this channel are covered in each well of 96 or 384 wells (Coming # 3614) and grown before detection. To confluence. On the day of testing, cells were filled with a 1: 1 mixture of 2 mM Calcium Green 1, AM (Molecular Detector Corporation) and 20% Pluranic F-127 (Molecular Detector Corporation) dissolved in anhydrous DMSO. This solution was directly added to the growth medium of each well to a final concentration of 2 #M. The cells were incubated with the dye for 60 minutes at 37 ° C and washed with denatured Earle's balanced salt solution (MMEBSS), as described in WO 00/73431. Adjust the MMEBSS ion state as described in WO 00/73431 to maximize the flux of calcium ions through the chimeric α7-5ΗΤ3 ion channel. The activity of the compound on the chimeric α7-5ΗΤ3 ion channel was analyzed on FLIPR. Using 500 milliwatts of power, this instrument was set to an excitation wavelength of 488 nanometers. With an appropriate F-stop, measure fluorescence emission above 525 nm to maintain the highest signal-to-noise ratio. The activator activity of each compound is obtained by directly adding the compound to the cells expressing the chimeric α7-5ΗΤ3 ion channel, and measuring the increase in intracellular calcium (which is due to the activator of the chimeric ion channel). Induced activation -138- 200300673 Description of invention 11 Stomach (133) --- Caused by measurement). This test was quantitative so that the concentration-dependent increase in intracellular # 5 was measured by the concentration-dependent change in Calcium Green fluorescence. The effective concentration required for the compound to cause a maximum 50% increase in intracellular calcium is referred to as EC50. Examples 6 (b) and 12 are inactive; the remaining examples have EC50 values from about 100 nM to about 10,120 nM.

Binding constant: Another way to measure the activity of a7 nAChR activator is to determine the binding constant of the potential activator in the competitive binding assay. For the a7 nAChR activator, there is a good correlation between the functional EC50 value of the chimeric α7-5ΗΤ3 ion channel as the drug target and the binding affinity of the compound for the endogenous a7 nAChR. Cell membrane preparation Sacrifice male Sprague-Dawley rats (300-350 g) by decapitation, and quickly dissect the brain (whole brain minus cerebellum), weigh, and at 9 vol / Gram wet weight of ice-cooled 0.32 M sucrose was homogenized using a rotary pestle at a setting of 50 (10 up and down strokes). Centrifuge the homogenate at 1,000 X g for 10 minutes at 4 ° C. The supernatant was collected and centrifuged at 20,000 x g for 20 minutes at 4 ° C. The formed pellets were resuspended to a protein concentration of 1-8 mg / ml. Freeze 5 ml homogenate at -80 ° C until detection is required. On the day of the test, the thawing was thawed at room temperature and diluted with Kreb's 20 mM Hepes buffer pH 7.0 (at room temperature), which contained 4.16 mM NaHC03, 0.44 mM KH2 P04, 127 mM NaCl 5.36 mM KC1, 1.26 mM CaCl2 and 0.98 mM MgCl2, so add 25-150 micrograms of protein per tube. Proteins were measured by the Bradford method (Bradford, M.M., Anal. Biochem., 72, 248-254, 1976), using bovine -139-200300673 Description of the Invention ϋM (134)-serum albumin as a standard. Binding detection

For saturation studies, 0.4 ml of hook slurry was added to test tubes containing buffers and radioligands of different concentrations, and incubated in a final volume of 0.5 ml for 1 hour at 25 ° C. Non-specific binding was added in the presence of 0.05 ml of MLA, before the radioligand was added to a final concentration of 1 // M, and determined in parallel cultured tissues. In competition studies, drugs were added to test tubes to increase the concentration before adding 0.05 ml [3 H] -MLA to a final concentration of 3.0 to 4.0 nM. The culture was terminated by rapid vacuum filtration through a Whatman GF / B glass filter paper loaded on a 48-well Brandel cell harvester. The filter was previously immersed in 50 mM Tris-HCl pH 7.0-0.05% polyethyleneimine. The filters were quickly washed twice in 5 ml portions of cold 0.9% saline, and radioactivity was counted by liquid scintillation spectrometry. Data Analysis In the competition binding study, the inhibition constant (Ki) is calculated from the concentration-dependent inhibition of [3H] -MLA binding, which is derived from the non-linear regression anastomosis procedure and performed according to the Cheng-Prusoff equation (Cheng, YC and Prussoff , WH ·, Biochem. Pharmacol, 22, pp. 3099-3108, 1973). Hill coefficients were obtained using non-linear regression (GraphPad Prism S-shaped dose response with variable slope). -140-

Claims (1)

200300673 Patent application scope ι · A compound of formula i: R type Where the acridine bicyclic ring is: X is 0 or S; W is CH or N; Y is 0, CRY or C (Ry) 2, provided that when Y is CRY, one R6 is a bond to CRY, and further conditions are Y or Z At least one is 0; each RY is independently fluorene, F, Br, Cl, CN, alkyl, haloalkyl, substituted alkyl, alkynyl, cycloalkyl, -Oh i or -Nd 丨) 2, The condition is that when Y is C (RY) 2, and the further condition is that when one RY is F, Br, Cl, CN, -ORi i or -N (Ri i) 2, the other RY is Η; Z is 〇, CRZ or C (Rz) 2, the condition is that when Z is CRZ, one R4 is a bond to CRZ, and the further condition is that at least one of Y or Z is 0; When not in use, please note and use the continuation page) 200300673 Patent application scope continuation page Each RZ is independently Η, F, βΓ, 〇, CN, environment group, haloyl, substituted alkyl, alkynyl, Cycloalkyl, _01111, or MU], the condition is that when Z is C (RZ) 2, and the further condition is that when f, so, α 'CN, -ORn, or collar i) 2, the other Rz is η; R0 is fluorene, lower alkyl, substituted lower alkyl, or lower alkyl &Amp; is independently fluorene, alkyl, cycloalkyl, halogenated alkyl or aryl; each R2 is independently F, Cl, Br small alkyl, halogenated alkyl, substituted alkyl, naphthenic Group, aryl group, or & does not exist, provided that h, 1¾, IC5 or k6 is 0, R2-3 is fluorene, F, Cl, Br, [, alkyl, halogenated alkyl, substituted Group, cycloalkyl or aryl; lq is 0 or 1; k2 is 0 or 1; k5 and k6 are independently 0, 1 or 2; & is fluorene, alkyl, alkenyl, alkynyl, cycloalkyl , Heterocycloalkyl, halo 'halogenated oligosyl, alkynyl, halocycloalkyl, halocycloalkyl, substituted alkyl, substituted fluorenyl, substituted alkynyl, Substituted cycloalkyl, substituted heterocycloalkyl, aryl, heart,%, -〇R8, -OR15, -SR8, -SR17, F, C1, Br, J, Vision, _NRsR ", Vision 16r16 , -C (0) R8, -CN, -C (0) NR8R8, -NR8C (〇) R8, -s (o) r8, -7, -0S (0) 2 r8, -nr8 s (o) 2 r8, -N02 or -n (h) c (o) n (h) r8; each R4 is independently H, alkyl, substituted