TWI333489B - Novel amines as histamine-3 receptor ligands and their therapeutic applications - Google Patents

Description

1333489 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a compound which can be used for treating a disease or condition caused by histamine 3-receptor activity to cause bite aggravation, a pharmaceutical composition containing such a compound, and the use of the same A method of treating a compound. [Prior Art] Histamine is a well-known mediator in allergic reactions such as allergy, hay fever and asthma, and is usually treated with an antagonist of histamine or "antihistamine". It has also been established that histamine receptors exist in at least two different forms, called HjaH2 receptors. It is believed that the third histamine receptor (H3 receptor) plays a role in the nerve conduction in the central nervous system, and it is believed that the sputum receptor is here in the form of a presynaptic formula in histaminergic On the nerve ending (Nature, 3〇2m_8p (1983)). The presence of the Η3 receptor has been confirmed by the development of selective % receptor agonists and antagonists (NatUre, 327, 1 17_123 (1987)), and has subsequently been shown in both the central nervous system and surrounding organs, In particular, in the lungs, cardiovascular system and gastrointestinal tract, the release of other neurotransmitters is regulated. A large amount of money or money can be treated with a histamine 3 receptor conjugate, wherein the % ligand can be an antagonist, agonist or partial agonist. Such diseases or conditions include cardiac A-tube disorders such as acute myocardial infarction; memory procedures, dementia and cognitive impairments such as Alzheimer's syndrome and attention deficit hyperactivity; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy and seizures or convulsions; cancer, such as skin cancer, thyroid thyroid cancer and melanoma; allergic rhinitis; respiratory disorders, like 98683.doc 1333489 asthma; sleep disorders , such as narcolepsy; vestibular dysfunction, such as otic vertigo; gastrointestinal disorders, inflammatory reactions, migraine, motion sickness, obesity, pain, and septic shock. SUMMARY OF THE INVENTION A brief description of the invention

In a specific embodiment thereof, the invention is directed to a compound of formula (1): or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof, wherein A is selected from a carbonyl group or a covalent bond; D is selected from hydrazine or S ; L is selected from a lower alkyl alkyl group, a fluorine alkyl group or a hydroxy alkyl group; P and Q together form a covalent bond or both are hydrogen;

Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkyl, heterocyclyl, heterocyclo, pyrenyl 'alkenyl or alkynyl; The ruler 2 together with the nitrogen atom attached thereto forms a heterocyclic ring; R·3 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyl lactyl, alkyl aryl, Hyunji continued, thiol, aryl, sulfhydryl, decyl, cyano, cyanide, carbyl, halogen, dentate, halogen, heterocyclic, hydroxy, hydroxyalkyl , fluorenyl, nitro, _nrarb, (nrarb) alkyl, (nrarb) carbonyl or (nrarb) sulfonyl; R·4, R·5, 尺6 and R7 are respectively selected from hydrogen, alkoxy, alkoxycarbonyl , alkyl, 98683.doc 1333489 alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxyl, carboxyalkyl, cyano, cyanoalkyl, Cycloalkyl, methionyl dentate, haloalkoxy, decyl, heterocycle, hydroxy, hydroxyalkyl, decyl, nitro, -nrarb, (nrarb)alkyl, (nrarb), (nrarb) grade base, -L2R20 or -R20L3R22; L2 is selected from alkylene , alkenyl, hydrazine, S, s(0), S(0)2, c(=o), C=(NOR2l) or N(RA); L3 is selected from the group consisting of a covalent bond, an alkylene group, and an alkylene group. a group, 0, s, c (= 〇), n (= OR21) or n (ra); R 2 〇 is selected from aryl, heterocyclic or cycloalkyl; selected from hydrogen or alkyl; R22 is selected from aryl, Heterocyclic or cycloalkyl;

Ra and RB are each selected from the group consisting of hydrogen, alkyl, alkylcarbonyl or carbenyl; the limitation is that at least one of ~, ~, and is aryl 'heterocyclic, cycloalkyl, -L2R20 or R2gL3R22. The compound can be incorporated into a pharmaceutical composition and can be used in a method of treating or preventing a disorder associated with histamine-3 receptor modulation. The compound, a composition comprising the compound, and a method of treating or preventing a disorder by administering the compound are described herein. DETAILED DESCRIPTION OF THE INVENTION The present invention discloses compounds and compositions thereof that can be used to selectively modulate the effects of _ _ _ _ _. The 5 treatments of the present invention can be used to prevent the disorder of histamine _3 - cough and sputum. Typically, the disorder is one that is improved by stalking the histamine _3 receptor 98683.doc 1333489 selectively. A method of the present invention is available for treatment selected from the group consisting of acute myocardial infarction, asthma, bipolar disorder, cognitive improvement, cognitive deficit in mental disorders, skin cancer, drug abuse, depression, gastrointestinal disorders, inflammatory response, jet Hysteresis, medullary thyroid cancer, melanoma, allergic nasal dogs, ear vertigo, migraine, mood and attention changes, motion sickness, neurogenic inflammation, obsessive-compulsive disorder, pain, Parkinson's disease, Schizophrenia, seizures, septic shock, TGumteis syndrome, dizziness or insomnia (4). This method is useful for the treatment of premature aging syndrome, overreaction hyperactivity disorder, epilepsy, narcolepsy, and disorders related to “Knowledge and Syndrome, such as moderate cognitive impairment, memory deficits and learning. Defects, as well as dementia, may be particularly useful. Noun Definitions The following nouns have a recognized meaning when used in connection with the present invention. As used herein, the term "alkenyl" means a straight or branched hydrocarbon containing from 2 to 1 carbon and containing at least one carbon formed by the removal of two hydrogens. - Carbon double bond. Representative examples of alkenyl groups include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptyl Alkenyl, 2-methyl-1-heptenyl and 3-decenyl. The term "alkenyl" refers to a divalent group derived from a straight or branched hydrocarbon having from 2 to 1 carbon atoms and containing at least one double bond. A representative example of an alkenyl group, These include, but are not limited to, _CH=CH-, «=〇Ή2>, -CH=CH2CH2-, -CH2CH2C(=CH2)CH2-, -ch2ch2c(=chch3)ch2-, and -ch=c(ch3)ch2-. The term "alkoxy" as used herein, means that an alkyl group, as defined herein, 98683.doc 1333489, is trapped by attachment to the parent molecular moiety according to the oxygen moiety as defined herein. Representative examples of morphoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term "alkoxyalkyl" as used herein, means that an alkoxy group as defined herein is appended to the parent molecular moiety through an alkyl group as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-f oxyethyl, and methoxymethyl. The term "alkoxycarbonyl," as used herein, means that an alkoxy group as defined herein is appended to the parent molecular moiety via a carbonyl group as defined herein. Representative examples include, but are not limited to, f oxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The term "alkyl" as used herein, means a line or branch containing from 1 to 10 carbon atoms. Chain hydrocarbons. Representative examples of alkyl groups, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, second butyl, iso-butyl, third -butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dipentyl, 2,3-dimethylpentyl, n-heptyl, n. Octyl, n-decyl and n-decyl. The term "alkol" as used herein, means an alkyl group as defined herein, appended via a carbonyl group as defined herein. Representative examples of alkylcarbonyl groups on the parent molecular moiety, including but not limited to ethenyl, 1-oxopropyl, 2'2-dimethyl-!-oxopropyl, j-oxo-butyl And oxy-pentanyl. The term "alkyloxy as used herein, refers to a carbonyl group as defined in 98683.doc • 10-1333489 herein, via oxygen as defined herein. The base moiety is attached to the parent molecular moiety as a representative example of an alkylcarbonyloxy group including, but not limited to, an ethenyloxy group, an ethylcarbonyloxy group, and a third-butylcarbonyloxy group. The term "extension" means a divalent group derived from a hydrocarbon having a straight or branched chain of from 1 to 1 carbon atoms. Representative examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CHr, and -CH2CH(CH3)CH2-indole, "alkylsulfinyl," The term, meaning an alkyl group as defined herein, appended to the parent molecular moiety via a sulfinyl group as defined herein. Representative examples of alkyl sulfinyl, including but not Restricted to indolylsulfinyl and ethylsulfinyl. The term "alkylsulfonyl" as used herein, means an alkyl group as defined herein, according to the disclosure herein. A defined sulfonyl group is attached to the parent molecular moiety. Representative examples of alkyl sulfonyl groups include, but are not limited to, ethyl sulfonyl, isopropyl sulfhydryl, and fluorenyl. The term "alkylthio" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety, via a sulfur atom as defined herein. Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tri-butylthio, and hexylthio. The term "aryl" as used herein, refers to a monocyclic ring system or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings are aromatic. Representative examples of aryl groups include, but are not limited to, fluorenyl, molyl, decyl, hydroquinone, fluorenyl, fluorenyl, phenyl, and tetrahydronaphthyl. Substituting 0, 1, 2, 3, 4 or 5 substituents for the aryl group of the invention, 98683.doc 1333489 which are each selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl , alkoxymethyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl , aryl, halogen, alkenyloxy, haloalkyl, hydroxy, hydroxyalkyl, decyl, decyl, aryl, nNRAR, (nrarb)alkyl, (nrarb)carbonyl and (NRaRb) continuation . The term "aralkyl" as used herein, means that an aryl group as defined herein is appended to the parent molecular moiety via an alkyl group as defined herein. Representative examples of aralkyl groups include, but are not limited to, decyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphthalen-2-ylethyl. The term "arylcarbonyl," as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety, via a carbonyl group as defined herein. Representative examples of arylcarbonyl, including But not limited to alum, phenethyl, 3-oxophenethyl, 3-decyloxyphenidinyl, 4-fluoro-3-methylsulfonyl, 3-phenylpropenyl "carbonyl" as used herein, means the _(:(0)_ group. The term "carboxy" used in this text means _co2h. The term "alkylalkyl" as used herein, means a carboxyl group as defined herein, appended to the parent molecular moiety via an alkyl group as defined herein. Representative examples of radicals include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl. The term "cyano" as used herein, refers to a _CN group. The term "cyanoalkyl" as used herein, means a cyano group as defined herein, appended to the parent molecule via an alkyl group as defined herein. 98683.doc 12- 1333489 Partially representative examples of cyanide groups, including but not limited to cyanomethyl, gaseous ethyl and 3-cyanopropyl. The term "cycloalkyl" as used herein means saturated a cyclic hydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "cycloalkylalkyl" means a cycloalkyl group as defined herein appended to the parent molecular moiety via an alkyl group as defined herein. Representative of a cycloalkylalkyl group. Examples include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4·cycloheptylbutyl. The term "fluoroalkylalkyl" as used herein means Representative examples of fluoroalkylene groups, including but not limited to -CH2CH(F)-, -CH2C(F)2-, -CH2C(F, according to alkylene groups, as defined herein, containing one or more fluorine atoms. 2CH2- and -ch2ch2c(f)2-. The term ''mercapto') as used herein means a -C(0)H group. "Tooth" or "quote" as used herein. Halogen &quo The term "t," means _a, _Br, q or ρ* 〇 as used herein, the term "dentate alkoxy" means at least one dentate as defined herein, via Alkoxy groups as defined above are appended to the parent molecular moiety. Representative examples of !i alkyl include, but are not limited to, methoxy, 2-fluoroethoxy, trifluoromethoxy and pentafluoroethoxy The term "dentylalkyl" as used herein, means at least one dentate as defined herein, appended to the parent molecular moiety via an alkyl group as defined herein. Representative examples of haloalkyl include, but are not limited to, methmethyl, fluoromethyl, 2-oxoethyl, trifluoromethyl, pentafluoroethyl, and m-oxypentyl. 98683.doc Double ring The ring system used in this article for "heterocyclic" or hydrazine heterocycle. For example, single 3, think of a single ring or ~ early ring ring system & nitrogen and sulfur heteroatoms of any 3_ or 4 浐, '".., 3 have been selected from oxygen, sub-% a 6- or 7-membered ring wherein the heterozygous: has 1, 2 or 3 heterozygous 5-membered rings having from 0 to 2 double bonds, and 6• and ^ are selected from the group consisting of gas, oxygen and sulfur. Single 璟 or 么 w ^ member rings have 0-3 double bonds. Base, sputum, but not limited to milky butane, milk (4) county, nitrogen heterocycle (tetra), diazepine. Dioxin heart biting ritual base, di(tetra)yl group, fluorenyl group, imidazyl group sitting on the base, A t different 4 sitting base, different p plug salicyl, different (four) bite base, different ten sitting soil different ^ Sitting on the base, the different ten sitting base, the linalyloxazolyl group, the 唠-咄晗 „ Λ φ # ρ 圭 咬, 巧 唾 ” ” 唾 唾 & & & & & & & & & & 嗤 嗤Dingji, Liujing/, Hydrogen 峨 基 ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” , 5-diaza_1Η·h, each pyrrolyl group, pyrrolinyl group, pyrrolidinyl 'tetrahydrofuranyl group, tetramurenyl group, tetramorphyl, tetrazolyl, indole disaliyl, far disalicylinyl, Pyrimidine, thiazolyl, thiazolyl, thiazolidinyl, pyrenyl, thiomarinyl, 1,1 -dioxo bridge (dioxido) thiotropin (thio? ": Lin Biao), sulfur In particular, examples of the monocyclic ring system may include, but are not limited to, 1-azacyclopentyl, (3S)-3-( Dimethylamino>pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazolyl-yl, (3han)-3-hydroxypyrrolidinyl, (3S)_3 _hydroxy-]μ pyrrolidinyl, (2S)_2_(mmethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)·2,6-dimethylhexa-argon Pyridyl, 4-methyl-1-hexahydroacridinyl, 2-methyl_1_, gas acridinyl, 1-hexahydropyridyl, (2R,5R)-2,5-diinyl L-pyridine 986 83.doc 1333489 base, (cis)-2,5-monomethyl p ratio d acesulfame, 丨-pyrrolidinyl, 2-methyl-2-azetidyl, (2R)-2·methyl ^Pyridine, (2S)-2-methyl-Ι-t»Bilobite, (2R)-2-methyl-5-oxo-i 匕,, (2S)-2- Methyl-5-oxo-!pyridyl, 3,6-dioxa U2H)-pyridyl, (2S)-2-(methoxycarbonyl)-pyrrolidinyl, (2R)_2·( Methoxypyridylcarbonyl)·Κpyrrolidinyl, (2S)-2-(fluoromethyl)]· 咐 slightly biting, (2R)-2-(fluoromethyl, gas methyl) small, pyrrolidine (2R)-2·Ethyllobylpyridinyl, 2,2-dimethyl t-pyridyl, (2S)-2-ethyl_1·pyrrolidinyl 4-morpholinyl, 2 -咩-5-azabicyclodene 1_2.2.1]g _5-yl, and 1,4-two"»咢_8_ oxaspiro[4.5]癸-8-yl, 1__fine; Heterocyclopentyl, 4-morpholinyl, hexahydropyridinyl, 1-hexahydropyridyl, 1 Λ-pyridyl, 1-pyrrolidyl, 2,5-dihydropyridinium Base, κ 吨 s s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s. a monocyclic heterocyclic ring system in combination with a ring system according to the aryl group defined herein, according to the cycloalkyl group defined herein, or another monocyclic heterocyclic ring system. A representative example of a ring system of a double ring, Including but not limited to, stupid (tetra), benzo-p-phenyl, benzo-4-phenyl, benzo-xyl, butyl, benzo (tetra), thiol, stupid and dioxon, 1,3-benzodioxenyl, porphyrin, carbazolyl, fluorenyl, porphyrin, ♦ well, sulfhydryl, 3 Η "米唾和[4,5_ Small bite base, heterogeneous and succinyl, isobenzo phenyl, isodecyl, iso-yl, isoquinolyl, hydrazine, piperidinopyridyl, porphyrin, hydrazine , porphyrinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroporphyrinyl and thiopiperidinyl. The heterocyclic ring of the present invention is substituted with 0, 1, 2 or 3 substituents, which are respectively selected from 98683.doc -15·Ϊ333489 from an alkenyl group, an alkoxy group, an alkoxyalkyl group, an alkoxycarbonyl group, an alkyl group or an alkylcarbonyl group. , alkyl carbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aralkyl, carboxyl, carboxyalkyl, cyano, cyanoalkyl, decyl, dentate, halane Oxyl, from alkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, decyl, nitro, oxo, -NRARB, (NRARB) alkyl, (NRARB), and (NRaRb) continuation. The term "heterocycloalkyl" as used herein, means a heterocyclic ring as defined herein appended to the parent molecular moiety via an alkyl group as defined herein. Representative examples of heterocycloalkyl include, but are not limited to, pyridine-3-ylmethyl and 2-pyrimidin-2-ylpropyl. The term "heterocyclic carbonyl" as used herein, means that a heterocycle as defined herein is appended to the parent molecular moiety via a carbonyl group as defined herein. Representative examples of heterocyclic carbonyl include, but are not limited to, hydrazine H-imidazol-1-ylcarbonyl, 4-morpholinylcarbonyl, 1-hexanitropyridinylcarbonyl, and cyclopentylamine. As used herein, the term "hydroxy," means the -OH group. The term "hydroxyalkyl" as used herein, means one or two hydroxyl groups, as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein. Representative examples of hydroxyalkyl groups include, but are not limited to, methyl, 2-ethyl, 3-propyl, 2,3-dipropyl and 2-ethyl-4-hydroxyl-heptyl The term "hydroxylalkyl", as used herein, means that the alkylene group as defined herein contains one or more hydroxyl groups. Representative examples of hydroxyalkylene groups include, but are not limited to, -CH2CH(OH)-, -CH2CH(〇H)CH2_, 98683.doc •16- 1333489 -CH2CH2CH(OH)-, and -CH2CH(OH)CH(OH )-. The term "low carbon number alkyl" as used herein, means a subgroup of alkylene groups as defined herein, and means a straight or branched hydrocarbon group containing from 1 to 6 carbon atoms. Representative examples of lower carbon alkyl groups are -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, and -CH2CH2CH2CH2-. As used herein, "巯基&quot The term "—SH group" as used herein. The term "nitro" as used herein means -N〇2 group. The term "-NRARB" as used herein means two a group, and rb, which are attached to the parent molecular moiety via a nitrogen atom, wherein Rb is independently selected from the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl and decyl. Representative examples of _nrarb include, but are not limited to, acetamino group, amine group, guanamine group, dimethylamino group, and methylamino group. The term "(NRARB)alkyl" as used herein, means a radical attached to the parent molecular moiety according to the -NRARB group as defined herein, via an alkyl group as defined herein. Representative examples of (NRARB)alkyl include, but are not limited to, (amino)methyl, (dimethylamino)methyl, and (ethylamino)methyl. The term "(NRARB)carbonyl" as used herein, means a moiety attached to a parent molecule according to a NRARB group as defined herein, via a carbonyl group as defined herein. Representative examples of (NRARB)carbonyl groups include, but are not limited to, amine groups, dimethylamino groups, and ethylamino groups. The term "(NRARB)sulfonyl," as used herein, means an amine group attached to a parent molecular moiety via a sulfonyl group as defined herein, in accordance with an amine group, as defined herein. Representative examples of sulfonyl groups include, but are not limited to, 98683.doc -17. 1333489 in the aminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl groups. • The term, meaning a C(=NOR99)Rioo group, wherein R99 and Rioo are each selected from the group consisting of hydrogen and alkyl. The term "oxo" as used herein means the moiety =0. The term 'oxyl', as used herein, means the-0-part. The term "sulfinyl" as used herein refers to a -s(0)- group. The term "sulfonyl" as used herein refers to the -S02- group. The compound of the present invention includes at least one of the substituents represented by r4, r5, r6 or 尺7' selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, dazzle Isosulfonyl, alkylsulfonyl, thiol, aryl, carboxyl, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, dentate, ii alkoxy, tooth burn Base, heterocyclic, meridinyl, alkyl, sulfhydryl, nitro, -NRaRb, (NRaRb), (NRaRb), (NRaRb) %, -L2R20 or -R20L3R22; The substituent 'represented by r4, r5, 尺6 and r7' is selected from hydrogen or alkyl. The specific group having a substituent of R4, R5, 6 and the substituent may be selected from those of the formula (I) wherein hydrogen, an alkyl group, a heterocyclic ring, _L2R2 fluorene and -R2 〇 L3R22. The compound of the present invention may also have the formula (I) wherein A is a covalent bond; D is hydrazine; L is -CHzCH2 · P and Q form a covalent bond; the core and R2 are attached thereto. The nitrogen atoms together form a heterocyclic ring; R_3, R4, & and anaesthes 7 are hydrogen; and the ruler 6 is acetylene. The heterocyclic ring formed by Ri and R2 may include, but is not limited to, azacyclopentyl, anthracene, an imidazolyl group, a hydrazinyl group, a hexahydropyridinyl group, a hexahydropyridyl group, a pyridyl group. , pyrrolidinyl, (2R)-2-fluorenyl_ι-pyrrolidinyl, 2,5_two 98683.doc -18- 1333489 gas 1H v to thiol" ratio. each group, 3,6-dihydrogen ((2H)-峨 基 ' 'thio- linyl group and 1,1-dioxo bridge thiomorpholinyl. Specific examples of the heterocyclic ring of the compound of the present invention are, for example, 1-azacyclopentyl, (3S)_3_(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazolium, (3R) 3hydroxypyrrolidinyl, (3S)- 3-hydroxy-1-pyrrolidinyl, (2S)_2_(hydroxymethyl)pyrrolidinyl, (2R)-2-(methyl group> piroxime, (cis)-2,6 difyl Hexahydropyridinyl, 4-methyl hexahydropyridinyl, 2-methyl-b-hexahydropyridyl, anthracene hexahydropyridyl, (2R,5R)-2,5-dimethylpyrrolidinyl , (cis)_2,5-dimethylpyrrolidinyl, 1-pyrrolidinyl, 2_f-yl-pyridylpyridinyl, (2R)_2-methyl-brypyrrolidinyl, (2S)-2-methyl Base-1-pyrrolidinyl, (2R )_2_Methyl _ oxo- 卜 p 洛 咬, (2S)-2-methyl-5-oxo-oxime-峨嘻, 3,6-dihydro-1(2H)- Pyridyl, (28)_2_(曱-oxycarbonylpyrrolidinyl, (2R)_2-(methoxy)-1-pyrrolidyl, (2S)_2·(fluoromethyl)-丨-pyrrolidinyl, (2R)-2-(fluoromethyl)_〗 pyrrolidinyl, (2R)_2•ethyl-丨-pyrrolidinyl, 2,2-monomethyl-1·pyrrolidinyl, (2S)-2 -ethyl-1-pyrrolidinyl 4_heptyl, 2·唠-5-azabicyclo[2.2.1]hept-5-yl or 1,4-diox-8-azaspiro[4.5癸-8-yl. (2R)-2-methyl-1-pyridinyl group is preferred. The group of h may include, but is not limited to, a group represented by the formula L2R2〇, an alkylcarbonyl group. a heterocyclic ring or a group represented by R2〇L3R22. Where r^l2r2(), the specific group at this position may include, but is not limited to, L2gC(=〇) and r2〇 is an aryl group; L2 is C (=0) and Rm is a cycloalkyl group; 12 is an alkylene group or an alkenyl group, and R2 is an aryl group. For R2(), a specific aryl group includes, but is not limited to, a stylyl group. 'It may be substituted with 0, 1, 2 or 3 substituents selected from hydrogen, alkoxy, alkyl, Alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy 98683.doc -19- 1333489, cyano, decyl, dentate, alkyl, dentate, hydroxyalkyl, fluorenyl, (nrarb) a carbonyl group or a nrarb. A heterocyclic group suitable for R_6 is, for example, 吱π南基'β-saltyl, iso-p-Senyl, isothiazolinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyridinium , pyrazolyl, pyridyl, pyrimidinyl, hydrazine, pyrrolyl, tetrazolyl, pyrimazolyl, thiazolyl, thienyl, tridecyl, triazolyl, benzimidazolyl, benzindene Mercapto, benzo-p-enyl, benzoxazolyl, benzofuranyl, porphyrin, carbazolyl, fluorenyl, hydrazine, acridinyl, isobenzofuranyl, isobenzo Thienyl, isodecyl, isoquinolyl, porphyrinyl, hydrazine, 4-terpenyl or 4-carbolinyl. Substituting a heterocyclic group of r6 with hydrazine, 1, 2 or 3 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy Base, alkylsulfinyl, alkylsulfonyl, alkylthio, aralkyl, carboxyl, carboxyalkyl, cyano, cyanoalkyl, formazan Sr, halogen, _ alkoxy, tooth burn a group, a benzyl group, a carbyl group, an alkyl group, a fluorenyl group, a nitro group, an oxo group, a NR-R a, a (NRaRb) alkyl group, a (NRaRb) carbonyl group, and an (nrarb) sulfonyl group; wherein, and Rb are in the formula (1) The definition in . The specific heterocyclic ring for R6 is 12,4-oxadiazole·3_yl, 3·pyridyl, 4-isoxazolyl and 1Η-imidazolium-fluorenyl group, wherein fluorene is selected from argon. A substituent of an alkyl group, a dentate alkyl group or a hydroxyalkyl group is substituted for the heterocyclic ring. Where R6 is R^I^R22, the specific group at this position may include, but is not limited to, wherein the ruler 2 is a heterocyclic ring, L3 is a covalent bond or a stretching group, and r22 is an aryl group; R2〇 is a heterocyclic ring, La is a covalent bond or an alkylene group, and R22 is a heterocyclic ring, particularly a 2-sulfenyl group; Ru is an aryl group, particularly a phenyl group, q is c(=〇) and is a cycloalkyl group; Is an aryl group, especially a phenyl group, La is C (=〇) and R22 is an aryl group; 98683.doc •20-1333489 is an aryl group, L3 is a covalent bond or an alkyl group, and R22 is a heterocyclic ring. 'Specially those of the 2 thiophene. Phenyl is particularly suitable for aryl r22. 〇, 丨, 2 or 3 are selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, decyl, haloalkoxy, acyl, _ Substituents such as hydroxy, hydroxyalkyl, hexavalent, (nrarb) and (NRaRb) are substituted for such phenyl. In a particular embodiment, the compound of the invention has the formula (1) wherein A is a covalent bond; 0 is hydrazine; L is _CH2CH2_; p and q are formed to form a covalent bond; Ri and R2 are attached to The nitrogen atom thereon forms a heterocyclic ring together, and is selected from the group consisting of azacyclopentyl, azetidinyl, imidazolyl, morpholinyl, hexahydropyranyl 'hexahydropyridyl, pyridyl, pyrrolidinyl , (2R)_2-methyl-丨-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, 3,6-dihydro·1(2Η)·pyridyl, thiomorpholinyl And 1,1-dioxo bridge thiomorpholinyl; p_3, Re, & and &hydrogen; R6 is L2R2〇; L2 is c(=0); and r2Q is aryl. In another embodiment, the compound of the present invention has the formula (1) wherein A is a covalent bond; D is hydrazine; l^_CH2CH2_; hydrazine and hydrazine together form a covalent bond; and R1 and R2 are attached thereto The nitrogen atoms together form a heterocyclic ring selected from the group consisting of: azacyclopentyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R) 3 (dimethylamino)pyrrolidinyl, 1H -Imidazolyl, (3R)-3-hydroxypyrrolidinyl, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)_2-(hydroxyindenyl)pyrrolidinyl, (2R)-2-(oxindole) Pyrrolidinyl, (cis)-2,6-didecylhexafluoropyridyl, analginyl-1-hexahydropyridyl, 2-indenyl-hydrazine-hexahydropyridyl, anthracene hexahydropyridyl , (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-[pyrrolidinyl, ( 2R)_2·indolyl·丨_pyrrolidinyl, (2S)-2-methyl-b, pyrrolidinyl, (2R)_2_methyl_5_oxo small tons of 98683.doc •21· 1333489 bite base, (2S)-2-methyl-5-oxo-1-1» piroxime, 3,6-dihydro-(ι) (2Η)-ι» bite base, (2S)-2 -(methoxy group)-ΐ-υBilo bite base, (2r)_2_( Oxylyl)_ι_pyrrolidinyl, (2S)-2-(fluoroindolyl)-1·pyrrolidinyl, (2R)_2_(fluoromethyl)pyrrolidinyl, (2R)-2·ethyl-1 - pyrrolidinyl, 2,2-dimethyl-indolylpyrrolidinyl, (2S)-2-ethyl-1-pyrrolidinyl-4-morpholinyl, 2-indole-5-azabicyclo[ 2.2.1] hept-5-yl or 1,4-diox-8-azaspiro[4.5]dec-8-yl; ft. 3, 114, Κ·5 and R7 are hydrogen, R6 is L2R2G; L2 is C(=〇); and r2〇 is an aryl group. In another embodiment, the compound of the invention has the formula (I) wherein A is a covalent bond; D is hydrazine; L is -CH2CH2-; P and Q together form a covalent bond; The nitrogen atoms attached thereto form a heterocyclic ring (2R)_2-methyl-1-pyrrolidinyl; R3, R4, 5 and 5 are hydrogen; "^; £2 is C(=0) And R20 is 〇, 丨, 2 or 3 selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxyl, cyano, decyl, haloalkyl, halogen a phenyl group substituted with a substituent of an alkyl group, a hydroxy group, a hydroxyalkyl group, a fluorenyl group, a (NRaRb)carbonyl group or a _NRaRb. In another specific embodiment, the compound of the invention has the formula (I) wherein A is a total a valence bond; D is a hydrazine; a hydrazine and a hydrazine form a covalent bond; a heart and a stalk 2 together with a nitrogen atom attached thereto form a heterocyclic ring selected from a nitrogen heterocyclopentyl group, azetidinyl group , imidazolyl, morpholinyl, hexahydropyridinyl, /, hydropyridyl, (7-pyridyl, indole, (2R)_2_methyl_丨_pyridinyl, 2,5 -dihydro-1Η-pyrrolyl, pyrrolyl, 3,6-dihydro^(inhibited)^pyridyl, thio a morphyl group and a 1,1-dioxy bridge thiomorpholinyl group; &, r4, 5 and R7 are hydrogen 'R4L2R20; L2 is C(=〇); and r2〇 is a cycloalkyl group. In the examples, the compound of the present invention has the formula (1), wherein 98683.doc -22- 1333489 wherein A is a covalent bond; D is hydrazine; L is -CKCH2·; P and Q form a covalent bond; And the ruler 2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from the group consisting of azacyclopentanyl, (3S)-3-(dimethylamino)p, piroxime, (3R)j_( Dimethylamino)pyrrolidinyl, 1H-imidazol-1-yl, (3R)_3_hydroxy-indole-pyrrolidinyl, (3S)-3-hydroxy-1·pyrrolidinyl, (2S)_2_(hydroxyl Methyl)pyrrolidinyl, (2R)-2-(hydroxyindenyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridinyl, 4-methyl-1-hexahydropyridinyl, 2- Methyl-1-hexahydropyridinyl, hydrazine-hexahydropyridinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5·dimercaptopyrrolidinyl, 1- Pyrrolidinyl, 2-methyl-1-pyrrolidinyl, (2R)_2·methyl-pyridrolidyl, (2S)-2-methyl·ι·pyrrolidinyl' (2R)_2-methyl _5_oxo-pyrrolidinyl, (2S)-2-A -5-oxo-1-pyrrolidinyl, 3,6-dihydropyridyl, (2S)-2-(methoxycarbonyl)pyrrolidinyl, (2R)_2-(methoxycarbonyl)-pyrrolidinyl (2S)-2-(fluoromethyl)·ι_pyrrolidinyl, (2R)_2_(fluoromethyl)pyrrolidinyl, (2R)-2-ethyl-1-pyrrolidinyl, 2, 2-Dimethylpyrrolidinyl, (2S)-2-ethyl-1·pyrrolidinyl-4-morpholinyl, 2__5-azabicyclo[2.2.1]hept-5-yl or 1 , 4-diindole-8-azaspiro[4.5]癸-8-yl; 113, 114, R5 and R7 are hydrogen; R^L2R2〇·, 1^ is (:(=〇); and r2〇 is Cycloalkyl. In another specific embodiment, the compound of the present invention has the formula wherein A is a covalent bond; D is hydrazine; l*_CH2Ch2_; together form a covalent bond, and 1 and 112 together with the nitrogen atom attached thereto A heterocyclic ring (2R)_2-mercapto_1-pyrrolidinyl group is formed; R3, R4, Rs and R7 are hydrogen; 116 is L2R20; L2 is c(=o); and R2Q is a cycloalkyl group. In another specific embodiment, the compound of the present invention has the formula (J) wherein A is a covalent bond; hydrazine is hydrazine; [is _(: 112 (:112· ; ? and 〇 together form a covalent 98683.doc • 23· 1333489 bond;: ^ and ruler 2 together with the nitrogen atom attached thereto form a heterocyclic ring, selected from the group consisting of aza-pyrene, azetidin, U-β, and P-lin Base, hexazapine, hexahydro, guanidine, indopidine, indole, (2R)_2-methylindole, 2,5-dihydro-1H-pyrrolyl, pyrrolyl , 3,6·dihydropyridinyl, thiomorpholinyl and 1,1-dioxobridge thiomorpholinyl; R3, r4, R·7 are rats, Re is; L2 is selected from the group and the extension In another embodiment, the compound of the present invention has the formula (1), wherein A is a common bond, D is 0, L is -CH2CH2-; P and Q are formed together. It is a valence bond; 1^ and R2 together with a nitrogen atom attached thereto form a heterocyclic ring, selected from the group consisting of a ring, a (3S)-3-(dimethylamino)p, a butyl group, (3 r) _ 3 -(dimethylamino)pyrrolidinyl, 1H-imidazol-1-yl, (3R)_3-hydroxy·ι_ 吨哈 bit, (3S)-3- -1 -pyrrolidinyl, (2S)-2-(hydroxyindenyl)pyrrole, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis) 2,6-dimethylhexahydro Pyridyl, 4-methyl-1-hexahydropyridyl, 2-mercapto-1-hexahydropyridinyl, indole hexahydroindole, (2R,5R)-2,5-monomethyl 1 »Bilo bite, (cis)-2,5-dimethylu ratio „Eight bite, 1-pyrrolidinyl, 2-mercapto-1-pyrrolidinyl, (2R)_2-fluorenyl·l峨洛基基, (2S)-2-methyl-14rrolidinyl, (2r)_2-methyl-5-oxo-dioxazolidinyl, (2S)-2-methyl-5-oxygen Generation _1_leaf b-pyridinyl, 3,6-dihydro·1 (2H bbityl, (2S)-2-(methoxy)--1-p than each bite, (2R) _2-(Methoxymethyl)_ι_pyrrolidinyl, (2S)-2-(fluoromethyl)-1-pyrrolidinyl, (2R)-2-(imethyl)pyrrolidinyl, (2R)- 2-ethyl-1-pyrrolidinyl, 2,2-dimethylpyrrolidine, (2S)-2-ethyl-Ι-p ratio σ each bite 4-merinyl, 2-» _5-heterobicyclo[2.2.1]hept-5-yl or 1,4-di-11-8-8-heterospiro[4.5]癸-8-yl; r3, r4, R5 and R7 are wind, R*6 is L2R20; L2 is selected from the group consisting of a stretching base and a stretching base; and 98683.doc • 24_ 1333489 is In another embodiment, the compound of the invention has the formula G) wherein A is a co-paraffin bond 'd is 0, L is -CH2CH2-; P and Q together form a covalent bond, R>R2 and The nitrogen atoms attached thereto form a heterocyclic (2R) 2 fluorenyl-1-pyrrolidinyl group; R 3 , r 4 , r ^ R 7 are hydrogen; R ^ L 2 R 2 〇; L 2 is selected from the group consisting of a stretching base and a stretching base; And Rm is 〇, 1, 2 or 3 selected from hydrogen, decyloxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, decyl, haloalkoxy, halane A phenyl group substituted with a substituent of a halogen, a hydroxyalkyl group, a fluorenyl group, a (NRaRb)carbonyl group or a -NRARB. In another embodiment, the compound of the invention has the formula (1) wherein A is a covalent bond, d is Ο; L is -CH2CH2-; P and Q together form a covalent bond; The nitrogen atoms attached thereto form a heterocyclic ring, and are selected from the group consisting of azacyclopentadienyl, azetidinyl, imidazolyl, hydrazino, hexahydro-pyridyl, hexahydropyridyl, pyridyl , pyrrolidinyl, (2R)_2_methyl-丨-pyrrole, 2,5-indol-1Η-Ι»pyrrolyl, p-p-group, 3,6-dihydro-1 (2H )-p is a thiol group, a thiomorpholinyl group, and a 1,1-dioxo bridge thiomorpholinyl group; r3, R4, and L are hydrogen; and R6 is an alkylcarbonyl group. In another specific embodiment, the compound of the invention has the formula (1) wherein A is a covalent bond; d is Ο; L is -CH2CH2-; P and Q together form a covalent bond; Rja R2 is attached to The nitrogen atom thereon forms a heterocyclic ring together, and is selected from the group consisting of a gas, a (3S)-3-(dimethylamino group, a dimethyl group, and a (3r) _3 _ (diamylamino group). Pyrrolidinyl, 1H-imidazol-1-yl, (3R)-3-hydroxy-^piroxime, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)-2-(hydroxymethyl ) tons of each bite, (2R)-2-(hydroxyindenyl)pyrrolidinyl, (cis) 2,6-dimethylhexahydropurine bite, heart 98683.doc •25· 1333489

Methyl-1-hexahydropyridyl, 2-mercapto-1-hexahydropyridyl, 1-hexahydropyridyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)- 2,5-Dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, (2R)-2-methyl-1-pyrrolidinyl, (2S)-2-indole -1 -pyrrolidinyl, (2R)-2-methyl-5-oxo-1-pyrrolidinyl, (2S)-2-methyl-5-oxo-1-pyrrolidinyl, 3, 6-Dihydro-l(2H)-pyridyl, (2S)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2R)-2-(methoxycarbonyl)-1-pyrrolidinyl, 2S)-2-(fluoromethyl)-1-pyrrolidinyl, (2R)-2_(fluorofyl)-1-pyrrolidinyl, (2R)-2-ethyl-1-pyrrolidinyl, 2 , 2-dimethyl-1-pyrrolidinyl, (28)-2-ethyl-1-11 ratio >1 each bite base 4-?1»linyl, 2-17-5-aza-di Ring [2.2.1] hept-5-yl or 1,4-dioxan-8-azaspiro[4.5]dec-8-yl; R3, R4, R5 and R7 are hydrogen; In a specific embodiment, the compound of the present invention has the formula (1) wherein hydrazine is a covalent bond; D is hydrazine; L is -CH2CH2-; Ρ and Q are formed to form a co-loss bond, and Ri and R2 are attached to The nitrogen atoms on it together form a heterocyclic ring (2R) 2-Methyl-1-pyrrolidinyl; &, &, heart and ruler 7 are hydrogen; & is an alkylcarbonyl group.