alkyl'haloalkyl, cycloalkyl, heterocycloalkyl, or To the bond of Z, With the proviso that Z is CRZ; vu〇 / 3 Scope of patent application continued page Heterocyclic ring, alkyl, substituted alkyl, cycloalkyl, halogenated alkyl, theaminyl, substituted heterocycloalkyl, substituted phenyl, or substituted each Still above ρ cyclic cyclic glycan '^ is Η, alkyl, substituted alkyl, halogenated alkyl, eryl, hetero ρ ρ, 迚, coating group' or the bond of Υ, provided that Υ is CRY; Although the member is an aromatic monocyclic partial group, it contains 1-3 in the ring and is selected from the group including -N (R14)-, -〇-, and -S-, and has 0-1 selected from Ri8 'and It further has 0 to 3 substituents, and independent Br or 1 'or R7 is a 9-membered fused ring moiety, which has been fused to a 5-membered ring, including the following formula: trans 7 is 5, heterogeneous Is selected from the following: Wherein GA, q, ^ (Ri8) or N 'and each G2 # G3 is independently selected from C (Ri8) 2, C (Ri8) N and N (Rl8), provided that g2 and g3 are not both. It is not S at the same time or 0 and s, or CQ, where G is qRi8) or N, and each g2 and g3 are independently selected from CXh8) 2, C (Ri8) N and N (R14), each 9-membered fused ring moiety has 0-1 substituents, selected from Ri 8, and further has 0-3 substituents, independently selected from F, Cl, Br or I, in which part of the R7 group is connected to other substituents as defined in formula I, and at any position on any ring when the valence bond allows; each R8 is independently fluorene, alkyl, halogenated alkyl, via Substituted alkyl, cycloalkyl, functionalized cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R7, R9, phenyl, or having 1 substituent is selected from R20 and further has 0-3 substituents independently selected from phenyl groups of F, C1, Bi * or I, or substituted phenyl groups; R9 is a 6-membered heteroaromatic monocyclic ring Part of the group, containing 1-3 heteroatoms in the ring, selected from = N- and has 0-1 substituents, selected from R20, and 0-3 substituents, independently selected from F, C1, BΓ or I, or R9 is a 10-membered heteroaromatic bicyclic moiety Group, containing 1-3 heteroatoms in one or two rings, selected from = N-, including but not limited to quinolinyl or isoquinolinyl, each 10-membered fused ring moiety group, having 0-1 substituents, selected from Ri 8, and 0-3 substituents, independently selected from F, C1 ′ Βι * or I, and having a point of attachment at any position on R9 where valence bonding allows; each Ri 〇 is independently fluorene, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with one substituent selected from Ri 3, cycloalkyl substituted with one substituent selected from Ri 3, Heterocycloalkyl, haloalkyl, halocycloalkyl, halocycloalkyl, phenyl, or substituted phenyl substituted with 1 substituent selected from R! 3; each Ri 丨 is independently Hydrazone, alkyl, cycloalkyl, heterocycloalkyl, halogenated 200 300 673 Alkyl, halogenated cycloalkyl, or _heterocycloalkyl; Ri 2 is -ORu, -SRn, alkyl, cyclopentyl, heteroalkyl, haloalkyl, dendritic cycloalkyl, commercial heterocyclic Cycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, Ri1, 々)% i, -N〇2, ((Ο 魏 " Rii, -CN , Depending on nC (0) Rll… S (〇) 2NRnRn or -nr " s (o) 2ru; Rn is -〇RU, -SR ", -NRuRll, _c (0) Rll, {(0) NRnRu,-CN, -cf3, -N〇2, _NRllC (0) R " ... s (0) 2nRiiR ", -NRiiS ^ Rll, or phenyl, optionally substituted by up to 3 halo atoms' and further optionally substituted by a substituent selected from r12; RM is independently Η, Alkyl, haloalkyl, substituted tiger, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl or substituted heterocycloalkyl; & 5 is fluorene, alkylated, substituted alkyl, sulfanyl, self-cycloalkyl, substituted cycloalkyl, heterocycloalkyl, cycloalkyl, substituted Cycloalkyl, R7,%, phenyl or substituted naphthyl; each Ri6 is independently alkyl, functional alkyl, substituted tertiary, tetradentyl, trihalide, substituted ring Alkyl, hetero-environment, heterocycloalkyl, substituted cycloalkyl, alkenyl,%, phenyl, etc. 1. Halogenate a substituent selected from R2O and further. Step 1 has 0-3 independently selected or have a: Br or I substituents; 2. From F, C1 each R17 is H, Alkyl, substituted cycloalkyl, substituted cycloalkyl, substituted cycloalkyl, heterocyclic fluorenyl 3, cycloalkyl, substituted heterocycloalkyl, oxo or r9; 200300673 Patent Application Range $ Sale Page Each Ri 8 is independently fluorene, F, Cl, Br, I, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, or Substituted cycloalkyl, substituted heterocycloalkyl, -CN, -N〇2, -ORi 1, -SRi 1, -NRj 1 Rj 1, _C (0) Ri 1, _C (0) NRi 1 Ri 1. -NRnCCCORn, -SCOhNRuRn, -NRnS (0) 2Rn, or a bond directly or indirectly connected to the core molecule, provided that there is only one bond of the pair of core molecules in the 9-membered fused ring moiety Within the group, the further condition is that where the valence bond allows, the fused ring moiety has 0-1 substituents selected from alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, Halogenated heterocyclic alkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, -ORi i, -SRn, -NRi 丨 丨, -C (〇) Rn, -N〇2 , -CCCONRnRn, -CN,! QO)! ^!, -S (〇) 2 i R! I or -NRj! S (0) 2Ru, and further provided that the fused ring moiety has 0-3 Substituent, selected from F, Cl, Br or I; R2O is alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, functional Cycloalkyl, halogenated heterocycloalkyl, -〇Rn, -SR! 1, -NRi iii, -C ^ NRuRn ^ -CN > -NRnC ^ Rn ^ -S (0) 2 ^^-NRnS (0) 2Rn, -N02, substituted by 1-4 alkyl groups independently selected from F, Cl, BΓ, I or R13, substituted by 1-4 alkyl groups independently selected from F, Cl, Br, I or R 3 Substituted cycloalkyl, or a heterocycloalkyl substituted with 1-4 substituents independently selected from F, Cl, Br, I, or &3; or a pharmaceutical composition, a pharmaceutically acceptable salt thereof, Racemic mixtures or pure palmar isomers. 2. The compound according to item 1 of the scope of patent application, wherein X is 0. 200300673 Continuation of the scope of patent application 3. The compound according to item 2 of the scope of patent application, whose center is fluorene, alkyl or cycloalkyl. 4. The compound according to item 3 of the scope of patent application, wherein r3 is η, a lower alkyl group, a lower carbon substituted alkyl group, a cycloalkyl group, a heterocycloalkyl group, a lower carbon substituted block group, a substituted Heterocycloalkyl, -〇R8, -ORi 5, -SR8, -SRi 7 -CN, -C (0) NR8R8, -nr8c (o) r8, -S (0) R8, -S (〇) R17, -〇S (0) 2R8, -NR8S (0) 2R84-N (H ) C (0) N (H) R8, where R8 is H, lower alkyl, lower alkyl, lower alkyl substituted, cycloalkyl, functional cycloalkyl, substituted ring Alkyl, heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl; its center 5 and Ri 7 are independently fluorene, lower alkyl, lower alkyl halo, lower substituted Alkyl, cycloalkyl, i-cycloalkyl, substituted alkyl, heterocycloalkyl, halocycloalkyl, or substituted heterocycloalkyl; and wherein R1 6 is a lower alkyl Group, low-carbon halogenated alkyl, low-substituted k-group, cycloalkyl, functionalized cycloalkyl, substituted cycloalkyl, heterocyclic alkyl, or substituted heterocyclic alkyl . 