In another embodiment, the compound of the present invention has the formula G), wherein AA is a covalent bond; D is hydrazine; L is ·CH2CH2_; and 卩 together form a covalent bond; Ri and is attached thereto The nitrogen atoms together form a heterocyclic ring, and are selected from the group consisting of azacyclofilament, azetidin, imidazole, oxime, hexanitrogen, and hexahydroindenyl. (2R)_2·Methyl such as 鸣^, hydrogen 1H_P than aryl,? The pyrrolyl group, the M-dihydro-1(2H)-carbosome group, the 4 group and the la•dioxo bridge thiophenanthyl group; ^ and R*7 are gases, and R6 is a heterocyclic ring. In another embodiment, the compound of the present invention has the formula (1), wherein 98.683.doc -26 - 1333489 wherein A is a covalent bond; d is hydrazine; l is -CH2CH2-; P and Q form a covalent bond ; 1 and I together with the nitrogen atom attached thereto form a heterocyclic ring selected from the group consisting of azacyclopentyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)_3_(two Methylamino)pyrrolidinyl, 1H-imidazol-1-yl, (3R)-3-hydroxypyrrolidinyl, (3S)-3-hydroxy-1-pyrrolidinyl, (2s)-2-(hydroxymethyl) Ethrolidinyl, (2R)-2-(hydroxyindenyl)pyrrolidinyl, (cis)·2,6•dimercaptohexahydropyridyl, 4-decyl-1-hexahydropyridyl, 2—A Hexahydropyridyl, hexahydropyridyl, (2R,5R)-2,5cmethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1-pyrrolidinyl, 2- Mercapto-kappy pyrrolidinyl, (2R)_2•indolyl-pyridylpyridinyl, (2S)-2-methylindolyl, (2R)2-methyl-5-oxo疋 疋 (2S)-2·methyloxo-i-leafin, 3,6-dihydro-(I)-exoacridinyl, (2S)-2·(methoxycarbonyl) _Betrolidinyl, (2R)_2_(methoxycarbonylpyrrolidinyl (2S)-2-(fluorof-yl)-pyrrolidinyl, (2R)_2_(fluoromethylpyrrolidinyl, (2R)_2_ethyl small p-pyridyl, 2,2-dimethyl ^• 峨 啶 啶 、, (2S)-2-ethyl small p than butyl base 4 · 淋 基, 2 winter 5 _ aza bicyclo [2.2.1] G _5-based or 1,4 _ No. 11 _8_azaspiro[45]癸8 base;]^, heart, R5 and R·7 are hydrogen; and counter 6 is a heterocyclic ring. In another embodiment, the compound of the invention has the formula (〗), wherein A is a covalent bond; !) is 〇; L is · CH2CH2_; ^〇Q-forms a covalent bond; R, and R2 together with the nitrogen atom attached thereto form a heterocyclic ring, Selected from azacyclopentadienyl, azetidin, (tetra), morphinyl, hexanitroxyl, hexahydroacridinyl, pyridyl, pyrrolidinyl, (2R)_2-methyl Tons of biting, 2,5-dihydro-1H'syl, fluorenyl, 3,6-dihydro-I(2Η)-acridinyl, thio-tert-yl and U-dioxyl thio琳琳基;&,&,^ and 98683.doc •27· 1333489 R7 is hydrogen; R·6 is a heterocyclic ring selected from p-pain, salivary, iso-β-s, isothiazoline Base, isoxazolyl, oxadiazolyl, carbazolyl, pyridin , pyrazolyl, pyridyl, pyrimidinyl, morphine, pyrrolyl, tetrazolyl, beta-disodium, oxazolyl, thienyl, tri-negative, triazolyl, benzimidazolyl, benzo Pyrazolyl, benzopyrhenyl, benzoxazolyl, benzofuranyl, ruthenyl, oxazolyl, fluorenyl, fluorene, acridinyl, isobenzofuranyl, isophthalene And 0 thiophene, isodecyl, iso-U-quilinyl, s- s- lin, jun                       Substituting the heterocyclic ring, the substituent is selected from an alkenyl group, an alkoxy group, an alkoxyalkyl group, an alkoxycarbonyl group, an alkyl group, an alkylcarbonyl group, a hydrylcarbonyloxy group, an alkyl sulfonyl group, an alkyl sulfonyl group. , alkylthio, aralkyl, carboxyl, carboxyalkyl, cyano, cyanoalkyl, methionyl, halogen, alkenyloxy, functional alkyl, dentylcarbonyl, hydroxy, hydroxyalkyl, fluorenyl, Nitro, oxo, -NRARB, (NRARB)alkyl, (nrarb)carbonyl and (NRARB)sulfonyl; wherein RA is as defined in formula (1). In another embodiment, the compound of the invention has the formula (I) wherein A is a covalent bond; D is Ο; L is -CH2CH2-; P and Q together form a covalent bond; 1^ and 2 The nitrogen atoms attached thereto form a heterocyclic ring (2R) 2 -methyl-1-pyrrolidinyl; r3, R4, 5 and 5 are hydrogen; r6 is a heterocyclic ring selected from 12, 4_ ° sit-3-yl, 3-p ratio bite group, 4-iso-" thiol or 1H-micro-sodium-based group, wherein 〇, 1 or 2 are selected from hydrogen, alkyl, dentate or A substituent of a hydroxyalkyl group substitutes the heterocyclic ring. In another specific embodiment, the compound of the present invention has the formula (I) wherein A is a covalent bond; D is hydrazine; L is _Ch2CH2_; forming a covalent bond; and the heart and I are attached thereto The nitrogen atoms together form a heterocyclic ring selected from nitrogen 98683.doc -28- 1333489 heteropentyl, azetidinyl, imidazolyl, morpholinyl, hexahydropyrryl/hydropyridyl, pyridine , pyrrolidinyl, (2R)-2-methyl-1-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, 3 6-dihydro-1(2H)pyridyl, sulfur a morpholino group and a u-dioxo bridge thiomorpholinyl group; &, R4, R5 and 1 are hydrogen 'R0 is -RmI^R22; Rm is a heterocyclic ring; L3 is selected from a covalent bond and an alkylene group; R22 is an aryl group. In another specific embodiment, the compound of the present invention has the formula (1) wherein A is a covalent bond; D is hydrazine; and p*Q together form a covalent bond, and R! and R2 are attached thereto The nitrogen atom together form a heterocyclic ring selected from the group consisting of azacyclopentyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)_3_(dimethylamino)pyrrolidinyl, 1H-imidazole ·丨·基, (3R)_3_hydroxy···pyrrolidinyl, 〇S)-3-hydroxy-1-pyrrolidinyl, (2S)_2_(hydroxymethyl)pyrrolidinyl, (2R)-2 -(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridyl, 4-methyl-1-hexahydropyridyl, 2-methylhexahydropyridyl, hexahydropyridyl , (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-dimercaptopyrrolidinyl, 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, 2R)_2_Methylpyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl, (2R)_2_methyl_5_oxo-pyrrolidinyl, (2S)-2-A 5-O-oxo-i-pyrrolidinyl, 3,6-dihydro-1(2H)-pyridyl, (2S)-2-(methoxycarbonyl)pyrrolidinyl, (2R)_2 (methoxy Carbonylbupyridyl, (2S)-2-(fluoroindolyl)·ι_ Pyrrolidinyl, (2R)_2_(fluoromethyl)pyrrolidinyl, (2R)-2-ethyl-1-pyrrolidinyl, 22-dimethyl-pyrrolidinyl, (2S)-2 -ethyl-1-pyrrolidinyl 4_morpholinyl, 2呤_5_azabicyclo[2.2.1]hept-5-yl or 1,4-indol-8-azaspiro[45]癸_8_ base; rule 3, rule 4, R5 and R7 are hydrogen, Han 6 is -R2〇L3R22; r2〇 is a heterocyclic ring; "selected from covalent bond and 98683.doc •29·1333489 extended base; And rZ2 is an aryl group. In another embodiment, the compound of the present invention has the formula (1), wherein A is a covalent bond; D is a hydrazine; [Which is called; miso-forming forms a covalent bond; 112 together with the nitrogen atom attached thereto forms a heterocyclic ring (2R) 2-methyl·bipinyl group. 'R3, R4, R々R7 are nitrogen; r6 is -R2〇l3.R22; & Is 1,2'4-oxadiazole, 3 · group; I; selected from a covalent bond and an alkylene group; and is 0 2 2 or 3 selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, An alkylcarbonyl group, an alkylthio group, a carboxyl group, a cyano group, a decyl group, a dentate group, a dentate group, a (4) group, a substituted group substituted with an alkyl group, a fluorenyl group, a (NRARB)carbonyl group or a substituent of _NRaRb. Another specific In the examples, the compound of the present invention has the formula (Z) wherein A is a total of <Bei, D is 〇, L is -CH2CH2-; P and Q are covalently bonded; and 1 and 112 are attached The nitrogen atom thereon forms a heterocyclic ring together, selected from the group consisting of azacyclopentyl, azetidinyl, imidazolyl, morpholinyl, hexahydropyrrole, hexahydropyridyl, pyridyl, pyrrolidine Base, (2R)_2_fluorenyl-丨-pyrrole, 2,5-dihydro-lH-p than loryl, p to t», 3,6-dihydro-...print-bamboo bite a thiomorpholinyl group and a 1,1-diguanidine thiomorpholinyl group; r3, R4, 5 and Κ7 are hydrogen, Re is -R2〇L3R22; Κ·20 is 1,2,4嗤二嗤-3· group; L3 is selected from a covalent bond and an alkylene group; and R22 is a heterocyclic ring. In another embodiment, the compound of the invention has the formula (I) wherein A is a covalent bond; D is Ο; L is -CH2CH2-; P and Q form a covalent bond; The nitrogen atoms attached thereto form a heterocyclic ring, which is selected from the group consisting of 1_argoncyclopentyl, (3S)-3-(diguanylamino)p, and each of the bite groups, (3r)_3_ (dimethylamine) Pyrrolidinyl, 1H-imidazol-1-yl, (3R)-3-hydroxypyrrolidyl, 98683.doc -30- 1333489 (3S)-3-hydroxy-1-pyrrolidinyl, (2S) -2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridinyl, 4-methyl-1 - Hexahydropyridyl, 2-methyl-1 -hexahydropyridyl, 1 -hexahydropyridyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)_2,5 · dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, (2R)-2-methyl-1-pyrrole, (2S)-2-mercapto-1 -P-pyridinyl, (2R)_2_indolyl_5_oxo-indolyl, (2S)-2-methyl-5-oxo-purin-p piroxime, 3,6 -Dihydro-1(2H)-»pyridinyl, (2S)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2R)_2-(methoxycarbonyl) Pyrrolidinyl, (2S)-2-(fluoroindolyl)-1-pyrrolidinyl, (2R)_2-(fluoromethyl)pyrrolidinyl, (2R)-2-ethyl-1-pyrrolidinyl, 2,2_Dimethylpyrrolidinyl, (2S)-2-ethyl-1-pyrrolidinyl-4·morpholinyl, 2-nazepine azabicyclo[2.2.1]hept-5-yl or 1 , 4·2哼-8-azaspiro[4_5]癸_8·yl; R3, R4, R5 and R7 are hydrogen; RA-R2()L3R22; ^ is oxadiazole_3_yl; L3 It is selected from a covalent bond and an alkylene group; and r22 is a heterocyclic ring. In another specific embodiment, the compound of the invention has the formula (i) wherein A is a covalent bond; D is hydrazine; L is _CH2Ch2_; 卩 and 卩 together form a covalent bond; R^R2 is attached to The nitrogen atom thereon forms a heterocyclic (2R)-2-methyl-1·pyrrolidinyl group; r3, r4, 5 and 1 are hydrogen; 1 is ^〇^22; R2〇 is 丨, 2, 4-"Deoxadiazole~3_yl; L3 is selected from a covalent bond and an alkylene group; and R22 is a 2-thienyl group. In another specific embodiment, the compound of the present invention has the formula (I) wherein A is a hydrazone bond, 〇 is 〇; L is · C &CH2; and 卩 together form a covalent jR2 and is attached thereto The nitrogen atoms together form a heterocyclic ring selected from the group consisting of azacyclohexyl, a sulfonium, a sulfhydryl, a thiol, a hexahydropurine 98683.doc 1333489, a hexahydropyridyl, a pyridyl, a pyrrole Pyridyl, (2R)_2-methylpyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, 3 6 dioxo (2 acridinyl, thiomorpholinyl and ι,ι_) Dioxa bridge thiomorpholinyl; R3, R4, heart and R7 are hydrogen; 116 is -2 (^3 ft. 22; r20 is aryl; L3 is c(=〇); and ruler 22 is cycloalkyl In another embodiment, the compound of the invention has the formula (1) wherein A is a covalent bond, D is 0, L is -CH2CH2.; p and q together form a covalent bond; 1 and 1 are attached The nitrogen atom attached thereto forms a heterocyclic ring, which is selected from the group consisting of aza-nitro-fentyl, (3S)-3-(diguanylamino)p, piroxime, (3r)_3_(dimethylamine) Pyrrolidinyl, 1H-imidazole-1.yl, (3R)-3-hydroxypyrrolidinyl, (3S)-3-hydroxy-1-pyrrolidine , (2S)-2·(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridinyl, 4-fluorenyl 1-hexahydropyridyl, 2-methyl-1-hexahydropyridinyl, hydrazine-hexahydropyridyl, (211,51〇-2,5-diamidinopyrrolidinyl, (cis)_2,5 _Dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, (2R)_2-methyl_1·pyrrolidinyl, (2S)-2-methyl-1- Ethrolidinyl, (2R)-2-methyl-5-oxo-1-pyrrolidinyl, (2S)-2-methyl-5-oxo-indole-p-pyridyl, 3,6 _Dihydropyridinyl, (2S)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2R)_2-(methoxycarbonyl)-1-pyridinyl, (2S)-2-( Fluoromethyl)-1-pyrrolidinyl, (2R)_2-(fluoromethyl)-1-pyrrolidine, (2R)-2-ethyl-Ι-p piroxime, 2,2- Dimethyl- Ι-p ratio 0 each bite, (2S)-2-ethyl-Ι-p piroxicam 4- morphyl, 2-吟-5-azabicyclo[2.2.1] Hg-5-yl or 1,4-diox-8-azaspiro[4.5]dec-8-yl; R3, R4, R5 and R7 are hydrogen; R6 is -R2〇L3R22; R20 is aryl; L3 Is C(=0); and ^22 is a cycloalkyl group. 98683.doc -32- 1333489 in another In a specific embodiment, the compound of the present invention has the formula (ί), wherein Α is a covalent bond; 〇 is 〇; L is · CH2Ch2_ ; and 〇 together form a covalent bond 'R> R2 and attached thereto The nitrogen atom __ forms a heterocyclic ring ((8)-2_methyl-1-carbocarbyl group, R3, r4, heart and heart are hydrogen; &Κ2〇Ι^_Κ22; r2〇 is phenyl; h Is C(=〇); and r22 is a cycloalkyl group. In another specific embodiment, the compound of the present invention has the formula (1) wherein A is a covalent bond; 〇 is 〇; L^CH2CH2· ; together forms a covalent bond 'to form a nitrogen atom attached thereto The heterocyclic ring is selected from the group consisting of azacyclopentadienyl, azetidinyl, and (iv). Lin, hexahydro (tetra), hexahydropyridyl, pyridyl, pyrrolidinyl, 2-methylpyrrolidine 2,5-hydro-1H-pyrrolyl, pyrrolyl, 3,6-dihydro- K2H)·pyridyl, thio-naphthyl and dioxo-bromo-thio-l-based; R3, R4, heart and R7 are gas; m〇L3R22; R2. Is an aryl group; L3 is C(=0); and r22 is an aryl group.

In another embodiment, the compound of the present invention has the formula wherein A is a covalent bond; D is a hydrazine; B is a hydrazine; and a co-bonding '1^ and a stalk 2 are formed and attached thereto The nitrogen atoms together form a heterocyclic ring selected from the group consisting of aza-anthracyl, (3S)-3-(dimethylamine-cyclohexyl, (3R)3.(diamino)indenyl, IHUi., ( 3R)_3 via ketones (3S)-3-hydroxypyrrolidinyl, (2s) 2_(hydroxymethyl)pyrrolidinyl (2卟2-(hydroxymethyl).pyrrolidyl, (cis) 2,6-dimethylhexahydropyridine:, methyl]•hexahydropyridyl, 2-methyl+hexahydropyridyl, 丨_hexahydropyridine as 2R'5R)-2,5-di T Base ton, bite base, (cis) _2,5_ dimethyl thiol bite base than sulfhydryl group, 2-mercapto lobular stellate base, (2R) _2 _ methyl small ton 98683.doc • 33 · 1333489, (2S)-2-mercapto-1-pyrrolidinyl, (2R)_2_methyl_5_oxo-pyrrolidinyl, (2S)-2-methyl-5-oxo -1-pyrrolidinyl, 3,6-dihydro-1 (2H-pyridyl, (2S)-2-(methoxycarbonyl)_1-pyrrolidinyl, (2R)_2-(methoxycarbonyl) 1 pyrrole Pyridyl, (2S)-2-(fluoromethyl)-1-pyrrolidinyl, (2r)_2_( Fluoropyryl pyrrolidinyl, (2R)-2-ethyl-1-pyrrolidinyl, 2,2-dimethyl-indenyl pyridinyl, (2S)-2-ethyl-indole-p ratio Bite base 4·Nupipyl, 2_g_5_azabicyclo[2.2.1]hept-5-yl or 1,4-diox-8-azaspiro[4.5]癸-8-yl; ruler 3, ruler 4,

R5 and R7 are hydrogen; R6 is -R2〇L3R22; R20 is aryl; [3 is c(=〇); and Κ·22 is aryl 8

In another embodiment, the compound of the invention has the formula (1) wherein hydrazine is a covalent bond; D is 0; L is -CH2CH2-; Ρ and q together form a covalent bond; heart and heart are attached The nitrogen atoms thereon form a heterocyclic ring (2 phantom _2-methyl-1-pyrrolidinyl; r3, r4, r#r7 are hydrogen; Re_R2QL3_R22; R2. is phenyl; 1^ is (:(= 0); and R22 is 〇, 1, 2 or 3 selected from the group consisting of hydrogen oxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, aryl, halooxy, a phenyl group substituted with a halogen, a halogen, a hydroxyalkyl group, a fluorenyl group, a (NRaRb) carbonyl group or a substituent of -NRaRb. In another embodiment, the compound of the invention has the formula wherein A is a covalent bond, D is 0, L is -CH2CH2-; P and Q together form a covalent bond; RjaR2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from azetidinyl, azetidinyl, Imidazolyl, morpholinyl, hexa-argon, hexahydropyranyl, pyridyl, pyrrolidinyl, (2R)_2-methyl-indenyl-pyridyl, 2,5-dihydro-1H- Pyrrolyl, pyrrolyl, 3,6-dihydro-indole (2]9[)-pyridyl Thiomorpholyl and 1,1-dioxo bridge thiomorpholinyl; 尺3, r4, ^ and 98683.doc -34- 1333489 R7 is hydrogen, ruler 6 is -R2〇L3R22; Κ·20 is fang Base; L3 is C(=0); and R22 is

miscellaneous . W In another embodiment, the compound of the invention has the formula (1) wherein A is a covalent bond; D is 0; L is -CH2CH2; P and Q together form a covalent bond, and R2 is attached The nitrogen atoms thereon form a heterocyclic ring selected from h azacyclopentyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R) 3 (dimethylamino)pyrrolidinyl , 1H-imidazol-1-yl, (3R)_3_hydroxypyrrolidinyl, (3S)-3-hydroxy-indole-pyrrolidinyl, (2S)_2-(hydroxymethyl)pyrrolidinyl, (2R) -2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridinyl, fluorenylmethyl-1-hexahydropyridinyl, 2-methylhexahydropyridyl, 丨_6 Hydropyridyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-1-pyrrolidine (2R)_2_methyl_i_pyrrolidinyl, (2S)-2-methyl-1·pyrrolidinyl, (2R)_2-methyl-5 oxopyrrolidinyl, (2S) -2-methyl-5-oxo-1-pyrrolidinyl, 3,6-dihydro-1 (2-deoxy-pyridyl, (2S)-2-(methoxycarbonyl)-pyrrolidinyl, ( 2R)_2_(methoxycarbonyl)pyrrolidinyl, (2S)-2-(fluoromethyl) )-i-pyrrolidinyl, (2R) 2 gas fluoromethyl pyrrolidinyl, (2R)-2-ethyl-1-pyrrolidinyl, 2,2-dimethyl-indole-pyrrolidinyl, 2S)-2-Ethyl-1-pyrrolidinyl 4-morpholinyl, 2•唠·% azabicyclo[2.2.1]hept-5-yl or 1,4-diazepine snail [ 4.5] 癸-8-yl; r3, r4, r#r7 are hydrogen; r6S-r2gl3r22; R2 is an aryl group; L3 is c(=〇); and R22 is a heterocyclic ring. In another embodiment, The compound of the present invention has the formula ([), wherein A is a covalent bond; D is hydrazine; L is -C^CH2·; p*Q together form a covalent bond, 1^ and the ruler 2 attached thereto The nitrogen atoms together form a heterocyclic ring (2R)_2A 98683.doc -35· 1333489 pyrrolidinyl; r3, r4, uldent 5 and uldent 7 are hydrogen; R6S-R20L3R22; R20 is a stupid group; L3 is C (=0) And R22 is 2-pyrimenyl. Roots According to other specific examples, the compounds of the invention have formula (II)

Or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof, wherein 1 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl 'alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl Alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, decyl, tex, alkoxy, dentate, hydroxy, hydroxyalkyl, decyl, nitro, -nrarb, (nrarb) alkyl, (nrarb) carbonyl or (nrarb) sulfonyl;

Rs is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclic carbonyl or (NRARB)carbonyl; R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy Base, base, base, base, base, base, sulphur, slow base, slow base, cyano, cyanogen, methionine, i, dentate, alkyl, hydroxyl , hydroxyalkyl, fluorenyl, nitro, -nrarb, (nrarb)alkyl, (nrarb)carbonyl or (nrarb)sulfonyl; X is selected from CH, CRX or N; Y is selected from CH, CRY or N; Selected from CH, CRZ or N;

The Rx, 1^ and Rz groups are respectively selected from the group consisting of alkoxy groups, oxycarbonyl groups, alkyl groups, and calcinations 98683.doc -36 - 1333489 carbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl , alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, decyl, i, alkoxy, haloalkyl, thiol, hydroxyalkyl, sulfhydryl, nitro, _nrarb, Nrarb) burnt base, (nrarb) base or (nrarb) continuation base; and a, 〇, L, Ra,

Rb, R1, R2, R3, ft 4 and Κ·5 are as defined in the formula (I). In another embodiment, the compound of the invention has the formula (π) wherein hydrazine is a covalent bond and D, L, RA, RB, R2, R3, r4, r5, R7, R8, R9, X , Y and Z are as defined in formula (I). In another embodiment, the compound of the present invention has the formula (π) wherein hydrazine is a covalent bond; and 1 and 2 are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Cyano; and D, L, RA, RB, R3, r4, r5, uldent 7 and r9, X, Y and Z are as defined in formula (I). In another embodiment, the compounds of the invention have the formula wherein L is -CH2CH2-; hydrazine is a covalent bond; and the heart and !^ are each selected from the group consisting of hydrogen, alkyl, trans-homo, alkenyl or alkynyl; R4, R5, R^R9 are hydrogen; r8 is cyano; X is CH; Y is CH; Z is CH; and D, RA and RB are as defined in formula (I). In another embodiment, the compound of the invention has the formula (11) wherein A is a covalent bond; the heart and heart are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl, and R8 is cyano. X is N; Y is CH; Z is CH; and D, L, RA, Rb, R3, R4, R5, R7 and Ruler 9 are as defined in Formula (1). In another embodiment, the compound of the invention has the formula (11) wherein A is a covalent bond; Ri and the rule 2 are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Cyclocarbonyl: and D, L, ra, rb, r3, r4, &, r7, 98683.doc • 37· 1333489 n9, X, Y and z are as defined in formula (1). In another specific embodiment, the compound of the present invention has the formula (II) wherein hydrazine is a covalent bond; Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Cyclocarbonyl' wherein the heterocyclic ring is selected from the group consisting of hydrazine-azetidinyl, 4-morpholinyl, 1-hexahydropyridinyl, hexahydropyridyl, 3-pyridyl, bupyridyl, 2 , 5-dihydro-1H-pyrrolyl, fluorenylpyrrolyl, 3,6-dihydropyridyl, 4-thiomorpholinyl and 1,1-dioxo bridge thiomorpholine _4• group; and D , L, RA, RB, r3, r4, R5, r7, &, χ, ¥, and z are as defined in equation (1). In another embodiment, the compound of the invention has the formula (π) wherein hydrazine is a covalent bond; the heart and the sizing 2 are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl, and Rs is hetero a cyclocarbonyl group, wherein the heterocyclic ring is a 4-morpholino group; and D, L, a heart 'KB' K3 'R4, R5, R7, R9, χ, 丫, and z are as defined in the formula (1). In another embodiment, the compound of the present invention has the formula (II) wherein A is a covalent bond; L^CH2CH2_; ~ and ^ are each selected from the group consisting of hydrogen, affinity, a thiol or alkynyl group; , Rule 4, R5, R7 and R9 are hydrogen; R8 is a heteronuclear carbonyl group, wherein the heterocyclic ring is a cardiomorpholinyl group; X is CH; Y is CH; Z is cn; and D, Ra*Rb is according to formula (1) ,Definition. In another specific embodiment, the compound of the present invention has the formula (Π) wherein ', oxime bond, heart and Rz are each selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or fast radicals. R8 is heterocycle a few groups; x is N; Y is CH; Z is CH; and D, L, Ra, Rb, R3, pu 3 R5, ruler 7, and ruler 9 are as defined in formula (I). In another specific embodiment, the compound of the present invention has the formula (11), wherein 98.683.doc -38· 1333489 is a covalent bond; Na is selected from the group consisting of hydrogen, affiliation, burnt base, dilute base or block R8 is a heterocyclic ring of the heterocyclic ring selected from the group consisting of azetidinyl, morpholinyl, hexahydropyridinyl, hexahydropyridyl, pyridyl, (tetra), 2,5-Dihydro·1H_"yl"-specific, 3,6-diazepine-U2H)-(tetra)yl, thio-, linyl and 1-decyloxy-thiol-based; 乂N Y is CH; Z is CH; and D'l, Ra, RbR3, r4, r5, r7 and R9 are as defined in formula (I). In another specific embodiment, the compound of the invention has the formula (Π), wherein A is a covalent bond; R丨 and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; and R8 is a heterocyclic group, wherein the heterocyclic ring is selected from a nitrogen heterocycle Ding Xuanji, 4 Malinky 1-', Hydropyridyl, Hexahydropyridyl, % Pyridyl, Bupyrrole, 2,5-Hydroxy-1Η-峨, K., 3,6_2 Hydrogen-(Η)· pyridyl, 4-thiomorpholinyl and anthracene dioxy bridge thiomorpholine _4_ group; X is ν ; CH ; Ζ is CH; and D, L, Ra, Rb, R3, R4, R5, 1 and 1 are as defined in formula (I). In another embodiment, the compound of the invention has the formula (π Wherein Α is a covalent bond; the heart and the rule 2 are respectively selected from hydrogen, an alkyl group, a hydroxyalkyl group, an alkenyl group or an alkynyl group, and Re is a heterocyclic carbonyl group, wherein the heterocyclic ring is a 4-morpholinyl group; N; γ is CH; Ζ is CH; and D, L, Ra, Rb, R3, R4, &, Ruler 7 and R9 are as defined in Formula (I). In another embodiment, the present invention The compound has the formula (π), wherein A is a covalent bond; L is -CHzCH2-; the heart and ^^ are respectively selected from hydrogen, alkyl, technical, dilute or block; &, I, R5, ruler 7 and R9 are hydrogen; R8 is a heterocyclic group 'wherein the heterocyclic ring is 4-morpholinyl; χ is n; γ is CH; Z is CH; 98683.doc •39· 1333489 and D, RA and heart follow In a specific embodiment, the compound of the present invention has the formula (9) wherein A is a covalent bond; R々R2 forms a heterocyclic ring with the nitrogen atom attached thereto, and D , L, RA, RB, R3, R4, R5, R7, R8, R9, x, y and Z according to In a further embodiment, the compound of the invention has the formula (9) wherein A is a covalent bond; RjnR2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from nitrogen Heterocyclic pentane, silk, azetidinium (tetra), (tetra)yl, morphinyl, hexahydro-t-well, hexahydroindenyl (4)yl" (iv) fluorenyl, (tetra)-2-methylpyrrolidyl, 2 , 5 · dihydro-1 Η pyrrolyl, pyrrolyl, 3,6 · digas 1 (2H) than sulfhydryl, thiomorphinyl and ii _ dioxo bridge thioprolin; ^ is cyano; And D, L,,, Rb, R3, R4, R5, R7, R9, χ, γ8 and z are as defined in formula (I). In another specific embodiment, the compound of the invention has formula (9) Wherein eight are covalent bonds; RAR2 is attached to the I atom attached thereto to form a smear from 1 azetiline, (3S)-3-(dimethylamino)pyrrolidinyl, 3R)-3-(dimethylamino), more than 0 each bite, m-salt small group (10) keto-based small pyrrolidinyl, (3S)-3-hydroxypyrrolidinyl, (2S)_2-( Hydroxymethyl)pyrrole, (2R)-2-(methyl)methyl thiol, (cis)-2,6-dimethylhexaaza(tetra)yl, 4-methyl Hexahydro, pyridinyl, 2-indenyl hexahydroacridinyl, hexahydroindolyl, (2R,5R)W·dimethyl(tetra)bite, (cis)_2,5-dimethylton each Base 1 ? ratio of each bite group, 2-methyl-1-P ratio bite group, (2R)_2_mercapto_i·pyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl , (2R)-2-methyl-5-oxo-perphenoline, (called 2.methyl_5_oxo) ♦ each bite, 3,6-two gas 98683.doc 1333489 -1 ( 2H)-pyridyl, (2S)-2-(methoxycarbonyl)-pyrrolidinyl, (2R)2(methoxybenzyl)-1-r-r-hexyl, (2S)-2-(fluoromethyl) Pyrrolidinyl, (2R)-2-(fluoromethyl)-1-pyrrolidinyl, (2R)-2·ethyl·pyrrolidinyl, 2,2·dimethyl-1-pyrrolidinyl (2S)-2-Ethyl-1-pyrrolidinyl-4·morpholinyl, 2_吟-5-azabicyclo[2.2_1]hept-5-yl or ι,4-diindole-8-nitrogen Heterospiro[4.5]癸-8-yl; R8 is a gas group; and D, L, RA, rb, r3, &, &, &, R9, X, Y, and z are in Formula (I) Definitions e In another embodiment, the compounds of the invention have the formula (II) wherein A is a covalent bond; L is -CHzCH2-; 1^ and 1^2 with a nitrogen atom attached thereto Forming a heterocyclic ring together, selected from the group consisting of azacyclopentyl, azetidinyl, imidazolyl, morpholinyl, hexahydropyrryl, hexahydropyridyl, pyridyl, pyrrolidinyl, (2R)- 2-methyl-1-pyrrolidinyl, 2,5-dihydro-exo-pyrrolyl, pyrrolyl, 3,6-dihydro-1(2H)-pyridyl, thiomorpholinyl and M-diox a bridge thiomorpholinyl; I, R4, & and I are each selected from the group consisting of hydrogen, alkyl, alkylcarbonyl and halogen; and Rs and R9 are each selected from the group consisting of hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, Carboxy, cyano, formyl, dentate, dentate, haloalkoxy, hydroxyalkyl or fluorenyl; X is selected from CH and CRX; γ is selected from CH and CRY; z is selected from CH and CRZ; Rx, rara are selected from alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, decyl, halogen, dentate, haloalkoxy, hydroxyalkyl or decyl. In another specific embodiment, the compound of the present invention has the formula wherein A is a covalent bond; 1 is -CHzCH2-; the cardinalization together with the nitrogen atom attached thereto forms a heterocyclic ring selected from the group consisting of i-nitrogen Heterocyclopentyl, (3S)_3_(dimethylamino) 11 is more specific than each bite, (3R)-3-(dimethylamino)p, slightly biting, 1H_imipropion, 98683.doc -41- 1333489 (3R)-3-hydroxy-1-pyrrolidinyl, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R) -2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-diamidinohexahydropyridyl, 4-methyl-1-hexahydropyridyl, 2-methyl-1-hexahydropyridine , 1-hexahydropyridyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-dimercaptopyrrolidinyl, 1-pyrrolidinyl, 2-methyl -1 -pyrrolidinyl, (2R)-2-methyl-1-pyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl, (2R)-2-methyl-5-oxy代-I-»»Bilo bite, (2S)-2-methyl-5-oxo-oxime-p-pyridyl, 3,6-dihydro-1(2H)-pyridyl, (2S )-2-(methoxycarbonyl>1-pyrrolidinyl, (2R)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2S)-2-(fluoromethyl)-1-p ratio · cryptyl, (2R)-2-(say methyl)-1 -p piroxime, (2R)-2-ethyl-1 -1»pyrrolidyl, 2,2-dimethyl- 1-pyrrolidinyl, (2S)-2-ethyl-1-pyrrolidinyl 4-morpholinyl, 2-indol-5-azabicyclo[2.2.1]hept-5-yl or 1,4 · Diterpene-8-azaspiro[4.5]癸-8-yl; feet 3, 1^4, 1^5 and 1^7 are respectively selected from hydrogen, affinity, carbonyl and halogen; R8 and R9 are respectively selected From hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxyl, cyano, methionyl, dentate, alkyl, haloalkoxy, hydroxyalkyl or decyl; X is selected from CH and CRX Y is selected from CH and CRY; Z is selected from CH and CRZ; and Rx, RY, and Rz are each selected from the group consisting of an alkoxy group, an alkyl group, an alkoxy group, a pyridyl group, a slow group, a cyano group, a thiol group, a dentate, a dentate group, a haloalkoxy group, a hydroxyalkyl group or an elbow group. In another embodiment, the compound of the invention has the formula (π) wherein A is a covalent bond; L is -CH2CH2. The ruthenium and R 2 together with the nitrogen atom attached thereto form a heterocyclic ring, and the heterocyclic ring is substituted with hydrazine, 1 or 2 substituents selected from an alkyl group; R 3 , R 4 , R 5 , 117 and R 9 are hydrogen; r 8 Is a cyano group; \ is CH; γ is CH; Z is CH. 98683.doc • 42· 1333489 In another embodiment, the compound of the invention has the formula (π) wherein L is —CH 2 CH”; VIII is a covalent bond; and attached thereto The nitrogen atom - to form a heterocyclic ring - from azacyclopentyl, azetidinyl, imidazolyl, morpholinyl, hexahydropyrrole, hexahydropyridyl, pyridyl, pyrrolidinyl (2R )-2-methyl]xinbibita, 2,5•diazepinelylpyrrolidyl, 3'6-dihydro-1 (211 bbityl, thio-r-decyl and 1, 1-Dioxy bridge thiomarinyl, R3 is a heterocyclic ring; R4, &, ~ and ~ are hydrogen; are cyano; χ is CH; Υ is CH; and ζ is CH. In another specific embodiment, the compound of the present invention has the formula (11) wherein L is -CHKH2-; hydrazine is a covalent bond; and the heart and the Han 2 together with the nitrogen atom attached thereto form a heterocyclic ring, From 1-azetidinyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3-(diamido)pyrrolidinyl, ιΗ_imidazole-丨-yl, (3R)-3-carbyl-1_indolyl, (3S)3-yl-pyridinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)_2_(hydroxyl Methyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridyl, 4-mercaptohexahydropyridyl, 2-methylhexahydro"biteryl, hydrazine-hexahydropyridyl, (2R,5R)-2,5-dimethylpyrrole, (cis)-2,5-dimethylpyrrolidinyl, i. pyrrolidinyl, 2-methylpyridylpyridyl, (2R -2-methyl_ι_ρ specific pyridyl, (2S)_2-methylpyrrolidinyl, (2R)-2-methyl-5-oxo-1-pyrrolidinyl, (2S)_2_A 5-Oxo-1-pyrrolidine, 3,6-dihydro·ι(2Η)-pyridyl, (2S)-2-(methoxycarbonyl)pyridinyl, (2R)-2 -(methoxycarbonyl)-1-pyrrolidinyl, (2S)-2-(fluoromethyl) 4-oxime each pyridine group, 2R)-2-(fluoromethyl)-1-pyrrolidinyl, (2R)-2-ethyl-1-tonridinyl, 2,2-diindenyl-yl-pyrrolidinyl, (2S) _2_Ethyl-丨-pyrrolidinyl 4-morpholinyl, 2-indol-5-aroxabicyclo[2.2.1]hept-5-yl or 1,4-diox-8-nitrogen 98683.doc -43· 1333489 Heterospiro[4.5]癸-8-yl; R3 is heterocyclic; r4, r5, r^r9 are hydrogen; 尺8 is cyano; X is CH; Y is CH; and Z is CH. In another specific embodiment, the compound of the present invention has the formula (II) wherein L is ·CHKH2-; A is a covalent bond; and 1 and 2 are together with a nitrogen atom attached thereto to form a heterocyclic ring ( 2R)-2-methyl-1-pyrrolidinyl; r3 is a heterocyclic ring selected from 2-indolyl '3-pyridyl and 2-nonyl, which is selected from hydrazine, 1 or 2 selected from hydrogen Substituting a substituent of an alkoxy group, an alkyl group, an alkoxycarbonyl group, an alkylcarbonyl group, a carboxyl group, a cyano group, a decyl group, a halogen, a halogen group, a dentate group, a hydroxy group or a fluorenyl group

Heterocycle; R4, R5, 尺7 and r9 are hydrogen; cyano; X is CH; γ is CH; and Z is CH. In another specific embodiment, the compound of the present invention has the formula (π) wherein hydrazine is a covalent bond; the core and the caliper 2 together with the nitrogen atom attached thereto form a heterocyclic ring 'R8 is a cyano group; X is N; Y is CH; Z is CH; and D, L, Ra, Rb, R3, R4, R5, 117 and r9 are as defined in the formula (1).

In another embodiment, the compounds of the invention have the formula (π) wherein A is a covalent bond; ^ together with the nitrogen atom attached thereto to form a heterocyclic ring 'selected from a nitrogen heterocyclopentyl' azetidin-based κ group, morphaki, hexahydro-t-well, hexahydro-ton-7-based ratio丝"Bilo bite, (2r)_2•methyl-1-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, 3, fluorene-dihydro-U2H)-filament, sulfur代琳琳基和191_二氧桥硫代琳基;^ is cyano; X is N; Y is CH; Z is CH; and D, L, Ra, Rb, ^ 8 R4, R5, R? And R_9 are as defined in equation (1). In another specific embodiment, the compound of the present invention has the formula (9), wherein A is a covalent bond; R>r2 forms a 98683.doc-44-1333489 ring' with the nitrogen atom attached thereto. 1-azetidinyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, iH-imidazol-1-yl, ( 3R)-3·hydroxy-1_ 峨 咬, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrole, (2R)-2-(hydroxy Methyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridyl, 4-methyl-i-hexahydropyridyl, 2-methyl-1-hexahydropyridyl, i•six Hydroquinone, (2R,5R)-2,5-dif-pyrrolidinyl, (cis)-2,5-dimethylpyridinyl, 1-pyrrolidinyl, 2-methyl-^ Pyrrolidinyl, (2r)_2-methylpyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl, (2R)-2-methyl-5-oxo-1_ (2S)_2-Methyl-oxo-i-pyrrolidinyl, 3,6-dihydro-1 (2HX dimethyl, (2S)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2R)_2_(Methoxymethyl)-1.pyrrolidinyl, (2S)_2_(fluoromethylpyrrolidinyl, (2R)-2' (fluoromethyl) Small pyrrolidinyl, (2R)-2-ethyl-1-indolepyridyl, 2,2-dimethyl-1-pyrrolidyl, (2S)_2-ethyl-indole-pyrrolidinyl 4 _ morpholinyl, 2_%-5-azabicyclo[2.2.1]g _5_yl or 1,4_di 11 _8_azaspiro[4.5]癸-8-yl, ruler 8 Cyano;;^N; 丫 is (3); B is (3); and D, L, A.

Rb, R3, R4, R5, r7 and Ruler 9 are as defined in the formula (1). In another specific embodiment, the compound of the present invention has the formula (η) wherein A is a covalent bond; the ratio and the ruler 2 together with the nitrogen atom attached thereto form a heterocyclic ring; R8 is a heterocyclic carbonyl group; And D, L, Ra, Rb, R3, &, &, I, r9, X, Y and z are as defined in formula (1) e. In another embodiment, the compound of the invention has formula (II) Wherein Α is a covalent bond; the heart and the dent 2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from the group consisting of azacyclopentyl, azetidinyl, oxazolyl, morphinyl/ , hydrogen pyridinyl, hexahydropyridyl, pyridyl, pyrrolidinyl, 986S3, doc-45-1333489 f-l-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, 3 a 6-dihydro-1(2H)-anthracene group, a thiomorpholinyl group and an azuronium oxymorpholinyl group; wherein is a heterocyclic carbonyl group, wherein the heterocyclic carbonyl heterocycle is selected from the group consisting of Azetidin-based, ··# base, hydrogen-hydrogen t-base, hexahydroindenyl group than biting base 'acridinyl, 2,5-dihydro-1H-pyrrolyl”-pyrrolyl, 3 6_Dihydro·1 (2H bupidyl, thiomorpholinyl and 1,1_dioxo bridge thio? Group; and square, L, Ra,

Rb, R3, R4, R5, R7, r9, χ, ¥ and z are as defined in the formula (1). In another specific embodiment, the compound of the present invention has the formula (π) wherein A is a covalent bond; and the core and 1 together with the nitrogen atom attached thereto form a heterocyclic ring selected from a nitrogen heterocyclopentyl group. , azetidinyl, imidazolyl, morpholinyl, ', hydroquinone, hydrazinyl, acetophenone, acetophenone, methylpyrrolidyl, 2,5-di Hydrogen·1H_pyrrolyl, pyrrolyl, 3,6•dihydro-1(2H)-pyridyl, thiomorpholinyl and anthracene, dioxo bridge thiomorpholinyl; heart is a heterocyclic group Wherein the heterocyclic ring is selected from the group consisting of i azetidinyl, cardinyl, hexahydropyridinyl, 1-hexahydropyridyl, 3-pyridyl, bupyridyl, 2, fluorene-hydrogen- 1H-indolyl, babi & base, 3,6-dihydro] (10) b-bityl, dethiomorpholinyl and anthracene, 1 · dioxo bridge thiomorpholin-4-yl; and D , [, Ra, Rb, H4 ' R5, R7, R9, χ, 丫 and 2 are as defined in the formula (1). In another specific embodiment, the compound of the present invention has the formula (Π) wherein Α is co-(iv); R#R2 forms a heteroquinone together with the gasogen + attached thereto, and is selected from the group consisting of a nitrogen heterocycle. Pentyl, (3S)_3_(dimethylaminocyclorrolidine, (3R)-3_(dimethylamino)oxaridinyl, 1H-imidazole·ι_yl, (3r)_3, hydroxy~1 _Pyrrolidinyl, (3S)-3-hydroxy-1-pyrrolidyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxyindenyl)pyrrolidinyl, (Shun) _26 dimethyl 98683.doc 1333489

1-hexahydropyridyl, (2R,5R)-2,5-dimethylpyrrole, (cis)·2,5-dimethylpyrrolidinyl, fluorenylpyridinyl, 2-indenyl _丨_pyrrolidinyl, (2r)_2 methyl-1-pyrrolidyl, (2S)-2-methyl-1-pyrrolidinyl' (2R)_2_甲芙_5

Bicyclo[2.2.1]hept-5-yl or 1,4-di-4-8-azaspiro[4.5]dec-8-yl; 118 is heterocyclic carbonyl' wherein the heterocyclic carbonyl heterocycle is selected Self-limiting includes azetidinyl, morpholinyl, hexahydropyridinyl, hexahydropyridyl, sulfanthene, piranthene argon-1(2H)·pyridyl, and D, L, RA, RB,

The definition in formula (1). In another specific embodiment, the compound of the present invention has the formula (π) wherein A is a covalent bond; the heart and the oxime together with the nitrogen atom attached thereto form a heterocyclic ring selected from the group consisting of 1-azacyclopentane Alkyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazolium-yl, (3R)-3-hydroxy-pyrrole Pyridyl, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)_2(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)_2, 6-Dimethylhexahydropyridyl, 4-mercapto-1-hexahydropyridyl, 2-methyl-hydrazine-hexahydropyridyl, hexahydrohydropterin, (2R,5R)-2,5 - dimethylpyrrolidinyl, (cis > 2,5-dimethyl ton 98683.doc -47· I333489 嘻01 base, Ι-ι» piroxime, 2-methyl-1-p bilo Ticone, (2R)-2-methyl-1-pyrrolidinyl, (2S)-2-methyl-1-pyridinyl, (2R)-2-methyl-5-oxo-1- Ethrolidinyl, (2S)-2-mercapto-5-oxo-indole-pyrrolidinyl, 3,6-dihydro-l(2H)-p ratio, (2S)-2-(曱Oxymethyl) carbyl, (2r)_2·(methoxycarbonyl)-1-pyrrolidinyl, (2S)-2-(fluoroindolyl)-i-pyrrole Pyridyl, (2R)-2-(fluoromethyl)-pyrrolidyl, (2R)-2-ethyl-I-pyridyl, 2,2-dimercapto-1-pyrrolidinyl, (2S)-2-Ethyl-1-pyrrolidinyl 4_morpholinyl, 2_$-5-azabicyclo[2.2.1]hept-5-yl or ι,4-dioxazaspiro[ 4.5]癸

-8-yl·, Re is a heterocyclic carbonyl group, wherein the heterocyclic ring is selected from the group consisting of azetidinyl, 4-morpholinyl, 1-hexahydropyridinyl, hydrazine-hexahydropyridyl, and %pyridyl ,pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, 1·pyrrolyl, 3 6-dihydroipH)·pyridyl, 4-thiomorpholinyl and benzodiazepine Morpholinyl; and 〇, L, RA, RB, R3, r4, r5, r7, &, χ, 丫 and z are as defined in formula (1). In another embodiment, the compound of the invention has the formula (11) wherein hydrazine is a covalent bond; Ri#oR2 together with the nitrogen atom attached thereto forms a heterocyclic ring selected from azeticycloalkyl , azetidinyl, imidazolyl, morpholinyl,

, hydrogen ratio well base, /, hydrogen, bite base "bite base" than the bite base, (π) · 2 ratio slightly bite base, 2,5-dihydro_1Η-峨 mouth base, mouth ratio a 3,6-di(indenyl)pyridinyl group, a thiomorpholinyl group and a dioxo bridge thiomorpholinyl group; a heterocyclic group wherein the heterocyclic ring is a 4-mercapto group; and D, L , Ra, r 4 5 R7, R9, X, ¥ and 2 are as defined in the formula (I). In another embodiment, the compound of the present invention has the formula (9), which is a "bean bond", and 1 and R2 together with the II atom attached thereto form 98683.doc • 48·1333489 ring 'selected from 1-nitrogen Heterocyclopentyl, (3S)-3-(diamido)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazol-1-yl, (3R)- 3-hydroxy-1-pyrrolidinyl, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)-2-(hydroxyindenyl)pyrrolidinyl, (2R)-2-(hydroxyl decyl) Pyrrolidinyl, (cis)-2,6-dimercaptohexahydropyridinyl, 4-methyl-1-hexahydropyridyl, 2-methyl-N hexahydropyridinyl, hexahydropyridyl, 2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, (2R -2-methyl-1-pyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl, (2R)-2-mercapto-5-oxo-1-