5. The compound according to item 4 of the scope of patent application, wherein the azine ring is I. 6. The compound according to item 5 of the scope of patent application, wherein R2 is a lower alkyl group, a lower alkyl group, a lower alkyl group, or does not exist, and the conditions are: 7. The compound according to item 6 of the scope of patent application, where Y is 0, and Z is 200300673. The scope of patent application is $ 8. 8. The compound according to the scope of patent application, wherein at least one R4 and at least one R6 are each Η, and the other R4 and R6 are each independently Η, alkyl, substituted alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, wherein each Ri 〇 is independently Η, low-carbon Alkyl, lower alkyl, cycloalkyl, heterocycloalkyl, or lower alkyl substituted with a substituent selected from Ri3. 9. The compound according to item 8 of the scope of patent application, wherein w is CH. 10. The compound according to item 9 of the scope of patent application, wherein the compound is: N-((3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl) -2,3-dihydro-1 , 4-benzodioxolane-6-isoamylamine; N-[(2S, 3R) -2-methyl-1-acylbicyclo [2 · 2 · 2] oct-3-yl]- 2,3-dihydro-1,4-benzodioxolene-6 rimoxamine; N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl]- 2-ethyl-2,3_dihydro], 4-benzodioxolene-7-carboxamide; 2 (R) -N-[(3R) -W bicyclic benzo [2 · 2 · 2 ] Oct-3-yl] -2-[(Usyloxy) methyl] · 2,3 · Dihydro-1,4-benzodioxolane-6-carboxamide; 2 (S)- N-[(3R) -W Bicyclo [2.2 · 2] oct-3-yl] -2-[(Usyloxy) methyl] · 23-dihydro-1,4-benzodioxolane -6-Chloramine; N-[(3R) Small acryl bicyclo [2.2.2] oct-3-yl] each [(benzyloxy) methyl > 2,3 • diaza 4,4 benzo Dioxolan ** 6-chitosamine; (3S) Zan [(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] each [(benzyloxy) methyl R3 Diazepine-1,4-epi-dilactone-co--6-tetra- 8¾amine; bicyclo [2.2.2] oct-3-yl] -3-[(sheepoxy) methyl] _2,3_ Dihydro 200300673 Scope of Patent Application Continued Lupin-6-carboxamidine; N-1-[(3RH4 bicyclic benzo [2.2.2] octyl-3.yl] · 3tramethyl> > 2,3-dihydro M · benzo-dioxolane Xanthen-6-Leptamine; (3S> N-[(3R) -W Bicyclo [2.2.2] octyl] · 3 · (phenoxymethyl) _2,3_dichloro1,4 -Benzodioxolum-6-carboxamide; & its pharmaceutically acceptable salt, the compound in the hydrazone is a pure para-isomer or a racemic mixture thereof. 11. According to the scope of the patent application N-[(3R) -W bicyclic benzo [2.2.2] oct-3-yl crushed methyl-2,3_dihydro · 1 / μbenzodioxolene -7-carboxyfluorenamine; (2R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] octyl] -2 · methyl-2,3 · dihydro], 4 · benzo Dioxolene-7-carboxamide; (2S) Zan [(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-methylw · dichloro • benzene Benzodioxolene-7-carboxamide; φ (2R) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-ethyl-2,3 · Diazo • Benzodioxolene-7-carboxamidine; (2S) Zan [(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-ethyl_2 , 3 · Dichloro-M • benzodioxolene-7-carboxamide; N-[(3R) Small acylbicyclo [2 2 · 2] octyl] -2-methyl_2,3_dihydrosyn 4-benzodioxolane-6-fermentamine; (2S) -N-[(3R) -1- Acrylbicyclo [2.2.2] oct-3-yl peak methyl · 2,3 · dichloro_ 丨, each carboxamide of wood benzodioxolene; (2R) -N-[(3R) small Azabicyclo [2.2.2] oct-3-yl] -2-methyl-2,3-diazabenzodioxan-6-carboxamidine; 200300673 Application for patent scope continued N-[( 3R) -1-acylbicyclo [2 · 2.2] oct-3-yl] -2-ethyl-2,3-dihydro-1, 'benzodioxol-6-carboxamide; ( 2S) -N-[(3R) Small acryl bicyclo [2.2,2] oct-3-yl] -2-ethyl-2,3-dihydro-1Λbenzodioxolane-6-carboxyfluorene Amine; (2R) xian [(3R) -1-acylbicyclo [2.2.2] octyl! Yl] -2-ethyl-2,3-dihydrobenzodioxolane-6-endepiamine; (23,33) -N-[(3ΙΙ > · 1-azinebicyclo [2 · 2 · 2] oct-3-yl] -2,3-dimethyl-2,3 · dihydro-M-benzodioxolane-6-carboxamide; (2R, 3R) -N- [ (3R) -1-Methylbicyclo [2 · 2 · 2] oct-3-yl] -2,3-dimethyl-2,3-dichloro · ι, 4 · benzodioxolene -6-Carboxamidamine; (23,3Magazine [(311) Small acryl [2.2.2] oct-3-yl] -2,3-diethyl-253, dihydro_1, xylophone Dioxolan-6-kis (S) amine; (2R, 3R) -N-[(3R) Small acryl [2.2.2] octyl] -2,3-diethyl-2,3 -Dihydro-MIL and dioxolene-6-carboxamide; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2- [[(4-fluorobenzyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S) -N-[( 3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-[[(3-fluorobenzyl) oxy] methyl] -2,3-dihydro-1,4- Benzodioxolene-6-carboxamide; (2S) -N-[(3R) small acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[[(2-fluoro Benzyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S) -N-[(3R) small acryl Cyclo [2.2.2] oct-3-yl] -2-[[(4-chlorofluorenyl) oxy] methyl]-2.3-dihydro-1,4-benzodioxolene-6 -Carboxamide; (2S) -N-[(3R) -1-lipabicyclo [2.2.2] oct-3-yl] -2-[[(4-methylmethyl) oxy] methyl ]-2.3- Dihydro-1,4-benzodioxolene-6-carboxamide; -10- 200300673 Application for a patent application Continued on page (2S) -N-[(3R > 4-Acetylcyclo [ 2.2.2] oct-3-yl] -2-[[(4-hydroxyfluorenyl) oxy] methyl > 2.3-dihydro-1,4-benzodioxolene-6-carboxyfluorene Amine; (2S) -N-[(3RH-azepine bicyclic p.2.2] oct-3-yl] dong [[(4-methoxybenzyl) oxy] methyl] -2,3-dihydro -i, 4-benzodioxolene carboxamide; (2S) -N-[(3R) -1-azinecyclo [2.2.2] oct-3-yl] -2-[[( 4-cyanofluorenyl) oxy] methyl] -2,3-dihydro-i, 4-benzodioxolene-6-carboxamide; (2R) -N-[(3R), 1-azinebicyclo [2 · 2 · 2] oct-3-yl] -2-[[(4-fluoromethylfluorenyl) oxy] methyl] _2,3-dihydro-1,4-benzo Dioxolane-6-tetraamine; (2R) -N-[(3R) small acryl bicyclo [2 · 2 · 2] oct-3-yl] -2-[[(3-fluorobenzyl )] Oxy] methyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxamidine; (2R) -N-[(3R) Small acryl bicyclo [2.2.2] Xin! Group] -2-[[(2-fluoromethylfluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R) -1-azabicyclo [2 · 2 · 2] oct-3-yl] -2-[[(4-chlorobenzyl) oxy] methyl] · 2.3-dihydro- 1,4-benzodioxolene-6- double fluorene amine; (2R) -N-[(3R) -1-azinecyclo [2.2.2] oct-3-yl] -2-[[ (4-methylfluorenyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolane-6-carboxamide; (2R) -N-[(3R) -1- Azabicyclo [2 · 2 · 2] oct-3-yl] -2-[[(4-hydroxyfluorenyl) oxy] methyl 2.3-dihydro-1,4-benzodioxolene- 6-carboxamidine; (2R) -N-[(3R)-: l · azinebicyclo [2 · 2 · 2] oct-3-yl] -2-[[(4-methoxybenzyl) Oxy] methyl] -2,3-dihydro-1,4-benzodioxolene carboxamide; (2R) -N-[(3R) -1-azabicyclo [2.2.2 ] Oct-3-yl] -2-[[(4-cyanofluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxofluorene-6-compound Amine; N-[(3R) small acylbicyclo [2.2.2] oct-3-yl] -2- (hydroxymethyl) -2,3-dihydro · 1,4-benzodioxolene Each Carboxamidamine; -11-200300673 Application for Patent Continued (2R) -N-[(3R) -1-Acridine [2.2.2] oct-3-yl]- 2- (hydroxymethyl) -2,3-dihydro-1,4, benzodioxolane-6-stilbeneamine; (2S) -N-[(3R) -1-acylbicyclo [ 2 · 2 · 2] oct-3-yl] -2- (hydroxymethyl) -2,3-dihydro-1,4, benzodioxo-6-carboxamide; (2S)- N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-[(4-fluorophenoxy) methyl], 2.3-dihydro-1,4-benzene Benzodioxolene-6-chipinamine; (2S) -N-[(3R) -K bicyclo [2 · 2 · 2] oct-3-yl] -2-[(3-fluoroylbenzene (Oxy) methyl] 2.3-dihydro-1,4-benzodioxopropan-6-amidine; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] Oct-3-yl] -2-[(2-fluorophenoxy) methyl], 2.3-dihydro-1,4-benzodioxolene-6-carboxamide; (2S ) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-chlorophenoxy) methyl] 2.3-dihydro-1, 4-benzodioxolane-6-carboxamidine; (2S) Zan [(3R) -1-acylbicyclo [2 · 2 · 2] octyl] -2-[(4-methyl Phenyloxy) methyl ^ 2.3-dihydro-1,4-benzodioxolane-6-carboxamidine; (2S) shan [(3R) small acylbicyclo [2.2.2] octane-3 -Yl] -2-[(4-hydroxyphenoxy) methyl] 2.3-dihydro-1,4-benzodioxolene-6-carboxyl Amine; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] -2-[(4-methoxyphenoxy) methyl] -2 , 3-Dihydro-1,4-benzodioxolane, each carboxyfluorenamine; (2S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] octyl]- 2-[(4-cyanophenoxy) methyl] _ 2.3-dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R)- 1-Acrylcyclo [2.2.2] octyl] -2-[(4-fluorophenoxy) methyl > 2.3-Dihydro-1,4-benzodioxolane, each carboxyfluorene Amine; (2R) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-[(3-fluorophenylphenoxy) methyl] · 2.3-dihydro -1,4-benzodioxolane-6-carboxamidine; -12-200300673 Scope of patent application continuation (2R) -N-[(3R) -1-acylbicyclo [2 · 2 · 2 ] Oct-3-yl] -2-[(2-fluorophenylphenoxy) methyl] _ 2.3-dihydro-1,4-benzodioxolane-6-carboxamide; (2R) -N-[(3R) -1-azabicyclo [2.2.2] octyl] -2-[(4-chlorophenoxy) methyl] · 2.3-dihydro-1,4-benzo Dioxolene-6-carboxamide; (2R) Zan [(3R) Small acridine [2.2.2] oct-3-yl] -2-[(4-methylphenoxy) methyl ] _ 2.3-Dihydro-1,4-benzodioxolene-6-carboxyfluorene ; (2R) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -2-[(4- || ylphenoxy) methyl] 2.3-dihydro -1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R) leaflet bis% [[2 · 2 · 2] oct-3-yl] -2- [ (4-methoxyphenoxy) methyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (2R) -N-[(3R)- l-pf bis- [2 · 2 · 2] oct-3-yl] -2-[(4_ arsylphenoxy) methyl] · 2.3-dihydro-1,4-benzodioxolane F-6-Epiridamine; (3S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] octyl] each [[(4-fluorobenzyl) oxy] methyl []]]]-Aza-1,4- + dioxolan-6-tetracycline; (3S) -N-[(3RH-acylbicyclo [2 · 2 · 2] oct-3-yl] each [[(3-Fluorofluorenyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolene-6-¾amidamine; (3S) -N-[( 3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] each [[(2-fluoromethylfluorenyl) oxy] methyl] -2,3-dihydro-1,4- Benzodioxolene carboxamides; (33) -N-[(3ΙΙ) -1-azabicyclo [2'2 · 2] oct-3-yl] chlorofluorenyl) oxy] methyl ] · 2 > Dihydro-I, 4-benzodioxolanthine carboxamide; (3S) Sian [(3RH · acylbicyclo [2 · 2.2] xin Each group] each carbamoyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxocarboxamidine each carboxyfluorenamine; (3S) -N-[(3RM-acylbicyclo Benzo [2.2.2] oct-3-yl] each [[(4-hydroxyfluorenyl) oxy] methyl] _ 2.3-dihydro-1,4-benzodioxolane carboxamidine; -13- 200300673 Scope of patent application_Stomach (3S) -N-[(3R) Small acryl bicyclo [2 · 2.2] oct-3-yl] Each [[(4-methoxybenzyl) oxy] 曱[]]-2,3-dihydro-ι, 4-benzodioxolane-6-cobalamine; (3S) -N-[(3R) -1-azabicyclo [2 · 2 · 2 ] Octyl]] [[(4-cyanobenzyl) oxy] methyl] -2,3-monofluorene-1,4-benzodioxolane-6-fluorenamine; (3R ) -N-[(3RH-azinebicyclo [2 · 2 · 2] oct-3-yl] each [[(4-fluorobenzyl) oxy] methyl] -2,3-dihydro-1 , 4-Benzodioxolene Carboxamides; (3R) -N-[(3R) -1-Acridine [2 · 2 · 2] octyl]] [[(3-Fluoro Benzyl) oxy] fluorenyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxamidine; (3R) -N-[(3RH-azinebicyclo [2.2 .2] oct-3-yl] -3-[[(2-fluoromethylfluorenyl) oxy] fluorenyl] -2,3-dihydro-1,4-benzodioxolane-6- Carboxamidine; (3R) -N-[(3R) [2 · 2 · 2] oct-3-yl] -3-[[(4-chlorofluorenyl) oxy] methyl] · 2.3-dihydro-1,4-benzodioxolane-6 -Carboxamidine; (3R) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -3-[[(4-methylbenzyl) oxy] fluorenyl] · 2.3-Dihydro-1,4-benzodioxolene-6-carboxamide; (3RHsH (3R) -1-azinebicyclo [2 · 2 · 2] oct-3-yl] each [ [(4-hydroxyfluorenyl) oxy] methyl] · 2.3-diaza-1,4-epi- "Oxyluridine-6-chimonamine; (3R) -N-[(3R)- 1-azinebicyclo [2.2.2] oct-3-yl] each [[(4-methoxybenzyl) oxy] fluorenyl] -2,3-dihydro-1,4-benzodioxy Each carboxylic acid hydrazone; (3R) -N-[(3R) small acryl bicyclo [2 · 2 · 2] oct-3-yl] each [[(4-cyanofluorenyl) oxy] methyl []]-2,3-dihydro-1,4-benzodioxolane-6-quinolamine; (3R) -N-[(3R) small acylbicyclo [2.2.2] octyl- 3-yl] -3- (hydroxymethyl > 2,3-dihydro · M · benzodioxolane, each carboxypyramine; (3S) -N-[(3R) small acylbicyclo [2 · 2 · 2] oct-3-yl] each fluorenylmethyl) · 2,3 · dihydro · 丨, 4 • benzodioxolane each carbamidine; -14- 200300673 Application for Patent Continued ( 3S) -N-[(3R) -1-azabicyclo [2.2.2] ocin-3- Group] each [(4-fluorophenylphenoxy) methyl]-2.3-diaza-1,4-benzodioxolyl-6-vinylamine, (3S) -N-[(3R) -1-Acridinebicyclo [2.2.2] oct-3-yl] E each [(3-fluorophenylphenoxy) fluorenyl]-2.3-diaza-1,4-pyridodioxine-6 -S & amine, (3S) -N-[(3R) -1-acylbicyclo [2 · 2 · 2] oct-3-yl] · 3-[(2-fluorophenoxy) methyl ]-2.3-Dihydro-1,4-benzodioxolene-6 picoamine; (3S) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl ] -3-[(4-Chlorophenoxy) methyl]-2.3-diaza-1,4-Mercaptolactam-6-formamide, (3S) -N-[(3R ) -1-Acridinebicyclo [2.2.2] oct-3-yl] -3-[(4-methylphenoxy) methyl]-2.3-diaza-1,4-mercapto ^ monooxo Gardener-6-Techlinamine, (3S) -N-[(3R) Small acryl bicyclo [2.2.2] oct-3-yl] -3-[(4-hydroxyphenoxy) methyl]- 2.3- Dihydro-1,4-benzodioxolene-6-carboxamide; (3S) -N-[(3R) Small acridine [2.2,2] oct-3-yl] each [ (4-methoxyphenoxy) methyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (3S) -N-[(3R)- 1-Acridinebicyclo [2 · 2 · 2] oct-3-yl] each [(4-cyanophenoxy) methyl]-2.3- Hydrogen-1,4-benzodioxolene-6-carboxamide; (3R) -N-[(3R) small acylbicyclo [2.2.2] oct-3-yl] -3-[( 4-Fluorophenoxy) methyl]-2.3-dihydro-1,4-benzodioxolene ############### PERMETHYLAMINE; (3R) -N-[(3R) Small acryl bis [2 · 2 · 2] oct-3-yl] -3-[(3-fluorophenylphenoxy) methyl]-2.3-dihydro-1,4-benzodioxolane-6-chipinamine ; (3R) -N-[(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -3-[(2-fluorophenoxy) methyl]-2.3-diaza- 1,4-benzodioxolane-6-rejuvenated amine, (3R) -N-[(3R) -1-azinecyclo [2 · 2 · 2] oct-3-yl] -3- [(4-chlorophenoxy) methyl]-2.3-dihydro-1,4-benzodioxolene-6-carboxamide; -15- 200300673 ) Zhen [(3R) -1-acylbicyclo [2.2.2] oct-3-yl] -3-[(4-methylphenoxy) methyl] _ 2.3-dihydro-1,4-benzene Benzodioxolane-6- double acid amines; (3R) -N-[(3R) -1-azinebicyclo [2.2.2] oct-3-yl] -3-[(4-quinylbenzene (Oxy) methyl] · 2.3-dichloro-1,4-maldioxofuran-6-rejuvenated amine; (3R) -N-[(3R) -1-azabicyclo [2 · 2 · 2] Oct-3-yl] -3-[(4-methoxyphenoxy) methyl] -2,3-dihydro-1,4- Benzodioxolan-6-polyamidine; (3R) Zan [(3R) Small acryl bicyclo [2 · 2 · 2] octyl]] [(4-cyanophenoxy) methyl 2.3- Dihydro-1,4-benzodioxolane-6-chitosamine; N- (l- (2-methyl) -azinecyclo [2 · 2 · 2] oct-3-yl ) -2,3-dihydro], benzodioxinylamine-6-technolamine, N- (l- (6-methyl) -azabicyclo [2.2.2] octyl) -2 , 3-dihydro- 丨, 'benzodioxolene-6-carboxamide; or a pharmaceutically acceptable salt thereof, wherein the compound is a pure para-isomer or a racemic mixture thereof. 