Outside hip-hop bite, (2S)-2·methyl-5-oxo-1-pyrrolidinyl, 3,6-dihydro-1(2Η)-say bite base, (2S)_2•(曱氧Carbonyl pyrrolidinyl, (2r) 2 (decyloxy)-1-pyrrolidinyl, (2S)_2_(fluoromethyl)-indolylpyrrolidinyl, (2R)-2-(fluoromethyl)_ Bupyridyl group, (2R) 2 ethyl]-pyrrolidinyl, 2,2-dimercapto-1-pyrrolidinyl, (2S)_2-ethylpyrrolidinocardyl morpholino, 2_ 噚_5_ Azabicyclo[2.2.1]hept-5-yl or 1,4-dioxa-8-azaspiro[4.5]癸-8-yl; R8 is a heterocyclic carbonyl group, wherein the heterocyclic ring is 4-? Lolinyl; and D, l,

Ra, Rb, R3, R4, r5, r7, R9, χ, ¥ and z are as defined in the formula (1). In another embodiment, the compound of the present invention has the formula (I) wherein A is a covalent bond; and R#R2 forms a ring together with a nitrogen atom attached thereto, selected from the group consisting of a heterocyclic Newnesyl group,氡 氡 院 院, (4), hexahydroindolyl, hexahydro (tetra), cardinal, silk, 2 soil 1 than bite base, 2,5-_ gas_1Η_ρ ratio base, ground Loki, 36·: base, sparse ruthenyl and u•dioxo bridge rhyme base is nitrogen; R8 is a heterocyclic group, wherein the heterocyclic ring is 4 98683.doc -49- I333489 · X is CH; Y is CH; Z is CH; and D, L, RA Rb are as defined in formula (I). In another embodiment, the compound of the invention has the formula (Η) wherein Α is a covalent bond; Ri and Rz together with the nitrogen atom attached thereto form a heterocyclic ring selected from 1-azacyclopentane Alkyl, (3S)_3_(diamido)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, iH-imidazole-i-yl, (3R)_3-hydroxy·ι_pyrrole Pyridyl, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyridinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis _2,6-Dimethylhexahydropyridyl, 4-methylhexahydropyridyl, 2-methylhexahydropyridinyl, fluorenyl-hexahydropyridinyl, (2R,5R)-2,5-dimethyl Pyrrrolidinyl, (cis)-2,5-dimercaptopyranyl, Ι-ι»Biha, 2-methyl-lp ratio, (2R)-2-methyl_ι_ Pyrrolidinyl, (2S)-2-mercapto-1-pyrrolidinyl, (2R)-2-methyl-5-oxo-1-11 piroxime, (2S)-2-methyl- 5-oxo-1-pyrrolidinyl, 3,6-dihydro-1(2H)-p-pyridyl, (2S)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2R)_2 ·(Methoxymethyl)-1-pyrrolidinyl, (2S)_2_(fluoroindolyl)_i_pyrrolidinyl, (2R)-2-(fluoroquinone Pyrrolidinyl, (2R)_2·ethylpyrrolidinyl, 2,2·dimethyl-1-pyrrolidinyl, (2S)-2-ethyl-1-pyrrolidinyl 4-morpholinyl, 2 -11--5-azabicyclo[2.2.1]hept-5-yl or 1,4-dioxa-8-azaspiro[4·5]dec-8-yl; R3, r4, r5, r^r9 is hydrogen; r8 is a heterocyclic carbonyl group, wherein the heterocyclic ring is 4-morpholinyl; X is Ch; γ is CH; Z is CH; and D, L, Ra and Rb are as defined in formula (1) In another embodiment, the compound of the present invention has the formula (11) wherein A is a covalent bond; 1 and R 2 together with a nitrogen atom attached thereto form a heterocyclic ring; R 8 is a heterocyclic carbonyl group; X is N; Y is CH; Z is CH; and D, L, RA, 98683.doc • 50- 1333489

Rb, r3, r4, r5, ruler 7, and ~ are as defined in the formula (1). In another embodiment, the compound of the present invention has the formula (9), and the second is a covalent bond; L^CH2CH2_; R?R2 together with the gas atom attached thereto forms a heterocyclic ring? Qianji, azetidinyl fluorenyl, hexahydro (tetra) (tetra), hexafil, helix "pyridinyl, 2-mercapto]-pyrrolidinyl, 2 5 -dihydro·m Pyrrolyl, pyrrolyl, 3,6-dihydro·1(2Η)_Ρ 咬 咬, thio-primate and u-dioxo bridge thio- 啦 基 · RA RA RA RA RA RA RA RA RA RA RA RA It is selected from the group consisting of azetidin, 4-merinyl, hexahydrohydrocarbyl, hexanitroxyl, 3 ton, 1-pyrrolidyl, 2'5·dihydro-1H- Pyrrolyl, byryl, 3,6-dihydropyridyl, 4·thiomorpholinyl and u-dioxo bridge thiomorpholine _4_ group; X is N; Y is CH; Z is CH; D ' L, Ra, Rb, R 3 , R 4 , R 5 , R 7 , and R 9 are as defined in formula (I). In another specific embodiment, the compound of the invention has the formula (π) wherein A is Covalent bond; L is -CHzCH2-; the core and the nitrogen atom attached thereto form a heterocyclic ring selected from 1-azacyclopentyl, (3S)_3_( Methylamino)pyrrolidinyl, (3R)-3-(dimethylamino)indolepyridyl, 1H imidazolyl, (3R)-3-hydroxy-1-pyrrolidinyl, (3S)_3_ Hydroxy-pyridylpyridinyl, (2S)-2-(hydroxyindenyl)pyrrolidinyl, (2R)_2-(hydroxymethyl)pyrrolidyl, (cis)-2,6-dimethylhexahydro Pyridyl, 4-methyl-bishexahydropyridyl, 2-methyl-1-hexahydropyridyl, 1-hexahydropyridyl, (2R,5R)_2,5-dimethylpyrrolidinyl, Cis)-2,5-dimethylpyridinyl, specific pyridine, 2-methylpyridinyl, (2R)-2-methyl-1-pyrrolidyl, (2S)_2_ Methyl pyrrolidinyl, (2R)-2-mercapto-5-oxo-1-pyrrolidinyl, (2S)_2-mercapto-5-oxopurine/pyridyl 98683.doc •51 · 1333489 Base, 3,6·dihydro·1(2H)-fluorenyl, (2S)2(f-oxyl-yl)pyrrolidyl (2R)-2-(methoxy-l-butyl group, (2s) _2_(say methyl) lobular guanidine, (2R)-2-(fluoro) quinone, (2r) 2 ethylpyrrolidinyl, 2,2-dimethyl + pyrrolidine (2S)_2-Ethylpyrrolidinyl 4-hydrazino, 2 Winter 5_Azabicyclo[221]hept-5•yl or Μ_ϋAzaspiro[4.5]夭8 And r8 is a heterocyclic group, wherein the heterocyclic ring is selected from the group consisting of azetidinyl, 4-morpholinyl, "hexahydropyrryl, 1-hexahydropyridyl, 3-pyridyl, i-pyrrole Pyridyl, 2,5•dihydro.pyrrolyl, bupyrolyl, 3,6-dihydro-1 (2 ketone, 'thiomorphinyl and oxothiomorpholin-4-yl; X is γ; γ is CH; 4CH; and D, Bu, Rn R4, R5 'I and R9 are as defined in the formula (1). In another embodiment, the compound of the invention has the formula (8) wherein A is a covalent bond; 1 is -CH2CH2_; RliaR2 forms a heterocyclic ring with a nitrogen atom attached thereto, selected from a nitrogen heterocycle Ethyl ketone, heterocyclobutanyl, imipenyl, hydrazino, hexahydropurine, hexahydropurine, bismuth, (2R)-2-methyl oxime (tetra) 2,5-Dihydro-m-based" ratio #咯基,3,6-^-1(2Η)·ρ-pyridyl, thio-rutyl, and oxa-hydrocarbazide环诚, the heterocyclic ring in the 为 为 is 4 吗 琳 基 基;; 1 γ is CH, · Z is CH; and D, L, Ra, Rb, R3, R4, R5, ^ and heart according to the formula (I In another specific embodiment, the compound of the present invention has the formula (Io), wherein _A is a covalent bond; L is _Ch2CH2·; R> R2 and a nitrogen atom attached thereto A heterocyclic ring is formed together, selected from the group consisting of: 1. azacyclopentyl, (3S) 3 (dimethylamino) pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazole丨-基\ 98683.doc -52- 1333489 (3R)-3-yl-pyridyl, (3S)_3_------,,,,,,,,,,,,,,, A Pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrole, (cis)-2,6-dimethylhexahydropyridyl, 4-methyl-1-hexahydropyridyl, 2_ Methyl-1-hexahydropyridyl, 1-hexahydropyridyl, (2R,5R)-2,5-dimethylpyrazole, (cis)-2,5-dimethylpyrrolidinyl, Pyrrolidinyl, 2-methylpyrrolidinyl, (2R)-2-methyl-1-pyrrolidinyl, (2S)-2-mercapto-1-pyrrolidinyl, (2R)-2-methyl -5-oxo-1-pyrrolidinyl, (2S)-2-methyl-5-oxopyloline, 3,6-dihydro-1(2H)-p-pyridyl, (2S) -2-(methoxycarbonyl)pyridinyl, (2R)-2-(methoxycarbonyl)pyrrolidinyl, (2S)_2_(fluoromethylbubbitin, (2R)-2 -(fluoromethyl)_!·pyrrolidinyl, (2R)-2-ethyloxazolidinyl, 2,2-dimethyl-hydrazine-pyrrolidinyl, (2S)_2-ethylpyrrolidinyl 4-morpholinyl, 2-indol-5-azabicyclo[2.2.1]hept-5-yl or 1,4-dioxazaspiro[4.5]dec-8-yl; Rs is heterocyclic carbonyl Wherein the heterocyclic ring is a morpholino group; X is N; Y is CH; z is CH; and D, L, Ra, Rb, r3, R4, R5, R·7 and R_9 are as defined in formula (1) In another one In the embodiments, the compound of the present invention has the formula (II) wherein A is a covalent bond; L is; Rj〇R2 forms a heterocyclic ring with a nitrogen atom attached thereto, and is selected from a nitrogen heterocyclopentyl group, Azetidinyl, immortalin, hexahydropyrene, hexahydro-P, bite, bite, P to P, thiol, (2R)·2' fluorenyl-i-pyrrolidinyl, 2,5-Dihydro-1H-pyrrolyl, pyridyl '3'6·dihydro-U2H)• acridinyl, thiomorpholinyl and 1,1-dioxo bridge thiophene. p „ ^ i, R4, R5, 117 and R9 are hydrogen; R8 is a heterocyclic carbonyl group, wherein the heteropoly is 4-morpholinyl; X is n; γ is ch; Z is CH; and D, L A Rb Han 3, R4, r5, ruler 7, and ruler 9 are as defined in the formula (1). 98683.doc • 53· 1333489 In a further embodiment, the compound of the invention has the formula (1)) wherein A is a covalent bond; LA rtr and _eH 2 CH 2 ; R 1 and R 2 are attached to the nitrogen attached thereto The atom is a heterocyclic ring selected from the group consisting of azacyclopentadienyl, (3S)-3-(dimethylamino), and each sulfhydryl group (3R)_3_(dimethylamine-based, slightly bite-based, ,•,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -2-(methyl)p piroxime, (cis)_2'6-dimethylhexahydrocarbazide, 4-methyl-1-hexahydroindole, 2-methyl 1_', Hydroquinone, 1_hexahydropyridyl, (2R,5R)_2,5:methylpyrrolidine-ruthenium (K) 2,5-methyl oxime-bite base '1· 口比洛基基,曱Base - I. mouth ratio bite base, (2R)-2-methyl ratio bite base, (2S)_2_methyl xiaoluo bite base, (2R)-2·methyl _5 oxo H Each 0^ group, (2S)-2·methyl·5-oxo-1-oxaridinyl '3,6-dihydro-U2H)-pyridyl, (2S)-2-(methoxycarbonyl) -1-pyridinyl, (2R)·2·(methoxy)]-anthracene, (2S)-2-(aeromethyl)-1-pyridyl , (2R)_2_(fluoromethyl)pyrrolidinyl, (2R)_2_ethyl_丨_pyrrole, 2,2'-dimethyl-I-11-pyridyl, (2S) 2-ethyl-l-oxaridinyl 4-morpholinyl, 2-P-5-azabicyclo[2.2.1]hept-5-yl or 1,4-diox-8-nitrogen R. snail [4_5] 癸-8-yl; r3, r4, R5, R々R9 are hydrogen; the heterocyclic carbonyl group wherein the heterocyclic ring is 4-morpholinyl; X is n; Y is CH; Z is CH; and D, L, RA, RB, R3, R4, R5, as defined in formula (1). In another specific embodiment, the compound of the invention has formula (II) wherein A is a base Ri and the ruler 2 are respectively selected from the group consisting of 1, thiol, alkyl, alkenyl and alkynyl; and Rs is selected from the group consisting of a cyano group and a heterocyclic carbonyl group; and D, L, RA, RB, R3, R4, r5, The anaphylaxis 7 and the ruler 9 are as defined in the formula (1). In another specific embodiment, the compound of the present invention has the formula (11), wherein 98.683.doc - 54 - 1333489 wherein A is a group; RjpR2 is selected separately Included from the group consisting of hydrogen, hydrazino, alkyl, dilute and alkynyl; and Rs is selected from the group consisting of cyano and heterocyclocarbonyl, wherein the heterocyclic carbonyl heterocycle is selected from the group consisting of azetidine , morpholinyl, hexahydropyridinyl, hexahydropyridyl, pyridyl, pyrrolidinyl 2,5·dihydro-1H-pyrrolyl, pyrrolyl, 3,6-dihydro·1(2Η) - acridinyl, thio-allinyl and anthracene, _ dioxo bridge thiomorpholinyl; and D, L, RA, RB, r3, r4, r5, ruler 7 and ruler 9 according to formula (1) definition. In another embodiment, the compound of the present invention has the formula (II) wherein A is a carbonyl group; R1 and R2 are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; Including a cyano group and a heterocyclic carbonyl group, wherein the heterocyclic ring of the heterocyclic carbonyl group is selected from the group consisting of 1-azetidinyl, 4-morpholinyl, indole hexahydropyridinyl, 1-hexahydropyridyl, 3-pyridyl, i-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, 1-pyrrolyl, 3,6-dihydropyridinyl, 4-thiolupyl and 1,1-di Oxy-bridge thiomorpholine _4_ group; and D, [, RB, R3, R4, R5, R7 and R_9 are as defined in formula (1). In another embodiment, the compound of the present invention has the formula (II) wherein A is a carbonyl group; 1 and I together with a nitrogen atom attached thereto form a heterocyclic ring; and the rule 8 is selected from the group consisting of a cyano group. Or a heterocyclic carbonyl; and D, [, Ra, Rb, &, &

Rs, R7, R_9, X, 丫 and z are as defined in the formula (1). In another specific embodiment, the compound of the present invention has the formula (π) wherein A is a carbonyl group; and the heart and the Han 2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from a nitrogen heterocyclopentyl group, Azetidinyl, imidazolyl, morpholinyl, hexapyridinyl, hexahydropyridyl, pyridyl, pyrrolidinyl, (2R)_2-methyl 1 than a thiol base, 2,5-one Hydrogen-Up, sulphate, p, hexyl, 3,6-dihydro-1(2H)- 98683.doc •55- 1333489 pyridyl, thiomorpholinyl and 2-oxo-bridged thiomorpholine The base 8 is selected from the group consisting of a cyano group or a heterocyclic carbonyl group, wherein the heterocyclic ring is selected from the group consisting of 1-azetidinyl, 4-morpholinyl, 1-hexahydropyrryl, κ丄, Indole pyridyl, 3-pyridyl, i-pyrrole, 2,5-di-C-l- yl, s-(4), 3,6-dihydrona", thiol, 4-thio- phenanthyl i mountain dioxo bridge thio- merlin ice base; and 〇, l,

Ra, Rb, Κ·3, R4, R5, R7, R v R9 'X, Y and z are as defined in the formula (1). In another specific embodiment, the compound of the present invention has the formula (I), wherein A is a group; R々R2 forms a heterocyclic ring with a nitrogen atom attached thereto, and is selected from a pure heterocyclic ring. Newtyl 1 heterocyclic butyl group, light base, chlorinated group, hexahydro-t-well, hexahydro (tetra)-based group, bite group, fluorenyl group, (called 2_methyl-1-峨 咬 base, 2,5-dihydro-1H_t each group, 3,6-diazaindene H)-(tetra)yl, thio-allinyl w-san oxa bridge thio-decaline; ^ selected from including cyano And a heterocyclic ring (tetra), wherein the heterocyclic ring of the heterocyclic ring (tetra) is selected from the group consisting of: -azetidinyl, 4-morpholinyl, hexahydrogen, hexahydroacridinyl, 3-anthracene Base, 〗 〖 Tao Luo gnach, 2,5 • dihydro-1H4 yl, b φ rr, 3'6-dihydro-1 (2 Η)-pyridyl, 4 thiomorpholinyl and u ·: Oxy-bridge thiomorpholin-4-yl; and D, L, RA, RB, r3, R4, &, &, &, X, Y and Z are as defined in formula (I). In another specific embodiment, the compound of the present invention has the formula (π) wherein A is a carbonyl group; and I forms a heterocyclic ring together with a nitrogen atom attached thereto, selected from the group consisting of 1-azopentyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, iH-imidazole-1.yl, (3R)_3-hydroxy-ι-pyrrolidine (3S)-3-hydroxy-1-pyrrolidinyl, (2S)_2_(hydroxyindenyl)pyrrole 98683.doc -56- 1333489 pyridine, (2R)-2-(hydroxymethyl)pyrrolidinyl , (cis)-2,6-dimethylhexahydropyridinyl, 4-methyl-1-hexahydrop-bite, 2-methyl-1-hexahydrocarbyl, 1-hexahydropyridyl , (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, (2R)-2-methyl-1-pyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl, (2R)-2-methyl-5-oxo-pyrrolidinyl, (2S -2-methyl-5-oxo-pyrrolidinyl, 3,6-dihydro-1(211)-11 than dimethyl group, (2S)-2-(methoxybenzylbicarbyl) (2R)_2_(methoxycarbonyl)-1-pyrrolidinyl, (2S)-2-(fluoromethyl)_1_pyridyl, each (2R)- 2-(fluoromethyl)-1-pyrrolidinyl, (2R)-2-ethyl-1·pyridinyl, 2,2-monomethyl- Ι-p ratio, (2S)-2 -Ethyl-Ι-p is more than a bite base 4_?p-lin, 2-

-8-yl; Rs is selected from cyano or heterocyclic carbonyl, wherein the heterocyclic ring is selected from the group consisting of i-azetidinyl, 4-morpholinyl, 1-hexahydropyridinyl, hexahydropyridyl , 3_ pyridyl, 1-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, bupyrolyl, 3,6·

According to the definition in formula (I). According to other specific embodiments, the compound of the present invention has the formula (〖Η)

Or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of hydrogen, a gas, a ketone, an ester, a guanamine or a prodrug, an alkoxy group, an alkyl carbonyl group, an alkyl group, an alkyl group, wherein the carbonyl group and the alkane are burned. Alkyl carbonyl 98683.doc -57. 1333489 oxy, alkyl sulfinylene, alkyl sulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, decyl, halogen, alkane Oxyl, dentate, hydroxy, hydroxyalkyl, decyl, nitro, -nrarb, (nrarb)alkyl, (nrarb)carbonyl or (NRaRb)sulfonyl; r8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl , cyano, cycloalkylcarbonyl, heterocyclic carbonyl or (NRARB)carbonyl; r9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl' Sulfosyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, methionyl, halogen, aldentyloxy, dentyl, hydroxy, hydroxyalkyl, decyl, nitro, -NRaRb , (NRaRb)alkyl, (NRaRb)carbonyl or (NRaRb)sulfonyl; X is selected from CH; Y is selected from CH, CRY or N; Z is selected from CH, CRZ or N;

Rx, RY and Rz are each selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkyl oxy, alkyl, aryl, thiol, sulfo, carboxylic acid Base, cyano, cyanoalkyl, formamyl, _, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, decyl, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRARB)sulfonyl; and a, D, L, RA, RB, R!, R2, R3, R4 and R5 are as defined in formula (I). In another embodiment, the compound of the invention has the formula (III) wherein A is a covalent bond; and D, L, RA, RB, R2, R3, R4, R5, R6, R8, R9, X , Y and Z are as defined in formula (I). In another embodiment, the compound of the present invention has the formula (III), 98683.doc -58-^^489 wherein A is a covalent bond; Ri and R2 are each selected from the group consisting of hydrogen, affiliation, thiol, and dilute Or alkynyl, Rs is selected from cyano or heterocyclic; and d, l, ra, rb, r3, 5 R6 R9, x, y and z are as defined in formula (I). In another specific embodiment, the compound of the present invention has an octavalent bond in the formula (IH) '' and R2 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl: R8 is selected from the group consisting of cyanide Or a heterocyclic group, wherein the heterocyclic ring is selected from the group consisting of aza-alkyl-butanyl, 4-morpholinyl, "hexahydropyridinyl, hexahydropyridyl, 3-pyridyl, h-pyrrol Pyridyl, 2,5-dihydro-cardiylpyrrolyl, bultrolyl, 3-winter-nitrogen-1 (2Ηbubidinyl, 4-thiopheninyl and U-dioxobridge thiomorpholine 4-base, and D, L, Ra, Rm4, r5, r6, r9, X, 丫 and 2 are as defined in formula (I). In another embodiment, the compound of the invention has the formula (III), wherein A is a covalent bond; R々R2 forms a heterocyclic ring together with a nitrogen atom attached thereto; R8 is selected from a cyano group or a heterocyclic group; and D, L, Ra, Rb, R3, R4, R5, R6, R9, χ, 丫 and 2: as defined in formula (1). In another embodiment, the compound of the invention has the formula (ιπ), wherein Α is a covalent bond; R>R2 Forming a heterocyclic ring with a nitrogen atom attached thereto, selected from a nitrogen heterocyclopentyl group, a nitrogen heterocycle Butyryl, imidazolyl, morpholinyl\hexapyridinyl, hexahydropyridyl, pyridyl, pyrrolidinyl, (2 ft) 2 -methyl-1-pyrrolidinyl, 2,5-dihydro -1H_pyrrolyl, pyrrolyl, L-dihydro-K2H)-cut group, thio-center and u-dioxo bridge thiol ^ selected from the group consisting of a cyano group or a heterocyclic group, wherein the heterocyclic ring Is selected from the group consisting of !, azetidinium 8-alkyl, 4-morpholinyl, hexahydropyridinyl' hexahydropyridyl, %pyridine 2, 1 pyrrolidinyl, 2,5-dihydro-1H -pyrrolyl,pyrrolyl,36_2^ 98683.doc -59- 1333489 ) mercapto, 4-thiomorpholinyl and U-dioxo bridge thiomorpholine-4-L Ra ' Rb, R3 , R 4 , R 5 , R 6 , R 9 , X , Y and Z are as defined in the formula (I). In the embodiment, the compound of the invention has the formula (III), wherein A is a covalent bond; R々R2 forms a heterocyclic ring with a nitrogen atom attached thereto, and is selected from the group consisting of a 1, azacyclopentyl group, a 3-(dimethylamino) (tetra) octyl group, () (monomethylamino) pyrrole Pyridyl, 1H-imidazol-1-yl, (3R)-3-hydroxy-1·b slightly biting, (3S)-3·transbasic carbaryl, (2S)-2-(methyl meth Ruthenium, (2R)-2-( Methyl>pyrrolidyl, (cis)-2,6-dimercaptohexahydropyridyl, 4-methyl·i-hexahydroindole, 2·methyl hexahydrotetrakis, hexa-nitrogen Chinyl, (2R,5R)-2,5.dimethyl dimethyl carbyl, (cis) _2,5-dimethylpyridinyl, 1-pyrrolidinyl, 2-methylpyrrolidinyl, (2R)_2_methyl,pyrrolidinyl,(2S)-2-mercapto-1-pyrrolidinyl, (2R)_2_mercapto-5-oxo-pyridyl, (2S)-2 _Methyl-5-oxo-1-pyrrolidinyl, 3,6-di-argon only) Ρ 咬 咬, (2S)-2_(methoxycarbonyl)-1-pyrrole, (2R)- 2-(methyl carbonyl)-1-pyrrolidinyl, (2S)-2-(fluoroindolyl)-1-pyrrolidinyl, (211)-2-(fluoroindolyl)-!-pyrrolidinyl, (2R)_2_ethyl·pyridrolidinyl, 2,2·methyl-Ι-p piroxime, (2S)-2-ethyl-Ι-p piroxicam 4- morphin, 2-呤·5-Azabicyclo[2.2.1]hept-5-yl or l,4-diindole-8-azaspiro[4.5]dec-8-yl, Rs selected from cyano or heterocyclic carbonyl Wherein the heterocyclic ring is selected from the group consisting of azetidin, 4-merinyl, 1-hexahydropyridinyl, 1-hexahydropyridyl, 3-hydrazone, 1-pyrrolidyl, 2, 5-dihydro-1H-pyrrole , 1-pyrrolyl, 3,6-dihydro-1(2H)-pyridyl, 4-thiomorpholinyl and oxo-thio-n- 4-, and D, L, RA, RB, R3, R4, R5, r6, r9, X, 丫 and 2 98683.doc -60- 1333489 are as defined in formula (i). In another embodiment, the compound of the invention has the formula (III) wherein A is a group; and D, L, RA, rb, r2, r3, R4, R5, R6, Rs, R9, X, Y and Z are defined by the formula (1). In another embodiment, the compound of the invention has the formula (III) wherein A is a carbonyl group; the core is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl, respectively; 118 is a cyano group; D, L, RA, rb, r3, r4, r5, r6, r9, X, Y and Z are as defined in the formula (I). In another embodiment, the compound of the present invention has the formula (πΐ) wherein L is -CH2CH2-; hydrazine is a carbonyl group; and 1 and 2 are respectively selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkyne R3 is methyl, r4, r5, Rd〇R9 are hydrogen; Rs is cyano; X is CH; Y is CH; Z is CH; and D, 11 and RB are as defined in formula (I) . In another embodiment, the compound of the invention has the formula (JH) wherein A is carbonyl; each selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Rs is heterocyclo; and D , L, RA, rb, r3, r4, r5, r6, R9, X, Y and Z are as defined in the formula (I). In another embodiment, the compound of the present invention has the formula (ΙΠ) wherein hydrazine is a carbonyl group; Ri and R2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and Rs is a heterocyclic carbonyl group, Wherein the heterocyclic ring is selected from the group consisting of azetidinyl 4-morpholino, 1-hexahydropyrryl, b hexahydropyridyl, 3•pyridyl, benzopyrylene, 2,5- Dihydro-1H-P ratios, Ι-p ratio σ groups, 3,6-dihydro-1(2Η)·pyridyl, 4-thiomorpholinyl and ij•dioxo bridge thiomorpholine _4 base; and D, L, Ra, RB, R3, r4, r5, r6, r9, χ, γ, and ζ according to formula (1) 98683.doc -61 - 1333489

The definition in . In another specific embodiment, the compound of the present invention has the formula (ιπ), wherein A is (iv); R#R2 forms a heterocyclic ring with a nitrogen atom attached thereto, and R8 is a gas group, and d, 1, Ra, Rb, R3, R4, R5, R6, R9, X, Y and Z are as defined in the formula (I). In another specific embodiment, the compound of the present invention has the formula (111) wherein A is a carbonyl group; and R1 and R2 together with a nitrogen atom attached thereto form a heterocyclic ring selected from a nitrogen heterocyclopentyl group, Azetidinyl, imidazolyl, morpholinyl, hexahydropyridinyl, hexahydropyridyl, pyridyl, pyrrolidinyl, (2R)_2-methyl-1-pyrrolidyl, 2,5 - dihydro-1H-pyrrolyl, pyrrolyl, 3,6-dihydro-1(2H)-pyridyl, thiomorpholinyl and anthracene, 丨-dioxo bridge thiomorpholinyl; & And D, L, RA, RB, r3, r4, R5, R6, R9, χ, γ and z are as defined in formula (I). In another embodiment, the compound of the present invention has the formula (Πϊ) wherein A is a carbonyl group; and the core and the rule 2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from 1-azacyclopentane. , (3 S)-3-(diamido)pyrrolidinyl, (311)-3-(dimethylamino)? piroxime, 11{-imdol-1-yl, (3 feet) )-3-amino-1-ylide 各 each bite, (3S)-3-hydroxy-Ι-p piroxime, (2S)-2-(hydroxymethyl)pyridine, (2R )-2-(hydroxyindenyl)pyrrolidinyl, (cis)-2,6-dimercaptohexahydropyridyl, 4-methyl-1-hexahydrop-pyridyl, 2-methyl-1-hexa Hydrogen p is more than a bite group, 1_hexahydro 17 is a bite base, (2R,5R)-2,5-dimethyl p is a bite base, (cis)-2,5·didecyl p is a pyridyl group. , 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, (2R)-2-mercapto-1-pyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl, (2R )-2-mercapto-5-oxo-1-ylidene slightly biting base, (28)-2-methyl-5-oxo-1-? piroxime, 3,6-di-argon 986S3. Doc • 62· 1333489 -U2H)4 bite base, (2S)_2(methoxy group) ten each bite base (tetra)·2 (methoxycarbonyl Μ-pyrrolidinyl, (2S)_2_(fluoromethyl)_ Pyridinium (R), (2R)-2-(fluoromethyl) small (tetra) dimethyl, (2R) _2 _ _ 峨 峨 、 、 、 、 、 、 、 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 · A glimmer of heart: base, ': ten 5-aza-bicyclic ring-like base or M• twenty-eight gas worms 累 癸 I base; thought cyano; and D, L, Ra, Rb, &, &, &, &, r9, X, Y, and z are as defined in formula (I).

In another specific embodiment, the compound of the present invention has the formula (III) wherein L is a cation; A is a group; R>R2 forms a heterocyclic ring with a gas atom attached thereto, ϋ From Ihecyclopentane, azetidin, azetidin, tetramethyl, hexahydro, (tetra), hexahydro, bis-(tetra)-based bis-heptidyl, (2R)-2-methyl -1- (four) bite base, 2,5 • two gas than sulfhydryl, pyridyl, 3'6-dihydro-1 (2 heart ratio bite base, thiomorpholino and dioxin bridge sulfur

Dimorpholinyl; R3 is methyl; r4, Rs, heart and hydrogen are hydrogen; rule 8 is cyano; X

Let Ct Y be CH; ZgH; and d, l, r^Rb be as defined in formula (1). In another specific embodiment, the compound of the present invention has the formula (ΙΠ) ' wherein L is -CH2CH2_; hydrazine is a carbonyl group; and Ri and Rz together with the nitrogen atom attached thereto form a heterocyclic ring selected from the group consisting of 1-nitrogen Heterocyclopentyl, (3S)_3_(diguanyl)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazolyl], (3R)-3-hydroxyl 1_pyrrolidinyl, (3S)_3_hydroxypyrrolidinyl, (2S)-2_(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)- 2,6-dimercaptohexahydropyridyl, 4-methyl i•hexahydropyridyl '2-methyl-1-hexahydropyridyl, 1-hexahydropyridyl, (2R,5R) 2,5 Dimethylpyrrolidine 98683.doc -63- 1333489, (cis)-2,5-dimethylpyrrolidinyl, pyrrolidinyl, 2-methyl-1-p ratio % pyridine, (2R) -2-methyl-1·Blowing, (2s)_2-methyl-Ι-p-pyridyl, (2R)-2-methyl-5-oxo-indole-p-pyridyl , (2S)_2_methyl_5_oxo-7% pyridyl, 3,6-dihydro-1(2H)-pyridyl, (2S)-2-(oximeoxycarbonylpyrrolidinyl, (2R )-2-(methoxycarbonyl)_丨·pyrrolidinyl, (2S)-2_(fluoromethyl 11-pyridyl) , (2R)-2-(fluoroindolyl)_ι-pyrrolidinyl, (2r)_2_ethyl_丨_torostidine, 2,2-dimethyl-1-pyrrolidinyl, (2S) _2·Ethylpyrrolidinyl

4-morpholinyl, 2-indol-5-azabicyclo[2.2.1]hept-5-yl or 1,4.dioxa-8-azaspiro[4.5]dec-8-yl; R3 is Methyl; r4, R5, r6 and &hydrogen; ^ is cyano; X is CH; Y is CH; Z is CH; and D'L, RB are as defined in formula (I). In another specific embodiment, the compound of the present invention has the formula (ΠΙ), wherein A is a carbonyl group; I and Rz together with a nitrogen atom attached thereto form a heterocyclic ring; R8 is a heterocyclic carbonyl group; and D, L , Ra, Rb, R3, R4, R5, Ruler 9, X, Y and Z are as defined in the formula (1).

In another embodiment, the compound of the present invention has the formula (ΙΠ) f wherein Α is a group; the heart and heart together with the nitrogen atom attached thereto form X is selected from the group consisting of aziridine and nitrogen heterocycles. Aromatic base, a base, a hydrazino hexahydropyrazine, a hexahydropyridyl group, a pyridyl group, a pyrrolidinyl group, a 2-yl-1-pyrrolidinyl group, a 2,5-dihydro-1 fluorenyl group , 咐 、, 二 (called cleavage, thio- phenanthyl and u _ dioxo thiol sulfhydryl): a heterocyclic group wherein the heterocyclic ring is selected from the group consisting of U-heterocyclic ketone , ^6^井基,卜六氢吨基基基比比基,卜比(四)基,5, hydrogen·1Η·pyrrolyl, i-pyrrolyl, 3,6-dihydro_ι(2η)·pyridine Base 98683.doc -64- 1333489 4_thiomorpholinyl and dioxo bridge thiomorpholin-4-yl; and D, L, RA, RB ' R3 ' R4, R5, R6, R9, X, Y And Z are as defined in formula (1). In another embodiment, the compound of the invention has formula (III) wherein A is a carbonyl group; Ri and a nitrogen atom attached thereto form a heterocyclic ring, From ι_azetidinyl, (3S)_3_(dimethylamino)pyrrolidinyl, dimethylamino) Pyridyl, 1H-imidazol-1-yl, (3R)-3-hydroxypyrrolidinyl, (3S)-3-hydroxypyrrolidinyl, (2S)_2-(hydroxymethyl)pyrrolidinyl, (2R) -2-(Hydroxymethyl)pyrrolidinyl, (cis)-2,6-didecylhexahydropyridinyl, 4-methyl-i-hexahydropyridyl, 2-methyl-hydrazine-hexahydropyridine , 丨_hexahydropyridyl, (2R,5R)-2,5-dimercaptopyrrolidinyl, (cis)-2,5-dimethylpyrrolidinyl, 1-pyrrolidinyl, 2_fyl-丨_Pyrrolidinyl, (2R)_2-methyl-^pyrrolidinyl, (2S)-2-methyl-1-pyrrolidinyl, (2R)_2·methyl·5_oxo· 峨 咬, (2S)-2-methyl-5-oxo-pyridyl, each bite group, 3,6-dihydro-1(2H)-acridinyl, (2S)-2-(methoxycarbonyl)•pyridyl „ Each pyridine, (2R)_2_ (methoxyl-butyryl, (28) 1 (fluoromethyl H. pyrrolidinyl, (2R)-2-(fluoromethylpyrrolidyl, (2R) 2 ethylpyrrolidinyl, 2 2_ φ monomethyl-1-pyrrolidinyl, (2S)-2-ethyl-1-pyrrolidinyl 4-morpholinyl, 2_ 噚-5-aza a ring [2,2.1]hept-5-yl or ι,4·diindole-8-azaspiro[4 5]dec-8-yl; RS is a heterocyclic carbonyl group, wherein the heterocyclic ring is selected from Heterocyclic butane, 4-morpholinyl, 1-hexahydropyridinyl' 丨·hexahydropyridyl, iripyridyl, 丨-pyrrolidine, 2,5-dihydro-exo-saltyl , 1·tonyl, 3 6-diaza·pyridyl, 4-thiomorpholinyl and U1-dioxo bridge thiomorpholine·4—yl; and 〇, L, RA, RB, R3, r4 , r5, r6, &, χ, ^, and z are as defined in equation (1). 98683.doc 65- According to other specific embodiments, the compounds of the invention have formula (IV)

Rs (IV), or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof, wherein R7 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkane Isosulfonyl, alkylsulfonyl, alkylthio, carboxyl, carboxyalkyl, cyano, cyanoalkyl, decyl, halogen, ii alkoxy, alkyl, hydroxy, hydroxyalkyl, Sulfhydryl, nitro, -nrarb, (nrarb)alkyl, (nrarb)carbonyl or (nrarb)sulfonyl; r8 is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclic carbonyl or NRARB) carbonyl; R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxyl, carboxylic acid Base, cyano, cyanoalkyl, decyl, halogen, haloalkoxy, alkenyl, hydroxy, hydroxyalkyl, decyl, nitro, -nrarb, (nrarb)alkyl, (nrarb) carbonyl or Nrarb)sulfonyl; X is selected from CH, CRX or N; Y is selected from CH, CRY or N; Z is selected from CH, CRZ or N;

Rx, RY and Rz are each selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxyl, carboxyalkyl , cyano, cyanoalkyl, decyl, dentate, dentate, halo 98683.doc -66- 1333489, hydroxy, hydroxyalkyl, thiol, nitro, _NRaRb, (NRaRb) alkyl , (NRARB) a group or (NRARB) a fluorenyl group; and D, L, Ra, Rb, Ri, R_2, R3, R4 and Rs are as defined in the formula (1). In another embodiment, the compound of the invention has the formula (IV) wherein A is a covalent bond; and D, L, RA, rb, r, r2, R3, R4, R5, R7, R8, R9 , X, Y and Z are as defined in the formula (1).

In another embodiment, the compound of the present invention has the formula (IV) wherein A is a covalent bond; and 1 and 2 are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Cyano; and D, L, RA, RB, R3, R4, R5, R7, R.9, X, Y and Z are as defined in formula (I). In another specific embodiment, the compound of the present invention has the formula (IV) wherein L is -CH2CH2-; A is a covalent bond; and the core is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkyne, respectively. R3, R4, r5, ft. 7 and 119 are hydrogen; r8 is cyano; X is CH; Y is CH; Z is CH; and D, RA and RB are as defined in formula (1).