12. The compound according to item 8 of the scope of patent application, wherein w is N. 13. The compound according to item 12 of the scope of the patent application, wherein the compound is. N-[(3RH-acylbicyclo [2 · 2 · 2] octyl!]]-2,3-dihydro-dioxolane [2,3-c] pyridine-7-carboxamide; or a pharmaceutically acceptable salt thereof, in which the compound is a pure palmitoyl isomer < its racemic mixture. 14. According to item 12 of the scope of patent application Compound, wherein the compound is N- [l- (2S, 3R) -2-methylfluorenebicyclo [2 · 2 · 2] oct-3-ylR3 · dichloroκdioxolene [2 , 3-c] pyrimidin-7-fluorenamine; NH-P methylpyridine bicyclo [2.2.2] oct-3-yl] -2,3-dihydro 16- 200300673 The scope of the patent claims p-[[2,3-c] pyridine-7-azepine]; N- [l- (6-methyl) _azabicyclo [2 · 2 · 2] octyl ] -2,3_dihydro · 丨 dioxobenzopyridine [2,3-c >pyridine_7-carboxamide; or a pharmaceutically acceptable salt thereof, wherein the compound is pure para-isomer Or a racemic mixture thereof. 15. The compound according to item 6 of the scope of the application, wherein γ is 0, and z is CRz or C (Rz) 2, or wherein Y is CRY or C (RY) 2, and z 0. 16. According to item 15 of the scope of patent application Compounds where 2 is CRZ and R4 is = knot, or where γ is CRy and reduced to a bond, provided that only one of the heart or ^ is a bond. The compound according to item 16 of the scope of the patent application , Where w is CH. The compound according to item 17 of the scope of application for a patent, wherein the compound is: ^ 1X31 ^: ^ Ya bicyclo [2 · 2 · 2] octyl] _2H-bite · 6-carboxamide; [() 1 ρ "bicyclo [2.2.2] oct-3-yl] -2-methyl-2Η-bita-6-chizamine; or a pharmaceutically acceptable salt thereof, wherein the compound is a pure pair Palm isomers or racemic mixtures thereof. 19. The compound according to item 17 of the scope of application for a patent, wherein the compound is: M (3RM-azabicyclo [2 · 2 · 2] octyl] ice methyl ketone Each carboxamidine; [(311)] ^ "bis per benzo [2.2.2] oct-3-yl] -4-ethyl-211-17 g fu-6-rejuvenated amine; team deduction 11), 1 · Acridine bicyclo [2 · 2 · 2] oct-3-yl] -4-fluoro-2H-bene-6-carboxamide; Ne [(3R) Small acryl bicyclo [2 · 2 · 2] Octyl-3-yl] -4-chloro-2H-pinene-6-carboxyfluorenamine; N-[(3R), l · Dicyclo [2 · 2 · 2] octyl-Hongyl] i bromo · 2Ή-pinene-6-carboxamide; N-[(3R) + azepine bicyclofluorene [2.2.2] octyl-3-yl] -4- -2H-fluorene-6-carboxamide; N-[(3R), 1, acridinebicyclo [2 · 2 · 2] oct-3-yl] -4-ethynyl-2El · pinene-6 -Carboxamide; -17- 200300673 N-[(3R) Small acryl bicyclo [2.2.2] oct-3-ylfluorenyl-methyl-2H-folium carboxamidine 'N-[(3R) -1-acyl bicyclyl [2.2.2 ] Oct-3-ylfluorenyl-ethyl-2 '"keene > Carboxamide' N-[(3R) Small acryl [2 · 2 · 2] oct-3-yl] dongfluoro-2H- Pinene I Carboxylamide; N-[(3R) -1-acylbicyclo [2.2.2] octyl] -4-chloro-2Η-pinene-7-carboxamide · 'N-[( 3R) small acylbicyclo [2.2.2] oct-3-yl] -4-bromo-2H-pinene-7-carboxycarcinamide; φ N-[(3R) small acylbicyclo [2.2.2] Octyl-3-yl H-cyano-2H-fluorene-7-carboxypyramidamine; N-[(3R) Small acrylbicyclo [2.2.2] octyl] -4-ethynyl-2H-bitene Carboxamide; or a pharmaceutically acceptable salt thereof, wherein the compound is a pure para-isomer or a racemic mixture thereof. 20. The compound according to item 15 of the scope of patent application, wherein γ is 0, and Z is C (RZ) 2, or Z is 0, and γ is c (RY) 2, and at least one of R4 and at least one of R6 is Each is Η, and the other R4 and R6 are each independently Η, alkyl, substituted alkyl, functional alkyl, cycloalkyl, or heterocycloalkyl, Φ wherein each Ri 0 is independently Η , A lower alkyl group, a lower alkyl halide alkyl group, a cycloalkyl group, a heterocycloalkyl group or a lower alkyl group substituted with a substituent selected from R13. 21. The compound according to claim 20, wherein W is CH. 22. The compound according to item 21 of the scope of application for a patent, wherein the compound is: N-[(3RH-acylbicyclo [2 · 2 · 2] octyl]] Carboxamide; ΝΚ311) · 1 · Acridine bicyclic [2,2.2] Oct-3-ylfluorene-7-carboxamide; or a pharmaceutically acceptable salt thereof, wherein the compound is a pure para-isomer or a racemic mixture thereof. 23. The compound according to item 21 of the scope of patent application, wherein the compounds are: * 18- 200300673 The scope of patent application continues on N- (1- (2S, 3R) -2 · methyl ^ cyclobicyclo [2.2.2] xin Each group) gram of each compound donkey amine; N- (l- (2-methyl) -azinebicyclo [2 · 2 · 2] oct-3-yl) -fluorene-6 cyanamide; N- ( l- (6-methyl) -azinebicyclo [2 · 2 · 2] octyl)] ▲ Carboxamide; N- (l- (2S, 3R) -2-methyl-πγbicyclic [2.2.2] oct-3-yl produces g-7-benzamine; N_ (l- (2-methyl) -azinebicyclo [2.2.2] oct-3-yl) "-7-carboxy Amidine N- (l- (6-methyl) -azabicyclo [2.2.2] oct-3-yl) -fluorene-7-carboxamidine; or a pharmaceutically acceptable salt thereof, wherein the compound is pure palmar Isomers or racemic mixtures thereof. 24. The compound according to item 20 of the application, wherein w is N. 25. The compound according to item 24 of the scope of application for a patent, wherein the compound is: N-[(3R) -W bicyclic benzo [2 · 2 · 2] octyl] · 3,4dihydrokappa [2, 3_c] pyridine-6-carboxamide, wherein the compound is a pure para-isomer or a pharmaceutically acceptable salt thereof and a racemic mixture thereof. 26. The compound according to item 4 of the scope of patent application, or V 0 wherein the azine ring is Π and k 2 and k 5 are 0 or 1. _Where R2 is an alkyl group, halo, provided that 1¾ or k5 is 27. Compound according to item 26 of the scope of patent application, 28. Compound alkyl group, substituted alkyl group according to scope 27 of the patent application, or 0 029 does not exist. 0 according to the scope of patent application. 