In still further embodiments, the compounds of the invention have formula (V)

(V), or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof, wherein R6 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkyl Sulfosyl, alkylsulfonyl, alkylthio, carboxyl, carboxyalkyl, cyano, cyanoalkyl, methionyl, dentate, haloalkoxy, #alkyl, 98683.doc -67- 1333489 hydroxy, hydroxyalkyl, decyl, nitro, -nrarb, (nrarb)alkyl, (nrarb)carbonyl or (NRaRb)sulfonyl; R8 is selected from the group consisting of hydrogen, alkylcarbonyl, arylcarbonyl, cyano, naphthenic a carbonyl group, a heterocyclic carbonyl group or a (NRARB)carbonyl group; R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkane Thio, carboxyl, carboxyalkyl, cyano, cyanoalkyl, methionyl, dentate, haloalkoxy, alkenyl, hydroxy, hydroxyalkyl, decyl, nitro, -NRaRb, (NRaRb) alkane (NRaRb) carbonyl or (NRaRb)sulfonyl; X is selected from CH, CRX or N; Y is selected from CH, CRY or N; Z is selected from CH, CRZ or N;

Rx, RY and Rz are each selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkyl &oxy, alkyl, aryl, thiol, thiol, carboxy Alkyl, cyano, cyanoalkyl 'mercapto, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, decyl, nitro, _NraRb, (Nrarb)alkyl, (NRARB)carbonyl or NRARB)sulfonyl; and A, D, 1, RA, RB, R!, R2, R3, R4 and R5 are as defined in formula (I). In another specific embodiment, the compound of the present invention has the formula (V) wherein hydrazine is a covalent bond; and D, L, RA, Rb, R1, r2, r3, R4, R5, R6, R8, R9, X, Y and Z are as defined in formula (I). In another embodiment, the compound of the invention has the formula (V) 'wherein A is a covalent bond; 1 and 2 are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Cyano; and D, L 'RA, rb, r3, r4, r5, R6, R9, 98683.doc • 68· X, Y and Z are as defined in formula (I). In another specific embodiment, the compound of the invention has the formula (V) wherein L is -CH2CH2-; A is a covalent bond; and Ri and R2 are initially selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or Alkynyl; R3, R4, R5, R6 and R9 are hydrogen; R8 is fluorenyl; X is CH; Y is CH; Z is CH; and D, RA and RB are as defined in formula (I). In still further embodiments, the compounds of the invention have formula (VI)

Or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof, wherein R.sup.5, R.sup.6 and R.sup.7 are selected from the group consisting of hydrogen, alkoxy, oxo, thiol, decyl, decyloxy,烧 亚 醯 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Alkyl, fluorenyl, nitro, -NRARB, (NRARB)alkyl, (nrarb)carbonyl or (nrarb)sulfonyl; R.8 is selected from the group consisting of hydrogen, stearyl, aryl, cyano, cyclodextrin a heterocyclic carbonyl group and a (NRARB)carbonyl group; R_9 is selected from the group consisting of hydrogen, a methoxy group, a oxyalkyl group, a decyl group, a carbonyl group, a carbonyloxy group, a decyl group, a ruthenium group, and a gg group. Sulfur-based, renegic, rebel, cyano, aroma, ketone, genomic, acyloxy, dentate, thiol, thiol, weiji, ruthenium, -NRARB, NRARB)alkyl, (nrarb)carbonyl or (nrarb)sulfonyl; 98683.doc -69- 1333489 X is selected from CH, CRX or N; Y is selected from CH, CRY or N; Z is selected from CH, CRZ or N ;

Rx, RY and Rz are respectively selected from the group consisting of an alkoxy group, an alkoxy group, a pyridyl group, a pyridyl group, a pyridyloxy group, a pyrene base, a base, a sulfur group, a radical, Rebel, cyano, cyanogen, aryl, dentate, alkoxy, dentate, hydroxy, hydroxyalkyl, decyl, nitro, -NRARB, (NRARB) alkyl, (NRARB a few groups or (NRARB) zeolitic; and A, D, L, RA, RB, R2 and R3 are as defined in formula (I). In another embodiment, the compound of the invention has the formula (VI) wherein A is a conjugated bond, and 1^ and & together with the nitrogen atom attached thereto form a heterocyclic ring; P, Q, D, L, RA, RB and R3 are as defined in formula (1), and R5, R6, R7, ruler 8 and ruler 9 are as defined in formula (vi). In another embodiment, the compound of the present invention has the formula (VI) wherein A is a covalent bond; the core and the rule 2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from azacyclopentane Base, azetidinyl, imidazolyl, morpholinyl, hexahydropyrrole, hexahydropyridyl, pyridyl, pyrrolidinyl, (2R)_2-

And R5, Re, R7 and R9 are as defined in formula (VI). In another specific embodiment, the compound of the present invention has the formula (VI), the nitrogen atom of L together form a heterodimethylamino)pyrrolidinyl group, wherein A is a covalent bond; and the heart and Han 2 are attached thereto The upper ring is selected from the group consisting of 1-azacyclopentyl, (3S)_3_(two 98683.doc 70·(3R)-3·(diamido)pyrrolidinyl, 1H imidazole small group, (3R)_3· Hydroxypyrrolidinyl, (3S)-3-hydroxypyrrolidinyl, (2S)_2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxyindenyl)pyrrolidinyl, (cis)-2, 6_Dimercaptohexahydropyridyl, 4-methyl-1-hexahydropyridyl, 2·methyl-丨·hexahydropyridyl, ^hexahydro"bite base, (2R,5R)-2 , 5-dimethylpyrrolidinyl, (cis)·2,5·dimethylpyrrolidinyl, 1-pyrrolidinyl, 2-methyl-4-pyrrolidinyl, (2R)2methyl-pyrrolidinyl , (2S)-2-mercapto-b pyrrolidinyl, (2R)_2_ fluorenyl oxy-oxo 咐 各 each bite base, (2S)-2·methyl·5·oxo_丨· Pyrrolidinyl, 3,6-dihydro U2H)-pyridyl, (2S)-2-(methoxycarbonyl)-pyrrolidinyl, (2R)_2·(methoxycarbonyl)-1-pyrrolidinyl, (2S)_2_(fluoroanthryl)_丨_pyridyl Pyridyl, (2 phanyl-2-(fluoromethyl)-1-pyrrolidinyl, (2R)_2-ethyl-indole-pyrrolidinyl, 2,2-methyl-1-pyrrolidinyl, (2S) 2-ethyl-1-pyrrolidinyl 4-morpholinyl, 2-indol-5-azabicyclo[m]heptyl-5-yl or 14-diindole-8 azaspiro[45]癸•8 - base; rule 8 is cyano; and p 'Q' D, L, Ra, Rb and heart are as defined in formula (1), and Rs, , and I are as defined in formula (VI). In a specific embodiment, the compound of the present invention has the formula (V^), wherein L is -CI^CH2-; A is a covalent bond; the heart and the heart together with the nitrogen atom attached thereto form a heterocyclic ring, From azacyclopentadienyl, azetidinyl, pyridyl, morphinyl, hydrogen, phenanthrenyl, hexahydrocarbyl, benzyl, hydrazine-lH-p Benzoate, (2R)-2-methyl-I-pyrrolidine, 2,5-pyrrolyl, 3,6-dihydro-1(2H)-pyridyl, thiomorpholinyl and anthracene, 〗 〖 Dioxo bridge thiol # base, · R3, r5, r6, R # R9 is hydrogen; & is cyano; 乂 is CH; Y is CH; and z is CH. In another embodiment The compound of the present invention has the formula (νι) 98683.doc • 71 · 1333 489 wherein L is -Cf^CH2. A is a covalent bond; the heart and the ruler 2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from the group consisting of azacyclopentane, (33)_3_(di) Amino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazolium-yl, (3R)-3-ylpyrazine, (3S)_3· -]-bromopyridyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)_2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylhexahydro-P Than a base, 4-methyl_ι_hexahydro? than a butyl group, 2·methyl-1-hexahydropyridyl, 1-hexahydropyridyl, (2r,5R)_2,5-dimethylpyrrole Pyridyl, (cis)-2,5-dimercapyryrrolidinyl, [-pyrrolidinyl, 2-methyloxaridinyl, (2R)-2-methyl-1-pyrrolidinyl, 2S)-2-mercapto-1-pyrrolidinyl, (2R)_2-methyl-5-oxo-1-pyrrolidinyl, (2S)-2-methyl-5-oxo-1-pyridyl 11 each bite group, 3,6-di-argon-1(2H)-pyridyl, (2S)-2-(methoxycarbonyl)-1-pyridyl 11 each, (2R)-2-(methoxycarbonyl) )-1-pyrrolidinyl, (2S)-2-(fluoroindolyl)-1-pyrrolidinyl, (2R)-2-(fluoromethyl)-1-pyrrolidinyl, (2R)-2- Ethyl-1-pyrrolidinyl, 2,2-Dimercapto-1-pyrrolidinyl, (28)-2-ethyl-1-pyrrolidinyl 4-morpholinyl, 2-indol-5-azabicyclo[2.2.1]g -5-yl or 1,4-diox-8-azaspiro[4.5]dec-8-yl; ft. 3, 1^5, ul. 6, 1 <_7 and uldent 9 are hydrogen; 118 is cyano; X is CH; Y is CH; and Z is CH. In still further embodiments, the compounds of the invention have formula (VII)

(VII), or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof, wherein 98683.doc -72· 1333489 R4, 116 and R7 are selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, Alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxyl, carboxyalkyl, cyano, cyanoalkyl, decyl, dentate, i alkoxy , haloalkyl, hydroxy, hydroxyalkyl, decyl, nitro, -NRARB, (NRARB)alkyl, (NRARB)carbonyl or (NRaRb)sulfonyl; R.8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl a cyano group, a cycloalkylcarbonyl group, a heterocyclic carbonyl group, and a (NRARB) group; R9 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, Alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, methionyl, ii, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, decyl, nitro, -nrarb, (nrarb)alkyl, (nrarb)carbonyl or (NRaRb)sulfonyl; x is selected from CH, CRX or N; Y is selected from CH, CRy or N, Z is selected from CH, CRz or N; Rx,尺¥ and Rz are respectively selected from alkoxy groups, alkoxycarbonyl groups, alkyl groups, and alkane Base, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxyl, carboxyalkyl, cyano, cyanoalkyl, methyl, carbene, alkoxy, Halogenated group, mercapto group, burnt group, sulfhydryl group, schlossyl group, -nrarb, (nrarb) alkyl group, (nrarb) group or (NRaRb) continuation base; and L, A, D, R, R2 R3, ra and rb are as defined in the formula (1). In another specific embodiment, the compound of the present invention has the formula (νπ), wherein A is a covalent bond, and the core and the ruler 2 together with the nitrogen atom attached thereto form a heterocyclic ring; P, Q, D, L , RA, rb and I are as defined in formula (1), and R4, R6, R7, ruler 8 and ruler 9 are as defined in formula (VII). In another specific embodiment, 'the compound of the invention has the formula (Yu), 98683.doc -73- 1333489 wherein A is a covalent bond; the heart and the ruler 2 together with the nitrogen atom attached thereto form a heterocyclic ring , selected from azacyclopentyl, azetidinyl, imidazolyl, morpholinyl, hexahydropyrrole, hexahydropyridyl, pyridyl, pyrrolidinyl, (2R)_2-methyl- 1-pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, pyrrolyl, 3,6-dihydro-1(2H)-pyridyl, thiomorpholinyl and benzodiazepine Morpholinyl; the heart is a cyano group and the 尺^^'b is defined as in the formula (1), and R_4, R6, R7 and R$ are as defined in the formula (Vii). In another specific embodiment, the compound of the present invention has the formula (νπ), wherein A is a covalent bond; and 1 and 2 are together with a nitrogen atom attached thereto to form a heterocyclic ring selected from 1-aza Cyclopentyl, (3S)-3-(dimethylamino)pyrrole, (311)-3-(dimethylamino)1» than 1» each bite, out-glutinous rice saliva-1_ Base, (3 ft) _3-trans-base_1-pyrrolidinyl, (3S)-3-hydroxy-1-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrole, (2R)-2 -(hydroxyindole>pyrrolidinyl, (cis)-2,6-dimethylhexahydropyridyl, 4-methyl-1-hexahydropyridyl, 2-mercapto-1-hexahydropyridyl , i•hexahydropyridyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5·dimethylindole, lp piroxicam, 2-mercapto -Ι-p piroxime, (2R)-2-methyl_ι_pyrrolidinyl, (2S)-2-mercapto-1-pyrrolidinyl, (2R)-2-mercapto-5-oxygen代-1-叶匕0 each bite, (2S)-2-methyl-5-oxo-1 · p piroxime, 3,6-dihydro-1(2Η)-ι» ratio bite , (2S)-2-(methoxyxo)-1-ρ piroxime, (2R)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2S)-2-(fluorof-yl) )_1_ Pyrrole cough base, (2R)-2-(indenyl)-lp ratio each bite group, (2R)-2 -ethyl-l-p ratio bite base, 2,2_dimercapto-1 ratio n Biting group, (2S)-2-ethyl-1 -p ratio slightly biting 4-thyl, 2-*^--5-heterobicyclo[2.2.1]g, 5-yl or 1, 4-II>»#-8-heterospiro[4.5]癸-8-yl; R8 is cyano; and P, Q, D, L, RA, RB and r3 are in the formula 98683.doc-74- 1333489 (), and R4, Rs, 1 and 9 are as defined in the formula. In another embodiment, the compound of the invention has the formula (10)), "where L is CHzCH2 - 'A is a covalent bond; the core and r2 are heterocyclic to the nitrogen atom attached thereto', and are selected from the group consisting of a nitrogen heterocyclic group, aziridine, anthracene, hydrazino, and Hydrogen, hexammine, acridinyl, indole, (2R)-2-methylindolyl, 2,5-dihydro-m-pyrrolyl, pyrrolyl, 3 ,6·Dihydro-1(2Η)·pyridyl, thiomorpholinyl and anthracene oxalate; R3, R4, I, R7 and R9 are hydrogen; R8 is cyano; X is CH; Y is CH; and Z is CH. In another embodiment, the invention is The compound has the formula (VII), wherein L is ·*(:Η2(:Η2-; A is a covalent bond; the core and r2 together with the nitrogen atom attached thereto form a heterocyclic ring selected from a nitrogen heterocycle Pentyl, (3S)_3_(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, 1H-imidazol-1-yl, (3R)-3-yl咐 咐 、, (3S) _3 hydroxy 丨 pyrrolidinyl, (2S)-2-(hydroxymethyl) pyrrolidinyl, (2R) 2 - (hydroxymethyl) pyrrolidinyl, (cis) - 2,6-Dimethylhexahydropyridyl, 4-methyl-bishexahydropyridyl, 2-methyl-bishexahydropyridyl, 1-hexahydropyridyl, (2r,5r)_2,5- Dimethylpyrrolidinyl, (cis)-2,5-dimercaptopyrrolidinyl, pyrrolidinyl, 2-methyl-1-(1-pyrrolidyl, (2R)-2-methyl- 1-pyrrolidinyl, (28)·2-methyl d•pyrrolidyl, (2R)-2-methyl-5-oxo-small-bite, (2S)_2_mercapto_5_oxygen Small p-pyrrolidyl, 3,6-dihydro-1(2H)-pyridyl, (2S)-2-(methoxycarbonyl)-1-pyrrolidinyl, (2R)·2·(oxygen Carbonyl)-1-pyrrolidinyl, (2S)-2-(fluorofyl)-pyrrolidinyl, (2R)-2-(fluoromethyl)-1-pyrrolidinyl (2r)-2-Ethyl-1-pyridyl 0 each biting group, 2,2-dimethyl-I-Bilo bite group, (2S)_2_ethyl_ip ratio d each bite 98683.doc - 75- 1333489 4-Noryl, 2ϋ azabicyclo[221]g _5_yl or ^2噚^azaspiro[4.5]癸I group; R3, R4, heart, R^R9 are gas; Atom; X is CH; Y is CH; and Z is CH. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (IVH) in admixture with a pharmaceutically acceptable carrier. According to another specific embodiment, the invention provides a method of selectively modulating histamine-3 receptor in a mammal (IV) comprising administering an effective amount of a compound of formula (I-VII). According to another specific embodiment, the invention provides a method of treating or preventing a disorder which is ameliorated by modulation of a histamine-3 receptor in a mammal, comprising administering an effective amount of a compound of formula (i-VII). According to another embodiment, the invention provides a treatment selected from the group consisting of acute myocardial infarction, bipolar disorder, cognitive improvement, cognitive deficit in mental disorders, skin cancer, drug abuse, depression, gastrointestinal disorders, inflammatory response, jet Hysteresis, medullary f-adenocarcinoma, melanoma, allergic rhinitis, ear vertigo, migraine, mood and attention changes, motion sickness, neurogenic inflammation, obsessive-compulsive disorder, pain, Parkinson's Methods of schizophrenia, schizophrenia, seizures, septic shock, Duruit's syndrome, dizziness or insomnia. According to another embodiment, the invention provides a method of treating a syndrome of Alzheimer's disease by administering an effective amount of a compound of formula (I-VH). According to another embodiment, the present invention provides a method for treating insufficiency of overreaction by administering an effective amount of a compound of the formula σ-νπ). 0 98683.doc -76 - According to another specific embodiment 'The present invention provides a method for treating epilepsy by administering an effective (I-VII) compound.

According to another embodiment, the present invention provides a method of treating narcolepsy by administering an effective amount of a compound of formula (I-VII). X According to another embodiment, the present invention provides a method of treating obesity by administering an effective amount of a compound of formula (I-VII). According to another embodiment, the present invention provides a method of treating a disorder selected from the group consisting of moderate cognitive impairment memory deficits and learning deficits' and dementia by administering an effective amount of a compound of formula (I-VII). Representative compounds of the invention include, but are not limited to, 4-(2-{2-[(2R)-2-methyl, beloridinyl]ethyl}

Benzonitrile; A 4-{2-[2-(l-pyrrolidinyl)ethylbenzofuran-5-yl}benzonitrile; 4-{2·[2-(2-methyl·1·pyrrolidine) Ethyl)benzofuran_5_yl}benzonitrile; i 4-{2-[2-(1-hexahydro-butyryl)ethyl]-1-benzofuran_5_yl} Benzonitrile; 4_{2-[2-(monoethylamino)ethyl]-1-benzopyrifin-5-yl}:^: nitrile; 4-{2-[2-(2-A -1--1-hexahydropyridyl)ethyl]-i_benzofuran-5 base} phthalonitrile; ι 4-(2-{2-[(3R)-3-hydroxypyrrolidinyl]ethyl}- 1·benzopyran·5 base) phthalonitrile; 4-{2·[2-(1Η-imidazol-1-yl)ethyl]-bubenzofuran-5-yl}Xin riding; 4-(2 -{2-[(3S)-3-(didecylamino)pyrrolidinyl]ethylidene-phenyl-5-yl)benzonitrile; 98683,doc -77- 1333489" 4_(2-{2_ [(2s)-2-(hydroxymethyl)pyrrolidinyl]ethyl}-i-benzofuranyl] 猜 guess; 4-(2-{2_[(2R,6s)26•dimethyl6 Hydroquinone; ethyl bromide; brom-5-yl) gambling; fur 4-(2-{2-[(2R,5R)-2,5-dimethylpyran-5-yl) 卞月青; Pyryryryl)ethyl}_丨_ phenyl 4-{2-[2-(1-azopentyl)ethyl] benzofuranyl}

4-{2-[2-(4-methyl·hexahydropyridinyl)ethyl] benzofuranbenzonitrile; ^ 4-(2·{2-[(2-呲-r-pyridinyl) carboxylic acid Salt)]ethylidene 1- benzofuran·5_yl)benzonitrile; {[(, monohydro-1(2Η)-ρ 唆 ))ethyl]_ ι_ 吱 吱 _ 5 5 _ _ ; 4-(2-{2-[(2R)_2_(曱曱风的咯毛基基)ethyl}小笨和决喃_5_基)benzonitrile; 4-(2-{2·[Third- Butyl (mercapto)amino]ethyl}1 benzofuran_5yl) #benzonitrile; 4-(2-(2-[isopropyl(indenyl)amino)ethylbubbenzofuran %()-benzonitrile; 4-(2-{2.[isobutyl(methyl)amino]ethyl η-benzofuran-5-yl)phthalonitrile; 4-(2-{2-[ethyl( Isopropyl)amino]ethylidene bromidefuran·$yl)phthalonitrile; 4 (2-(2-[ethyl(propyl)amino)ethyl bup benzofuran·$•) Betting; 98683.doc • 78· 1333489 4-(4-{2-[2-(2-Methyl-1-pyrrolidinyl)ethyl]-1-benzofuran-5-yl} benzamidine Morpholine; 4-(4-{2-[2-(1-hexahydropyridyl)ethyl]-1-benzofuran-5-yl}benzylidene)morpholine; N,N- Diethyl-N-(2-{5-[4-(4-?*)-phenyl)phenyl]-1-benzophenone-2- 4-(4-{2-[2-(2.methyl-1-hexahydropyridyl)ethyl]-1-benzofuran-5-yl}benzhydryl) Morpholine; (3R)-l-(2-{5-[4-(4-morpholinylcarbonyl)phenyl]-1-benzofuran-2-yl}ethyl)-3-ρ ratio (pyrrolidinol); 4-[4-(2-{2-[(2R,5R)-2,5-dimethylpyrrolidinyl]hexyl}-i-benzofuran-5-yl)benzylidene ]morpholine; 4-[4-(2-{2-[(2R,6S)-2,6-dimethylhexahydropyridinyl]ethyl}-benzofuran-5-yl)benzimidazole 4-morphine; 4-(4-{2-[2-(吖呼)ethyl]-1-benzofuran-5-yl}benzhydryl) B Lin; 4-(4-{ 2·[2-(4-Methyl-1-hexahydropyridinyl)ethyl]_ι_benzofuran-5_yl}] 笨 酿 )); 4-(4-{2-[2-( 4-morpholinyl)ethyl]-1-benzofuran_5-yl}benzhydryl) Ρ林; 4-(4-{2-[2-(3,6-dihydro-1() 2Η)-pyridyl)ethyl]_ι_benzofuran-5_yl}benzyl) Ρ林; 4-(4-{2-[2-(2S)pyrrolidinyl decyl)ethyl] -1·benzofuran_5_yl}, stupid base), lin; 98683.doc -79- 1333489 N-(second-butyl)-N-methyl-N-(2-{5-[ 4-(4-morphinylcarbonyl) stupyl] small benzofuran-2-yl}B Amine; N-isopropyl-N-methyl-N-(2-{5-[4-(4-morpholinylcarbonyl)phenyl]-anthracene] benzofuran-2-yl}ethyl) Amine; N-isobutyl-N-methyl-N-(2-{5-[4-(4-morpholinylcarbonyl)phenyl]q•benzofuran-2-yl}ethyl)amine; N -ethyl-N-isopropyl-N-(2-{5-[4-(4-morpholinocarbonyl)phenyl] benzofuran-2-yl}ethyl)amine; hydrazine, hydrazine-dimethyl Ν-Ν-(2-{5-[4-(4-morpholinecarbonyl;)phenyl]-benzofuran-2-yl}ethyl)amine; Ν-ethyl-Ν-(2-{ 5-[4-(4-morpholinecarbonyl)phenyl]_丨_ benzofuran-2-yl}ethyl)-N-propylamine; 4-{4-methyl-2-oxo-3_[2 -(1-pyrrolidinyl)ethyl b 211_nonene_7_yl}benzonitrile; 4-{4-methyl-2-oxo-3-[2-(1-hexahydropyridinyl) Base]_211_pinene_7_ base} yeue greece; 4-{3-[2-diethylamino)ethyl]-4-indolyl-2-oxo-2H-nonene-7-yl} Benzonitrile; 4-[(6-{2-[2-(1-pyrrolidinyl)ethyl]-1- benzofuran-yl hydrazinyl) benzyl]]#; 4-{ [6-(2-{2-[(2R)-methylpyrrolidinyl]ethyl)m-benzofuran-5-yl)-3-pyridyl]carbonyl}morpholine; 4-[(6-{ 2-[2-(1-hexahydro 1» than dimethyl)ethyl]-1-benzopyrene (7-South-5-yl}-3-1 »比基基)基基]林林; 98683.doc -80- 4-[(6-{2-[2-(N,N-Diethyl)ethylbubbenzofuran_5_基卜(3R)-l_(2-{5-[5-(4-morpholinecarbonyl)_2pyridinyl]benzophenan-2-yl}ethyl)-3 -p biloyl alcohol; 4_{[6_(2-{2-[(2S,5S)-2,5-dimethylpyrrolidinyl)ethyl benzofuran-5-yl)-3- Pyridyl]carbonyl}morpholine; 4-{[6-(2-{2-[(2R,6S)-2,5-dimethylhexahydropyridyl]ethyl b i•benzopyran-5 -yl)-3-indenyl]carbonyl}-lin; 4-{[6-(2-{2-[1-ahecyclopentenyl]ethylidene-benzofuran_5_yl)- 3 - than a bite base] a few base} u forest; 4-[(6-{2-[2·(4-methyl-1-hexahydropyridinyl)ethyl]_丨_ 并 呋 呋 ___ Base}·_3-ρ than bite base) a few bases]?p forest; 4-[(6-{2-[2-(4-)-ethyl)ethyl]-1-stupidyl 11 South_5- }}-3-1» 咬 )) carbonyl]morpholine; Ν-(second-butyl)-Ν-methyl-Ν-(2-{5-[5-(4-?)-lin N-isobutyl-N-methyl-N-(2-{5-[5-(4-loryl) -2-p ratio bite base]-1- and bite °N-2-yl}ethyl)amine; N-isopropyl -N-methyl-N-(2-{5-[5-(4-?p-linwei)-2-p-bite base]-1-brow and eat pain-to-yl}ethyl)amine; N -ethyl-N-isopropyl-indole·(2 - { 5-[5-(4-?ηη林基)-2-u ratio) 1-benzopyran-2-yl }ethyl)amine; N-dimethyl-N-(2-{5-[5-(4-morphinyl)_2-ρ ratio octyl]-1-benzopyrene °N-2-yl }ethyl)amine; 98683.doc -81 - 1333489 N-ethyl-N-propyl-N-(2-{5-[5-(4-morpholinylcarbonyl)-2-pyridyl]-1· Benzobite-2 -yl}ethyl)amine; 8-(2-{5-[5-(4-morpholinylcarbonylpyridyl)"-benzofuran-2-yl}ethyl)-1, 4-IIU·Azaspiro[4.5]癸炫; 5-(2-{5-[5-(4-morpholinecarbonyl)_2_pyridyl]_丨_benzofuran-2-yl}ethyl )-2-4-5-azabicyclo[2_2.1]g Hyun;

(2S)-l-(2-{5-[5-(4-morpholinecarbonylpyridinyl)benzofuran-2-yl}ethyl)-pyrrolidinol; N-allyl-N-( 2-{5-[5-(4-morpholinylcarbonyl)-2-pyridyl]-1-benzofuran-2-yl}ethyl)amine; 3-[(2-{5-[5-( 4-morpholinecarbonyl)_2_acridinyl]]benzofuran-2-yl}ethyl)amino]-1-propanol; N-(2-{5-[5-(4-morpholinylcarbonyl)) _2_pyridyl]-indole benzofuran-2-yl}ethyl)-indole-propylamine; 4-(2-{2-[(3R)-3 arylmethylamine ketone] ethyl} small Benzoin

-5 - base) gambling; 4-(2)2-[(2R) methyl (tetra) silk] ethyl} 2 3 diazepines and biting -5 -yl) 卞 guess; p-pyridyl Ethyl}-1-phenyl(4-fluorophenyl)(2-{2-[(2R)-2-methylbit.South-5·yl)caro 1 ; 17 each bite]ethyl }-1-Bist (3-fluorophenyl)(2-{2_[(2R)-2-methylpyridan-5-yl)methanone; (2-fluorophenyl)(2_{2_[( 2R)_2_methylhydrazin-5-yl)methanone; a group]ethyl stupid 98683.doc -82 - 1333489 (3-gas radical) (2-{2-[(2R)-2-曱) Base - lp than 嘻 ] ] 乙基 乙基 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙Hip-hopping base] ethyl b 1 -benzopyran-5-yl)methanone; (4-methoxyphenyl) (2-{2-[(2R)-2-methyl-I-? ratio咬 基 】 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙 乙Pyridyl]ethyl}-1_ benzofuran-5-yl)methanone; cyclopropyl (2-{2-[(2R)-2-methyl-1-indolyl)ethyl bromide_ Benzofuran-5-yl)fluorenone; 3-ethyl-1-l-(2-{2-[(2R)-2-mercapto-1-P ratio α-fluorenyl) ethyl bup benzofuran -5-yl)pentanone; (4-gas-3-tolyl) (2- {2-[(2R)-2-Methyl·i•pyrrolidinyl]ethylbenzoquinone-5-yl)carboxamidine; (2-{2-[(2R)-2-methyl-1) -pyrrolidinyl]ethylidene-benzofuran_5·yl)[4-(methylthio)phenyl]methanone; [4-(didecylamino)phenyl](2-{2- [(2R)-2-methyl·pyrrolidinyl]ethyl}-1-bens and pfu--5-yl)carboxamidine; (4-tolyl)(2-{2-[(2R)) -2-methyl-1-pyrrolidinyl]ethyl bj benzopyran--5-yl)fluorenone; (3,5-difluorophenyl)(2-{2-[(2R)- 2-methyl fluorenyl]ethyl}1_benzofuran-5-yl)methanone; (2-methoxyphenyl)(2-{2-[(2R)-2-methyl oxime) Oleto] ethyl} small benzofuran-5-yl) ketone; 98683.doc • 83· 1333489 (3-oxophenyl) (2_{2_[(2) 2 methyl-b-pyrrolidine Ethyl]ethyl benzopyran-5-yl)methyl _ ; (2-{2-[(2R)-2-methyl-1·pyrrolidinyl]ethyl benzofuran _5_yl ((基) ketone; 4-(2-{2-[(2R)-2-methyl-i-pyrrolidinyl)ethyl hydrazide _ benzofuran · 4 yl) phthalonitrile; 2- { 2-[(2R)-2-methylpyrrolidinyl]ethylbububenzofuran-6-nitrile; 3-(2-{2-[(2R)-2-methylpyrrolidinyl) Ethyl bromide _5_ 基))-5-(p-cephen-2-ylmethyl)-1,2,4-*». Sitting; 4-[3-(2-{2-[(2R)-2-methylp-pyridyl)-yl]ethyl bromide-benzofuran-5-yl)-l,2,4- Tf-di-salt-5-yl]-s-nitrile; 5_(cardiochlorophenyl)-3-(2-(2-[(2R)-2-methylpyrrolidine·1]yl) °南-5-yl)-l,2,4- No.2 β-seat; 5-(2-indolyl)-3-(2-{2-[(211)-2-methylpyrrolidine-1 -yl]ethyl}-1_benzophenan-5-yl)-l,2,4-ff di-beta; 5-(4-fluoro-yl)-3-(2-{2-[( 2R)-2 -Methyl I» than 0 each bit-1-yl]ethyl}-ΐ-lu benzophenan-5-yl)-1,2,4-p#n n sitting; 5-( 4-methoxyindolyl-3-(2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}-1-benzophenone °N-5-yl)-l , 2,4-ff No. 2. Sit; 3-{[3-(2-{2-[(2R)-2 -methyl p is more than π each bite-1-yl]ethyl}·1· stupid Bite-5-yl)-1,2,4-oxadiazol-5-yl]fluorenyl}benzonitrile; 3-(2-{2-[(2R)-2-methylpyrrolidine-1- Ethyl]ethyl}-benzofuran-5-yl)-5-phenyl-1,2,4-oxadiazole; 5-(4-fluorophenyl)-3-(2-{2-[ (2R)-2-methylpyrrolidin-1yl]ethyl}-l- 98683.doc • 84- 1333489 benzopyran-5-yl)-1,2,4-11 diazole; 5-(3- gas-4-fluorophenyl)-3-(2-{2-[(2R)- 2-methyl p-Bityl]ethyl}-1-benzofuran-5-yl)-1,2,4-oxadiazole; 5·(gas sulfhydryl)-3-(2-{2 -[(2R)-2-methylmenta piroxicam]ethyl benzofuran-5-yl)-1,2,4-oxadiazole; 3- (2-{2-[(2R)曱-2-mercaptopyrrolidin-1-yl]ethylbub benzofuran _5_yl)-5-propyl-l,2,4-ff bis <» sitting; 5-ethyl-3 -(2-{2-[(2R)-2.methylpyrrolidin-1-yl]ethyl}dodofuran-5-yl)·1,2,4-oxadiazole; 5-fluorenyl -3-(2-{2-[(2R)-2-methylir pirin-1 base] ethyl benzopyran-5-yl)-l,2,4-4:« 4-(3-bromo-2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}·ι_ benzofuran-5-5-yl) nitrite; 4 -(3-(2-furyl)_2-{2-[(2R)-2-indolylpyrrolidin-1-yl]ethylbobbenzofuran-5-yl)benzonitrile; 4-[2 -{2-[(2R)-2-indolyl-1-pyrrolidinyl]ethyl}-3-(3-pyridyl)benzophenan-5-yl)benzonitrile; 4 [2 {2- [(2R)_2-fluorenyl-ip piroxime]ethyl}-3-(3-ρ塞基基)_ι·benzofuran_5·yl)benzonitrile; 4-(3_(2-A) Mercapto-3-pyromyl)-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-indolofuran-5-yl)benzonitrile; 2-methyl-4-(2-{2_[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzopyran-5-yl); nitrile; 3-methyl -4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-phenylene 98683.doc -85- 1333489 pf-5-yl) 4-(6-Methyl-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)indole; 4-( 4-methyl-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzo-b--5-yl) gambling; 4-(7·A 4-(2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzo-p-pentan-5-yl) gamma; 4-(7-fluoro-2 -(2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)-labeled wax; 2- gas- 4- (2-{2-[ (2R)-2-methyl-Ι-p ratio 0 each bite group] ethyl}·_1-benzox-f--5-yl)+ wax; 3-(2-{2-[(2R)- 2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile; (2R)-l-{2-[5-(4-fluorophenyl)-1- Benzo-bromo-2-yl]ethyl}-2-methylpyrrolidine; (2R)-l-{2-[5-(3,4-dioxa)-1-benzofuran-2 -yl]ethyl}-2-methylpyrazine; (2R)-2-mercapto-l-{2-[5-(2-indolyl)-1-benzofuran-2-yl] Ethyl}p ratio σ each bite; (2R)-2-mercapto -1-{2-[5-(3-indolyl)-1-benzofuran-2-yl]ethyl}p piroxime; (2R)-2-methyl-1-{2-[ 5-(4-indoleyl)-1-benzofuran-2-yl]ethyl}p piroxime; 4-{2-[2-(2-methylpyroxy-1-yl) -ethyl]-benzobenzopyran-5-yl}-benzene 98683.doc -86- 1333489 methyl formate; (2R)-1-{2-[5_(2-methoxyphenyl)-1-phenyl And biting the taste of-2-yl]ethyl}-2-methylpyrobitine; (2R)_l-{2-[5_(3·methoxyphenyl)-1_benzofuran_2_yl] (2-R)-l-{2-[5_(4.methoxyphenyl)4•benzofuran-2-yl]ethyl 2-methyl Pyrrolidine; (2R)_1_{2-[5-(3-fluorophenyl)-1-benzofuran-2-yl]ethyl}-2-methyloxime 11 each bite; (2R)_1_ {2-[5-(2-Chlorophenyl)-1-benzofuran-2-yl]ethyl}·2-methylpyrrolidine; (2Κ)_Κ{2_[5·(3-Phenylphenyl) )-1- benzofuran-2-yl]ethyl}-2-methyl p is a bit different from B; 1 {2 [5-(4-phenylphenyl)_ benzofuran-2-yl]-B (2R)-2-f^-i_(2-{5-[3-(^ I yl)phenyl]-1-phenylidene P-pyran-2-yl) Ethyl)I»Bilo bite; (2R)-2-methyl small (2_{5_[4_(trifluoromethyl)phenyl η benzo) (2R)-2-methyl-1-(2-{5-[3-(trifluoromethoxy)phenylimι_ benzofuran-2-yl} (2R)-2-methyl-1-(2-{5-[4-(trifluoromethoxy)phenyl benzofuran-2-yl}ethyl)pyrrolidine (211)-1-{2-[5-(3,4-indolylphenyl)_1_benzofuran-2-yl]ethyl b 2_ 98683.doc •87· 1333489 methyl than winter bite; 2R)-l-{2-[5-(3,5-Dichlorophenyl) benzofuran·2·yl]ethyl b 2_methylpyrrolidine; (211)-1-{2-[5 -(3,5-dimethylphenyl)-1-benzo17-pentan-2-yl]ethyl}_2_methylpyrrolidine; [4-(2-{2-[(2R)-2-methyl)小峨洛基基]ethyl}小笨和吱痛_5_ base) phenyl]methanol; 3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl b丨_Standenfuran_5_yl)pyridine; 9 (2R)-l-(2-{5-[2-(4-fluorophenyl)vinyl]·丨_ benzofuran-2-yl}ethyl) -2-methyl p ratio τ» bite; l-[3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl bup bromide-5-yl Phenyl]ethanone; 1-[3-(2-{2-[(2R)-2-indolyl-1-pyrrolidinyl]ethylidene-benzofuran-5-yl)phenyl] Ethanol; 2- [3-(2-{2-[(2R)-2-mercapto-1- Pyrrrolidinyl]ethylidene i- benzofuran-5-yl)benyl]-2-propanol; l-[3-(2-{2-[(2R)-2-methyl-lp ratio) A bite base] ethyl bromide 吱-5-yl) phenyl] b- elbow; l-[3-(2-{2-[(2R)-2_methyl- Ι-p ratio slightly bite Base] ethyl} small stupid and sputum. Nan-5-yl)phenyl]ethanone oxime-methyl hydrazine; l-[3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1· Stupid and shouting -5-yl)phenyl]ethanone oxime ethyl rib; l-[3-(2-{2-[(2R)-2-mercapto-1-pyrrolidinyl]ethyl} -1-笨和吱0南98683.doc -88- 1333489 •5-yl)phenyl]ethanone oxime·(third _ butyl) monthly loss; 3-(2-{2-[(2R)- Ethyl 2-methylpyrrolidinyl]ethyl}-1_benzofuran·5-yl)benzoate; 3-(2-{2-[(2R)-2-methyl-indole-pyrrolidine Ethyl]ethyl}-1_benzofuranyl)benzoic acid; N-methoxy-N-methyl_3_(2_{2_[(2R)_2-methyl-1-pyrrolidinyl]ethyl} 1--1-benzofuran-5-yl) benzoic acid; l-[3-(2-{2-[(2R)-2-methyl_1_pyrrolidinyl]ethyl b 1_benzo Furan-5-yl)benyl]-1-propane mesh; cyclopropyl[3-(2-{2-[(2R)_2-methyl-1-pyrrolidyl]ethyl b 1_stupid Furan-5-yl)phenyl]formin; 3-methyl-l-[3-(2-{2-[(2R)-2-mercapto-1-pyrrolidinyl]ethyl) -5-5-yl)phenyl]-1·butanone; 3-(2-(2-[(2R)-2-methyl-1-pyrrolidinyl)ethyl}p-benzofuranyl)benzaldehyde ; 3-(2-{2-[(2R)-2-decylpyrrolidinyl]ethyl bup Furan _5_yl)phenyl](2-pyrimenyl)methyl mesh; (3-fluorophenyl)[3-(2-{2-[(2R)-2-methyl_1_tonrolidinyl) Ethyl benzofuran-5-yl)phenyl]methanone; [3-(2-{2-[(2R)-2-methyl-indolyl)-ethyl bromide] Stupid and furan·5_yl) stupyl] decyl alcohol; (2R)-l-[2-(5-benzyl-1·benzofuran-2-yl)ethyl]·2_methylpyrrolidine; -(2-{2-[(2R)-2-indolyl-indole-pyrrolidinyl]ethyl bup bromoxyfuran ^ 98683.doc • 89- 1333489 base)-1Η-imidazole; 4-(3 -Bromo-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-l- benzofuran-5-yl)-2-methylindole, 4-(3 - gas-2 - {2 - [(2R)-2-subyl- Ι-p-pyrrolidine] ethyl benzo-bate-5-yl) yoghurt; 4 (3,6 - two gas - 2 - {2 - [( 2 R) - 2 - fluorenyl-Ι-p ratio 17 each bite base] ethyl}-1-benzoate bite 0 south-5-base) gambling; 4-(3-iodine -2-{2-[(2R)-2-fyl-1-pyrrolidinyl]ethyl b 1_benzofuran-5 ·yl) gambling; 4-(2 - {2 - [(2R) -2-methyl-5-oxo-decyl]ethylbenzoin-5-yl)-labeled wax; 4-(3-ethylindenyl-2-{2-[(2R)-2-methyl- 1-pyrrolidinyl]ethyl}-1-benzobenzoin-5-yl)+wax; ring [4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)phenyl]anthone; 3,5· Dimethyl-4-(2-{2-[(2R)-2.methyl-1-pyrrolidinyl)ethylidene 1-benzofuran-5-yl)iso-xazole; 4-[2- (2-Aminoethyl)-1_benzoquinone-5-yl)Ura; 4-(2_{2-[(2R)-2-ethyl-1-峨0 decyl]ethyl} -1-Benzobenzopyran-5-yl) yoghurt; 4-(2-{2-[(2S)-2-(gas fluorenyl)-lp piroxicam]ethyl}-1- stupid Bite _ 5 -yl) Yuyue Axe 5 4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl) Wax; 98683.doc • 90- 1333489 4-(2-{2-[(2S)-2-methylpyrrolidinyl]ethyl}-l-benzofuran-5-yl)phthalonitrile; (2 R ) - 2-mercapto-l- [2-(5-phenoxy-1-benzo-dopyridin-2-yl)ethyl]p piroxime; (2R)-l-(2-{5- [(3-Fluorophenyl)thio]-1-benzofuran-2-yl}ethyl)-2-indenyl ρ ratio 51 each bite; 3-(2-{3-[(2R)-2 -Methyl- Ι-p than Hatch base] propyl}-1-benzo-bate-5-yl) car July paste; ^ 3-(2-{[(2R)-2-methyl-1 -pyrrolidinyl]methyl}-1-benzofuran-5-yl)benzonitrile; 3-(2-{4-[(2R)-2-methyl-1-pyrrolidinyl]butyl}- 1-benzofuran -5-基) 节月青» 4- (4-{2-[2-(2S)-fluorenyl- lp ratio 0 each bite) ethyl]-1-benzopyrifin 0 south-5-yl }benzylidene)morpholine; 4-{4_methyl-2-oxo-3-(2-(2S)-methyl-Ι-p ratio σ each bite ethyl]-2H-bite -6-yl} nitrile; Lu 4-{4-methyl-2-oxo-3-[2-(2R)-methyl-1-pyrrolidylethyl]-2Η-decene-6- Benzyl nitrile; 4-{[6-(2-{2-[(2S)-methylpyrrolidinyl]ethyl}-1-benzofuran-5-yl)-3-pyridyl]carbonyl} Morpholine; 4-(2-{2-[(2R)-methyl ρ piroxime]ethyl}-2,3 -diqi-1-benzoin-5-yl) -(2-{2-[(2S)-2-indolyl-1·ρ-pyridyl)ethyl}-1-benzofuran-4-yl) loyalty! 98683.doc -91 - 1333489 4-{2-[2-(2(S)-Mercapto-pyrrolidin-1-yl)-ethyl]-benzofuran-6-yl}- 3- (2-{2-[(2S) -2-mercapto-purine-p-biheptyl]ethyl}-1-benzo-p-flavor-5-yl) yoghurt; 4-(2-{2-[(2S)-2-methyl) - Ι-p 比洛基基] hexyl}-1-benzocypanf-5-yl) Ye Yuecang> 4-(2-{2-[(2S)-2-Ethyl-1-pyrrole 4-(2-{2-[(2R)-2-ethyl-1-pyrrolidinyl]ethyl b 1 · pyridine]ethyl}-1-benzofuran-5-yl) Benzofuran-5-芊 芊 ;; 4-(2-{2-[2-ethyl-Ι-p than 嘻 ] ] 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 4- 4-) 4-(2-{2-{ 2-[(2S,5S)-2,5-dimethylpyrrolidinyl]ethyl}-1-benzofuran-5-yl) word bet; 4- (2-{2-[(reverse)- 2,5-Dimethylpyrrolidinyl]ethyl b-benzofuran-5-yl) wax; 3,5-dimethyl-4-{2-[2-(2 ft)-fluorenyl -? Bilto-1-yl-ethyl]-benzopyran-5-yl}-iso-β. Sitting; 5-{2-[2-(2R)-methyl-p to π-indol-1-yl-ethyl]-benzonof-5-yl}-2-phenyl-oxazole; 2-{2-[2-(2R)-methyl-pyrrolidin-1-yl-ethyl]-benzofuran-5-yl}-pyrazole; 4-{2-[2-(2R)- Methyl-pyrrolidin-1-yl-ethyl]-benzofuran-5-yl}-1 syrazole; 98683.doc -92- 1333489 4-{2-[2-(2R)-methyl- Pyrrolidin-1-yl-ethyl]-benzofuran-5-yl}-1-phenyl-1H-pyrazole; 1-methyl-4-{2-[(2R)-(2-methyl) -pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-111-imidazole; 4-{2-[2-(2R)-methyl-pyrrolidin-1-yl-ethyl ]-Streptofuran-5-yl}-P tomb α sitting; 2-{2-[2-(2R)-indolyl-pyrrolidin-1-yl-ethyl]-benzofuran-5-yl} -1 imidazole; 4-{2-[2-(2R)-methyl-ρ ratio B each 1-yl-ethyl-benzo]-5-*}-quinone-benzimidazole; 3-methyl-6-{(2R)-[2-(2-methyl-p ratio π each -1-yl)-ethyl]-benzop-pentan-5-yl}-α , 2-{2-[2-(2R)-fluorenyl ratio σ each -1-yl-ethyl]-benzocyt. South-5-based}-leaf cultivating; 5-{2-[2-(2R)-fluorenyl-ρ piroxime-1-yl-ethyl]-benzoquinone-5-yl}-pyrimidine ; 5-{2-[2-(2R)-methyl-ρ is more than -1-yl-ethyl]-benzoquinone-5-yl}_ 嗒-4-ylamine; 5-{ 2-[2-(2R)-methyl-pyrrolidin-1-yl-ethyl]-benzofuran-5-yl}-in nicotinonitrile; 4-{2-[2-(2R )-mercapto-pyrrolidin-1-yl-ethyl]-benzofuran-5-yl}-111-thirsty; 4-{2-[2-(2R)-fluorenyl-pyrrolidine-1- -ethyl]-benzofuran-5-yl}-phthalonitrile; 98683.doc -93- 1333489 5-{2-[2-(2R)-methyl-pyrrolidin-1-yl- Ethyl]-benzofuran-5-yl}-hydroindol-1-one; 1-{2-[5-(5,6-diaza-2H-17-endan-3-yl-benzoquinone 17)喃-2-yl]-ethyl}-(211)-methyl-pyrrolidine; 1-[2-(5-cyclohept-1-enyl-benzofuran-2-yl)-ethyl]- (2R)-methyl-pyrrolidine; (2R)-methyl-1-(2-{5-[2-(11Η-10-喽-dibenzo[a,d]cycloheptene-5- ))-ethyl]-benzo-Bind α-A-2-yl}·-ethyl)-1» ratio. Each bite; 4- {2-[2-(2R)-methyl-ρ 比洛. -1-yl-ethyl]-benzop-pentan-5-yl}-p ratio bite; 3,5-dimethyl-4-{2-[2-(2R)-fluorenyl-pyrrolidine- 1-base- Ethyl]-benzopyran-4-yl}-isoxazole; 5-{2-[2-(2R)-methyl-P to 1yl-ethyl]-benzobenzopyran-4. }-2-phenyl-carbazole; 2-{2-[2-(2R)-methyl-pyrrolidin-1.yl-ethyl]-benzofuran-4-yl}-plug. -{2-[2-(2R)-methyl-p-Bile-1-yl-ethyl]-benzoquinone--4-yl}-111-pyrazole; 4-{2-[2-( 2R)-Methyl-p ratio 。..-1-yl-ethyl]-benzoquinone-4-yl}-1-phenyl-1H-pyrazole; 1-methyl-4-{2- [(2R)-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-4-yl b 1H-imidazole; 4-{2-[2-(2R)-methyl- Pyrrrolidin-1-yl-ethyl]-benzofuran-4-yl}-pyrazole; 98683.doc -94- 1333489 2- {2-[2-(2R)-Methyl-ρ 比洛 bite- 1-yl-ethyl]-benzoheptan-4-yl}-111-imidazole; 4-{2-[2-(2R)-methyl-pyrrolidin-1-yl-ethyl]-benzo Furan-4-ylpyr 1H-benzimidazole; 3-mercapto-6-{(2R)-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran- 4-{2-}-α荅; 2-{2-[2-(2R)-methyl-ρ pirodi-1-yl-ethyl]-benzocypan-4-yl}_ p ratio Plowing; 5-{2-[2-(2R)-methyl-p-Big·π-l-l-yl-ethyl]-benzoheptan-4-yl}-pyrimidine; 5-{2-[ 2-(2R)- --ρ 比洛唆-1-yl-ethyl]-benzobenzopyrim-4-yl}·α合11 Well-4-ylamine, 5-{2-[2-(2R)-fluorenyl- ρByrrolidin-1-yl-ethyl]-benzofuran-4-yl}-nicotinyl nitrile; 4-{2-[2-(2R)-methyl-ρ 比洛 bit-1-yl -ethyl]-benzoxaffran-4-yl}-111-indole; 4-{2-[2-(2R)-fluorenyl-p-Bista-1-yl-ethyl]-benzene弁 喃-4-yl}_ phthalonitrile; 5- {2-[2-(2R)-fluorenyl-ρ ratio 0 each -1-yl-ethyl]-benzo aceton-4 -yl}_hydroquinone-1 -one; 1-{2-[4-(5,6-dihydro-2H-flavor. South-3-base)-benzoate bite. South-2 -yl]-ethyl}-(21〇-methyl-pyrrolidine; 1-[2-(4-phospho-l-]-yl-benzopyran-2-yl)-ethyl] -(2R)-methyl-ρ-pyrrolidine; 98683.doc -95- 1333489 (2R)-methyl-1-(2-{4-[2-(11Η-10-pyrene-dibenzo[a] , d]cycloheptene-5-yl)-ethyl]-benzoquinone σNan-2-yl}-ethyl)-ι» than 17 bites; 4 - {2-[2-(2R) - fluorenyl-ρ ratio ° bit -1-yl)-ethyl]-benzoxaffran-4-yl}-pyridine; 3,5-dimethyl-4-{2-[2-(2 (R)-Methyl-pyrrolidin-1-yl)-ethyl]-benzoheptan-6-yl}-iso-p-azole; 5-{2-[2-(2(R)-methyl) -pyrrolidin-1-yl)-ethyl]-benzofuran-6-ylbu-p-phenyl-^, 2-, | 2- {2-[2-(2(R)-methyl-pyrrolidine -1-yl)-ethyl]-benzofuran-6-yl}-pyrazole; 4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl] -benzofuran-6-yl}-111-pyrazole; 4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-6- Keb 1-phenyl-1H-pyrazole; 1-methyl-4-{2-[2(R)-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran- 6-yl}-111-imidazole; 隹4-{2-[2-(2(R)-indolyl-pyrrolidin-1-yl)-ethyl]-benzofuran-6-yl}- farazole ; twenty two- [2-(2(R)_methyl-? ratio ° bit-1-yl)-ethyl]-benzop-pentan-6-yl}-11·!-imidazole; 4-{2-[ 2-(2(R)-methyl-ρ ratio 0 each 1-yl-1-yl)-ethyl]-benzocypan-6-*}-1Η-benzimidazole; 3-decyl-6- {2(R)-[2-(2-Methyl-pyrrolidin-1-yl)-ethyl]-benzofurazan-6-yl}-. Answer whistle; 98683.doc -96- 2-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-6-yl}-p ratio Plough; 5-{2-[2-(2(R)-fluorenyl-pyrrolidin-1-yl)-ethyl]-benzofuran-6-yl}-mouth bite; 5-{2-[2 -(2(R)-fluorenyl-pyrrolidin-1-yl)-ethyl]-benzofuran-6-yl}-indole-4-ylamine; 5-{2-[2-(2( R) -Methyl-p ratio 11 each bit-1-yl)-ethyl]-benzo ρ is lost. Nan-6-yl}-nicotinyl nitrile; 4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-6-yl}- 111-Anthraquinone; 4-{2-[2-( 2 (R)-fluorenyl-p-succinyl-1-yl)-ethyl]-benzo benzoyl-6-yl}-o-phenylene Benzonitrile; 5-{2-[2-(2(R)-methyl ratio σ each -1-yl)-ethyl]-benzo benzoyl-6-yl}·hydroquinone-1-one; 1-{2-[6-(5,6-Dihydro-2Η-endan-3-benzoheptan-2-yl]-ethyl}-2(11)-fluorenyl-pyrrolidine; 1- [2-(6-cycloheptan-1-yl-benzopyran-2-yl)-ethyl]-2(R)-methylpyrrolidine; 2(foot)-methyl-1- (2-{6-[2-(11«;-10-thia-dibenzo[&,£1]cyclohepten-5-yl)-ethyl]-benzobenzoin-2-yl }-ethyl)-p piroxime; 4-{2-[2-(2(R)-indolyl-pyrrolidin-1-yl)-ethyl]-benzofuran-6-yl}- Bite; 3,5-dimethyl-4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-7-yl}-iso Carbazole; 98683.doc -97- 1333489 5-{2-[2-(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-7-yl} - 2 - Phenyl-deficiency, 2-{2-[2-(2(R)-methyl-p-pyridyl-1-yl)-ethyl]-benzocyspin-7-yl}-thiazole; 4 -{2-[2-(2(R)-methyl-ρ 0 唆-1-yl)-ethyl]-benzobenzopyran-7-yl}-111-pyrazole; 4-{2-[2-(2(R)-methyl-pyrrolidine-1- -ethyl]-benzofuran-7-yl}-1-phenyl-1H-pyrazole; 1-methyl-4-{2-[2(R)-(2-methyl-pyrrolidine) -1-yl)-ethyl]-benzofuran-7-yl}-1Η-imidazole; 4 - { 2-[2-(2(R)-methyl-p is 0 c--1-yl) -ethyl]-benzo-Bind α-N-7-yl}-U 嗤; 2- {2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzene And furan-7-yl}-11^imidazole; 4-{2-[2-(2(R)-indolyl-pyrrolidin-1-yl)-ethyl]-benzofuran-7-yl}- 111-benzimidazole; 3-mercapto-6-{2(R)-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-7-yl}-oxime Tillage; 2-{2-[2-(2(R)-methyl-haha-n-yl)-ethyl]-benzo-bungan-7-yl}_ 匕 匕 1 ; 5- { 2-[2-(2(R)-methyl-ρ ratio σ each 1-yl-1-yl)-ethyl]-benzoheptan-7-yl}-pyrimidine; 5-{2-[2-( 2(R)-indolyl-pyrrolidin-1-yl)-ethyl]-benzofuran-7-yl}-indole-4-ylamine; 98683.doc -98- 1333489 5-{2_[2 -(2(R)-fluorenyl-pyrrolidin-1-yl)-ethyl]-benzofuran-7-yl} nicotine nitrile; 4-{2_[2-(2(R)•methyl -pyrrolidin-1-yl)- ]]-benzofuran·7. }}-1沁吲哚; 4-{2-[2_(2(R)-methyl-tonrrolidin-1-yl)-ethyl]-benzofuran _ 7_yl}. phthalonitrile; 5-{2-[2-(2(R)-indolylpyrrolidinyl)ethyl]•benzofuran·7-kibazole-1 -嗣; 1_(2_[7·(5'6-dihydro-2Η- shode-3-yl)-benzofuran-2-yl]-ethyl}-2(1^)-methyl than each bite ; 1 [2-(7·ί 庚 稀 benzofurazan-2-yl)-ethyl]_2(R)·methyl·pyrrolidine; (R)methyl 1-(2·{ 7-[2-(11Η-10-ρ塞-dibenzo[a,d]cyclohexadelidene 5yl)ethyl]-bens 17f-am-2-yl}-ethyl)-P ratio Bite; 4~{2_[2·(2(ΙΙ)-methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-7-yl}_ 0 bite; methylpyrrolidine-yl )·ethyl]_benzofuran·5_ kib 1Η·imidazol-4,5-dicarbonitrile; 4,5_diox-l-{2-[2-(2(R)-methylpyrrolidine- 1-yl)ethyl]- benzopyran-5-ylindole-1-imidazole; 1_dU-(2(R)-decylpyrrolidinyl-!•yl)·ethyl]•benzofuran_5_ Keb 1H-stupid imidazole; ([2-(2(R)-fluorenyl u) benzoate-1 -yl)-ethyl]-benzoate bite base 3H-isoxazole [4,5 c ]p pyridine; 98683.doc • 99· 133 3489 (5-Hydroxymethyl-3-{2-[2-(2(R)-methylpyrrolidin-1yl)-ethyl]-benzofuran-5-yl}-311-imidazole-4 -yl)-nonanol; l-{2-[2-(2(R)-decylpyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-111-pyrrole; (l-{2-[2-(2(R)-Methyl ρBile-1-yl)-ethyl]-benzoquinone--5-yl} -1Η-p-Bilo-3-yl) - acetamidine, 3-methyl-l-{2-[2-(2(R)-fluorenyl p, butyl-1-yl)-ethyl]-benzop-am-5-yl} 1Η-p bilo, l-{2-[2-(2(R)-methylpyrrolidinyl-bu)-ethyl]-benzofuran-5-yl}-3,4-di-trifluoro Mercapto-1H-pyrrole; l-{2-[2-(2(R)-methylpyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-111-pyrazole; 4 -methyl-l-{2-[2-(2(R)-methylpyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-111-pyrazole; l-{2 -[2-(2(R)-Methylpyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-111-pyrazole-4-carboxylic acid ethyl ester; l-{2- [2-(2(R)-methyl p is more than π each -1-yl)-ethyl]- benzo-pyran-5-yl}-111-pyrazole-4-carbonitrile; 4-chloro-l - {2-[2-(2(R)-Methyl ρ, butyl-1-yl)-ethyl]- benzoheptan-5-yl}-111-pyrazole; 3,5-di Mercapto-1-{2-[2-(2(foot)-methylpyridyl) (pyridine-1-yl)-ethyl]-benzopyran-5-yl}-1Η-ρ-biazole; (4-methoxy-phenyl)-indenyl-{2-[2-(2( R) _ fluorenyl- fluoren-1-yl)-ethyl]-benzop-pentan-5-yl}-amine; -100- 98683.doc 1333489 benzo[1,3]dioxan Pentene-5-yl-methyl-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-benzonitrile**N--5-yl}-amine, cyclohexyl -Methyl-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzo-Bind σ-N--5-yl}-amine, and {2-[2 -(2(R)-Methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}--(tetrazalpin-4-yl)-amine. Determination of Biological Activity To determine the efficacy of a representative compound of the present invention as a histamine-3 receptor ligand (H3 receptor ligand) according to the previously described method (European Journal of Pharmacology, 188: 219-227 ( 1990); Journal of Pharmacology and Experimental Therapeutics, 275: 598-604 (1995); Journal of Pharmacology and Experimental

Therapeutics, 276:1009-1015 (1996); and Biochemical

Pharmacology, 22: 3099-3108 (1973)), the following tests were carried out.

Briefly, brain cortex of Sprague-Dawley rats was homogenized in a 50 mM Tris-HCl/5 mM EDTA containing a peptone inhibitor cocktail (Calbiochem) using a homogenizer set at 20,500 rpm. (1 g tissue/10 ml buffer solution). The mixture was homogenized by centrifugation at 40,000 xg for 20 minutes. The pellet was resuspended by homogenization of 40 ml of a 50 mM Tris-HCl/5 mM EDTA with a peptone inhibitor and centrifuged at 40,000 xg for 20 minutes to resuspend the pellet. In a volume of 6.25 times (wet weight per gram of pellet) in a 50 mM Tris-HCl/5 mM EDTA with peptone inhibitor, fresh aliquots were frozen in liquid N2 and stored at -70 °C Until used in the assay. In a total culture volume of 0.5 ml 50 mM 50683.doc • 101 - 1333489 D 1^-110:1/5 1111^〇丁八(?117.7), the rat cortical membrane (12 mg wet weight/test tube) was (3Η)-Ν-α-methylhistamine (approximately 0,6 ηΜ), cultured with or without a Η3 receptor antagonist. The test compound was dissolved in DMSO to provide a 20 mM solution. Dilution, and then added to the culture mixture before starting the culture assay by adding the membrane. Non-specific binding was determined using Thioperamide (3 μΜ). The binding culture was carried out at 25 ° C for 30 minutes, by the addition of 2 ml of ice-cold 50 mMTris-HCl (pH 7.7), and by a single-filter paper tray (Packard) soaked with 0.3% polyazide. filter. The filter paper was rinsed an additional 4 times with 2 ml of ice-cold 50 mM Tris-HCl and dehydrated for 1 hour. Radioactivity was determined using liquid scintillation counting techniques. The results were analyzed by HiU transformation, and the Ki value was determined using the Cheng-Prusoff equation. Table 1 Example number Ki(nM) 1 4.44 2 46.8 3 7.45 4 58.8 5 49.4 6 44.9 7 94.9 8 1995 9 136 10 22.9 11 19.3 12 38.4 13 78.4 14 25.1 15 1000 16 92.2 17 165 18 60.5 98683.doc • 102- 1333489 19 77.7 20 180 21 44.4 22 69.2 23 1.97 24 11.7 25 14.4 26 27.2 27 55.4 28 9.24 29 8.46 30 13.7 31 24.6 32 265 33 32.3 34 6.89 35 67.9 36 52.1 37 248 38 26.0 39 148 40 32.2 41 51.5 42 41.8 43 14.6 44 17.2 45 1.61 46 18.5 47 59.8 48 30.8 49 14.4 50 37.1 51 3.07 52 162 53 242 54 197 55 575 56 105 57 115 58 133 59 79.1 60 1000 61 143 98683.doc -103- 1333489 98683.doc 62 112 63 1000 64 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 12 90 21 91 10 92 15 93 6 94 16 95 12 96 223 97 1.4 98 0.7 99 3.6 100 6 101 3.4 102 18 103 13 104 41 105 6 -104- 1333489 106 2.3 107 8 108 8 109 10 110 6 111 9 112 3 113 77 114 97 115 33 116 30 117 110 118 42 119 66 120 23 121 51 122 17 123 16 124 34 125 63 126 81 127 120 128 110 129 150 130 60 131 22 132 19 133 6.4 134 3.2 135 31 136 0.4 137 2.8 138 1.2 139 3.1 140 21 141 44 142 29 148 19 149 3.3 150 3.6 151 53 152 2.6 153 32

98683.doc -105- 1333489 154 2 155 16 156A 3.7 156B 9.7 157 8.4 158 >1000 159 14 160 7.6 161 1.6 162 581 163 3.7 164 24 165 16.8

As shown by the data in Table 1, the compounds of the present invention bind to histamine-3 receptors and thus may be useful in the treatment of diseases or conditions which are improved by the histamine-3 receptor ligand.

The compound of the present invention is a histamine-3 receptor ligand which modulates the function of the histamine-3 receptor by antagonizing the activity of the receptor. These compounds may be reverse agonists which inhibit the basic activity of the receptor, or they may be antagonists that completely block the action of the agonist of the activation-receptor. These compounds may also be partial agonists, partially blocking or partially activating the histamine-3 receptor receptor, or they may be agonists of activating receptors. Abbreviations The abbreviations that have been used in the planning and illustrations are as follows: Ac is an ethylene group; DCM is a di-methane; DMF is N,N-dimercaptocarboxamide; DMSO is diterpenoid; EtOAc is ethyl acetate HPLC is high pressure liquid chromatography; Me is methyl; NMP is 1-methyl-2-pyrrolidone; i-Pr is isopropyl; TFA is trifluoroacetic acid; TosCl is p-toluenesulfonate; TBDMS is Ternary-butyldimethylmethylalkyl; TLC is thin layer chromatography; THF is tetrahydrofuran; 98683.doc • 106- 1333489 TMEDA is ruthenium, osmium, iridium, Ν-tetramethylethylenediamine; p_TSA is p-toluenesulfonic acid. Preparation of Compounds of the Invention The compounds and processes of the invention will be more fully explained in conjunction with the following synthetic schemes and methods, which will explain the methods by which the compounds are prepared. The compounds of the invention can be prepared by a variety of synthetic procedures. A representative program will be presented in the plan 丨_12, but is not limited to this. Plan 1

The benzofuran of the formula (5) can be produced according to the description in Scheme 1, wherein L, R!, R2, R3, R4, R5, r5, heart and ruler 7 are as defined in the formula (1). The phenol of the formula (1) can be treated with sodium hypocarbonate, sodium hydride and sodium hydroxide in a solvent such as methanol to give an iodide of the formula. The general formula (2) can be treated by heating in a solvent such as DMF by using a substituted propargyl alcohol, dichlorobis(triphenylphosphine), copper sulfide such as triethylamine. The iodide gives the benzofuran of the formula (3). In a solvent such as a gas or a THF, methanesulfonyl chloride or decanesulfonic anhydride, 98683.doc • 107· 1333489 such as triethylamine, diisopropylethylamine or N-methyl The base of the morpholine is treated with an alcohol of the formula (3) to give a methanesulfonate of the formula (4). The methanesulfonic acid salt of the formula (4) can be treated with a secondary or primary amine in a solvent such as DMF or THF to give the amine of the formula (5). Alternatively, in the presence of a test such as triethylamine, diisopropylethylamine or N-mercaptopurine, in a solvent such as DMF or THF, using heat to a secondary or primary amine The mesylate salt of the formula (4) is treated with a hydrochloride to give the benzofuran of the formula (5).

The benzofuran of the formula (10) can be prepared as described in Scheme 2, wherein L, R!, R2, R3, R4, R5, r7, r8, r9, X, γ and z are in accordance with formula (II). In the middle of it. Under the age of wood, 'like tetravalent (triphenylphosphine), a base such as aqueous sodium carbonate, treated with boric acid of the general formula (7) by heating in a solvent such as a stupid The halide of the formula (6) gives a second-butyldimethyl-stone-protected alcohol of the formula (8). Treatment of the protected alcohol of the formula (8) with tetrabutylammonium fluoride in a solvent such as THF gives the formula (9). The phenol of the formula (9) is treated under the conditions described in the scheme 1 to obtain the benzofuran of the formula (10). 98683.doc -108- 1333489 Plan 3

The benzofuran of the formula (12) can be prepared as described in the scheme 3, wherein L, Ri, R2, R3, R4, R5, r6, χ, γ, Z, 118 and R9 are in the formula ( Definition in III). The boronic acid of the formula (11) can be treated with a halide as described in Scheme 2 to give a compound of the formula (丨1 a). The compound of the formula (11a) can be treated with tetrabutylammonium fluoride, and then the benzofuran of the formula (12) can be obtained as described in Schemes 1 and 2.

0H I B

0H

Rr 1)n-BuLi/TMEDA Η) 2) DMF (R3 Rt〇4) or ethyl chloroformate (R3 = alkyl group)

98683.doc • 109- 1333489

The terpene of the formula (19) can be prepared as described in Scheme 4, wherein L, R!, R2, R3, R4, r5, r7, R8, r9, X, 丫 and z are in the formula (π) The definition in . The boric acid of the formula (13) can be treated by heating with a halide of the formula (6), a tetravalent (triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene, The compound of the formula (14) is obtained. The compound of the formula (14) can be treated with n-butyllithium, N,N,N',N,-tetramethylethylenediamine, followed by treatment with DMF or acetonitrile to give a compound of the formula (15). It can be treated with [2-(dimethylamino)_2-oxoethyl]lithium in a solvent such as THF to give a compound of the formula (16). The compound of the formula (16) is treated with acetic acid by heating to obtain a terpene of the formula (17). Treating the ocene of the formula (I?) with butyllithium, ruthenium, osmium, iridium, N-tetramethylethylenediamine, followed by treatment with ethylene oxide or oxetane to give the formula (18) Alcohol. Alternatively, treatment with butyl lithium, N,N,N,,N,-tetramethylethylenediamine and (2-bromoethoxy)th.sup.-butyldimethyloxane (17) followed by fluorine tetra Deprotection of butylammonium to give an alcohol of the formula (18). The alcohol of the formula (18) can be converted to the corresponding oxime sulfonate and further treated with an amine as described in Scheme 1 to give a terpene of the formula (19). Plan 5

La) n-Bu4NF lb) Tf20, pyridine

2) Pd(PPh3)2CI2t Cs2C03l DMF, heating f9

H〇, B又Χ, Ύ (23) OH 98683.doc 110- 1333489 Alternatively, the terpene of the formula (24) can be prepared as described in Scheme 5, wherein L, r2, r3, r4, r5, R7, R8 and R9 are as defined in formula (II). The compound of the common structure (21) can be prepared from Scheme 4 by substituting the compound of the formula (20) with the compound of the formula (14). The compound of the formula (2?) can be treated with n-butyllithium, followed by treatment with DMF or acetonitrile to give a compound of the formula (20a). The compound of the formula (2〇a) can be treated with [2-(dimethylamino)-2.oxoethyl]lithium, followed by treatment with acetic acid and heating to give the terpene of the formula (21). The compound of the formula (21) can be treated with n-butyllithium, hydrazine, hydrazine, hydrazine, Ν'-tetramethyldiethylamine, followed by treatment with ethylene oxide or oxetane to give an alcohol The alcohol can be treated with a sulfonium chloride, a base such as triethylamine, diisopropylethylamine or hydrazine-methylmorpholine in a solvent such as dioxane or THF. The oxime sulfonate can be treated with a secondary or primary amine by heating in a solvent such as DMf or THF to give an amine of the formula (22). The amine of formula (22) can be treated with tetrabutylammonium fluoride' followed by heating in a solvent such as DMF with trifluoro

Treatment with hydrazine gives the compound of the formula (24). Plan 6

(28) R5 98683.doc -Ill - 1333489 or a terpene of the formula (28) may be prepared as described in Scheme 6, wherein Ri, R2, r3, r4, r5, heart and ruler 7 are in the formula ( Definition in 111). The phenol of the formula (25) can be treated with acetic acid in the form of a compound of the formula (26) and hydrobromic acid in acetic acid to give a compound of the formula (27) which can be obtained as described in Scheme 4. Terpene of the formula (28). Plan 7

The terpene of the formula (3〇) can be prepared as described in Scheme 7, wherein l ' Ri, R 2 , R 3 , R 4 , R 5 , r 6 , Rs, r 9 , χ, ¥ and z are in the formula (111) Definition in 98683.doc. The boronic acid of the formula (29) can be treated as described in Scheme 4 to give a terpene of the formula (30). Plan 8

Re

Amines (35)

(36) -112- 1333489

The compound of the formula (36) can be prepared as described in Scheme 8, wherein L, Ri, R2, R3, r4, r5, r7, Rs, R9, X, γ and Z are in accordance with formula (IV) definition. Heat can be used to treat the iodide of the common structure (31) with 5_substituted methoxypentadiene and acetic acid to obtain a dihydrocarbamate of the common structure (32), which can be heated in aqueous acetone. Treatment of the dihydrofuran with p-toluenesulfonic acid affords the compound of formula (33). The alcohol of the formula (34) can be obtained by reducing the compound of the common structure (33) using sodium borohydride in a solvent such as methanol. The formula (34) can be treated with methanesulfonyl chloride in a solvent such as di-methane or THF using a reagent such as triethylamine, diisopropylethylamine or N-methylphenoxide. The alcohol is obtained to obtain the methanesulfonate of the formula (35). The methanesulfonic acid salt of the formula (35) can be treated with a secondary or primary amine in a solvent such as DMF or THF to give the amine of the formula (36).

Re

Re

~ 衣切切·二二氢吱, 中R丨, R2, R3 I, R5, r6, R8, &, χ, ¥ and z are as defined in the formula (in accordance with the description in Plan 8) The oxime of the formula (37) is treated to obtain the dihydrofuran of the formula (38). 98683.doc -113, 1333489 Scheme 10

Township - apricot acid heating

Pd(Ph3P)4 Na2C03, heating

OH

The benzo, phenanthene of the formula (43) can be prepared as described in Scheme 10, wherein L, Ri, R2, R3, R4, r5, r7, R8, r9, X, 丫 and z are as per

Definition in formula (I). The compound of the formula (39) can be treated with poly-phosphoric acid by heating to give a stupid thiophene of the formula (40). The benzothiophene of the formula (4〇) can be treated by heating in a solvent such as toluene with a boric acid, tetravalent (triphenylphosphine) palladium or a base such as aqueous sodium I. a compound of the formula (4)). The compound of the formula (41) can be treated with n-butyllithium, ruthenium, osmium, iridium, osmium tetradecylethylenediamine, followed by treatment with ethylene oxide to give the alcohol of the formula. The alcohol of the formula (42) can be converted to the methylate salt, and (10) the stepwise treatment in Scheme 1 can be carried out to obtain the benzoheptene of the formula (4)).

Plan 11

Re 98683.doc -114· 1333489 The benzo, phenanthene of the formula (45), wherein Ri, R2, r3, R4, R5, R6, R8, R9, and X, can be prepared as described in Scheme 11. Y and Z are defined by A?, in formula (I). The compound of formula (44) can be treated as described in Scheme 10 to provide a compound of the formula. Plan 12 R, i

NH base R, i r2 (48)

Re Rz X (47) N- R’2 (48)

Re Rr

The benzofuran of the formula (49) can be prepared as described in Scheme 12, wherein Ri, R2, r3, r4, r5, uldent 6 and r7 are as defined in the formula (1). A base such as potassium carbonate (325 mesh, powdered), and an alkyne of the formula (47), wherein χ=α, Br, dike s(〇) 2CH3 or 〇Ts may be used to treat primary and secondary The amine gives an alkyne of the formula (48). In a solvent such as acetonitrile, a phenol of the formula (2), a palladium catalyst such as palladium acetate, a triarylphosphine 'iodine such as a tris-phosphine or a tris(phosphonium)phosphine Copper and an alkyne of the formula (48), such as diisopropylamine, are heated to give a benzofuran of the formula. The invention will be explained by reference to the following examples, which are intended to be illustrative. [Embodiment] A complete understanding of the compounds of the present invention is not intended to limit the scope of the invention. EXAMPLES Example 1 _3.doc . „5. 1333489 4-(2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl} benzopyrene _

5 -Base) Yu Yue Fen Example 1A V - Meridazole-3'-broken [1,1'-biphenyl]-4- guess under 0C 'in 45 minutes' will be a solution of sodium subgas (4 7 ml of 5.25% (:1〇1*(^1^, 2.29 g, 30.8 mmol) was added to 4-hydroxy-4·-cyanobiphenyl (6.00 g, in methanol (9 mL) 30.8 millimoles), sodium iodide (4 61 grams, 30.8 millimoles) and sodium hydroxide (1.23 grams, 30.8 millimoles). The mixture was stirred ice-cold for 1 hour and warmed to ambient temperature. It was diluted with sodium thiosulfate solution (10 ml), water (80 ml), and adjusted to pH 7 by adding dihydrogen hydride. The mixture was extracted with methylene chloride (2 X 90 ml). The mixed organic extracts are dehydrated (NadO4), simmered and concentrated under reduced pressure to give a white powder. The solid is crystallized from dichloroethane/hexane and chromatographed on a stone. Using the second gas institute, the title compound (5.19 g, 53%) was obtained.]^(0(:1)111/2 339 []^+1^4+]+.

Example 1B 4-[2-(2-Ethyl)-1-benzo-c-butan-5-yl]nonanonitrile, copper iodide (0.46 g, 2.4 mmol) and two at 20 ° C Gas bistriphenylphosphine palladium (0.56 g, 0.80 mmol) was added to Example 1A (5.19 g, 16.2 mmol), triethylamine (5.6) in dimercaptocaramine (13 mL). 〇ml, 4〇4 mM) and 3-butyn-1-ol (1.90 g, 27.2 mmol) solution. The mixture was stirred at 65 ° C for 12 hours, then cooled to ambient temperature and diluted with di-methane (20 mL) and hexane (100 mL). Add diatomaceous earth (5 grams), mix and remove and remove the solids by filtration. Rinse with water (6 ml) 98683.doc -116· 1333489

filtrate. The organic layer was separated and the layers were extracted with di-methane (3×1 00 mL). The organic solution of the decanter & is dehydrated (ν & 2 § 4), filtered and concentrated under reduced pressure to give a tan solid. The title compound (4.02 g, 95%). MS (DCI) m/z 263 (M+H)+.

Example 1C 2-[5·(4-indolyl)-i_benzofuran-2-yl]methyl succinate ethyl ester at 2 ° C, methane sulfonium chloride (〇 79 g, 4 5 To a solution of Example 1B (0 57 g, 2 2 mmol) and triethylamine (0.9 mL, 6.5 mmol) in dioxane (10 mL). The mixture was stirred for 3 minutes, diluted with dichloromethane, washed with water, dried (Na.sub.2), filtered and concentrated under reduced pressure. The residue was chromatographed eluted EtOAcqqqqq MS (DCI) m/z 359 (M+H)+.

Example ID 4-(2-{2-[(2R)-2-indolyl-1-pyrrolidinyl]ethylidene-benzofuran_5_yl) indole in acetonitrile (0.4 ml) Example ic (0.19 g, 0.55 mmol), (2R)-2-methylpyrrolidine hydrobromide (〇17 g, 1 〇 mmol) and sodium carbonate (0.23 g '2.2 mmol) suspension The liquid was heated to 50 ° C and stirred for 48 hours. The reaction was cooled to ambient temperature, diluted with acetonitrile and centrifuged to remove the supernatant and rinsed with acetonitrile. The mixed liquid was concentrated under reduced pressure and the residue was purified by EtOAc EtOAcjjjjjj iHNMR (300 megahertz, CD3OD) 5 7.88 (m, 1H), 7.71 (m, 4H), 7.50 (m, 2H), 6, 82 9S683.doc -117- 1333489 (s, 1H), 3.72-3.9 ( m, 2H), 3.58 (m, lH), 3.25-3.5 (m, 4H), 2.48 (m, 1H), 2.05-2.2 (m, 2H), 1.75 (m, 1H), 1.50 (d, J= 6 Hz, 3H); MS (DCI) m/z 33 1 (M+H)+. Example 2 4-{2-[2-(l-Pyrrolidinyl)ethyl]-l- benzofuran-5-yl}carbonitrile was treated as described in Example 1D to give the product from Example 丨c and Pyrrole bite' gave the title compound. 1HN^IR (300 MHz, CD3OD) (57.7 (m, 5H), 7.50 (d, J = 8.7 Hz, 1H), 7_42 (dd, J = 8.7, 1.5 Hz, φ 1 Η), 6.51 (s, 1H) ), 3.1 (m, 2H), 2.95 (m, 2H), 2.65 (m, 4H), 1.9 (m, 4H); MS (DCI) m/z 317 (M+H), Example 3 4-{2 -[2-(2-Mercapto-1pyrrolidinyl)ethyl]-benzofuran-5-yl}benzonitrile The product from Example 1c and 2-A were treated as described in Example 1D. Base-pyrrolidine, the title compound is obtained. ΗΝΜΪΙ(300 megahertz, CD3OD) 5 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.8-3.9 (m, 2H), 3.58 (m, 1H), 3.25-3.5 (m, 4H), 2.48 (m, · 1H), 2.05-2.2 (m, 2H), 1.75 (m, 1H), 1.50 (d, 3H, J=6 Hz); MS (DCI) m/z 331 (M+H)+. Example 4 4-{2-[1-(l-hexahydropyridyl)ethyl bromide·benzofuran- 5_Methyl}benzonitrile The title compound was obtained from the product of Example 1C and hexanes hexanes as described in Example 1D. 1HN]VIR (3 00 MHz, CD3 OD) 5 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.65 (m, 2H), 3.55 (m, 2H), 3.33 (m, 2H), 3.05 (m, 2H), 2.0 (m, 986 83.doc • 118- 2H), 1.5-1.9 (m, 4H); MS (DCI) m/z 331 (M+H)+. Example 5 4-{2-[2-(diethylamino)B The title compound was obtained from the product from Example 1C and diethylamine as described in Example 1D. NMR (300 MHz, CD3OD) δ 7.75 (m) , 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.85 (s, 1H), 3.6 (t, J=7.5 Hz, 2H), 3.25-3.5 (m,0H), (t, 6H , J = 6.0 Hz); MS (DCI) m/z 319 (M+H) +. Example 6 4-{2-[2-(2-Methyl-1-hexahydropyridyl)ethyl]-indole _Benzofuran-5-ylbenzonitrile was treated as the product from Example 丨c and 2-methylhexahydropyridine as described in Example 1D to give the title compound <RTI ID=0.0># </RTI> NMR (300 MHz, CD3 OD) δ 7.88 ( m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, 1H), 3.1-3.8 (m, 7H), 1.6-2.1 (m, 6H), 1.45 (d, 3H, J=6 Hz); MS (DCI) m/z 345 (M+H)+. Example 7 4-(2-{2-[(3R)-3-Hydroxypyrrolidinyl]ethyl}_i_benzofuran-5-yl)benzonitrile was obtained as described in Example 1D. The product of c and 3·(R)-hydroxypyrrolidine gave the title compound. lHNMR (3 00 megahertz, CD3OD) (J 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.80 (s, 1H), 4.55 (bs, 1H), 3.8-3.9 ( m, 4H), 3.25-3.5 (m, 4H), 2·05_2·4 (m, 2H); MS (DCI) m/z 333 (M+H)+. Example 8 4-{2·[2- (1Η-Mimi-l-yl)ethyl]-l-benzopyrene. South_5_yl) Ye Gua 98683.doc •119- 1333489 Processed from the product of Example 1C as described in the example ID And Mi Jun' got the title compound. 1H NMR (300 megahertz, CD3OD) occupies 8.88 (s, 1H), 7.88 (m, 1H), 7.80 (m, 5H), 7.60 (m, 4H), 6.75 (s, 1H), 4.7 (t, J = 6.3 Hz, 2H), 3.5 (t, J = 6.3 Hz, 2H); MS (DCI) m/z 3 14 (M+H). » Example 9 4&lt;2-{2_[(3S)-3- (Dimethylamino)pyrrolidinyl]ethyl}·^ benzofuran-5-yl)benzonitrile The product from Example 丨c and 3-(S)-(II) were treated as described in Example 1D. Methylamino)pyrrolidine gave the title compound. lH nmR (300 megahertz 'CD3〇D) 6 7.88 (m, 1H), 7.80 (m, 4H), 7.58 (m, 2H), 6.80 (s, 1H), 4.43 (m, 1H), 3.6-3.9 (m, 4H), 3.35-3.45 (m, 4H), 2.95 (s, 6H), 2.6 (m, 1H), 2.35 (m, 1H); MS (DCI) m/z 360 (M+H)+ . Example 10 4-(2-{2-[(2S)-2-(Hydroxyfluorenyl)pyrrolidinyl]ethylbenzofuran-5-yl)benzonitrile was treated as described in Example 1D from Example 1C. The product and 2-(S)-(Methyl-bromopyridine) gave the title compound. MS (DCI) m/z 347 (M+H)+. Example 11 4_(2_{2-[2,6- Methyl hexahydropyridyl]ethyl bromobenzofuran _5 yl carbonitrile The product from Example 1 C and dimethyl hexahydropyridine were obtained as described in Example 1D to give the title compound. MS (DCI) m/z 360 (M+H) + 98683.doc - 120 - 1333489 Example 12 4-(2-{2-[(2R,5R)-2,5-dimethylpyrrolidinyl] Ethyl}-l-benzofuranyl-5-yl)ium sulphate The product from Example 1C and (2R,5R)-dimethylpyrrolidine were treated as described in Example 1D to give the title compound. (DCI) m/z 345 (M+H). Example 13 azacyclopentyl)ethyl]-i-benzofuran-5-yl}benzonitrile was obtained as described in Example 1D. The product of Example ic and oxime gave the title compound "MS (DCI) m/z 345 (M+H) +. Example 14 4-{2-[2-(4-methyl-1-hexahydropyridyl) Ethyl]·!•benzofuran_5_yl The benzonitrile was treated as described in Example 1D, and the title compound was obtained from the product of Example </ RTI> and 4-methyl hexahydro hydrazide to give the title compound. MS (DCI) m/z 345 (M+H)+. 4-(2-{2-[2-Pyrrolidinylmethylcarboxylate]ethyl}-1_benzofuran-5-yl)carbonitrile was processed according to the description in Example 1D. The product of 丨c and (L)-methyl carbamic acid gave the title compound. MS (DCI) m/z 375 (M+H)+. Example 16 4-{2-[2-(3,6- Dihydro-i(2H)-pyridyl)ethyl]-benzofuran-5-ylbenzonitrile was treated as described in Example 1D from Example 1 (: product and 1, 2, 3, 6-tetrahydropyridine, the title compound is obtained.ms (〇◦)) Μ (M+H)+. 98683.doc •121- 1333489 Example 17 4-(2-{2-[(2R)-2-( Hydroxymethyl)pyrrolidinyl]ethylidenebenzofuran-5-yl)benzonitrile The product from Example hydrazine and (pro)ol were obtained as described in Example 1D. The title compound. Ihnmr (3〇〇 megahertz, CD3OD) J 7.87 (m, 1H), 7.82 (m, 4H), 7.58 (m, 2H), 6.80 (s, 1H), 3.95 (m, 2H), 3.72 (m, 2H), 3.58 (m, 1H), 3.35-3 .4 (m, 4H), 1.95-2.3 (m, 4H); MS (DCI) m/z 347 (M+H)+. Example 18 4-(2·{2_[Third-butyl(indenyl)amino]ethyl}-l-benzofuran-5-yl)benzonitrile was treated as described in Example 1D. The product of 丨c and the t-butyl(indenyl)amine gave the title compound. MS (DCI) m/z 333 (M+H)+. Example 19 4-(2-{2-[Isopropyl(methyl)amino)ethyl bromide-benzofuran-5-yl)carboxonitrile The product from Example 1C was treated as described in Example 1D. And isopropyl(indenyl)amine' gave the title compound. MS (DCI) m/z 3 19 (M+H)+. Example 20 4-(2-{2-[Isobutyl(methyl)amino]ethyl bromide-benzofuran-5-yl)carbonitrile was treated as described in Example 1D from Example 1C. The product and isobutyl (methyl)amine' gave the title compound. MS (DCI) m/z 333 (M+H)+. Example 2 1 4-(2-{2-[Ethyl(isopropyl)amino)ethyl bromidefuran-5-yl)benzonitrile was treated as described in Example 1D. The product and ethyl (isopropyl)amine gave the title compound. MS (DCI) m/z 333 (M+H)+. 98683.doc -122- 1333489 Example 22 4-(2-(2-[Ethyl(propyl)amino)ethyl}_Nbenzofuran-5(5)ylbenzonitrile was treated as described in Example 1D The product from Example lc and ethyl (propyl)amine afforded the title compound. MS (DCI) m/z 333 (M+H)+ Methyl-1-pyrrolidinyl)ethylbobbenzofuran_5_yl}benzyl)

Example 23 A 4'-(4-Merlinyl-Rexyl)[ΐ,ι'_biphenyl]colyl alcohol 1-[3-(dimethylamino)propyl]_3_ethylcarbodiimide The hydrochloride salt was added to 4-hydroxy-biphenyl-4,-rebel (5.35 g, 25.0 mmol) and morpholine (2.39 g, 27.5 mmol) in di- methane (100 mL). ) and a solution of triethylamine (3.5 ml, 2 5 mmol). The mixture was taxed for 16 hours and diluted with aqueous NaH2P〇4 and filtered. The solid was rinsed with 1⁄2 bis of water/water (1 mL) and then washed with water (400 ml). The solid was dried in vacuo to give the title compound (5.89 g, 83%). ]\45(0&lt;:1) 111 284(]\/1+11)+. Example 23 Β 3-iodo-4'-(4-morpholinylcarbonyl)[1,1,-biphenylyl-4-ol was treated as described in Example 1 ' to give the title compound. . MS (DCI) m/z 410 (M+H)+.

Example 23C 2-{5-[4-(4-Moryl)phenyl]-1-benzofuran-2-yl}ethanol The product from Example 23B was treated as described in Example 1B. , the title compound was obtained. MS (DCI) m/z 352 (M+H)+. 98683.doc -123 - 1333489

Example 23D 2-{5-[4-(4-morpholinecarbonyl)phenylidene benzofuran-2-yl}ethylmethane continued acid _ The product from Example 23C was processed as described in Example 1C. , the title compound was obtained.