30. According to the scope of the patent application, at least one R6 is a compound of 28 items each, among which Y4Q, 29 compounds, at least one of which is & H, alkyl, substituted alkyl, halogenated alkyl, naphthenic / alkyl, P group, where each R! 0 is independently η, lower alkyl, lower carbon 70. π 4 Lower carbocycloalkyl, heterocycloalkyl or monoalkyl substituted with a substituent selected from R13. 31. The compound according to item 30 of the scope of patent application, wherein w is. 32. The compound according to item 31 of the scope of patent application, wherein the eight compounds are: • outward_4⑸N- (K bicyclo [[1] heptyl [U1] heptyl-2,3-dihydro. 6-Chloro-SS amine; N-[(3R, 5R) -1-Methylbicyclo [m] octyl! Yl] _2,3, dihydrogen to ten-juice monooxan-6-carboxamide Or a pharmaceutically acceptable salt thereof, wherein the compound is a pure para-isomer or a racemic mixture thereof. 33. The compound according to item 31 of the scope of patent application, wherein the servant t /, τ 1C * compound is ... N-[(3R, 5R) -1-acylbicyclo [3.2.1] oct-3-yl] -2-methyl-23-hepta,., Lice-1,4-benzoxyluridine, -7-chidonylamine, (2R) -N-[(3R, 5R) -1-acylbicyclo Ac [3 · 2 · 1] oct-3, yl] pyrene-methodioxol-7-carboxamidine; the radical '2,3 · dihydro-1,4-benzene (2S) -N- [(3R, 5R) -1-azabicyclo [3 · 2 · 1] octyl >2-methyldioxolene-7-carboxamidine; 2,3-dihydro-1, 4-Benzyl N-[(3R, 5R) small azine bicyclic carbonyl P.2.1] oct-3-yl] -2-ethyl_2,3, dioxolidine-7-chipinamine; qi-I , 4-benzobis (2R) -N-[(3R, 5R) small acrylbicyclo [3 · 2 · 1] octyl] -2 · acetyldioxolidine-7-carboxamide; Base, 2,3_ difluorene-1,4-benzene-20- 200300673 Scope of patent application Continued (2S) Shan [(3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] · 2- Ethyl-2,3dihydro · 丨, 4 · benzodioxolane-7-carboxamidine; N-[(3R, 5R) small acylbicyclo [3 · 2 · 1] oct-3- Phenyl] -2-methyldihydrofluorene-4 · benzodioxolene-6-chipinamine; (2S) -N-[(3R, 5R) -1-azabicyclo [3 · 2 · 1] octyl] methyl_2,3-dichloro · 14 benzodioxolan carboxypyridamine; (2R) Zan [(3R, 5R) small acridine bis [3.2.1] octyl- 3-yl] -2-fluorenyl · 2,3_digas · 14 benzodioxolidine, each carboxamidine; N-[(3R, 5R) -1-acylbicyclo [3.2.1] octyl -3-yl] -2-ethyl_2,3, dihydrobenzodioxolane-6-carboxamidine; (2S) -N-[(3R, 5R) small acylbicyclo [3 · 2 · 1] octyl] -2-ethyl-23 · one-earth- "monooxy_i, 4-benzodioxo-6-carboxamide; (2R) -N-[(3R ， 5R) small acyl bicyclic benzo · 2 · 1] octyl-3-yl] -2-ethyl-2,3 · dichloro-14 · benzodioxolidine-6-carboxamide; '( 2S, 3S) -N-[(3R, 5R) Small acryl bicyclo [3 · 2 · 1] oct-3-yl] -2,3-dimethyl_2,3-dichloro1,4-benzene Benzodioxol-6-carboxamidine; (2R, 3R) -N-[(3R, 5R) -1-azinebicyclo [3 · 2 · 1] oct-3-yl] -2,3 -Dimethyl_2,3_digas_1,4-benzodioxolene-6-carboxamide; (2S, 3S) -N-[(3R, 5R) small acylbicyclo [3 · 2 · 1] oct-3-yl] -2} diethyl j, 3-dihydro. 1,4-benzodioxolene-6-carboxamide; (2R, 3R) -N- [(3R, 5R) -1-azabicyclo [3.2.1] octyl] -2,3-diethyl -2,3_dihydro_ 1,4-benzodioxolene-6-carboxamide; (2R) shan [(3R, 5R) small acylbicyclo [3 · 2 · 1] xin-3 -Yl] -2 · (hydroxymethyl) -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; -21-200300673 Application for patent scope $ Sale page (2S) -N-[(3R, 5R) Small bicyclo [3.2.1] octyl] -2- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxolene- 6-Carboxamidamine; (2R) -N-[(3R, 5R) Small acrylbicyclo [3.2.1] oct-3-yl] -2-[(; oxy) methyl R3-dihydro-1 , 4-Benzodioxolene-6-carboxamide; (2S) -N-[(3R, 5R) Small acridine [3 · 2 · 1] oct-3-yl] -2- [ (Fluorenyloxy) methyl] -2,3-dichloro-1,4-benzodilactone hydrazine-6-chitosamine; (2R) Zan [(3R, 5R) -P-Y-Bicyclo [ 3 · 2 · 1] oct-3-yl] -2-[[(4-fluorobenzyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxolane -6-Carboxamidamine; (2S) [[3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] -2-[[(4-fluorobenzyl) oxy] methyl ] -2,3-dihydro-1,4-benzodioxorox-6-chitosamine; (2R) -N-[(3R, 5R) -1-acylbicyclo [3.2.1] Octyl-3-yl] -2-[[(4-methylamino) oxy] methyl] -2,3-dihydro-1,4-benzo Oxaloxamine-6-seamylamine; (2S) -N-[(3R, 5R) -1-acylbicyclo [3 · 2 · 1] octyl] -2-[[(4-formamidine ) Oxy] fluorenyl] -2,3-dihydro-1,4-benzodioxolan-6-carboxamidine; (2R) -N-[(3R, 5R) small acyl bicyclic [3.2 · 1] oct-3-yl] -2-[[(4-methoxyhexyl) oxy] methyl] -2,3-dihydro-1Λbenzodioxo-6- Carboxamidine; (2S) -N-[(3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] -2-[[(4-methoxybenzyl) oxy] methyl ] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (2R) -N-[(3R, 5R) -1-acylbicyclo [3.2.1] Octyl-3-yl] -2- (phenoxymethyl) · 2,3 · dihydro-1,4-benzodioxolidine-6-carboxamide; (2S) -N-[( 3R, 5R) -1-acylbicyclo [3.2.1] oct-3-yl] -2- (phenoxymethyl) · 2,3dihydro-1,4-benzodioxolidine · -6-Chloramine; (2R) Zan [(3R, 5R) Small acryl bicyclo [3.2.1] octyl] -2-[(4-fluorophenoxy) methyl] -2,3 -Dihydro-1,4-benzodioxolane-6- double acid amine; -22- 200300673 Scope of patent application Continued (2S) Shan [(3R, 5R) -1-acylbicyclo [3 · 2 · 1] oct-3-yl] -2-[(4-fluorophenoxy) methyl] -2,3-dihydro-1 , 4-Benzoyl hydrazone and each acid amine; (2R) -N-[(3R, 5R) -W bicyclo [3.2.1] oct-3-yl] -2-[(4-form Phenylphenoxy) methyl] -2,3-dihydro-1,4-benzodioxolane-6-polystrienylamine; (2S) Zhen [(3R, 5R) 3 · 2 · 1] octyl] -2-[(4-methylphenoxy) methyl] -2,3-dichloro-1,4-benzo ^ monooxylurethane-6-plex Fermented amines; (2R) Zan [(3R, 5R) -1-acylbicyclo [3.2.1] octyl] -2-[(4-methoxyphenoxy) fluorenyl] -2,3- Diazepine-1,4- + and dioxotriol-6-rejuvenated amine; (2S) -N-[(3R, 5R) -1-acylbicyclo [3.2.1] oct-3-yl] -2-[(4-methoxyphenoxy) methyl] -2,3-dihydro-1,4-benzodioxolene-6-carboxamide; (3R) -N- [ (3R, 5R) Small acryl bicyclo [3 · 2 · 1] oct-3-yl] -3- (hydroxymethyl) -2,3-dihydro-1,4-benzodioxolane- 6-Carboxamidamine; (3S) -N-[(3R, 5R> 1-1-azabicyclo [3 · 2 · 1] oct-3-yl] (hydroxymethyl) -2,3-dihydro- 1,4-Benzodioxolene-6-carboxamide; (3R) -N-[(3R, 5R) Small acridine [3 · 2 · 1] oct-3-yl] -3- [(Fluorenyloxy) methyl] · 2,3-dihydro · 1,4-benzodioxolane-6-carboxamide; (3S) -N-[(3R, 5R) -1 -Acridinebicyclo [3 · 2 · 1] oct-3-yl] -3-[(fluorenyloxy) methyl] _2,3-dihydro-1,4-benzodioxolene-6- Carboxamidine; (3R) -N-[(3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] each [[(4-fluorobenzyl) oxy] methyl] -2 , 3-dihydro-1,4-benzodioxo-terpinene-6-carboxamide; (3S) Zan [(3R, 5R) -1-acylbicyclo [3.2 · 1] ocin-3- Yl] -3-[[(4-fluorobenzyl) oxy] methyl] -2,3-dihydro-1,4-benzodioxo-6-benzylamine; (3R) -N-[(3R, 5R) Small acryl bicyclo [3.2.1] oct-3-yl] -3-[[(4-fluorenyl) oxy] methyl] -2,3-dihydro- 1,4-Benzodioxolene Carboxamides; -23- 200300673 Claims Patent Scope Sheet (3S) -N-[(3R, 5R) Small acridine bis [m # each base] each [[(4.methylamino) oxy] methyl] -2,3-dihydro-1,4-benzodioxolene, each carboxyamidamine; (3R) -N-[(3R, 5R ) -1-Acrylbicyclopyrene octyl] dong [[(4-methoxybenzyl) oxy] methyl] _2,3-dihydro-I, 4-benzodioxolene Chloramine; (3S) -N-[(3R, 5R) Small acryl bicyclo [υ.ηoctyl] each [[(4-methoxybenzyl) oxy] methyl] -2,3 -Difluorene-l, 4-benzodioxolane-6-famidamine ; (3R) -N-[(3R, 5R) -1-acylbicyclo [3 · 2 · ΐ] oct-3-yl] each (phenoxymethyl) -2,3-dihydro-1, 4-benzodioxofluorene-6-chitosamine; (3S) -N-[(3R, 5R) -1-acylbicyclopyridyl] each (phenoxymethyl) _2,3 • di Hydrogen-1,4-benzodioxolane-6-fermenting amine; (3R) -N-[(3R, 5R) -1-leafbicyclo [3.2.1] oct-3-yl]- 3-[(4-Fluorophenoxy) methyl] -2,3-dihydro-1,4 · benzodioxolane-6-stilbeneamine; (3S) -N-[(3R , 5R) small acridine bicyclic and each group] each [(4-fluorophenylphenoxy) methyl] -2,3-dihydro-1,4-benzodioxolane-6-carboxamide; (3R) -N-[(3R, 5R) Small acryl bicyclo [m] octyl] [[4-methylbenzyloxy) methyl] -2,3-dihydro-1,4-benzene Benzodioxamine-6-rejuvenated amine; (3S) -N-[(3R, 5R) -1-acylbicyclo [3.2.1] octyl] each [(4-methylbenzyloxy ) Methyl] -2,3-dihydro-1,4-benzodioxolene, each carboxyamidamine; (3R) -N-[(3R, 5R) -1-acylbicyclo [3.2.1 ] Oct-3-yl] -3-[(4-methoxyphenoxy) methyl] -2,3-dimurine-1,4-bendioxolan-6-diofoate; (3S) -N-[(3R, 5R) Small acryl bicyclo [3 · 2 · 1] octyl] each [(4-methoxy (Phenoxy) methyl] -2,3--murine-1,4-dongodioxo-diamine-6-k, or a pharmaceutically acceptable salt thereof, in which the compound is pure para-isomer Or its racemic mixture. -24- 200300673 Scope of Patent Application Continued 34. The compound according to item% of the scope of patent application, where γ is 0 and z is CRz or C (RZ) 2, or where γ is CRY or C (RY) 2, and Z is 0. 35. The compound according to item% of the patent application park, where z is CRz and R4 is a bond, or where γ is CRy and r6 is a bond, provided that only one of R4 or R6 is a bond. 36. The compound according to item 35 of the application, wherein W is CH. 37. The compound according to the permissible item in the scope of the patent application, wherein the compound is: N-[(3R, 5R) small acrylbicyclo [3 21] octyl] methylmethylglyoxamine; N-[( 3R, 5R) small acridine bicyclo [3.2.1] octyl] -4-ethyl-2H-beneene carboxamide; N-[(3R, 5R)-; ] Octyl] · Hydroxyfluoro-2H-diluted carbamidine; N-[(3R, 5R)] · Azabicyclo [3.2.1] oct-3-yl] -4-chloro-2H -Bentene-6-carboxamide; N-[(3R, 5R) -1-acylbicyclo [3 21] octyl] dongbromo-2H "crene-6-carboxamide; N- [ (3R, 5R) -1-acylbicyclo [3.2 · quinoctyl] -4-cyano-2H-bitan-6-carboxamide; N-[(3R, 5R) -1-acylbicyclo [3.21] Octyl] Ethynyl · 2Η-bene-6-carboxamide; N-[(3R, 5R) -1-azinebicyclo [3 · 21] octyl] -4-methyl -2fluorene-pinene-7-fluorenamine; N-[(3R, 5R)-; U acridine bicyclo [3 · 21] octyl] -4-ethyl-2fluorene-bene-7-carboxyfluorene Amine; N-[(3R, 5R) -1-acylbicyclo [3.2.1] oct-3-ylfluorenyl-fluoro-2fluorene-bene-7-carboxamide; N-[(3R, 5R) -1-acylbicyclo [3 · 2 · ι] octan-3-yl] -4-chloro-2H-pinene-7-carboxamidine; N-[(3R, 5RH-acylbicyclo [3.2. 1] Singki -2H-fluoren-7-carboxamidine; N-[(3R, 5R) ,: U acridine bicyclo [3 · 2.ι] octyl] -4-cyano-2H-fluorene-7 -Carboxamidine; N-[(3R, 5RH-azinebicyclo [3.2.1] oct-3-yl] -4-ethynyl-2fluorenylcarboxamide; or a pharmaceutically acceptable salt thereof, Wherein the compound is a pure para-isomer or a racemic mixture of -25-200300673 in the scope of patent application. 38. The compound according to item 4 in the scope of patent application, in which the azine ring is III, IV or VI. 39 The compound according to item 38 of the patent application, wherein the azabicyclo is III or IV, and R2_3 is fluorene, alkyl, or substituted alkyl, or where the azabicyclo is VI, k6 is 0 or 1, and R2 Is an alkyl group, a halogenated alkyl group, a substituted alkyl group, or does not exist, provided that k6 is 0. 40. The compound according to item 39 of the scope of patent application, wherein Y is 0 and Z is 0. 41. According to For the compound in the scope of patent application No. 40, at least one R4 and at least one R6 are each fluorene, and the other R4 and another R6 are each independently fluorene, alkyl, substituted alkyl, functional alkyl, Cycloalkyl or heterocycloalkyl Wherein each & 0 is independently fluorene, lower alkyl, lower alkyl, cycloalkyl, heterocycloalkyl, or low-carbon alkyl substituted by one substituent selected from Ri3. 42. The compound according to item 41 of the application, wherein W is CH. 43. The compound according to item 42 of the scope of application for a patent, wherein the compound is: N-[(3R) -1-acylbicyclo [3 · 2 · 2] non-3-yl] -2,3-dihydro- 1,4-benzodioxolene-6-chipinamine; N- (2-port f bis 3a [2 · 2 · 1] hept-5-yl) -2,3-diazine- 1,4- $ dioxolan-6-amine; N- (2- (2-methyl > azepine bicyclo [2.2.1] hept-5-yl) -2,3-dihydro -1,4-benzodioxolene-6-carboxamide; N- (2 ^ γbicyclo [2.2.1] hept-6-yl) -2,3-dihydro-1,4- Benzodioxolene-6- -26- 200300673 Scope of patent application Continued Carboxamidine; N- (2- (2-methyl) -Azabicyclo [2.2.1] heptyl) -2, 3-dihydro-1,4-benzodioxolene-6-carboxamide; or a pharmaceutically acceptable salt thereof, wherein the compound is a pure para-isomer or a racemic mixture thereof. 44. The compound according to item 41 of the scope of patent application, wherein W is N. 45. The compound according to item 44 of the scope of patent application, wherein the compound is: N- (2-azabicyclo [2.2.1] hept-5-yl) -2,3-dihydro-1,4-dioxolene [2,3-c] pyridine-7-carboxamide; N- (2- (2-methyl) -azepine bicyclo [2.2 .1] G-5 -Yl) -2,3-dihydro-1,4-dioxolene [2,3-c >pyridine-7-carboxamide; N- (2-azinebicyclo [2.2.1] Hept-6-yl) -2,3-dihydro-1,4-dioxolene [2,3-c] pyridine-7-carboxamide; N- (2- (2-methyl) -Acridinebicyclo [2.2.1] heptyl) -2,3-dihydro-1,4-dioxolene [2,3-c >pyridine-7-carboxamide; or its pharmacy Acceptable salts, wherein the compound is a pure para-isomer or a racemic mixture thereof. 46. The compound according to item 39 of the application, wherein Y is 0 and Z is C (RZ) 2, or wherein Y is C (RY) 2 and Z is 0. 47. According to the 46th compound of the application, at least one R4 and at least one% are each Η, and the other R4 and the other heart are each independently Hydrazone, alkyl, substituted alkyl, self-alkylated, cycloalkyl, or heterocycloalkyl, wherein each Ri 〇 is independently fluorene, lower alkyl, lower alkyl halo, -27- 200300673 Application Scope of the patent is continued on cycloalkyl, heterocycloalkyl or low-carbon alkyl substituted by a substituent selected from R1 3. 48. The compound according to item 47 of the patent application, wherein W CH. 49. The compound according to item 48 of the scope of application for a patent, wherein the compound is: N- (2-azabicyclo [2.2.1] hept-5-yl) -fluorene-6-carboxamide; N- (2 -(2-methyl) -azinebicyclo [2.2.1] hept-5-yl) -fluorene-6-carboxylic acid amine; N- (2-azinebicyclo [2.2.1] hept-5-yl) -Bite-7-carboxamide; Ν · (2- (2-methyl) -azinebicyclo [2.2.1] hept-5-yl) -pept-7-carboxamide; Ν- (2-azine Bicyclo [2.2.1] heptan-6-yl) -fluorene-6-carboxyfluorenamine; N- (2- (2-methyl) -azepine bicyclo [2.2.1] heptan-6-yl) -fluorene -6-Carboxamidine; Ν- (2-azinebicyclo [2.2.1] heptan-6-yl) -bita-7-polyamidamine; Ν- (2- (2-methyl) -azinebicyclo [2.2.1] hept-6-yl) -fluorene-7-carboxamide; or a pharmaceutically acceptable salt thereof, wherein the compound is a pure para-isomer or a racemic mixture thereof. 