Example 23E 4-(4-{2-[2-(2-Mercapto-1-pyrrolidinyl)ethylbobbenzofuran-5-yl} abbreviated base) according to Example 1D The product from Example 23D and 2-methyl-pyrrolidine were treated to give the title compound. iH NMR (3 〇〇 megahertz, Ο 曱 )) (? 7.83 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.57 (m, 2H), 7.52 (d, J = 8.4 Hz) , 2H), 6.80 (s, 1H), 3.2-3.9 (m, 7H), 2.35 (m, 1H), 2.10 (m, 2H), 1.76 (m, 1H), 1.48 (d, J = 7.2 Hz, 3H); MS (DCI) m/z 419 (M+H) + </RTI> Example 24 4-(4-{2-[2-(l-hexahydropyridinyl)ethyl]-indole·benzofuran·5 The product from Example 23D and the hexahydropyridine were treated as described in Example 1D to give the title compound. 4 NMR (300 MHz, CD3OD) δ 7.82 (m, 1H) , 7.73 (d, J=8.1, 2H), 7.54 (m, 2H), 7.51 (d, J=8, l hertz, 2H), 6.77 (s, 1H), 3.32-3.8 (m, 14H), 3.07 (m, 2H), 1.5-2.1 〇, 6H); MS (DCI) m/z 419 (M+H)+. Example 25 N,N-Diethyl-Ν_(2_{5·[4_(4_ Morpholine carbonyl)phenyl]small benzofuran 98683.doc -124- 1333489-2-yl}ethyl)amine The product from Example 23D and diethylamine were obtained as described in Example 1D to give the title compound. iH nmr (3〇〇 megahertz, CD3〇d)j 7.82 (m, 1H), 7.74 (d, J=8.1, 2H), 7.54 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 6.80 (s, 1H), 3.32-3.8 (m, 16H), 1.38 (t, J = 7.5 Hz, 6H); MS (DCI) m/z 407 (M +H)+. Example 26 4-(4-{2-[2-(2-methyl-indole-hexahydropyridyl)ethyl]•benzofuran_5-yl}benzhydryl)morpholine The product from Example 23D and 2: mercapto-hexahydropyridine were obtained as described in Example 1D to give the title compound. iH NMR (300 MHz, CD3 〇D) (5 7.82 (m, 1H)} 7.74 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.80 (s,1H), 3.4-3.78 (m, 15H), 1.6-2.1 (m , 6H), 1.46 (d, J = 6.3 Hz, 3H); MS (DCI) m/z 433 (M+H)+. Example 27 · (3R)-l-(2-{5-[4-(4-morpholinecarbonyl)phenyl]·丨_benzofuran-2-yl}ethyl)-3-&lt;» ratio &quot Each of the calcined alcohols was treated as described in Example 1D, and the product from Example 23D and the 3-(R)-p ratio of each of the succinic alcohols were obtained to give the title compound β ιΗ nmr (3〇〇 megahertz, CD3OD) &lt; 5 7.82 (m,1H), 7.73 (d, J=8.1 Hz, 2H), 7.55 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.78 (s, 1H), 3.35-3.8 ( m, 17H), 2.3-2.4 (m, 2H); MS (DCI) m/z 421 (M+H)+. Example 28 98683.doc -125- 1333489 4-[4-(2-{2-[(2R,5R)_2'5&lt;Methylpyrrolidinyl]ethyl}small benzofuran-5-yl) The product from Example 23D and (2R,5R)-methylpyrrolidine were treated as described in Example 1D to give the title compound. 1hnmr (3〇〇 megahertz ' CD3OD) 5 7.82 (m,1H), 7.76 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.81 ( s,1H),3.3-3.8 (m, 14H), 1.6-2.1 (m,4H), 1.50 (d, J=6.6 Hz, 3H), 1.38 (d, J=6.6 Hz, 3H); MS (DCI ) m/z 433 (M+H)+. Example 29 4-[4-(2-{2-[2,6-Dimethylhexahydropyridinyl]ethyl bromide/benzofuran_5-yl)benzyl]]-linin according to Example 1D Description: The product from Example 23D and -dimercaptohexahydropyridine were treated to give the title compound. A NMR (300 MHz, CD3OD) (5 7.82 (m, 1H), 7.74 (d, J = 8.1, 2H), 7.56 (m, 2H), 7.52 (d, J = 8.1 Hz, 2H), 6.80 ( s, 1H), 3.45-3.85 (m, 14H), 1.6-2.1 (m, 6H), 1.48 (d, J = 6.3 Hz, 6H); MS (DCI) m/z 446 (M+H)+ 〇 Example 30 4-(4_{2-[2-(Azepanyl)ethyl]-l-benzofuran-yl}benzamide) was synthesized as described in Example 1D. The title compound was obtained from the product of Example 23D and azacyclopentane. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.73 (d, J = 8.1, 2H), 7.56 (m, 2H) , 7.52 (d, J = 8.1 Hz, 2H), 6.77 (s, 1H), 3.3-3.8 (m, 16H), 1.6-2.1 (m, 98683.doc • 126- 1333489 8H); MS (DCI) m /z 433 (M+H)+ 〇Example 3 1 4-(4-{2-[2-(4-Mercapto-1-hexahydropyridinyl)ethyl]-1-benzofuran_5-yl The title compound was obtained as the title compound was obtained from the product from Example 23D and the title compound was obtained as described in Example 1D. 1H NMR (300 MHz, CD3OD) 5 7.82 (m, (1, H) H), 3.05 (m, 2H), 2.00 (m, 2H), 1.75 (m, 1H), 1.49 (m, 2H), 1.05 (d, J = 6.6 Hz, 3H); MS (DCI) m/z 433 (M+H)+. Example 32 4-(4·{2-[2-(4-morpholinyl)ethyl]-1-benzofuran-5-yl}benzylidene) The product from Example 23D was treated with the title compound in the procedure of Example 1D to give the title compound. 4 NMR (300 MHz, CD3 〇D) d 7.82 (m, 1H) ' 7.75 (d, J = 8.1, 2H)' 7.58 (m, 2H), 7.52 (d, J = 8.1 Hz, 2H), 6·80 (s, 1H), 3.32-3.8 (m, 16H), 3.37 (t, J = 7.5 Hz, 4H ); MS (DCI) m/z 421 (M+H)+. Example 33 4-(4-{2-[2-(3,6-Dihydro-1(2-indanyl)ethyl)benzobenzofuran. Nan_5_yl}phenylhydrazino)morpholine The product from Example 23d and the 1,2,3,6-tetrapyrimin ratio were treated as described in Example 1D to give the title compound. 1 NMR (3 00 Hz, CD3OD) (5 7.83 ( Tn, 1H), 7.74 (d, J=8.l, 2H), 7.58 (m, 2H), 7.5 l (d, J=8, l hertz, 2H), 6.80 (s, 1H), 6.05 (m , 1H), 5·79 (m, 98683.doc -127- 1333489 -1H), 3.4-3.8 (m,12H), 3.41 (t, J=7.5 Hz, 4H), 2,5 (m, 2H) MS (DCI) m/z 416 (M+H)+. Example 34 4-(4-{2-[2-(2S)-pyrrolidinylmethanol) ethyl bromobenzofuran _5-yl } 苯甲基基) I»林 According to the description in Example 1D, the product from Example 23D and 2-(S)-(|^methyl)p were compared to 嘻唆' to give the title compound. Megahertz 'CD3OD) 6 7.81 (m, 1H), 7.73 (m, 2H), 7.55 (m, 2H), φ 7.50 (dm 2Η, J=8.4 Hz), 6.77 (s, 1Η), 3.3- 4.0 (m, 17Η), 1.9-2.3 (m, 4H); MS (DCI) m/z 434 (M+H)+ 〇 Example 3 5 N-(T-Butyl)-N-Methyl-N -(2-{5-[4-(4-morpholinocarbonyl) The title compound was obtained from the product from Example 23D and the tris-butyl(methyl)amine as described in Example 1D. iHNMR (3〇〇 megahertz, CD3OD)5 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.55 (m, 2H), # 7.51 (d, J=8.1 Hz, 2H), 6.81 (s, IH), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 421 (M+H)+. Example 36 N-isopropyl Base-N-fluorenyl-N-(2-{5-[4-(4-morpholinocarbonyl) phenylidenefuran-2-yl}ethyl)amine was obtained as described in Example 1D. The product of Example 23D and isopropyl (methyl)amine gave the title compound: iH NMR (300 MHz, CD3 OD) </ RTI> 7.82 (m, 1H), 7.74 (d, J = 8.1, 2H), 7.58 (m, 2H), 98683.doc • 128- 1333489 7.52 (d, J=8.i Hertz, 2H), 6.81 (s, 1H), 3.3-3.8 (m, 13H), 2.97 (3, 3 printed '1.42 (£) 1,6.3 Hz, 311), 1.37 (£1, 6.3 Hz, 311);]\18 (DCI) m/z 407 (M+H)+ » Example 37 N-isobutyl-N-methyl-oxime -(2-{5-[4.(4-morpholinylcarbonyl)phenyl]-1-benzofuran-2-yl}ethyl)amine as described in Example 1D, Treatment of the product from Example 23D and isobutyl (meth) amine 'to give the title compound. NMR (300 MHz, CD3OD) (5 7.82 (m, 1H), 7.74 (d, J = 8.1, 2H), 7.58 (m, 2H), 7.51 (d, J = 8.1 Hz, 2H), 6.81 (s , 1H), 3.3-3.8 (m, 14H), 2.96 (s, 3H), 2.2 (m, 1H), 1·〇9 (d, J = 6.6 Hz, 6H); MS (DCI) m/z 421 (M+H)+. Example 38 N-Ethyl-N-isopropyl-N-(2-{5-[4-(4-morpholinylcarbonyl)phenyl]-i-benzofuran-2- The product from Example 23D and iso-propyl (ethyl)amine were obtained as described in Example 1D to give the title compound. ijj NMR (300 MHz, CD3OD) 5 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.80 (s,1H), 3.3-3.8 (m, 15H), 1.41 (m, 9H); MS (DCI) m/z 421 (M+H)+. Example 39 N,N-dimethyl-N-(2-{5-[4-(4-morpholinyl)benzene The title compound was obtained as described in Example 1D, and the product obtained from Example 23d and s. MS (dci) m/z 378 (M+H) +. </RTI> 40 N-ethyl-N-(2-{5-[4-(4-morpholinocarbonyl)phenyl]-1 -benzofuran -yl}ethyl)-oxime-propylamine The title compound was obtained from the product from Example 23D and ethyl (propyl)amine as described in Example 1D. NMR (300 MHz, CD3 〇D) 6 7.84 (m, 1H), 7.74 (d, J = 8.1, 2H), 7.58 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 6.82 (s, 1H), 3.32-3.8 (m, 14H), 3.20 (m, 2H), 1.80 (m , 2H), 1.38 (t, J = 7_5 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H); MS (DCI) m/z 421 (M+H) +. Example 41 4-{4- Methyl-2-oxo-3·[2·(ι-pyrrolidinyl)ethyl]_2H-nonene-6-yl}benzonitrile

Example 41A 3-(2-&gt;Styrosethyl)-6-Pentyl-4-Methyl-2H-Esophthene-2-indole Ethyl 2-butylidene Butyrate (5-8) ML, 54 mM) slowly added to resorcinol (7.03 g, 64.0 m) in a solution consisting of HBr (1 〇 4 mL, 422 mmol) and glacial acetic acid (1 mL) In the solution of Mohr). The mixture was warmed to ambient temperature and then heated to reflux for 2 h. The mixture was cooled to ambient temperature and filtered with water (3 50 mL). (15 5 grams, 850/〇). hNMRQOO megahertz, CD3OD) &lt;5 1〇·5 (s,1Η), 7.6 (&lt;1,]=8_7 Hz, 1), 6.8 (&lt;1&lt;1,]=6.6 Hz, 11.4 Hz, 111), 6.7 (d, J = 2.1 Hz, 1H), 3.6 (t, J = 7.5 Hz, 2H), 3·1 (t, J = 7.6 Hz, 2H), 2.4 (s, 3H); MS ( DCI) m/z 283, 284 (M+H)+. 98683.doc -130· 1333489

Example 41B 6-Hydroxy-4-methyl-3-[2-(l-pyrrolidinyl)ethyl]-2H-nonen-2-one in Example 41A (0.20 g, A solution of acetolidine (0.50 ml, 6.0 mmol) was heated to 75 t for 6 hours, cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 X 50 mL) . The combined ethyl acetate was dried (MgSO4), filtered and purified eluted eluted elut elut elut elut elut elut elut ). MS (DCI) m/z 274 (M+H)+.

Example 41C Triethylamine (0.68 mL, 0.48 mmol) was added to EtOAc (2 mL). A solution of saponin (3111 £'〇1^1111(16) (0.143 g, 0-38 mmol) was stirred. The mixture was stirred at ambient temperature for 12 hours to diethyl ether (4 mL). Dilute and rinse with aqueous NaOH (IN, 2 X 30 mL), water and brine, dehydrate (MgSCU), filtered and evaporated to give trifluorosulfonate. Sulfonate (〇.2 g, 0.49 mmol), 4-cyanophenylboronic acid (0.082 g, 0.54 mmol), Pd(PPh3)2Cl2 (〇.〇35 g) and CszC〇3 (0.96 g) , 2.9 millimolar) mixture for 5 hours, diluted with ethyl acetate, and continuously washed with aqueous NaOH (IN, 3 X 25 ml), water (3 χ 25 ml) and brine. Dehydrate the organic solution (MgS04) 'Filtering' and evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with methylene chloride, ethyl acetate, and methanol to give the title compound. , CDCl3), 7.75 (m, 3H), 7.5 (m, m), 7 2 (m, 2H) 98683.doc -131 - 1333489 ΊΛ (m, 1Η), 3.1 (m, 2H), 2.9 (m , 4H), 2.5 (s, 3H), 2.0 (m, 4H), 1.6 (m, 2H); MS (DCI) m/z 359 (M+H)+. Example 42 4_{4-methyl-2 -oxo-3_[2-(l-hexahydropyridyl)ethyl]-2H-nonene·6_yl}phthalonitrile

The title compound <1H NMR (300 MHz "CDCl3) d7.75 (m, 3H), 7.6 (m, 3H) was obtained from the product of Example 41 and the hexahydropyridine as described in Examples 41A and 41C. , 7.2 (m, 1H), 2.95 (m, 2H), 2.6 (m, 6H), 2.5 (s, 3H), 1.7 (m, 4H), 1.5 (m, 2H); MS (DCI) m/z 373 (M+H)+. Example 43 4-{3-[2-(Diethylamino)ethyl;j_4•methyl_2.oxo-2-indene-6-yl}benzonitrile as described in Examples 41A and 41C, Treatment of the product from Example 41 and diethylamine afforded the title compound. NMR (300 MHz, CDC13) δ 7.75 (m, 5H), 7.5 (m, 2H), 2.9 (m, 2H), 2.7 (m, 6H), 2.5 (s, 3H), 1.1 (t, J= 9 Hz, 6H); MS (DCI) m/z 361 (M+H)+.鲁 Example 44 4-[(6-{2-[2·(1-pyrrolidinyl)ethyl]-benzofuran_5_ylbu 3_pyridine

))carbonyl]morpholine Example 44A 4-[(6-Ga-3-pyridyl)carbonyl]morpholine was slowly added to morpholine (1.75 mL ' 2.00 mmol) at 〇 ° C The gas in the gas (5 house liters) was tested in a solution of chlorine (3.52 g, 2.00 mmol) and triethylamine (3.1 ml, 2.22 mmol). The mixture was warmed to 98683.doc • 132·1333489~~ ambient temperature 'washed with water (2x25 ml), brine (ι 25 ml), dehydrated (Na2S〇4)' filtered and concentrated under reduced pressure. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound (4 g, 88%). MS (DCI) m/z 227 (M+H)+ 〇

Example 44B 4-[5-(4-Morpholinecarbonyl)-i,6-dihydro-2-pyridinyl]phenol in toluene (60 mL) and aqueous sodium carbonate (2 76 g dissolved in 25 mL water) Examples 44Α (4.0 g, 17.6 mmol), Pd(Ph3P)4 (1.0 g, 〇·86 mmol), 4-0-T-butyldimethyldecylphenylboronic acid (4.9 g) The mixture of '23.6 mmol" was heated to reflux for 2 hours and then cooled to ambient temperature. The mixture was diluted with ethyl acetate (1 mL), rinsed with water (1 χ 5 mL) &apos; dehydrated (Na2S04), filtered and concentrated under reduced pressure. The residue was stirred in THF (200 mL) EtOAc (30 mL). The mixture was diluted with ethyl acetate (1 mL) and washed continuously with water (1×50 mL), aqueous ammonium sulfate (丨X 50 mL), brine (1×50 mL), and dehydrated (Na2s〇4) ), filtered and condensed under reduced pressure to give a solid. The title compound (4.27 g, 70%).

Example 44C 2-Moth-4-[5-(4-morphinyl)-2-p ratio thiophene] Example 44B (4.25 g, 15.0 mmol) heated and stirred in methanol (90 mL) A mixture of sodium iodide (2.36 g ' 15.7 mmol) and sodium hydroxide (0.63 g, 15 · 7 mmol) until a clear solution is obtained. Then, the &gt; trough solution was cooled to 〇 ° C ' and slowly added to hypochlorous acid 98683.doc -133 - 1333489 sodium (22 ml of 5.25%, 1.15 g, 15.5 mmol) in 45 minutes. Ear) (Cl〇roxTM) t. While continuing to maintain the process, two consecutive additions of Nal (0.3 g, 1.5 mmol) and Clorox (2.2 ml, 0.12 g, 1.5 mmol) were carried out after 2 hours and 4 hours. The mixture was simmered at ambient temperature for 2 hours, and the suspension was stopped by continuous addition of aqueous sodium thiosulfate (1 ml), water (8 ml), and sodium dihydrogenate was filled with sufficient water. (NaH2P〇4) Adjust the pH to 7. The mixture was extracted with dioxin and the mixed extract was dehydrated (NaaSO4) and filtered and concentrated under reduced pressure to give a brownish-brown. The product was crystallized from ethanol to give the title compound (3.78 g &apos; 61%). MS (DCI) m/z 411 (M+H)+.

Example 44D 2-{5-[5-(4-oxalinyl)-2-p ratio octyl]-1-phenylidene p-butan-2-yl)ethanol at 20 ° C 'will iodide Copper (0.2 g '1.0 mmol) and dichloroditriphenylphosphonium (0·24 g '0.35 mmol) were added to the example 44 〇 (2.85) in dimethyl decylamine (15 ml) Gram, 6.95 mmol, triethylamine (2.4 mL, 17.4 mmol) and 3-butyn-1-ol (〇·73 g, 10.4 mmol). The mixture was given for 1 hour' and then heated to 65 ° C for 16 hours. The reaction was cooled to 23 ° C and diluted with di-methane (200 mL) and water (1 mL). The mixture was kneaded with Shixiazao soil and then concentrated. The filtrate was washed with water (1×50 mL), and then organic layer was partitioned, dried (Na2S04), filtered and concentrated under reduced pressure to give a tan. The residue was chromatographed eluted eluted elut elut elut elut elut elut elut MS (DCI) m/z 353 (M+H)+.

Example 44E 98683.doc -134· 1333489 &gt;{5·[5-(4-morpholinecarbonyl)-2-pyridyl]-1-benzofuran-2-ylindoleethyl methanesulfonate according to the example The product from Example 44D was treated as described in 1C to give the title compound.

Example 44F-R-pyridyl)ethylbenzofuranyl}3pyridinyl)carbonyl]morpholine The title compound was obtained from the product of Example 44E and pyridine. iH NMR (300 MHz, CD3〇D) 8.7 〇 (m' 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.98 (m, 3H), 7.60 (d, 8.7 Hz, 1H), 6.84 (s,1H)' 3.3-3.8 (m,12H), 3.18 (m,2H), 2.0-2.25 (m,6H); MS (DCI) m/z 406 (M+H)+. Example 45 4-U6-(2-{2-[(2R)-fluorenylpyrrolidinyl]ethylbenzobenzoin·5_yl)-3 - p-bite base] a few base} Description in Example 1D 'Processing the product from Example 44E and 肇2-(R)-methylpyrrolidine' gave the title compound. Ms (DCI) m/z 420 (M+H)+. Example 46 4-[(6-{2-[2-(l-Hexhydropyridinyl)ethyl)- benzofuran-5-ylpyridinyl)carbonyl]morpholine as described in Example 1D The product from Example 44 and the hexahydro-diamine were taken to give the title compound. 1H NMR (3 00 megahertz, CD3OD) 6 8.70 (m, 1 Η), 8.22 (d, J = 1.8 Hz, 1H), 7 95 (m, 3 Η), 7 58 98683.doc • 135- 1333489 (d , J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 12H), 3·05 (m, 2H), 1.5-2.0 (m, 8H); MS (DCI) m/z 420 (M+H)+. Example 47 4-[(6-{2-[2-(N,N-Diethyl)ethyl]-1-benzofuran-5-yl}-3-pyridyl)carbonyl]morpholine according to the example The product from Example 44E and diethylamine were worked up to give the title compound. 111\河尺(3 00 MHz, 〇〇3〇〇) (5 8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, φ J =8.7 Hz, 1H), 6.84 (s, 1H), 3.3-3.8 (m, 12H), 1.38 (t, J = 7.5 Hz, 6H); MS (DCI) m/z 408 (M+H)+ » Example 48 (311)-1-(2-{5-[5-(4-Morpholinecarbonyl)-2-pyridyl]-1-benzofuran-2-yl}ethyl)-3-pbi The title compound was obtained by treating the product from Example 44 and 3-(R)-pyridylpyrrolidine as described in Example ID. 1hnMR (300 MHz, CD3〇D) 5 8.70 (m, 1H) , 8.24 (d, J = 1.8 Hz, 1H), 7.95 (m, · 3H), 7·58 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H), 4.55 (m, 1H), 3 -3-3.8 (tn, 16H), 2.0-2.4 (m, 2H); MS (DCI) m/z 422 (M+H), Example 49 U6 (2 {2-[(2R,5r)_2,5 _Dimethylpyrrolidinyl]ethylbenzofuran-5-yl)-3.pyridyl]carbonyl}morpholine was treated as described in Example 1D to give the product from Example 44 and (2, 5). : Ψ基吨Μ 'Get the title compound. 丨HNMR (300 dead 98683.doc • 136· 1333489 Hz 'CD3OD) (5 8.70 (m, 1H), 8.24 (d, J=1. 8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 6.80 (s, 1H), 3.3-3.8 (m, 12H), 1.2-2.4 (m, 10H); MS (DCI) m/z 434 (M+H), Example 50 4-{[6-(2-{2-[2,6-dimethylhexahydroacridinyl]ethyl b 1 benzopyrene The product of Example 44E and 2,6-dimethylhexahydropyridine were obtained as described in Example 1D to give the title compound. 300 MHz, CD3〇D)5 8.70 (m,1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.86 (s , 1H), 3.45-3.85 (m, 12H), 1.6-2.1 (m, 6H), 1.48 (d, J = 6.3 Hz, 6H); MS (DCI) m/z 448 (M+H)+ » Examples 5 1 4-{[6-(2-{2-[l-azetidinyl]ethyl i-benzofuran_5_yl)-3-p is a bite base] The product from Example 44E was treated in the titled compound to give the title compound. 1H NMR (300 megahertz, CD3OD) 68.70 (m, 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 6.86 (s, 1H), 3.3-3.8 (m, 16H), 1.95 (m, 4H), 1.75 (m, 4H); MS (DCI) m/z 434 (M+H)+. Example 52 4-[(6-{2-[2-(4-Methyl-1-hexahydropyridyl)ethyl]·1-benzofuran·5-yl}-3-pyridyl)carbonyl]morpholine The product from Example 44A and 4- 98683.doc.137 - 1333489 methyl hexahydropyridine were treated as described in Example 1D to give the title compound. 1H NMR (300 megahertz, CD3OD) (? 8.70 (m, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.97 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 14H), 3.05 (m, 2H), 1.95 (m, 2H), 1.75 (m, 1H), 1.5 (m, 2H), l.〇5 (d, J = 6.6 Hz, 3H); MS (DCI) m/z 434 (M+H) +. Example 53 4-[(6-{2-[2-(4 -?p-linyl)ethyl]-1 - Benzene p-pentam-5-yl}-3-'» carbyl] morpholine The product from Example 44E and the yelamine were obtained as described in Example 1D to give the title compound. 300 megahertz, CD3OD) &lt;5 8.7 〇 (m, 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 6.82 ( s, 1H), 3.3-4.1 (m, 16H), 3.37 (t, J = 7.5 Hz, 4H); MS (DCI) m/z 422 (M+H) +. Example 54 N-(Third-D) -N-methyl-N-(2_{5-[5-(4-morpholinylcarbonyl)-2-pyridinyl]-1-benzop-pentan-2-yl}ethyl)amine The product from Example 44E and the tri-butyl(methyl)amine were treated as described in Example 1D to give the title compound. ihnmr (3 〇〇 megahertz, CD3 〇D) (5 8.70 (m, 1H) , 8.24 (d, J=1.8 Hertz, 1H), 7.96 (m, 3H), 7.59 (d, J = 8.7 Hz, iH), 6.85 (s, 1H), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s , 9H); MS (DCI) m/z 422 (M+H) +. Example 55 N-isobutyl-N-indenyl-hydrazine·(2·{5-[5-(4-morpholinylcarbonyl) _2-pyridyl] benzofuran-2-yl}ethyl)amine 98683.doc -138- 1333489 The product from Example 44E and isobutyl(indenyl)amine were treated as described in Example 1D. The title compound is obtained. iH NMR (3 〇〇 megahertz, CD3 OD) 5 8.70 (m, 1H), 8.23 (d, j = 1.8 Hz, 1H), 7.98 (m, 3H), 7.59 (d, J = 8.7 Hz) , iH), 6.85 (s, 1H), 3.0-3.8 (m, 14H), 2.98 (s, 3H), 2.2 (m, 1H), 1.09 (d, j = 6.6 Hz, 6H); MS (DCI) m/z 422 (M+H)+. Example 56 N-Isopropyl-N-indenyl-N-(2-{5-[5-(4-morpholinylcarbonyl)-2-pyridinyl]-1-benzofuran-2-yl}B The product from Example 44 and isopropyl (methyl)amine were obtained as described in Example 1D to give the title compound. iH NMR (3〇〇 megahertz, CD3OD)5 8.70 (m,1H), 8.24 (d, J=i.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H ), 6.85 (s, 1H), 3 3_3 8 (m, 13H), 2.88 (s, 3H), 1.40 (d, 6.3 Hz, 3H), i 36 (d, 6 3 Hz, 3H); MS (DCI ) m/z 408 (M+H)+. Example 57 N-Ethyl-N-isopropyl-N-(2-{5-[5-(4-morpholinylcarbonyl)-2-pyridyl]·1·benzofuran-2-yl}ethyl) The title compound was obtained from the product from Example 44 and ethyl (isopropyl)amine as described in Example 1D. iH NMR (3 〇〇 megahertz, CD3 〇 D) (5 8.70 (m, 1H), 8.25 (d, J = 1.8 Hz, ie, 7.98 (m, 3H), 7.59 (d, J = 8.7 Hz, 1H) ), 6.85 (s, 1H), 3 3·3 8 (m, 15H), 1.4 (m, 9H); MS (DCI) m/z 422 (M+H) + e Example 58 98683.doc -139- 1333489 N,N-Dimethyl-N-(2-{5-[5-(4-?b-linyl)_2_^bityl]small benzop-pyran-2-yl}ethyl)amine The title compound was obtained as described in Example 1D &lt;RTI ID=0.0&gt;&gt;&gt; 1H), 7.96 (m, 3H), 7.59 (d, J_8.7 Hertz, 1H), 6.84 (s, 1H), 3.35-3.8 (m, 12H), 2·98 (s, 6H); MS (DCI) m/z 380 (M+H) + </RTI> Example 59 N-ethyl-N-propyl-N-(2-{5-[5-(4-morpholinecarbonyl). The title compound was obtained as the title compound was obtained from the titled compound of EtOAc (m.p.). CD3OD) &lt;5 8.70 (m,1H), 8.23 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.85 (s, 1 H), 3.2-3.8 (m, 14H), 3.20 (m, 2H), 1·80 (m, 2H), 1.38 (t, J = 7.5 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H MS (DCI) m/z 422 (M+H) +. Example 60 8-(2-{5-[5-(4-morpholinylcarbonyl)-2.pyridyl]-i-benzofuran -yl}ethyl)-1,4-dis-8-azaspiro-[5]nonane The product from Example 44A and 1,4-Di-8 were treated as described in Example 1D. - azaspiro[4.5]decane' gave the title compound. 1H NMR (300 MHz, CD3 〇D) (5 8.70 (m, 1 Η), 8.24 (d, J = 1.8 Hz, 1 Η), 7.95 (m, 3H), 7·58 (d, J=8.7 Hz, iH), 0.82 (s, 1H), 3.3-4.1 (m, 20H), 2.05 (m, 4H); MS (DCI) m/z 478 (M +H)+. 98683.doc -140· 1333489 Example 61 5-(2·{5-[5-(4-Merpinyl)-2-P ratio octyl]]•Stupidylfuranyl}ethyl)-2- Indole-5-azabicyclo[2 21]heptane was treated as described in Example 1D, and the product from Example 44 and 2- oxo-5-azabicyclo[2.2.1]heptane were obtained. Title compound. lH NMR (300 Hz, CD3 〇D) 58.7 〇 (m, 1H), 8 24 (4) J = 1 8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J-8.7 Hz, iH), 6.82 (s 1H) 4.7 (m, 1H), 4.55 (m, 1H), 3.3-4.0 (m, 14H), 2.4 (m, 2H), 2.2 (m, φ 2H); MS (DCI) m/z 434 (M+H)+. Example 62 (2S)-l-(2-{5-[5-(4-N-Phenylcarbonyl)-2-pyridinyl]-b-benzofuran-2-yl}ethyl)-2-p The title compound was obtained as described in Example 1D from &lt;EMI ID=9.1&gt;&gt; iH NMR (3〇〇死赫兹' CD3OD) accounted for 8.70 (m, 1H), 8.23 (d, J = 1.8 Hz, 1H), 7.98 (m, 3H), 7.57 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H), 3.3-4.0 (m, 15H), 1.9-2.3 (m, 6H); MS (DCI) m/z 436 (M+H)+. Example 63 N-allyl-N-(2-{5-[5-(4-morpholinylcarbonyl)-2-pyridyl]-l-benzofuran-2-yl}ethyl)amine as in the examples The product from Example 44E and the dilute propylamine were taken to give the title compound. NMR (300 MHz, CD3OD) (5 8.70 (m, 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J = 8.7 Hz, ih), 6.81 ( s, 1H), 5.95 (m, 1H), 5.55 (m, 2H), 98683.doc -141 - 1333489 3.25-3.8 (m, 14H); MS (DCI) m/z 392 (M+H)+. Example 64 3- [(2-(5-[5-(4-Morpholinecarbonyl)-2-pyridyl]benzophenazin-2-yl)ethyl)amino]-1-propanol Description in Example 1D 'Processing from the product from Example 44E and 3-amino-1-propanol afforded the title compound. NMR (300 MHz, CD3OD) 5 8.70 (m, 1H), 8.23 (d, J = 1.8) Hertz, 1H), 7.98 (m, 3H), 7.59 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H), 3.20-3.8 (m, φ 16H), 1.92 (m, 2H); MS ( DCI) m/z 410 (M+H) +. Example 65 N-(2-{5-[5-(4-morpholinylcarbonyl)-2-pyridyl;|_丨_benzofuran-2-yl Ethyl)-N-propylamine The product from Example 44E and propylamine were taken to give the title compound as described in Example 1D to give the title compound. HNMRGoo megahertz, CD3 〇d (58 7 〇(m, 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.98 (m, 3H), 7.58 (d, J = 8.7 Hz, 1H), 6.82 (s, 1H), 3 · 25_3.8 (m, 12H), 3.05 (t, · J = 7.5 Hz, 2H), 1.74 (m, 2H), 1.05 (t, J = 7 5 Hz, 3H); Ms (DCI) m/z 394 (M+H)+. Example 66 4-(2-{2-[(3R)-3-(dimethylamino)pyrrolidinyl]ethylbub benzofuran-5-yl)octonitrile The product from Example 丨c and 3-(R)-(dimethylamino)pyrrolidine were treated as described in Example 1D to give the title compound. MS (DCI) m/z 360 (M+H)+ ° 98683.doc 142· 1333489 Example 67 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-2,3-dihydro-1-benzofuran

喃-5-yl)carbonitrile Example 67A 4-{2-[(E)-2-methoxyvinyl]-2,3-dihydro-1-benzofuran-5-yl}benzonitrile under nitrogen pressure Example 1 Α (0·20 g, 0.623 mmol), 1-methoxybutadiene (0.18 g, 2.18 mmol), palladium diacetate (〇·〇〇) in DMF (3 ml) 7 g, 0.031 mmol, sodium bicarbonate (0.261 g, 3.11 mmol) A solution of Lu and tetrabutylammonium chloride (0.173 g, 0.623 mmol) was heated to 60 ° C for 36 hours. The reaction was cooled to 23 &lt;0&gt;C, diluted with EtOAc (EtOAc) The solution was concentrated under reduced pressure and the residue was purifiedjjjjjjjjjj *H NMR(CDC13): 3.05 (m, 1H), 3.40 (m, 1H), 3.60 (s, 3H), 5.00 (m, 1H), 5,22 (m, 1H), 6.72 (d, J= 14 Hz, 1H), 6.83 (d, J=7 Hz, 1H), 7.38 (m, 2H), 7.65 (m, 4H); MS (DCI)·· 278 (M+H+), 295 (M+NH) /). Call

Example 67B Example 67 4- (0.5 g, 4-[2-(2-oxoethyl)-2,3·dihydro-1-indolofuran-5-yl]benzonitrile in acetone (10 mL) 1.8 mM solution and p-toluenesulfonic acid monohydrate (0.51 g, 2.7 mmol) for 45 min, diluted with CH2C12 (150 mL), with ice-cold aqueous sodium bicarbonate (2 X 1 〇〇 ml) , 10% solution), water (2 X 100 ml) rinse, dehydrated (Na2S04),

Filtration and concentration under reduced pressure <RTI ID=0.0>: </RTI> </ RTI> <RTIgt; lH NMR 98683.doc -143· 1333489 (CDC13): 2.95 (m, 2H), 3.65 (m, 3H), 6.82 (d, J = 7 Hz, 1H), 7.40 (m, 2H), 7.62 (m, 4H), 9.55 (d, J=7 Hz, 1H); MS (DCI) 263 (M+), 281 (M+NH4+).

Example 67C 4-[2-(2-Hydroxyethyl)-2,3-dihydro-1-benzofuran-5-yl]nonanonitrile Example 67B (0.25 g, 0.95) in methanol (5 mL) Millol) and sodium borohydride (0.054 g ' 1.42 mmol) solution for 1 hour, cooling on ice 'and using aqueous NaHC〇3 (50 ml) to stop it with two gas (3x100) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 95%). *H NMR (CDC13): 1.90 (m, 2H), 2.90 (m, 2H), 3.46 (m, 2H), 5.40 (m,1H), 6.85 (d, J=7 Hz, 1H), 7.38 (m , 2H), 7.65 (m, 4H); MS (DCI) 265 (M+), 283 (M+NH4+).

Example 67D 2-[5-(4-Cyanobenyl)-2,3-anthracene-l-stupid and bite--5-yl]ethyl ketone vinegar at 〇 ° C 'Triethylamine (0.13 ml, 9.4 mmol) was added to a solution of Example 67C (0.23 g, 0.87 mmol) and methanesulfonyl chloride (0.075 mL, 0.96 mmol) in (1120:12 (5 mL)) The mixture was stirred for 3 minutes, diluted with CH2C12 (75 mL), rinsed with water (3 χ 1 mL), dehydrated (NadCU) 'over concentrated and concentrated under reduced pressure. Purified on Shi Xisheng Residue 'Use CH2C12' to give the title compound ( 〇 278 g, 9 〇 0 / 〇). iH nmR (CDCI3) : !H NMR : I.95 (m, 2H), 2.93 (m, 2H), 3.00 (s , 3H), 3.46 (m, 2H), 5.00 (m, iH), 6 81 (d, J = 7 Hz, 1H), 7 4 〇 (m, 98683.doc 2H), 7.65 (m, 4H); MS (DCI) 343 (M+), 361 (M+NH4+).

Example 67E 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-2,3-dihydro-1-indolofuran-5-yl) yue paste under nitrogen pressure Example 67D (0.2 g, 〇.5 8 mmol), R-2-decylpyrrolidinyl-(L)-tartrate (1.45 mmol) and cesium carbonate in acetonitrile (5 mL) The solution (0.95 g) was heated to 60 ° C for 48 hours. Allow the reaction to return to ambient temperature, dilute with CH2C12 (100 mL), rinse with aqueous NaHC03 (2 X 100 mL), 0 (1 X 100 mL), brine (100 mL), dehydrate (NazSCU), filter and Concentrate under reduced pressure. The residue was purified on EtOAc (EtOAc:EtOAc:EtOAc: 1H NMR (CDCl3): 1.10 ((i, J=7 Hz, 2H), 1.50 (m, 2H), 1.70 (m, 4H), 1.98 (m, 2H), 2.10 (m, 2H), 2.25 (m, 1H), 3.00 (m, 2H), 4.60 (m, 1H), 6.80 (d, J = 7 Hz, 1H), 7.45 (m, 2H), 7.70 (m, 4H); MS (ESI) 333 (M +H+). Example 68 (4-Fluorophenyl)(2-{2-[(211)-2-methyl-1-acridinyl)ethyl b-1-phenyl

Olfactory °N-5-yl)methanone Example 68A (4-fluorophenyl)(4-carbyl-3-mothyl)methanone is allowed to stir in concentrated ammonium hydroxide (770 ml) at 25 °C (4_Fluorophenyl)(4-hydroxyphenyl)methanone (20.0 g, 92.5 mmol) for 15 min, then a deuterated clock in water (185 ml) (74.79 g '450.5 mmol) Ear) and moth (23.48 grams, 92.5 millimoles). The reaction mixture was allowed to stir at 28t 18 98683.doc • 145 - hr' then filtered. The precipitate was dissolved in ethyl acetate, washed with water and brine, and then evaporated. NMR (300 MHz, CD3OD) (5 6.91 (d, 1 Η, J = 8.9 Hz), 7.26 (t, 2 Η), 7.64 (d, 1H, J = 8.9 Hz), 7.78 (t, 2H), 8.17 ( s, 1H); MS (DC1) m/z 342.9 (M+H)+, 360 (M+NH4)+.

Example 68B (2R)-l-(3-butyryl)-2·methyl p is bitten in a sealed bottle and will be (r)_2-mercaptopyridine in acetonitrile (60 ml) L) Tartrate (1.65 g, 7.00 mmol) and 325 mesh powdered mash (: 〇3 (2.03 g, 14.7 mmol) heated to 5 〇t: 24 hours. Allow the mixture to cool to Treated at room temperature with 3-butynyl 4-methylbenzoate (1.24 mL '7.0 mmol). The mixture was stirred at room temperature for 1 hour and then heated to 50 C for 24 hours. The mixture was cooled to room temperature, dried, and the filter cake was washed with acetonitrile. The filtrate was diluted with acetonitrile to a total volume of 7 liters and used as a solution of 〇.1M in a subsequent step.

Example 68C (4-Fluorophenyl) (2-{2-[(2 ft)-2-methyl-1-17 to 11 octyl] ethyl}_1_ benzofuran-5-yl) ketone 〇丨μ solution (230 ml, 23.0 mmol), Pd(OAc) 2 (0.127 g, 0.566 mmol), tris(4-indolyl)phosphine, obtained from the product of Example 68B in acetonitrile. (0.344 g, 1.130 mmol) and copper telluride (10 g, 95.72 mmol) of the product from Example 68A (6.5 g, 18.5 mmol). After 10 minutes of mixing at 25 C, the reaction mixture was treated with diisopropylamine (26.6 ml, 189 mmol) 98683.doc - 146 - 1333489 and then heated to 6 ° C for 16 hours under an inert atmosphere. The reaction mixture was allowed to cool to room temperature, transitioned through celite, and the filtrate was concentrated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjjj 4 NMR (300 MHz, CD3〇D) 5 1.09 (d, 3H, J = 6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.28 (m, 2H), 2-49 (m, 2H), 3.06 (m, 2H), 3.28 (m, 2H), 6.68 (s, 1H), 7.27 (t, 2H), 7.58 (d, 1H, J = 8.9 Hz), 7.71 (d, 1H, J=8.9 Hz), 7.86 (t, 2H), 7.97 (s, 1H); MS (ESI) m/z 352 (M+H)+. Example 69 (3-|1 base) (2-{2-[(211)-2-methyl-1-1»Bilobityl]ethyl}_1_benzofuran-5-yl)methanone

Example 69A (3-Fluorophenyl)(4-phenylphenyl)methyl mesh (3-fluorophenyl)(4-fluorenyloxy)anthracene (1.0) was stirred at -78 °C in 50 mL of DCM. Gram, 4.34 mmol, while dropwise treatment with 1 M boron tribromide (13.03 ml, 13·3 3 m) in 2 min. The mixture was allowed to warm to 25. (:, and stir for 18 hours. Treat the mixture with water (1 ml) and stir for 5 minutes, then treat with additional water (2 ml), stir (7) minutes, and finally treat with more water (50 ml) The mixture was stirred for 2 hrs. The mixture was extracted with EtOAc (EtOAc m. 0.69 g, 74% yield) e lH NMR (3〇〇 megahertz, CD3〇D) (56_92 (d, 2H, J=89 Hz), 7 26 (called ih), 98683.doc -147- 1333489 7.41- 7.58 (m, 3H), 7.79 (d, 2H, J = 8.9 Hz); MS (DCI) m/z 217 (M+H)+, 234 (M+NH4)+.

Example 69B (3-Fluorophenyl)(4-hydroxy-3-iodophenyl)methanone The product from Example 69A, potassium <RTI ID=0.0> 1H NMR (300 megahertz, CD3OD) occupies 6.92 (d, 1H, J = 8.9 Hz), 7.31 - 7.59 (m, 4H), 7.67 (d, 1H, Hertz), 8.18 (s, 1H); MS (DCI) m/z 343 (M+H)+, 360 (M+NH4)+.

Example 69C (3-F2-Phenylphenyl)(2-{2-[(2R)-2-methyl-1-pyridinyl)ethylid i-benzopyran-5-yl)methanone

The product from Example 69B and the product from Example 68B was worked up to give the title compound as described in Example 68C. 4 NMR (300 MHz, CD3OD) (5 1.26 (d, 3 Η, J = 6.1 Hz), 1.57 (m, 1H), 1.91 (m, 2H), 2.10-2.63 (m, 2H), 2.87 (m, 2H), 3.18 (m, 2H), 3.42 (m, 2H), 6.76 (s, 1H), 7.37-7.59 (m, 5H), 7.76 (d, 1H, J=8.9 Hz), 7.98 (s, 1H) MS (ESI) m/z 352.1 (M++1). Example 70 (2-fluorophenyl)(2-{2-[(2R)-2-methyl-1-pyrrolidinyl)ethyl }-i-benzo

Indole-5-yl)methanone Example 70A (2-Fluorophenyl)(4-hydroxy-3-iodophenyl)methanone (2-fluorophenyl) (4-) was treated as described in Example 68A Hydroxyphenyl) A 98683.doc • 148· 1333489 ketone, potassium iodide and iodine give the title compound e Ms (DCI) m/z 343 (M+H)+, 360 (M+NH4)+ 〇

Example 70B (2-airy base) (2-{2-[(2R)-2-indolyl-1-p ratio b each bite group] ethyl ι·benzo benzophenone-5-based brewing|

The product from Example 7 and the 0.1 M solution from the product of Example 68B was obtained to give the title compound. lH NMR (300 MHz, CD3〇D) 5 1.28 (d, 3H, J=6" Hertz), i.59 (m, 1H), 1.93 (m, 2H), 2.10-2.78 (m, 2H), 2.93 (m, 2H), 3.18 (m, 2H), 3.45 (m, 2H), 6.76 (s, 1H), 7.21-7.38 (m, 2H),

7.50-7.67 (m,3H), 7.79 (d, 1H' J=8.9 Hz, 7.99 (s, 1H); MS (ESI) m/z 352.1 (M+H)+. Example 71 (3-milk) (2-{2-[(2R)-2-methyl-1-? 〇 〇 each base bit) ethyl jie j benzo

Furan-5-yl)methanone Example 71A 4_(Benzyloxy)benzene is a 4-benzyloxybenzoic acid in di-methane (150 mL) and dimethylamine (75 mL) (15.0 g, 65.72 mmol) cooled to 〇 °c. After 3 minutes, the mixture was treated dropwise with neat grass chlorine (11 5 ml, 131 44 mmol) in 25 minutes. The resulting mixture was stirred at room temperature for 120 minutes, followed by reduced pressure. The solvent was evaporated to give the title compound (1. Towel NMR (300 megahertz ' CDC 13M 7.03 (d, 2H, J = 8.9 Hz), 7.23 - 7.43 (m, 5H), 98683.doc • 149. 1333489 8.07 (d, 2H, J = 8.9 Hz).