50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49 of the scope of patent application, an antipsychotic agent, and a pharmaceutically acceptable excipient. 51. The pharmaceutical composition according to item 50 of the scope of patent application, wherein the compound and the agent are to be administered rectally, topically, orally, sublingually or parenterally, after a therapeutically effective interval. 52. The pharmaceutical composition according to item 50 of the patent application range, wherein the compound is administered in an amount of about 0.001 to about 100 mg / kg of the mammal's body weight per day. 53. The pharmaceutical composition according to item 50 of the scope of patent application, wherein the compound -28-200300673 is in the scope of patent application. The continuation sheet is administered in an amount of about 0.1 to about 50 mg / kg of the mammal's body weight per day. 54. A pharmaceutical composition according to claim 50, comprising a compound according to any of claims 1-49, and a pharmaceutically acceptable excipient. 55. The pharmaceutical composition according to item 54 of the application, wherein the compound is administered rectally, topically, orally, sublingually, or parenterally, after a therapeutically effective interval. 56. The pharmaceutical composition according to item 54 of the application, wherein the compound is administered in an amount of about 0.001 to about 100 mg / kg of the mammal's body weight per day. 57. The pharmaceutical composition according to item 54 of the application, wherein the compound is administered in an amount of about 0.1 to about 50 mg / kg of the mammal's body weight per day. 58. The use of a compound according to any one of claims 1 to 49 for the preparation of a medicament for treating a disease or a symptom, wherein the mammal is administered a therapeutically effective amount of acetic acid test Receptor activators receive signs of relief. 59. According to the application of the scope of application for patent No. 58, wherein the disease or symptom is the symptoms of Alzheimer's disease and lack of attention, and neurodegeneration associated with the disease, such as Alzheimer's disease, Alzheimer's disease (moderate cognitive impairment) or Alzheimer's disease. 60. Use according to item 58 of the scope of patent application, wherein the disease or symptom is schizophrenia or psychosis. -29- 200300673 Application for profit-seeking scope | Sell_ 61 · According to the application of the scope of patent application No. 60, wherein the mammal is administered a therapeutically effective amount of nicotinic acid acetylcholine receptor activator and Psychotropic agents' have undergone therapeutically effective intervals, while receiving signs of relief. 62. Use according to item% of the scope of application, wherein the disease or symptom is depression, anxiety, general anxiety disorder or post-traumatic stress disorder. 63. The use according to item% of the scope of patent application, wherein the disease or symptom is a condition of insufficient attention or a condition of insufficient attention and activity. 64. Use according to item% of the scope of patent application, wherein the disease or symptom is mood and affective disorder, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, general and behaviors associated with brain tumors and Cognitive problems, AIDS dementia recurrence, dementia associated with Down's syndrome, dementia associated with Lewy body, Huntington's disease, Parkinson's disease, tardive dyskinesia, Pick's disease "Regulatory disorders of food intake" include bulimia and lack of appetite, neurotic symptoms, withdrawal symptoms associated with cessation of smoking and drug dependence, Gilles de la Tóurette's sign, and spot degeneration associated with aging. , Glaucoma, neurodegeneration associated with glaucoma, or symptoms associated with pain. 65. A method for treating a disease or symptom in a mammal in need, wherein the mammal is administrated by administering an acetylcholine receptor agonist to nicotinic acid, which comprises treating the mammal Administer a therapeutically effective amount of a compound according to any one of Patent Application ® $: ^. 66 · = Method of Patent Item No. 65] The disease or symptom is Arab League: Divine: Intellectual and Attention Symptoms, Related to the disease, 'I such as Alzheimer's disease, senile dementia- 30-200300673 Patent Application Continued (moderate cognitive impairment) or Alzheimer's disease. 67. The method according to item 65 of the application, wherein the disease or symptom is schizophrenia or psychosis. 68. The method according to item 67 of the scope of patent application, wherein the mammal receives a therapeutically effective amount of α7 acetic acid biliary test receptor activator and antipsychotic agent after receiving a therapeutically effective interval. Symptoms relieve. 69. The method according to item 65 of the patent application, wherein the disease or symptom is depression, or anxiety and general anxiety disorders, and post-traumatic stress disorders. 70. The method according to item 65 of the patent application, wherein the disease or symptom is a condition of insufficient attention or a condition of hyperactivity. 71. The method according to item 65 of the patent application, wherein the disease or symptom is mood and affective disorder, amyotrophic lateral sclerosis, borderline personality disorder, traumatic brain injury, general and behaviors associated with brain tumors and Cognitive problems, AIDS dementia recurrence, dementia associated with Down's syndrome, dementia associated with Lewy's body, Huntington's disease, Parkinson's disease, tardive dyskinesia, Pick's disease, Dysfunctions in regulating food intake, including bulimia and anorexia, withdrawal symptoms associated with stopping smoking and dependence on drugs, Gilles de la Tourette's syndrome, speckle degeneration associated with aging, glaucoma, and glaucoma Associated neurodegeneration or symptoms associated with pain. -31-200300673 Lu, (a), the designated representative of this case is: Figure _ (b), the component representative symbols of this representative map are simply explained:-Morning V Chai, if there is a chemical formula in this case, please disclose the chemical formula that is not the most obvious feature of the invention: -5-