Example 71B 4_(Benzyloxy)-N-methoxy-N-methylbenzimidamide N, 〇-dimethylhydroxylamine hydrochloride (7 83 g, 8 〇 % mmol) at room temperature The product from Example 71A (18 g, 72.96 mmol) was taken slowly in DCM. The mixture was cooled to hydrazine. The mixture was stirred for 3 minutes and treated dropwise with diethylamine (25.47 mL, 182.41 mmol). The mixture was allowed to warm to 25 C, stirred for 16 h and was taken in DCM (150 mL). The mixture was rinsed with saturated NaHC 3 , brine and water. The organics were taken from EtOAc (EtOAc)EtOAc. iH NMR (300 MHz 'CDC13) &lt;5 3.36 (s, 3H), 3, 56 (s, 3H), 6.98 (d, 2H, J = 8.9 Hz), 7.33-7.46 (m, 5H), 7.76 (d, 2H, J = 8.9 Hz); MS (ESI) m/z 272 (M+H)+.

Example 71C

4-Hydroxyindole-fluorenyloxy-N-mercaptobenzamide was treated with the product from Example 71B (18 6 g, 68-55 mmol) in 150 mL of methanol in decyl alcohol (1 mL) 1% of palladium charcoal (45 grams). The mixture was placed under a pressure of 67 psig of hydrogen. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by EtOAcqqqqqq NMR (300 dead Hz, CD3OD) occupies 3.32 (s, 3H), 3.58 (s, 3H), 6.81 (d, 2H, J = 8.9 Hz), 7.59 (d, 2H, J = 8.9 Hz); MS (DCI) m/z 182 (M+H)+, 199 (M+NH4)+. 98683.doc -150- 1333489

Example 71D 4-Hydroxy-3-iodo-N-methoxy-N-methylbenzamide The product from Example 71A was found in a concentrated hydroxide (400 mL) at 25 C ( 1 〇.3 g '56.84 mmoles) for 15 minutes, then treated with 1 (45.96 g, 276.83 mmol) and 12 (14.43 g, 56.84 mmol) in water (65 ml). After 16 hours at room temperature, the solvent was removed under reduced pressure and the residue was redissolved in DCM (500 mL) and rinsed with water (350 mL EtOAc). The organic phase was dehydrated, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut NMR (300 MHz, CD3〇D) (5 3.32 (s, 3H), 3.59 (s, 3H), 6.83 (d, 1H' J = 8.9 Hz), 7.58 (d, m, J = 8.9 Hz), 8.06 (s, 1H); MS (DCI) m/z 308 (M+H)+, 325 (m+nh4)+.

Example 71E N-Methoxy-N-methyl-2-{2-[(2R)-2-methyl-1.,pyrrolidinyl]ethylidene}-1-benzofuran-5-carboxylate The guanamine was continuously subjected to a 0.12 hydrazine solution (3 8 ml, 45.33 t mole), Pd(OAc) 2 (0-254 g, 1.13 mmol), tris(4-tolyl)phosphine (available from the product of Example 68). The product from Example 71D (11.6 g '37.773⁄4 ul) was treated with EtOAc (50 mL). After a drop of 1 minute at 25 C, the mixture was treated with disc bronze (2.158 g &apos; 11.33 mmol) and heated to 50 ° C for 18 hours under an inert atmosphere. The reaction mixture was allowed to cool to room temperature, filtered through <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue was purified with EtOAc EtOAcjjjjjj Towel NMR (300 MHz, CD3〇D) (5 1.18 (d, 3 Η, J = 6.1 Hz), 1.47 (m, 1 Η), 1.78 (m, 2H), 1.91-2.34 (m, 2H), 2.50 (m, 2H), 3.06 (m, 2H), 3.26 (m, 2H), 3.38 (s, 3H), 3.59 (s, 3H), 6.63 (s, 1H), 7.51 (q, 2H), 7.84 (1H); MS (ESI) m/z 317.2 (M+H)+.

Example 71F (3-Phenylphenyl) (2-{2-[(2R)-2-methyl-indole-p piroxicam]ethyl}···benzofuran-5-yl)methanone The product from Example 71 (5 g, 〇 158 mmol) was treated with phenylmagnesium bromide (1.58 mL, 0.79 mmol) in EtOAc. The mixture was allowed to warm slowly to 25 and was stirred under nitrogen for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with DCM (50 mL EtOAc). The organic phase was combined, dehydrated, filtered, and the filtrate was evaporated under reduced pressure. The HpLC purification residue was prepared on a Waters N〇va_pak HR C18 column (40 pens x 100 mm, 6 micron particle size) using 1% to 1% acetonitrile in 12 minutes: 〇 1% aqueous TFA Gradient (15 min execution time) at a flow rate of 7 mL/min to give the title compound. 111 should be 11 (3 〇〇 megahertz, (:]:) 3 〇 £)) 515 〇 ((1, 31^), 1.72 (m, 1H), 2.10 (m, 2H), 2.35 (m, 1H) , 3.30 (m, 4H), 3.55 (m, 1H), 3.80 (m, 2H), 6.90 (s, 1H), 7.50-7.80 (m, 6H), 8.02 (d, 1H); MS (ESI) m /z 368 (M+H)+. Example 72 98683.doc -152- 1333489 (4-chlorophenyl)(2-{2-[(2R)-2-methyl-i-pyrrolidinyl]ethyl The title compound was obtained from the product from Example 71E and the title compound was obtained as described in Example 71F. iH NMR (300 MHz, CD3OD) 1.18 (d, 3H, J = 6.1 Hz), i.46 (m, 1H), i 78 (m, 2H), 2.01-2.36 (m, 2H), 2.50 (m, 2H), 3.03 (m, 2H), 3.23 (m, 2H), 6.67 (s, 1H), 7.57 (m, 3H), 7.78 (m, 3H), 7.97 (s, 1H); MS (ESI) m/z 368.1 (M++ 1) Example 73 (4-oxophenyl) (2-{2-[(2R)-2-methyl]pyrrolidyl]ethylw- benzofuran-5-yl)methanone The title compound was obtained as described in Example 71F, mp. i 46 (m, 1 H), 2 〇 1_2 32 (m, 2H), 2.50 (m, 2H), 3.06 (m, 2H), 3.24 (m, 2H), 3.88 (s, 3H), 6.67 (s, 1H), 7· 05 (d, 2H, J = 8.9 Hz), 7.54 (d, 2H, _ J = 8.9 Hz), 7.68 (d, 2H, J = 8.9 Hz), 7.80 (d, 2H, J = 8.9 Hz), 7.92 (s, 1H); MS (ESI) m/z 364.1 (M++1) 〇 Example 74 (4-fluoro-3-methylphenyl) (2-{2-[(2R)-2-decyl) I. pyrrolidinyl]ethylbub benzofuran-5-yl)methanone was treated as described in Example 71F to give the product from Example 7 丨 ε and (4-fluoro-3-methyl) bromination. Phenyl lock' gave the title compound ^ NMR (300 megahertz 'CD3OD) to 1.17 (d, 3H), 1.45 (m, 1H), 1.80 (m, 2H), 98683.doc • 153- 1333489 2.0 (m, 1H ), 2.3 (m, 4H), 2.50 (mj 2H), 3.05 (m, 2H), 3.25 (m, 2H), 6.65 (s, 1H), 7.2 〇, 1H)s 7 57 a 1H)) 7 63 1H), 7.70 (dd, 2H), 7.95 (d, 1H); MS (ESI) m/z 366 (M+H) + ° Example 75 cyclopropyl (2-{2-[(2R)-2- Methyl hydrazine 4 octazone] ethyl bromobenzofuran-5-yl) ketone was treated as described in Example 71F, and the product obtained from Example 71E and bromopropyl bromide was obtained. Compounds. iH nmr (300 MHz, CD3〇D) occupies 1.10 (m, 5H), 1.28 (d, 3H), 1.78 (m, 1H), 2.10 (m, 2H), 2.38 (m, 1H), 2.9 (m) , 1H), 3.2-3.8 (m, 6H), 6.85 (s, 1H), 7.58 (d, 1H), 8.05 (dd, 1H), 8.33 (d, 1H); MS (ESI) m/z 298 ( M+H)+. Example 76 3-Ethyl-l-(2-{2-[(2R)-2-indolyl-l-pyridolidinyl]ethylidene-benzopyran-5-yl)-i-pentyl The product from Example 71E and 2-ethylbutylammonium bromide were treated as described in Example 71F to give the title compound. 1HNMR (300 MHz, CD3OD) (5 0.9 (m, 6H), 1.23 (m, 1H), 1.20 (m, 6H), 1.75 (m, 1H), 2.1 (m, 2H), 2.35 (m, 1H) ), 3.05 (m, 1H), 3.2-3.5 (m, 7H), 3.55 (m, 1H), 3.8 (m, 1H), 6.85 (s, 1H), 7.55 (d, 1H), 7.95 (dd, 1H), 8.24 (d, 1H); MS (ESI) m/z 342 (M+H) + s. 77 (4-chloro-3-tolyl) (2-{2-[(2R)-2- Methyl-1-pyrrolidinyl]ethyl bh benzofuran-5-yl)fluorenone 98683.doc • 154- 1333489 The product from Example 71E and 4·chloro- as described in Example 71F. 3-Methylbromide phenyl-locked to give the title compound. iH NMR (3 〇〇 megahertz, CD3 〇D) δ 1.47 (d, 3H), 1.75 (m, 1H), 1.80 (m, 2H), 2.10 (m, 2H), 2.38 (m, 1H), 2.44 (S} 3H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.5 ( m, 3H), 7.7 (bs, 1H), 7.79 (dd, 1H), 8.01 (d, 1H); MS (ESI) m/z 382 (M+H)+. Example 78 (2-{2-[ (2R)-2-Methyl-1-pyrrolidinyl]ethylidene benzofuran-5-yl)[4-(indolylthio)phenyl]methanone was treated as described in Example 71F. The product from Example 7丨E and 4-(indolylthio)phenylphenyl bromide, To the title compound. 1hnmr(3〇(^&amp; Hertz, cd3〇d) 5 K45 (d,3H), 175 (m,1H),} 8〇(m 2H), 2.30 (m, 2H), 2.38 ( m, 1H), 2.54 (s, 3H), 3.50 (m, 2H), 3.55 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.4 (dd, 2H), 7.7 (bs , 1H), 7.6 (dd, 1H), 7.75 (m, 3H), 8.0 (d, 1H); MS (ESI) m/z 380 (M+H) + 〇 Example 79 [4-(monoamine) Phenyl](2-{2-[(2R-)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)methanone as described in Example 71F, The product from Example 71E and 4 (monodecyl)phenylphenyl bromide were treated to give the title compound. lH NMR (3〇〇 dead Hertz, CD3〇D) 5 1.44 (d, 3H), 1.73 (m, 1H),! 8〇(m,2H), 2.15 (m,2H), 2.35 (m,1H), 3.18 (s,6H), 3.50 (m, 2H), 3.55 (m,1H), 3.80 (m,2H), 6 8〇(dd,2H),6(s,ih),7 %(iv), 98683.doc • 155- 1333489 1H), 7.65 (dd, 1H), 7.75 (dd, 2H), 7.95 (d, 1H) MS (ESI) m/z 377 (M+H)+. Example 80 (4-Tolyl)(2-{2-[(2R)-2-methyl-i-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)methanone as in Example 71F In the above description, the product from Example 71e and 4-Methyl-Phenyl-Phenylmagnamine were obtained to give the title compound: iH NMR (300 MHz, CD3OD) 5 1.48 (d, 3H), 1.75 (m, 1H), 2.1 (m, 2H), 2.38 (m, φ 1H), 2.45 (s, 3H), 3.30 (m, 4H), 3.57 (m, 1H), 3.80 (m, 2H), 6.85 (s, 1H), 7.38 (dd, 2H), 7.60 (dd, 1H), 7.70 (dd, 2H), 7.75 (dd, 1H), 8.0 (d, 1H); MS (ESI) m/z 348 (M+H)+. Example 81 (3,5-Difluorophenyl)(2-{2-[(2R)-2-methyl-ι-pyrrolidinyl)ethylbobbenzofuran-5-yl)methanone The product from Example 7A and the 3,5-difluorobromopyridyl magnesium were treated as described in Example 71F to give the title compound. 1hnmr (3〇〇兆赫唤^ * CD3〇D)^ 1.45 (d3 3H), 1.75 (m, 1H), 2.13 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3· 56 (m, 1H), 3.82 (m, 2H), 6.88 (s, 1H), 7.38 (dd, 2H), 7.30 (m, 3H), 7.63 (dd, 1H), 7.80 (dd, 1H), 8.05 (d, 1H); MS (ESI) m/z 370 (M+H)+. Example 82 (2-methoxyphenyl)(2-{2-[(2R)-2-methyl-pyrrolidinyl)ethylbububenzopyran-5-yl)-A The titled compound NMR (300 MHz 'CD3OD) d 1.42 (d, 3H) was obtained from the product of Example 71. ), 1.72 (m, 1H), 2.10 (m, 2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.55 (m, 1H), 3.70 (s, 3H), 3.80 (m, 2H) , 6.80 (s, 1H), 7.1 (m, 2H), 7.30 (dd, 1H), 7.53 (m, 2H), 7.75 (dd, 1H), 7.95 (d, 1H); MS (ESI) m/z 364 (M+H)+. Example 83 (3-methoxyphenyl)(2-{2-[(2R)-2-methyl-lu-pyrylene)ethyldi-p-benzopyran-5-yl)methanone The product from Example 71 and the phenylmagnesium bromide bromide were treated as described in Example 71F to give the title compound. iH NMR (3〇〇兆赫' CD3OD)5 1.42 (d,3H), 1.72 (m, 1H), 2.10 (m,2H), 2.35 (m, 1H), 3.30 (m, 4H), 3.55 (m , 1H), 3.80 (m, 2H), 3.83 (s, 3H), 6.83 (s, 1H), 7.2 (m, 1H), 7.30 (m, 2H), 7.45 (m, 1H), 7.60 (m, 2H), 7.80 (dd, 1H), 8.02 (d, 1H); MS (ESI) m/z 364 (M+H) + 〇 Example 84 (2-{2-[(2R)-2-methyl- 1-Pyrrolidinyl]ethylidene-benzofuran-5-yl)(phenyl)methanone was treated as described in Example 71F to give the product from Example 7丨e and phenylmagnesium bromide. Title compound. iHnmr (3〇〇 megahertz, CD3〇D) 5 1.15 (d,3H), 1.45 (m,1H), 1.80 (m,2H), 2.00 (m,1H), 2.30 (m,1H), 2.50 ( m, 2H), 3.30 (m, 4H), 6.63 (s, 1H), 7.55 (m, 3H), 7.65 (m, 1H), 7.80 (m, 3H), 7.98 (d, 1H); MS (ESI ) m/z 334 (M+H)+. • 157· 98683.doc 1333489 Example 85 4-(2-{2-[(2R)-2 -Methyl-1-it piroxicam]ethyl}-l-benzopyran-4-

Base) rare nitrile example 85A 2-iodo-1,3-benzenediol using iodine (6.7 g, 26.4 mmol) and NaHC03 (2.3 g, 27.4 mmol)' treatment in 20 ml water and ice Resorcinol (2.75 g, 25 mmol). After stirring for 1 hour, the precipitate was separated by filtration, and the filtrate was extracted twice with diethyl ether (2×75 ml). The organic phase was dehydrated with sodium sulfate and evaporated under reduced pressure. The solid was wet-milled with 20 ml of air and placed at -18 ° C for 24 hours. The solid was isolated by filtration to give the title compound (yield: 780 / EtOAc). NMR (300 MHz, CDC13) (5 4.85 (s, 1H), 6.30 (m, 2H), 6.95 (m, 1H). MS (CDI) m/z 237 (M+H)+.

Example 85B 2-(2-Ethyl)-1-benzop-pentan-4-ol as dichlorobis(triphenylphosphine)palladium (30 mg, 0.043 mmol), copper iodide under nitrogen (24 mg, 0.13 mmol), triethylamine (0.2 g, 2.12 mmol) and 3-butyne-1·ol (0.11 g, 1.53 mmol) obtained from 5 ml of DMF Product of 85 people (0.2 g, 0.85 mmol). The mixture was heated to 60 ° C for 14 hours. After filtration on diatomaceous earth, the mixture was diluted with 150 mL of CH2C12 and washed with sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml). The filtrate was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:丨111^]\411 (3 00 MHz, 〇0 (:13) (5 3.05 (claw, 2 print, 4.0 (111, 2H), 6.60 (m, 2H), 7.03 (m, 2H) 〇MS ( CDI) m/z 179 (M+H)+〇

Example 85C 2-(2-Ethyl)-1-benzobenzopyran-4-yl sulphonic acid g is intended to be triethylamine (0-11 g, 1.12 mmol) at 〇 °C. DMAP (7 mg, 0.056 mmol) and N-phenyl-trifluoromethanesulfonimide (0.22 g, 0.62 mmol) of product from Example 85B in 10 mL CH2C12 (0.1 g. Millions of ears). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 1 mL of CHAl2 and washed twice with water (2 X 1 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness eluting 4 NMR (300 MHz, CDC13) 3.10 (m, 2H), 4.0 (m, 2H), 6.60 (s, 1H), 7.15 (m, 1H), 7.22 (m, 1H), 7·45 ( m, 1H). MS (CDI) m/z 3 11 (M+H)+.

Example 85D 4-[2-(2-Hydroxyethyl)-1-benzofuran-4-yl]indoleonitrile was 4-oxo-based banic acid (〇.〇52 g, 0.35 mmol), Acetic acid treated (0.0032 mmol), biphenyl-2-yl-dicyclohexylphosphine (0.0048 mmol) and Na2C03 (2M, 0.87 mmol) in 8 mL benzene/ethanol (2:1) The product from Example 85C (1 g, 0.32 mmol) was obtained and heated to 75. 〇 14 hours. The mixture was diluted with 1003⁄4 liters of CHAl2 and washed successively with water (1 mL) and brine (100 mL), dehydrated over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc 1H NMR (300 megahertz, CDCl3) 98683.doc -159- 1333489 δ 3.10 (m, 2Η), 4.05 (m, 2H), 6.62 (s, 1H), 6.90 (m, 1H), 7.25 (m, 2H) , 7.52 (m, 2H), 7.73 (m, 2H). MS (CDI) m/z 264 (M+H)+.

Example 85E 2-[4-(4-Cyanophenyl)-1-benzofuran-2-yl]ethyl methanesulfonate at 〇 ° C with triethylamine (64 mg, 0.63 mmol) The product from Example 85D (0.15 g, 0.57 mmol) was taken from CH2C12 (10 mL). After 45 minutes at room temperature, the reaction was diluted with 50 mL CH.sub.2 C.sub.2, and the mixture was washed with water (2 X 50 mL). The organic phase was dried over sodium sulfate and evaporated to give the title compound (99% yield). 4 NMR (300 MHz, CDC13) 52.70 (m, 2H), 2.94 (s, 3H), 3.90 (m, 2H), 6.60 (s, 1H), 6.90 (m, 1H), 7.35 (m, 3H) , 7.69 (m, 4H). MS (CDI) m/z 342 (M+H)+.

Example 85F 4-(2-{2-[(2R)-2-indolyl-1-pyrrolidinyl]ethyl}_i_benzofuran-4-yl)hypo inoculae obtained from 2 ml of MeCN Example 85E product (0.086 g, 0.25 mmol), (211)-2-methylpyrrolidinium-1 tartaric acid (〇.12 g, 〇.5 mmol) and cesium carbonate (0.41 g, 1.26 mM) Mohr) and heated to 45. 〇 2 days. The mixture was diluted with 1 mL of CHsCl2 and washed with a saturated solution of sodium bicarbonate (5 mL), water (50 mL) and brine (5 mL). Dehydrate the organic layer and pass it through the mash. The residue was purified by column chromatography eluting eluting elut elut elut elut eluting H NMR (300 MHz, CDC13) 5 1.20 (d, 3H), 1.58 (m, 98683.doc -160 - 1333489 4H), 2.20-2.50 (m, 5H), 2.78 (m, 2H), 6.62 (s , 1H), 7.28 (m 3H), 7.69 (m, 4H). MS (CDI) m/z 331 (M+H)+. Example 86 4-(2-{2-[(2R)-2-methyl-i-pyrrolidinyl]ethyl bromide-benzofuranyl)octanoic acid Example 86A 4-iodobenzene-1,3-di Alcohol monohydrated iodine (8.2 g, 50.5 mmol) in anhydrous diethyl ether (1 mL) was added dropwise to the residue between the anhydrous ethylene (5 mL) in 45 minutes. An ice-cold solution of phenol (5.5 g, 49.9 mmol) ((rc)t. After stirring at room temperature for 1 hour, add 100 ml of water and gram of sodium sulfite. Separate the organic phase and rinse with 100 ml of ether. In the liquid phase, the mixed ethers were dehydrated with sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel using CH/kMeOH (1 〇〇: 1) % of the title compound. 1H NMR (300 MHz, CDC13) (5 4.95 (s, m), 6.23 (m, 1H), 6.55 (m, 1H), 7.43 (m, 1H). MS (CDI) m /z 237 (M+H)+ 〇

Example 86B 2-(2-Ethyl)-1-benzop-sigma _6-ol The title compound was obtained from the product of s. iH NMR (300 MHz, CDCi3) occupies 3. 〇〇 (m, 2H), 3·98 (m, 2H), 6.40 (s, 1H), 6.73 (m, lH), 6.90 (d, 1H)} 7.30 (m, lH). MS (CDI) m/z 179 (M+H)+.

Example 86C 98683.doc -161 - 1333489 2-(2-Hydroxyethyl)-1-benzofuran-6-yltrifluoromethanesulfonate The product from Example 86B was treated as described in Example 85C. The title compound was obtained. 1H NMR (300 MHz, CDC13) 6 3.00 (m, 2H), 4.2 (m, 2H), 6.65 (s, 1H), 7.20 (m, 1H), 7.22 (m, 1H), 7.35 (m, 1H) ) 〇MS (CDI) m/z 311 (M+H)+ »

Example 86D 4-[2-(2-Ethyl)-1. &lt;RTI ID=0.0&gt;&gt;&gt;&gt;&gt; 1H NMR (300 MHz, CDC13) 6 3.15 (m, 2 Η), 4.00 (m, 2H), 6.52 (s, 1H), 6.95 (m, 1H), 7.35 (m, 2H), 7.52 (m, 2H) ), 7.70 (m, 2H); MS (CDI) m/z 264 (M+H)+.

Example 86E 2-[6-(4-Cyanophenyl)-1-benzonyridin-2-yl]ethylmethyl sulphate. The product obtained from Example 86D was treated as described in Example 85E. The title compound was obtained. 1H NMR (300 MHz, CDC13) 5 2.65 (m, 2H), 2·99 (s, 3H), 3.95 (m, 2H), 6.45 (s, 1H), 6.95 (m, 1H), 7.30 (m , 3H), 7.69 (m, 4H); MS (CDI) m/z 342 (M+H)+.

Example 86F 4-(2-{2-[(2R)-2-methyl- Ι-t» ratio 0 octyl] ethyl benzopyran-6-yl) phthalonitrile

The product from Example 86E was treated as described in Example 85F to give the title compound. 1H NMR (300 MHz, CDC13) 5 1.20 (d, 3H), 1.58 (m, 4H), 2.20-2.50 (m, 5H), 2.78 (m, 2H), 6.52 (s, 1H), 7.40 (m , 1H), 7.58 (m, 1H), 7.60 (s, 1H), 7.73 (m, 4H); MS 98683.doc -162· 1333489 (CSI) m/z 331 (M+H), Example 87 3- (2-{2-[(2R)-2-Mercaptopyrrolidin-1-yl]ethylbobbenzofuran_5_yl)-5-(ι»cetin-2-ylindenyl)-1 , 2,4-»» No. 2. Sit. Example 87 Α 4-Hydroxy-3-detrinonitrile. In a 2 liter ml round bottom flask containing 10.0 g (843⁄4 mol) of 4-merine, add 450 ml of concentrated ammonium hydroxide and allow at 25. Spoil the contents under the arm for 15 minutes. The solution was quickly added to a solution of 67 9 g (409 mmol) of potassium iodide and 21.3 g (84 mmol) of iodine tablets dissolved in 1 mL of water. The reaction mixture was allowed to mix at 25 ° C for 18 hours' at which time the contents were filtered. Under the reduced pressure, the agricultural shrinkage liquid was dissolved again in 500 ml of methylene chloride. The organic layer was then washed twice with water (250 mL). lHNMR (300 megahertz, CDC13) 5 7.03 (d, 1H), 7.66 (dd, 1H), 7.98 (s, 1H); MS DCI m/e, 263 (M+NH4)+ 〇

Example 87B 2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}-i-benzofuran-5-nitrile (2R)-l in 0.1 Μ in acetonitrile -(3-butynyl)·2-methylpyrrole bite (490 ml, 48.9 mmol), ? (1 (manufactured by 〇2 (0.275 g, 1.22 mmol), Ptol3 (0.747 g ' 2.44 mmol) and copper iodide (1-16 g, 6.122 mmol) from the product of Example 87A (10.0 Grams, 40.81 mmol. After stirring at 25 ° C for 1 min, diisopropylamine (43.0 mL) was added and the reaction mixture was heated to 6 ° C for 16 h under inert atmosphere. 98683.doc • 163- 1333489 The mixture should be cooled, filtered through diatomaceous earth, concentrated under reduced pressure, and purified on Shi Xisheng, using 95% DCM, 9.5% MeOH, 0.1 〇/〇NH4OH ' to obtain a fading color. The title compound (2 56 g, 24.6% yield). NMR (300 MHz, CD3 OD) 5 1.09 (d, 3H, J = 6.1 Hz), 1.46 (m, 1H), 1.81 (m, 2H), 2.02-2.38 (m, 2H), 2.59 (m, 2H), 3.08 (m, 2H)S 3.28 (m, 2H), 6.70 (s, 1H), 7.58 (s, 1H), 7.97 (s , 1H); MS (ESI) m/e 255 (M+H)+.

Example 87C Ν'-Phenyl-2-{2-[(2R)-2-indolylpyrrolidin-1-yl]ethyl}-l-benzofuran-5-carbamidide (carbazole) The product from Example 87 (2.5 g of ' 9.83 mmol) was stirred in EtOH (200 mL) at 25 ° C for 1 min. The mixture was treated with hydroxylamine hydrochloride (71 g, 24 6 mmol) and potassium carbonate (4.49 g, 32-48 mmol), and the resulting mixture was heated to 95 ° C for 16 hours and stirred. The reaction mixture was then cooled, filtered through celite and concentrated under reduced pressure. The crude product was purified using EtOAcqqqqqq MS (ESI) m/e 288 (M+H)+.

Example 87D 3-(2-{2-[(2R)-2-Mercaptopyrrolidine-i-yl]ethyl}-i-benzofuran-5-yl)-5-decenophen-2-yl The product obtained from Example 87C (〇.〇6 g, treated with triethylamine (34.9 μl, 0.25 mmol) in trimethylamine (1 mL). 0.209 mmol) and stirred at 25 ° C for 10 minutes. The mixture was treated with thiophene-2-ylethenyl chloride (25.7 microliters, 0.25 millimoles) slow f Ai, and stirred at 25 ° C for 18 hours. The solvent was evaporated under reduced pressure of 98683.doc 1333489, dissolved again in dichloromethane (DCM) (25 mL), washed twice with water (25 liters), dehydrated and concentrated. The residue was redissolved in toluene (25 ml) and heated to U.sub.C for 16 hours in the presence of 3 angstrom molecular sieves. Heat the solvent and purify the crude product on a Waters Nova-Pak HR C18 column (40 mm X 100 mm '6 micron particle size) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous TFA in 5 minutes. The execution time) 'obtained at a flow rate of 70 ml/min' gave the title compound. iH NMR (300 Hz ' CD3OD) 5 1_42 (d, 3H, J = 6.1 Hz), 1_78 (m, 1H), 2.09 (m, 2H), 2.36 (m, 1H), 3.20-3.59 (m, 5H ), 3.78 (m, 2H), 4.59 (s, 2H), 6.82 (s, 1H), 7.01 (t, 1H), 7.09 (s, 1H), 7.38 (dd, 1H), 7.60 (d, 1H) , 8.01 (dd, 1H), 8.27 (s, 1H); MS (ESI) m/e 394 (M+H)+. Example 88 4-[3-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl bromide-5-yl)-1,2,4-oxadiazole_5 The benzylidene benzonitrile was treated as described in Example 87D to give the title compound. 1H NMR (300 megahertz 'CD3OD) (5 1.46 (d, 3H, J = 6.1 Hz), 1.78 (m, 1H), 2.09 (m, 2H), 2.36 (m, 1H), 3.18-3.79 (m, 7H), 6.82 (s, 1H)' 7.18 (m, 2H), 7.65 (d, 1H), 8.03 (d, 2H), 8.16 (dd, 1H), 8.41 (s, 1H); MS (ESI) m /e 399 (M+H)+. Example 89 5-(4-Phenylphenyl)-3-(2-{2-[(2 ft)-2-methyl 1»Bilo-1-yl] Ethyl}_1·benzofuran-5-yl)-i,2,4-indolediazole The 4-carbophthalide was treated as described in Example 87D to give the title 98683.doc-165·1333489 Compound MS (ESI) m/e 408 (M+H) +. Ethyl}small benzofuran-5-yl)-1,2,4-oxadiazole was treated as described in Example 87D to give the title compound as the title compound. 1HNMR (3 00 MHz) , CD3OD)5l.46(d,3H,J=6.1 Hz), 1.78 (m,1H), 2.11 (m,2H), 2.38 (m,1H),3.21-3.90 (m,7H),6.88 (s , 1H), 7.56-7.73 (m, 4H), 8.17 (m, 2H), 8.41 φ (s, 1H); MS (ESI) m/e 408 (M+H)+. Example 91 5-(4- Fluorobenzyl)-3-(2-{2-[(2R)-2-methyl) Pyrrrolidinyl]ethyl bromide benzobenzopyran-5-yl)-l,2,4-p-dione was treated as described in Example 87D to give (4-fluorophenyl)acetamidine chloride. The title compound: 1H NMR (300 MHz, cD3 OD) 5l.46 (d, 3H, J = 6.1 Hz), 1.78 (m, 1H), 2.11 (m, 2H), 2.38 (m, 1H), 3.21-3.90 ( m, 7H), 4.38 (s, 2H), 6.82 (s, 1H), 7.10 (m, 2H), · 7.42 (m, 2H), 7.59 (d, 1H), 7.99 (dd, 1H), 8.26 ( s, 1H); MS (ESI) m/e 406 (M+H)+. </RTI> <RTI ID=0.0></RTI> </RTI> 5-(4-methoxybenzyl)-3-(2-{2-[(2Κ). Pyrrridinyl]ethyl}-1-benzofuran-5-yl)_1&gt; 2,4-w-diazole The title compound was obtained after treatment of (4-oxophenyl)ethylhydrazine as described in Example 87D. 1H NMR (300 MHz, CD3〇D) 5丨46 (d, 3H, J-6.1 Hz), 1.78 (m, 1H), 2·1〇 (m, 2H), 2 38 (m, 1H), 98683.doc •166· 1333489 3,21-3.90 (m,7H),3.78 (s,3H), 4.28 (s,2H),6,83 (s,1H), 6.92 (d, 2H), 7.32 ( d, 2H), 7.59 (d, 1H), 7.99 (dd, 1H), 8.26 (s, 1H); MS (ESI) m/e 418 (M+H)+. Example 93 3-{[3-(2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}-l- benzofuran-5-yl)-1,2,4 -Oxadiazol-5-yl]fluorenyl}benzonitrile The 3-cyanobenzamide was treated as described in Example 87D to give the title compound. 1H NMR (300 megahertz, CD3OD) (5 1.46 (d, 3H, J = 6.1 Hz), 1.78 (m, 1H), 2.11 (m, 2H), 2.38 (m, 1H), 3.21-3.91 (m, 7H), 6.86 (s, 1H), 7.56 (m, 2H), 7.62 (d, 1H), 8.09 (dd, 1H), 8.21 (m, 1H), 8.38 (m, 2H); MS (ESI) m /e 399 (M+H)+. Example 94 3-(2-{2-[(2R)-2-methylpyrrolidin-1-yl]ethyl}_丨·benzopyran_5_yl) -5 - Stupid-1,2,4-indole 2. Sodium Benzoate was treated as described in Example 87D to give the title compound: MS (ESI) m/e 374 (M+H)+. Example 95 5-(4-Fluorophenyl)-3-(2-{2-[(2R)-2-methylp 嚷 嚷. 小小基]乙美)1 本 and 咬-5-yl) The -1,2,4-σ-numbered dioxime was treated as described in Example 87D to give the title compound. MS (ESI) m/e 392 (Μ+Η)+. Example 96 5-(3-Gas-4-fluorophenyl)-3-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-1-benzofuran-5- The title compound was obtained according to the procedure described in Example 87D. m.p. MS (ESI) m/e 426 (M+H)+. Example 97 5-(Gasyl)-3-(2-(2-[(2R)-2-methylpyrrolidin-1.yl]ethyl}·1_benzofuran-5-yl)-1 2,4-oxadiazole The gasified acetonitrile chloride was treated as described in Example 87D to give the title compound. 4 NMR (300 MHz, CD3OD) 5 1_46 (d, 3 Η, J = 6.1 Hz), 1 · 78 (m, 1H), 2.10 (m, 2H), 2.38 (m, 1H), 3, 21-3.90 (m5 7H), 4.96 (s, 2H), 6.83 (s, 1H), 7.61 (d, 1H), 8.02 (dd, 1H), 8.29 (s, 1H); MS (ESI) m/e 346 (M+H)+. Example 98 3-(2-{2-[(2R)-2-A Pyrrrolidin-1-yl]ethyl}-l-benzofuran-5-yl)-5-propyl-1,2,4-oxadiazole The butyl chloride was treated as described in Example 87D. The title compound. 1H NMR (300 MHz, CD3OD) 5 1-42-1.48 (m, 10 Η), 1.78 (m, 1H), 2.10 (m, 2H), 2.38 (m, 1H), 3.21-3, 90 (m,7h),4.96, 6.83 (s, 1H), 7.59 (d, 1H), 8.01 (dd, 1H), 8.27 (s, iH); MS (ESI) m/e 340 (M+H)+ Example 99 5-Ethyl-3-(2-{2-[(2R)-2-indolylpyrrolidin-1-yl]ethylbenzofuran-5-yl)-1,2,4-indole The oxadiazole was treated as described in Example 87D to give the title compound. MS (ESI) m/e 326 (M+H) +. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;乙乙乙乙苯苯咬-5-yl)-1,2,4-&gt;», etc. The two spurs were treated as described in Example 87D to give the title compound "MS (ESI) m/e 312 (M+H)+. Example 101 4-(3•Bromo-2-{2-[(2R)-2-methylpyrrolidinyl)-ethyl bromide-benzofuran- The 5-mer)benzonitrile was combined with the product from Example 1D (2-5 g, 5-2 mmol) and tris-acetic acid (40 mL) (TFA) and stirred at 25 ° C for 10 min. The mixture was slowly treated with Bo solution (450 microliters, 7.8 millimoles) in 10 ml). The mixture was allowed to mix at 25 C for 1 hour and then treated with saturated aqueous NaJO3. The mixture was concentrated and dissolved again in 5 mL of ethyl acetate. The organic phase was washed with 1 M NaOH and concentrated under reduced pressure to give the title compound (1. g, </ </ s> </ RTI> NMR (3 megahertz, CD3 OD) (5 1.16 (d, 3H, J = 6.1 Hz), 1.42 (m, 1H), 1.78 (m, 2H), 1.98 (m, 1H), 2.32 (m, 1H), 2.50 (m, 2H), 3.11 (m, 2H), _ 3.28 (m, 2H), 7.58-7.70 (m, 3H), 7.82 (m, 4H); MS (ESI) m/e 409 (M+H) + ° Example 102 4-(3-(2-biting base)-2-{2 -[(2R)-2-methylpyridyl 4 butyl group] ethyl) small benzofuran-5-yl) phthalonitrile with Pd(PPh3)4 (0.008 g, 0.0073 mmol)' 2-pyran The product obtained from Example 101 was treated with boronic acid (0.041 g &lt;&lt;RTIID=0.0&gt;&gt;&gt;&gt;&gt; Doc - 169 · 1333489 0.244 house Moules' and reflux the reaction mixture under inert pressure for 8 hours. Allow the mixture to cool to room temperature, filter through mash and filter under reduced pressure. The crude product was purified on a -Pak HR C18 column (40 mm X 100 mm, 6 micron particle size) using 10 ° / to 100% acetonitrile in 12 minutes: The gradient of the 1% aqueous TFA (15 minutes of execution time) was obtained at a flow rate of 70 ml/min. The title compound was obtained. iHNMR (300 MHz, CD3OD) was 1.46 (d, 3H, J = 6.1 Hz), 1.78 ( m,1H), 2.09 (m, 2H), 2.38 (m, 1H), 3.46-3.96 (m, 7H), 6.67 (s, 1H), 6.98 (s, 1H), 7.64-7.77 (m, 3H) , 7.81-7.92 (m, 4H), 8.16 (s, 1H); MS (ESI) m/e 397 (M+H)+. Example 103 4-[2-{2-[(2R)-2-曱Benzyl-1-pyrrolidyl]ethylidene 3-(3-pyridyl)benzophenanthrene-5-yl] granules treated with 3-pyridylboronic acid as described in Example 102 gave the title compound 1H NMR (300 megahertz, CD3OD) 6 1.46 (d, 3H, J = 6.l Hz), 1.78 (m, 1H), 2.06 (m, 2H), 2.37 (m, 1H), 3.20-3.96 (m , 7H), 7.73-7.87 (m, 8H), 8.36 (d, 1H), 8.76 (s, 1H), 8.92 (s, 1H); MS (ESI) m/e 408 (M+H)+. Example 104 4-[2-{2-[(2R)-2-indolyl-1-pyrrolidinyl]ethyl}_3-(3. phenyl)benzofuran-5-yl]benzonitrile according to the example The title compound was obtained as described in 102 to give the title compound. 1H NMR (300 MHz, CD3OD) (5 1.43 (d, 3H, j=6) Hz), 1.76 (m, 1H), 2.03 ( m, 2H), 2.35 (m, 1H), 3l8-3, 89 98683.doc -170- 1333489 (m, 7H), 7.42 (dd, 1H), 7.65-7.72 (m, 4H), 7.78-7.87 ( m, 5H); MS (ESI) m/e </RTI> (M+H) + </ RTI> Example 105 4-(3-(2-carbamidin-3-ylphenyl)-2-{2-[(2R) 2-Methyl-1-pyrrolidinyl]ethyl}-1-benzopyran-5-yl), and treated 2-methylmercapto-3-pyrimenyl as described in Example 102. Boric acid gave the title compound: MS (ESI) m/e 441 (M+H) + </RTI> Example 106 2-methyl-4-(2-{2-[(2R)-2-mercapto-1-pyrrolidine Base] ethyl}-l-benzophenan-5-yl)

Example 106A 4 methoxymethoxy-3-indolyl-1, fluorenyl-biphenyl-4-carbonitrile was treated with 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) 4-bromo-2-methylindoleonitrile (4.9 g, 25.0 mmol) in benzene (50 mL) and 2.0 Μ Na2CO3 (25 mL, 50.0 mmol), Pd(PPh3)4 (578 mg) ) and heated to 75 ° C for 17 hours. The mixture was allowed to cool to room temperature&apos; and the phase was separated. The liquid phase was extracted with diethyl hydrazine (3 χ 4 〇 ml). The original benzene layer and diethyl ether extract were mixed, transferred over diatomaceous earth, dehydrated with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified eluting elut elut elut elut elut elut elut elut elut Yield). NMR (300 megahertz, CDCl3) 5 2 35 (3H), 3 7 〇 (s, 3H), 6.80-7.50 (m, 7H); MS (DCI) m/z 224 (M+H)+.

Example 106B 98683.doc .171 - 1333489 4'-Hydroxy-3-methyl-1,1'-biphenyl-4-carbonitrile in 1 hour at 78 ° C with 1·0 Μ BBr3 (in CH2C12 The product from Example 106A (5.60 g, 25.4 mmol) was taken in <RTI ID=0.0># </RTI> <RTIgt; After stirring at room temperature for 14 hours, the mixture was warmed to hydrazine. 〇 (ice bath) and treat with water (0.5 ml). After 10 minutes, additional water (2.0 mL) was added, the ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with an additional 20 ml of water and allowed to stir for 45 minutes. The mixture was filtered and the filtrate was extracted with CH2C12. The mixture was extracted with EtOAc (EtOAc m.) Ifi NMR (300 MHz, CDC13) (5 2.35 (s, 3H), 5.0 (s, 1H), 6.79-7.50 (m, 7H); MS (DCI) m/z 210 (M+H)+. 106C 4, hydroxy-31-iodo-3-methyl-1,1,-biphenyl-4-carbonitrile The product from Example 106B (4.67 g, mp. 22.3 millimoles), Nal (3.343 grams, 22.3 millimoles) and ]^〇11 (892 mg'; 22.3 millimoles) and treated dropwise with bleach (5.25%, 31.6 grams) in 30 minutes After stirring for 80 minutes at 〇 °c, the mixture was quenched with 10% aqueous sodium thiosulfate (10 mL). The mixture was acidified with EtOAc (25 mL). And 'recooled to 0 C and simmered. The solid was rinsed with water, then the majority was dissolved in 5 % EtOAc / hexanes and filtered. At this time the filtrate was mostly concentrated to afford crystals. 20% EtOAc / The alkane formed a solid which was slurried by EtOAc (EtOAc) elute elute elute elute elute % yield). M S (ESI apci anion detection) m/z 334 (M-Η)·; NMR (300 MHz, d6-DMSO) (5 2.52 (s, 3H), 6.98 (d, lH), 7.58-7.63 (m, 2H), 7.73 (s, 1H), 7.78 (d, 1H), 8.06 (d, 1H), 10.66 (s, 1H).

Example 106D 2 -Methyl-4-(2-{2-[(2R)-2-methyl-l-ι»Bilobityl]Ethyl 1 benzofuran-5-yl)benzonitrile The product from Example I06C (670 mg, 2.00 mmol), palladium acetate (11) (22 mg '〇.1 〇 millimolar), tri-o-toluene scale (η mg, 〇 2 〇 millimol ), iodized steel (1) (114 mg, 0.60 mmol) and diisopropylamine (28 ml, 20 mmol) dissolved in (phanyl-butyn-, alkynyl-2-methylpyrrolidine) 〇MeCN solution (30 ml, 3_0 mmol) and heat to 55 ° C overnight. Cool the mixture to room temperature 'concentrate under reduced pressure and pass through a short column of silica gel chromatography with EtOAc / Gradient of 1 to 1 〇〇〇/0 of CHAl2 gave the title compound (55% yield) as an orange-brown foam, which was obtained by HPLC [Waters Nova-Pak HR C18 column (40 mm Χίοο mm, 6 μm) Particle size) 'Use 1 〇% to 1 〇〇〇/〇MeCN/〇. 1 〇 in 12 minutes. Gradient of aqueous TFA (15 minutes of execution time), purify one at a flow rate of 70 ml/min] TFA salt: MS (AP) m/z 345 (M+H)+; iHNMR (300 MHz, CD3〇D) 5 1.49 (d, 3H), 1.68-1.82 (m, 1H), 1.99-2.23 (m, 2H), 2.30-2.44 (m, 1H), 2.60 (s, 3H) ), 3.22-3.90 (m, 7H), 6.82 (s, 1H), 7.55-7.87 (m, 6H). Example 107 3-mercapto-4-(2-{2-[(2R)-2-曱) Base-1-p ratio π each bite base] ethyl-stupid 98683.doc -173- 1333489

Schiffon-5-yl) Wax Example 107A 4,-Hydroxy-3'-iodo-2-fyl-1,r-biphenyl-4-carbonitrile 4'-hydroxyl as described in Example 106C -2-Methyl-indole, ι·-biphenyl-4-carbonitrile afforded the title compound (yield: 69%). MS (ESI APCI anion detection) m/z 334 (Μ-Η)· ; 4 NMR (300 MHz, d6-DMSO) 52.27 (s, 3H), 6·96 (d, 1H), 7.23 (dd, 1H) ), 7.37 (d, 1H), 7.65-7.69 (m, 2H), 7.77 (d, 1H), 10.56 (s, 1H).

Example 107B 3-methyl-4-(2-{2-[(2R)-2-methyl-1-tonoxalidyl]ethyl benzofuran-5-yl)benzonitrile according to the example The product from Example i 〇 7A was treated as described in <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; lH NMR (3 megahertz, CD3OD) 5 1.49 (d, 3H), 1.68-1.83 (m, 1H), 1 98.2 24 (m, 2H), 2.29 (s, 3H), 2.29-2.43 (m, 1H)} 3.18-3.90 (m, 7H), 6.79 (s, 1H), 7.24 (dd, 1H), 7.39 (d, 1H), 7.50-7.70 (m, 4H) ° Example 108 M6-Methyl-M2 -[(2R)_2-Methyl small ^ each base] ethyl} small benzofuran-5-yl)benzonitrile and 4·(4-methyl-2]2_[(2R)_2_methyl small _ 咬] ethyl} small benzofuran-5-yl) benzonitrile 98683.doc -174- 1333489

Example 108 A 4匕hydroxy-5′-iodo-2′-mercapto-1,P-biphenyl-4-carbonitrile and 4′-hydroxy-3·-iodo-2^methyl-1,1·- Biphenyl-4-carbonitrile treated 4'-hydroxy-2.methylbiphenyl-4-carbonitrile as described in Example 106C except 2% after neutralization with acid-filled hydrogen The mixture was burned/EtOAc extracted outside the mixture. The 6:6:1 NMR (67% yield) of the title compound of the title compound was obtained as a white crystallite. . MS (ESI APCI anion detection) m/z 334 (MH)·; 1H NMR (3 00 MHz, CDCl3) ά 2.18 (s, 3H), 5.29 (s, 1H), 6.93 (s, 1H), 7.38 ( d, 2H), 7.48 (s, 1H), 7.69 (d, 2H) 〇

Example 108B 4-(6-Methyl-2-{2-[(2R)-2-methyl-1-p ratio: alkaloid] ethyl i-benzophenanth-5-yl) 4-(4-methyl-2-{2-[(2R)-2-methyl-1-pyridinyl]ethyl}_ι_benzop-an-5-yl) The residue was partitioned between CH2C12 and 10% aqueous ammonia, except for the 7.6:1 mixture of the <RTIgt; Residues from the stellate chromatography of the short tube column, using 〇% to 2%

MeOH/CH2Cl2 gradient' then using HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 micron particle size), using a 10% to 100% MeCN/Ο.Ι% aqueous TFA gradient in 12 minutes (15 minutes of 98683.doc -175 - 1333489 line 籣) 'purified at a flow rate of 70 ml/min> to obtain a brown-orange gum of the title compound TFA salt (23% yield) ° MS (ESI APCI m/z 345 (M+H)+ ; 4 NMR (300 MHz, CD3OD) 5 1.48 (d, 3H), 1.67-1.83 (m, 1H), 1.98-2.23 (m, 2H), 2.3-2.42 (m, 1H), 2.31 (s, 3H), 3.19-3.61 (m, 5H), 3.70-3.88 (m, 2H), 6.53 (s, 1H), 7.32 (s, 1H), 7.36 (s, 1H) ), 7.52 (d, 2H), 7.79 (d, 2H). Example 109 4-(7-Mercapto-2-{2-[(2R)-2-indolyl-1-p piroxy]ethyl benzo

Pf-am-5-yl)4 bet example 109 A 41-hydroxy-5'-iodo-3'-methylbiphenyl-4-carbonitrile 4·-hydroxy-3·-methyl-1,1' Biphenyl-4-carbonitrile (875 mg, 4.18 mmol) was dissolved in DMF (20 mL) and treated with yttrium-succinimide (1 </ RTI> <RTIgt; The solution was stirred at room temperature for four days. The mixture was then stirred with tetramethylguanidine (1 ml) for 10 minutes, poured into a mixture of aqueous NajO3 and NazCO3 and was then taken up to pH <RTIgt; The gum separated from the two phase mixture was dissolved in EtOAc and added to the rapidly mixed liquid and ether mixture. The organic phase is separated, filtered, mixed with the original ether, concentrated, and passed through a silica gel chromatography using 50% to 1 Torr. The title compound (17% yield) of MS (ESI APCI anion) m/z 334 (M-Η)'; 丨HNMR (300 MHz, CDC13) 5 2.38 (s, 3H), 7·26 (s, 1Η), 7.33 (d, 1Η), 7.60 (d, 2Η), 7.66-7.74 (m, 3Η).

Example 109B 98683.doc -176- 1333489 4_(7-methyl-2-{2-[(2R)-2-fyl-!.,Bihabite]Ethyl}1 benzopyran-5- The base benzonitrile was treated as described in Example 1G6D to give the title compound from Example (10). The title compound (44% yield) was obtained as a brown-yellow gum, by [Waters Nova_Pak HR c丨8 column (4 〇mmχι 〇〇 mm, 6 μm particle size), use 10% to 1〇〇0/〇MeCN/〇1〇/〇Water-bound eight gradient (15 minutes of execution time) to 7〇 in 12 minutes Flow rate in ml/min] Purified one 4 wound 'to get TFA salt. MS (ESI APCI) m/z 345 (M+H)+; 4 NMR φ (300 MHz, CD3OD) (5 1.49 (s, 3H), 1.68-1.83 (m, 1H), 1.99-2.23 (m, 2H), 2.30-2.43 (m, 1H), 2.57 (s, 3H), 3.21-3.64 (m, 5H), 3.71-3.91 (m, 2H), 6.79 (s, 1H), 7.41 (m, 1H) , 7.68 (d, 1H), 7.75-7.84 (m, 4H) » Example 110 4-(7-Fluoro-2-{2-[(2R)-2-methylpyrrolidinyl]ethyl benzene And furan-5-yl)benzonitrile Example 110A #3'·Fluoro-4·-hydroxy-5,-iodo-1,1'-biphenyl-4-carbonitrile 3'-fluoro-4'-hydroxyl linkage Phenyl-4-carbonitrile (32 mg, 丨5 mmol) was dissolved in DMF (7 mL) and treated with N-iodosuccinimide (36 mg, 16 mmol). The solution was stirred overnight at room temperature. The mixture was poured into a mixture of aqueous Na2S03 and Na.sub.2CO.sub.3, and taken to pH 9 s with aqueous dihydrogen phosphate and extracted with diethyl ether. The combined organic phases were dried (Na2SO4) and Concentration gave the title compound (1 </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> MS (ESI APCI anion detection) m/z 338 (M-Η)-. 98683.doc •177· 1333489

Example 11 OB 4-(7-fluoro-2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-l-benzofuran-5-yl) Description in 106D 'Processed the product from Example 110A, except that after heating the solution overnight, it was heated to 80 ° C for an additional 8 hours. The reaction mixture was cooled to room temperature and passed through a short-column gel chromatography using hexanes / CH.sub.2 C.sub.2, followed by 0 to 2% MeOH/CH.sub.2Cl. Concentrate the appropriate fractions and use a gradient of 10% to 100% MeCN/0.1% aqueous TFA in 8 minutes by HPLC [Waters Nova-Pak HR φ Cl8 column (25 mm Χ 100 mm, 6 μm particle size)). (Execution time of 10 minutes), purified at a flow rate of 40 ml/min to give the title compound (2% yield). MS (ESI) m/z 349 (M+H)+; 4 NMR (300 MHz, CD3 〇D) (? 1.18 (d, 3H), 1.39-1.53 (m, 1H), 1.74-1.86 (m, 2H), 1.95-2.09 (m, 1H), 2.26-2.38 (m, 1H), 2.44-2.63 (m, 2H), 2.98-3.36 (m, 4H), 6.72 (d, 1H), 7.37 (dd, 1H), 7.65 (d, 1H), 7.77-7.87 (m, 4H). Example 111 2-fluoro-4-(2-{2-[(2R)-2-indolyl-indole-p-pyrrolidine) Ethyl bromide

Example 5A 3-fluoro-41-methoxybiphenyl-4-enonitrile 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) The mixture was added to 4_bromo-2-fluoroindol (5 gram '25·0 mmol) and tetravalent (triphenylphosphine) palladium (578 mg' 在 in stupid (5 〇 ml) · 50 millimoles) 98683.doc • 178· 1333489 in solution. The resulting mixture was treated with a 2.01 aqueous solution of EtOAc (25 mL, 5 EtOAc) and briefly warmed to reflux and then cooled to room temperature overnight. And treated with 6.0 Μ aqueous NaOH. The liquid phase was separated and extracted with diethyl ether. The original organic phase was first filtered through diatomaceous earth, and then the ether-based rinse was filtered. The collection flask was replaced and washed with Et〇Ae. Solids over celite. Concentrate the ether broth and EtOAc EtOAc EtOAc (EtOAc) 5 3-82 (s, 3H), 7.07 (d, 2H), 7.72 (dd, 1H), 7.79 (d, 2H), 7.85 (dd, 1H), 7.95 (dd, 1H).

Example 11 IB 3 - chaotic - 4' - via base phenyl group - 4 month paste The product from Example 1 i丨a was treated as described in Example 106B, except for extraction with EtOAc. The title compound (100% yield) as a brown powder. MS (ESI APCI anion detection) m/z 212 (M-Η)· ; iHNMRQOO megahertz, CDC13)5 3.82 (bs, 1H), 6.94 (£ΐ, 2Η), 7·37 ((1ά,1Η), 7.4Ν7.49(ηι,3Η), 7.63(ίί£ΐ,1Η).

Example 111C 3-Fluoro-4'-hydroxy-3'-iodo-1,1'.biphenyl-4-carbonitrile The product from Example 111B was treated as described in Example 106C except The yeast and water were washed with ice-cold-filtered solids and dried under reduced pressure to give the title compound (86% yield). MS (ESI Anion Detection) m/z 338 (MH)·; iHNMRQOO megahertz, CDC13/CD30D)5 3·53 (bs,1H), 98683.doc -179· 1333489 6.96 (d, 1H), 7.34-7.49 (m, 3H), 7.65 (dd, 1H), 7.94 (d, 1H) °

Example m D 2-Fluoro-4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethylidene benzofuran-5-yl)indoleonitrile as described in Example 106D, The product from Example i丨丨c was treated except that the solution was heated to 50 ° C overnight and then at 8 ° C for 8 hours. The reaction mixture was cooled to room temperature&apos; and passed through a short column of silica gel chromatography using EtOAc to &lt Concentration of the appropriate fractions, which were then purified by chromatography on a short column of EtOAc (yield: 1% EtOAc/EtOAc, EtOAc) 28% production). MS (ESI APCI) m/z 349 (M+H)+ ; ^NMR (300 MHz Hz 'CD3〇D)6 1.40 (d,3H)' 1.60-1.77 (m, 1H), [1.97 (s)] , 1.97-2.11 (m, 2H), 2.20-2.36 (m, 1H), 2.99-3.10 (m, 1H), 3.16-3.76 (m, 6H), 6.79 (s, 1H), 7.58 (d, 1H) , 7.62 (dd, 1H), 7.64-7.70 (m, 2H), 7.81 (dd, 1H), 7.90 (d, 1H). Example 112 3-(2-{2-[(2R)-2-methyl-i-pyrrolidinyl]ethylidene·benzofuran_5_

Benzobenzonitrile Example 112A 4-&gt; Oxan-2 - The 4-bromophenol was treated as described in Example 106C except that after neutralizing the mixture, it was taken to 2% EtOAc/hexanes (250 The solution was divided between cc) and brine (5 liters), and the liquid phase was separated and re-extracted until the product of 98683.doc-180·1333489 was almost removed (TLC). The combined organic phases were washed with brine, dried (Na.sub.4) and concentrated to give (yield: A portion was purified by chromatography on Shishi gum using a gradient of 25 to 8 % Ch 2 Ci 2 / hexane. 1H NMR (300 megahertz, d6-DMSO) 5 6.83 (d, 1H), 7.36 (dd, 1H), 7.79 (d, 1H), 10.59 (s, 1H).

Example 112B 2-(5-Bromo-1-benzofuran-2-yl)ethanol The product from Example 112 (26.9 g, 90% pure, 80 m.m.). Alcohol (6.05 ml, 79.9 mmol) and copper (1) (715 g, 50.0 mmol) were suspended in a mixture of pyridine (4 mL) and methyl-2-pyrrolidone (16 mL) and heated to 7 〇 ° C overnight, then at 100 ° c for 3 5 hours. The mixture was cooled to room temperature, diluted with ether and filtered. The filtrate was diluted with additional diethyl ether and washed successively with 5% aqueous ammonia, &lt It was dehydrated (NajO4), concentrated, and concentrated again from Et〇Ac. A 2:1 hexane/CHaCh was added to the resulting syrup, and the mixture was cooled to -78 C^. Collect by filtration and rinse with 4:1 hexane / CH2C12 then rinse with hexane (8% yield). NMR (3 〇〇 megahertz, d6-DMSO) δ 2.92 (t, 2H), 3.75 (dt, 2H), 4.82 (t, 1H), 6.63 (S, 1H), 7.35 (dd, 1H), 7.48 ( d, 1H), 7.75 (d3 1H) 〇

Example 112C 3-[2-(2-Hydroxyethyldipyridin- benzofuran-5-yl)benzonitrile The product from Example 112B (193 mg, 〇8 〇 mM), 3 cyanophenylboronic acid (147 mg, i.oo millimolar) and tetravalent (triphenylphosphine) palladium (35 mg, 98683.doc • 181- 1333489 〇'〇30 mmol) suspended in dioxane (3 ml) and then Treated with 〇M aqueous 2C 〇 3 (2.1 liter, 2.13⁄4 mol). The mixture was heated to 9 Torr. 〇 3.5 hours, then cooled to room temperature, dissolved between Et 〇 Ac and water, The title compound (82% yield) was obtained as a brown syrup from EtOAc/EtOAc. iH NMR (300 megahertz, d6-DMSO) ^2.95 (t, 2H), 3.78 (dt, 2H), 4.83 (t, 1H), 6.70 (S} 1H), 7-59-7.61 (m, 2H) , 7.66 (dd, 1H), 7.80 (ddd, 1H), 7.91 (dd, old), 8.04 (ddd, 1H), 8_15 (dd, 1H).

Example 112D 2_[5-(3-Cyanophenyl)-1-benzofuran-2-yl]ethylmethanesulfonate The product from Example 112C (170 mg, 0.65 mmol) and triethylamine. (1 〇〇 microliter, 0.72 mmol) dissolved in CHKh (3 mL) and cooled to 0 °C. The solution was treated with methanesulfonate (55 μl '0.71 mmol) and allowed to slowly warm to room temperature after 1 min. Add more sulfonate (10 μl, 0.13 mmol) and triethylamine (10 μl, 〇.〇72 mmol) to stir the mixture until the reaction is almost complete, then continue with water Rinse with brine, dehydrate (N^SO4), concentrate, and use in the next step without further purification.

Example 112E 3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl bromide-benzofuran·5_ base bet on (2R)-2·methyl p ratio ° Approximately 0.2 MMeCN solution (16 ml, 毫. 3 mmol) of each bite was stirred from the crude product of Example U2D, (2R)_2_methyl 98683.doc • 182 - 1333489 pyrroleidine mono-( L)-tartrate (306 mg, 1.3 mmol) and Cs2C〇3 (652 mg, 2.0 mmol) Heat the mixture to 4: overnight. Add more CkCO3 (326 mg, h 〇mmol) and acetonitrile (〇5 ml), and the reaction was stirred at 40 ° for 4 days. The mixture was cooled to room temperature and diluted with CHWh, filtered and concentrated. The title compound (28% yield) was obtained as an orange-yellow-brown gel. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -1.54 (m, 1H), 1.75-1.87 (m, 2H), φ 1.96-2.09 (m, 1H), 2.27-2.39 (m, 1H), 2.46-2.63 (m, 2H), 2-95-3.15 (m, 2H), 3.20-3.35 (m, 2H), 6.63 (s, lH), 7-49-7.52 (m, 2H), 7.62 (dd, 1H), 7.67 (ddd, 1H), 7.78 (dd , iH), 7.90 (ddd, 1H), 7.98 (dd, 1H). Example 113 (211)-1-{2-[5-(4-fluorophenyl)_1-benzofuran-2-yl]ethyl b-2- Pyryrrolidine Example 113A · 2-[5-(4-Fluorophenyl)-benzofuran-2-yl]•ethanol The 4-fluorophenylboronic acid was treated as described in Example 112C to afford white crystallite solid. Title compound (79% yield). 4 NMR (3 00 MHz^*d6-DMSO) δ 2.94 (t, 2H), 3.77 (dt, 2H), 4.84 (t, 1H), 6.67 (s, 1H) , 7.28 (dd, 2H), 7.48 (dd, 1H), 7.56 (d, 1H), 7.70 (dd, 2H), 7.78 (d, 1H).

Example 113B (2R)-l-{2-[5-(4-Fluorophenyl)-1-benzopyran-2-yl]ethyl b-2-methyl 98683.doc •183· 1333489 Pyrrole The product from Example 113A was worked up to give the title compound (yield: EtOAc). WNMRGOO megahertz, CD3OD) &lt;5 1.17 (d,3H), 1.38-1.52 (m, 1H), 1.72-1.86 (m, 2H), 1.94-2.08 (m, 1H), 2.23-2.34 (m, 1H) ), 2.41-2.59 (m, 2H), 2.92-3.13 (m, 2H), 3.19-3.3 (m} 2H), 6.59 (s, 1H), 7.15 (m, 2H), 7.43 (dd, 1H), 7.46 (d, 1H), 7.61 (dd, 2H), 7.68 (d, 1H). Example 114 (2R)-l-{2-[5-(3,4-Dichlorophenyl)-1- benzofuran-2-yl]ethyl b 2-decylpyrrolidinide according to Examples 112C, 112D And in the description of 112E, the treatment of 3,4·dichlorophenylboronic acid 'except in the procedure of Example 112E, the reaction was carried out at 6 〇t overnight' and after the ether extract was filtered through diatomaceous earth, the condensed Liquid, and by HPLC [Waters Nova-Pak HR C18 column (40 mm χιοο mm, 6 μm particle size), a gradient of 10% to ι〇〇0/〇MeCN/0.1% aqueous TFA was used in 12 minutes ( The 15 min execution time) was semi-purified at a flow rate of 70 ml/min to give the title compound (62% yield) of TFA salt. MS (ESI APCI) m/z 374/376/378 (M+H)+ ; 4 NMR (300 MHz, CD3OD) (5 1.49 (d, 3H), 1.68-1.82 (m, 1H), 1.99-2.23 (m, 2H), 2.30-2.43 (m, 1H), 3.20-3.63 (m, 5H), 3.70-3.90 (m, 2H), 6.80 (s, 1H), 7.53-7.59 (m, 4H), 7.78 -7.82 (m, 2H). Example 11 5 98683.doc • 184-(2R)-2-methyl-l-{2-[5-(2-methylphenyl)·1-benzofuran-2-yl Ethyl}

Pyrrolidine Example 115A (2R)-l-[2-(5-indol-1-Benzo-p-pentan-2-yl)ethyl]_2-methyl glutinose bite 4-bromo-2-iodine Phenol (2.99 g, 90% pure '9 mmol), palladium acetate (11) (112 mg, 0.50 mmol), triphenylphosphine (262 mg, 1. 〇 millimol), copper iodide (1 (571 mg, 3.0 mmol) and diisopropylamine (14 ml, 1 mmol) dissolved in (R)-buty-3-ynyl-2-methylpyrrolidine 0.09 M MeCN solution (120 ml, 10·8 mmol) and stirred at room temperature for three days and then at 80 ° C overnight. The reaction mixture was cooled to room temperature, concentrated, and passed through a short-column gel chromatography using 2:1 hexane/CH.sub.2 C.sub.2, followed by a Meon/CHaCI2 gradient of 〇 to 〇/〇. The appropriate fractions were concentrated and the residue was extracted with EtOAc. The extract was concentrated and partitioned between CH.sub.2C.sub.sub.sub.sub.sub.sub.sub.sub.sub.

Example 115B (2R)-2-methyl-1-{2·[5·(2-indolyl)-1-benzofuran-2-yl]ethyl} 11°° Approximately 330 microliters of a solution of the product from Example n5A (650 mg '2.1 mmol) and tetravalent (triphenylphosphine) palladium (125 mg, 0.11 mmol) in benzene (62 mL) Add to a mixture of (2 tolyl) shed acid (about 24 mg 'about 〇 · ΐ 8 mmol) in ethanol (15 〇 microliter). The mixture was treated with 2. 〇 μ of aqueous NazCCh (200 μL, 04 mmol) and the reaction vial was sealed and placed on a heater-agitator unit and heated to 75 乞 4 days. 98683.doc •185· 1333489 Cool the mixture to room temperature, dilute 'transition' with 1:1 MeOH/DMSO (1 ml) and use 1 mm in 8 minutes by mm X 100 mm, 6 μm particle size) A gradient of 〇% to 100% MeCN/0.1% aqueous TFA (10 mins of execution time) was purified at a flow rate of 4 〇m/min to give the title compound. Ms (APCI) m/z 320 (M+H)+. Example 116 (2R)-2-Methyl-i_{2-[5-(3-indolyl)-1•benzofuran-2-yl]ethyl}p-Bilo bite as described in Example 115B Treatment of (3-tolyl)boronic acid gave the title compound. MS (APCI) m/z 320 (M+H)+. Example 117 (2R)-2-methyl-i-{2-[5-(4-tolyl)-1-benzofuran-2-yl]ethyl} 匕 π each bite according to Example 11 Description, treatment of (4-indolyl)boronic acid to give the title compound. MS (APCI) m/z 320 (Μ+Η)+. EXAMPLES 8 4-(2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-1- benzofuran-5-yl)benzoic acid methyl ester as in Example 11 5Β The treatment of (4-methoxycarbonylphenyl)boronic acid' gave the title compound. MS (APCI) m/z 364 (Μ+Η)+. Example 119 (2R)-i_{2-[5-(2-methoxyphenyl)-bromo-p-N-2-yl]ethyl}-2-methylpyrrolidine 98683.doc • 186· Treatment of (2-methoxyphenyl)boronic acid as described in Example 115B gave the title compound. MS (ESI) m/z 336 (M+H) + &lt;&quot;&&&&&&&&&&&&&&&&&&&&&& 2-Mercaptopyrrolidine (3-methoxyphenyl)boronic acid was treated as described in Example 115B to give the title compound. MS (APCI) m/z 336 (M+H)+. Example 121 (2RH-{2-[5-(4-indoxyphenyl)-1- benzofuran-2-yl]ethyl}-2-mercaptopyridyl B each bite as described in Example 1 5B (4-Methoxyphenyl)boronic acid afforded the title compound: MS (ESI) m/z 364 (M+H) +. </ RTI> </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </RTI> <RTIgt; m/z 324 (M+H)+. Example 123 (2R)-l-{2-[5-(2·Phenylphenyl)-1-benzofuran-2-yl]ethyl}-2-indole The base p ratio of 11 bites was treated as described in Example 1 15B, and the title compound was obtained as the title compound: MS (APCI) m/z 340 (M+H) + » Example 124 (2R) -l-{2-[5-(3-Chlorophenyl)-1-benzopyran-2-yl]ethyl}_2-methyl 98683.doc -187- 1333489 Pyrrolidine according to Example 115B Description, treatment of (3-chlorophenyl)boronic acid to give the title compound: MS (APCI) m/z 340/342 (M+H) +. Example 125 l-{2-[5-(4-Phenylphenyl) - benzofuran-2-yl]-ethyl}-2.methylpyrrole bite as described in Example 1 5, (4- Phenyl) boronic acid, to give the title compound .MS (ESI) m / z 340/342 (Μ + Η) +.

Example 126 (2R)-2-Methyl-1-(2-{5-[3-(trifluoromethyl)phenyl]-1-benzofuran-2.yl}ethyl)&gt; The bite was treated as described in Example 115, (3-trifluorophenylphenyl)boronic acid, and the title compound was obtained. MS (APCI) m/z 374 (Μ+Η)+. Example 127 UR)-2-methyl-indole-(2-{5-[4-(trifluoromethyl)phenyl]_ι· benzofuran-2-yl}ethyl)ρ ratio ° °

Treatment of (4-trifluoromethylphenyl)boronic acid as described in Example 115, gave the title compound. MS (APCI) m/z 3 74 (Μ+Η)+. Example 128 (2R)-2-Methyl_ι_(2-{5_[3·(Trifluoromethoxy)phenyl]"_benzofuran-2-yl}ethyl)pyrene The treatment of (3-trifluoromethoxyphenyl) succinic acid is described in the title compound (m.p.). MS (APCI) m/z 390 (Μ+Η)+. Example 129 (2R)-2-methyl·ΐ -(2_ρ_[4·(Trifluoromethoxy)phenyl hydrazide benzofuran 98683.doc -188 - 1333489 -2-yl}ethyl pyloric bite as described in Example 115B, treatment (4- <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; - 1 -benzofuran-2-yl]ethyl}-2. Methylpyrobitine The (3,4-dimethylphenyl)boronic acid was treated as described in Example 115, to give the title compound. m/z 334 (Μ+Η)+. Example 131 (2R)-l-{2-[5-(3,5-diphenyl)-1-benzofuran-2-yl]ethyl </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; +. Example 132 UP〇_l-{2-[5-(3,5-Diphenyl)-1-benzo (2,5-Dimethylphenyl)boronic acid was treated as described in Example 115B to give the title compound. MS (APCI) m/z 334 ( M+H)+. Example 133 [(2 {2-[(2R)-2-methyl-1-p 〇 咬 ])] ethyl}-1 _benzopyrene _5·yl) phenyl A solution of the product from Example 115 (350 mg, 1.1 mmol) (1.2 mL) in benzene (3.6 mL) was added to palladium acetate (11) (11 mg, 〇. 〇 5 mM) a mixture of aurant-2-yl-dicyclohexylphosphine (28 mg, 〇.08 mmol) 98683.doc -189-1333489 ^ followed by 4-(hydroxyl in ethanol (500 μl) The reaction mixture was treated with methyl phenylboronic acid (87 mg, s. 57 mmol) and then treated with 2M water Na.sub.2CO.sub.3 (50 g.). The mixture was thoroughly sifted overnight. Microliters), and the mixture was mixed for 4 days, diluted by filtration '' and passed through a short column of Shih-Xi, using a 〇 to 2_Me〇 〇 〇Ac gradient' by HPLC [Waters Nova_Pak HR C18 column ( 25 mm xioo milli, 6 micron particle size), at 8 Use a gradient of 1〇% to 1〇〇〇/〇MeCN/0· 1 /〇 aqueous TFA in the clock (execution time of 0 minutes), purify at a flow rate of 4〇ml/min, and then pass through the short tube column again. The title compound (12% yield) was obtained using EtOAc/EtOAc. MS (Ε§ι m/z 336 (M+H)+ ·' towel NMR (300 MHz, CD3〇d) occupies 21 (d, 3H), 1.42-1.58 (m, 1H), 1.77-1.91 ( m, 2H), 1.99-2.13 (m, 1H), 2.35-2.77 (m, 3H), 2.97-3.18 (m, 2H), 3.2-3.4 (m, 2H), 4.64 (s, 2H), 6.61 ( s, 1H), 7.42 (d, 2H), 7.45-7.48 (m, 2H), 7.60 (d, 2H), 7.72 (dd, 1H). Example 134 3-(2-{2_[(2R)-2 -methylpyrrolidinyl]ethylidene benzofuran _5_ yl)p bite

Treatment of 3-0,3,2-dioxaboran-2-yl)pyridine as described in Example 133 gave the title compound (1% yield). MS (ESI APCI) m/z 307 (M+H)+; lH NMR (300 Hz, CD3OD) &lt;5 1.20 (d, 3H), 1.41-1.56 (m, 1H), 1.76-1.89 (m, 2H), 1.97-2.12 (m,1H), 2.32-2.70 (m,3H), 2.98-3.19 (m,2H), 3.2-3.4 (m,2H),6.66 (d,1H),7.47-7.57 ( m, 3H), 7.80 (dd, 98683.doc • 190- 1333489 1H)' 8.10 (ddd, 1H), 8.49 (m, 1H), 8.81 (m, 1H). Example 135 (2R)-l-(2-{5-[2-(4-Fluorophenyl)vinyl]-1-benzofuran-2-yl}ethyl)-2-methyl p Treatment of the trans-2-(4-phenylphenyl)ethenyl acid was carried out as described in Example 133 to give the title compound (4% yield). MS (ESI APCI) m/z 350 (M+H) ten.

Example 136 l-[3-(2-{2-[(2R)-2-Mercapto-1-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)phenyl]etamine

Example 136A 1-(4·-Hydroxybiphenyl-3-yl)ethanone was mixed with 4-iodophenol (5.39 g, 24.5 mmol) in N,N-dimethylformamide (15 mL). 3-Ethyl stearylboronic acid (4.42 g, 26.95 mmol) was treated with 1.0 mL aqueous Na2CO3 (75 mL) and palladium acetate (m. The suspension was heated to 55 ° C for 1 hour and then returned to room temperature. CHzCl (100 ml) was added to the mixture, which was then filtered. The liquid layer of the filtrate was extracted with CHKh, and the mixed organic phase was washed successively with a pH 6 scale acid buffer solution and brine, then dehydrated (Na2S〇4), concentrated, and passed through a gelatin chromatography to utilize 33 to 1%. The hexane/CH2C12 gradient was followed by a gradient of 0 to 3% EtOAc/EtOAc. The impure fractions were combined, concentrated, and chromatographed twice to give the title compound as an oil which crystallised as a white solid (yield about 95% yield) upon standing. MS (ESI APCI anion detection) m/z 211 (MH)· ; lH NMR (300 MHz, CDC13) 98683.doc 191 - 1333489 (5 2.65 (S, 3H), 6.97 (d, 2H), 7.47-7.53 (m, 3H), 7.74 (ddd, 1H), 7.88 (ddd, 1H), 8.13 (dd, 1H).

Example 136B

1-(4'-Pyryl-3'-Moth-1,1'-biphenyl-3-yl)ethanone The product from Example 136A (5.76 g '27 mmol) was suspended in concentrated aqueous ammonia. (400 ml) and treated with a solution of potassium iodide (23 g, 140 mmol) and iodine (7.22 g, 28.5 mmol) in water (100 ml). Since the reaction was not completed, the mixture was treated a second time with a solution of an iodine clock (158 g, 95 mmol) and iodine (4.83 g &apos; 19 mmol) in water (50 ml). After 1 hour, ammonia was removed on the rotary evaporator under reduced pressure. The mixture was extracted with EtOAc, and the combined organic phases were washed successively with a potassium silicate buffer solution of pH 6 and brine, then dehydrated (Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub. The title compound (21% yield) was obtained as a brown powder. MS (ESI APCI anion detection) m/z 337 (MH)· ; 4 NMR (300 dead Hz, CDC13) (J2.65 (s, 3H), 5.37 (bs, 1H), 7.08 (d, 1H), 7.48 -7.55 (m, 2H), 7.71 (ddd, 1H), 7.88-7.93 (m, 2H), 8.09 (dd, 1H) 〇

Example 136C I-[3-(2-{2-[(2R)-2.methyl-1-pyrrolidinyl]ethyl}-l-benzofuran•5-yl)phenyl]ethyl hydrazine Product from Example 136B (1.15 g, 3.40 mmol), palladium acetate (yield) (38 mg, 0.17 mmol), biphenyl-2-yl-dicyclohexylphosphine (119 mg, 0.34 mmol) , diisopropylamine (4.8 ml, 34 mmol) and copper iodide 98683.doc -192· 1333489 (1) (76 mg, 0-40 mmol) suspended in (R)·Budin·3_alkynyl_ 2_Methylpyrrole bite in a solution of 0.09 MMeCN (45 mL '4.0 mmol). Add hydrazine, hydrazine-dimethylformamide (10 ml) and heat the mixture to 45 ° C overnight, cooled to room temperature, in CHsCb (1 mL) and 5. Dissolve between / 〇 ammonia (100 ml), usually gradually, but with 5% ammonia, filter and concentrate. The residue was dissolved in CHzCl2 and washed successively with water and brine, dried (Nae.sub.4), concentrated, and purified by silica gel chromatography using EtOAc/EtOAc. The title compound (30% yield) was obtained as a dark brown gum. MS (APCI) m/z 348 (M+H)+; iH NMR (300 MHz, CD3〇D) 5 j 17 (d,3H), 1.38-1.52 (m, 1H), 1.73-1.86 (m, 2H), 1.94-2.07 (m, 1H), 2.23-2.34 (m, 1H), 2.40-2.58 (m, 2H), 2.67 (s, 3H), 2.95-3.14 (m, 2H), 3.19-3.32 ( m, 2H), 6.62 (s, 1H), 7.49-7.52 (m, 2H), 7.57 (dd, 1H), 7.78 (dd, 1H), 7.88 (ddd, 1H), 7.96 (ddd, 1H), 8.22 (dd, 1H). Example 137 l-[3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethylidenebenzofuran-5-yl)phenyl]ethanol was argonized with boron Sodium treatment The product from Example 136C (46 mg, 〇·12 mmol) was concentrated in ethanol (2 mL) and tetrahydrofuran (5 mL) and passed through a short column of silica. Gradient to 1% MeOH / EtOAc / EtOAc - EtOAc - EtOAc (EtOAc) 1333489 6 ° ° C for 3 hours, treated with more 〇·1 Μ aqueous hydrogen acid (0.05 ml), heated to 60 ° C for 1 hour, concentrated, and passed through a short column of silica gel chromatography, using 2 to 10 % 2 Μ NH3 gradient (in MeOH / CH.sub.2Cl.sub.sssssssssssssssssssssssssssss 1.4-1.54 (m, 1H), 1.49 (d, 3H), 1.73-1.86 (m, 2H), 1.95-2.08 (m, 1H), 2.24-2.36 (m, 1H), 2.43-2.60 (m, 2H ), 2.93-3.14 (m, 2H), 3.19-3.33 (m, 2H), 4.89 (q, 1H), 6.59 (s, 1H), 7.32 (ddd, 1H) , 7.39 (dd, 1H), 7.45-7.47 (m, 2H), 7.49 (ddd, 1H), 7.62 (m, 1H), 7.71 (dd, 1H). Example 138 2-[3-(2-{2 -[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}_1·benzofuran-5-yl)phenyl]-2-propanol The product from Example 136C (87 mg, 0.25) Dissolved in tetrahydrofuran (5 ml), treated with diethyl bromomethylmagnesium bromide (0.3 ml, 0.9 mmol), stirred overnight, and quenched with 0.5 hr of aqueous dibasic hydrogen phosphate. And diluted with EtOAc and a small amount of CH2C12. The resulting emulsion was ultrasonically shaken, and the liquid phase was separated and extracted with EtOAc. The mixed organic phase was washed successively with 0.5 Μ aqueous dipotassium hydrogen phosphate and brine, and dehydrated (Na2S04) The title compound (about 33% yield) was obtained as an orange resin eluted from EtOAc EtOAc EtOAc (EtOAc) 4 NMR (3 00 megahertz, CD30D) &lt;5 1.20 (d,3H), 1.42-1.58 (m,1H), 1.58 (s, 6H), 1.76-1.90 (m, 2H), 1.96-2.12 (m , 1H), 2.3-2.7 (m, 3H), 2.97-3.13 (m, 2H), 3.22-3.4 (m, 2H), 6.62 (s, 1H), 7 .38 (dd, 98683.doc • 194- 1333489 1H), 7.40-7.46 (m, 2H), 7.46-7.48 (m, 2H), 7.72 (ddj iH) 7.76 (dd, 1H). Example 139 l-[3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl brom]-furan-5-yl)phenyl]ethanone The product from Example 136C (240 mg, 毫. 5 mmol) and hydroxylamine hydrochloride (139 mg, 2.00 mmol) were dissolved in methanol (2 mL) and Na NaCO3 (318 mg, 3.0 mM) )deal with. The suspension was stirred at room temperature and then heated to 70 C for 3 days. The mixture was cooled to room temperature and filtered, and the solid was washed with 50% MeOH / CHf. The filtrate was concentrated and then partitioned between water and MeOH/CHWh; some of the pure product remained undissolved and separated. The organic phase was concentrated, dissolved in a small amount of methanol, and then sown with the product collected. After the material was crystallized, the harvested product was washed twice with methanol and allowed to dehydrate to give the title compound (49% yield) as a white crystallite. lHNMR (300 MHz, CDCl3) 5l.l8 (d, 3H), 1.4-2.1 (m, 4H), 2.2-2.6 (m, 3H), 2.34 (s, 3H) 3.00-3.12 (m, 2H), 3.20-3.34 (m, 2H), 6.49 (s, 1H), 7.41-7.48 (m, 3H), 7.56-7.63 (m, 2H), 7.68 (dd, 1H), 7.7〇 (bs, IH), 7.88 (dd, 1H). Example 140 l-[3-(2-{2-[(2R)-2-Methyl-i-pyrrolidinyl]ethyl bj-benzofuran-5-yl)phenyl]ethanone oxime 曱Base Moon Defects The hydrazine-hydroxylamine was treated as described in Example 139, except that after completion of the reaction, 'WCH2C12 was diluted, filtered, concentrated, and passed through a short tube 98683.doc-195-column chromatography. The title compound (53% yield) was obtained as a brown gum. MS (ESI APCI) m/z 377 (M+H)+ ; NMR (300 MHz, CD3OD) 5 1·17 (d, 3H), 1-41-1.51 (m, 1H), 1.75-1.84 ( m, 2H), 1.96-2.05 (m, 1H)S 2.26 (s, 3H), 2.27-2.33 (m, 1H), 2.44-2.59 (m5 2H), 2.96- 3.11 (m, 2H), 3.20-3.3 (m, 2H), 3.98 (s, 3H), 6.60 (s, 1H), 7.45 (dd, 1H), 7.52-7.54 (m, 2H), 7.58-7.65 (m, 2H), 7.74 (s, 1H ), 7.89 (dd, 1H) 〇 Example 141 l-[3-(2-{2-[(2R)-2-methyl- Ι-p piroxime]ethyl}-i-benzopyran -5-yl)phenyl]ethanone oxime-ethyl yt-yield y-ethylhydroxylamine as described in Example 139. MS (ESI APCI) m/z 391 (M+H)+; hNMRpoO megahertz 'CD3OD)5 1.17 (d,3H), 1.33 (t, 3H), 1.41-1.51 (m, 1H), 1.75-1.85 ( m, 2H), 1.97-2.06 (m, 1H), 2.27 (s, 3H), 2.27-2.34 (m, 1H), 2.45-2.60 (m, 2H), 2.96- 3.12 (m&gt; 2H), 3.20- 3.3 (m, 2H), 4.23 (q, 2H), 6.60 (s, 1H), 7.44 (dd, 1H), 7.48 (s, 2H), 7.58-7.64 (m, 2H), 7.73 (s, 1H) , 7.89 (dd, 1H). Example 142 l-[3-(2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl}-i-benzofuran-5-yl)phenyl]ethanone oxime- (Third-Butyl) Monthly Deficit The indole-tert-butylhydroxylamine was treated as described in Example 139 to give the title compound (56% yield) as an orange gum. MS (ESI APCI) m/z 419 98683.doc -196- 13314^ (M+H)+ ; 4 NMR (300 MHz ' CD3〇D) J 1.17 (d, 3H), 1.37 (s, 9H), 1.41-1.51 (m,1H),1.75-1.84 (m,2H), 1.97-2.06 (m, 1H), 2.24 (s, 3H), 2.27-2.34 (m, 1H), 2.45-2.59 (m, 2H) ), 2.96-3.11 (m, 2H), 3.20-3.3 (m, 2H), 6.61 (s, 1H), 7.43 (dd, 1H), 7.47 (s, 2H), 7.57-7.64 (m, 2H), 7.72 (s, 1H), 7.89 (dd, 1H). Example 143 3-(2-{2-[(2R)-2-methyl-1-bambolanyl]ethyl}-i-benzofuran-5_

Ethyl benzoate Example 143A

4'-Phosphyl-1,1·-biphenyl-3-deoxalate ethyl ester was treated as described in Example 136, for the treatment of 4-indole and 3-ethoxylated phenyl-acids. The reaction was carried out overnight, and the title compound was obtained as white powder (yield: 71% yield) eluting with EtOAc EtOAc EtOAc. 1h NMR (300 megahertz, d6-DMSO) (5 1.34 (t, 3H), 4.34 (q, 2H), 6.89 (d, 2H), 7.50-7.59 (m, 3H), 7.83-7.89 (m, 2H), 8.11 (dd, 1H), 9.62 (s, 1H).

Example 143B 4'-Hydroxy-3,-iodo--phenylidene-3-carboxylate Ethyl ester The product from Example 143A (7 71 g, 31·8 mmol) was dissolved in hydrazine, hydrazine In a solution of amylamine (30 ml), diluted with ammonium water (32 ml), and simultaneously with moth (27.72 g, 167 mmol) and iodine (8.48 g) in water (1 ml) '33.4 millimolars of solution treatment. After stirring the mixture for several hours 98683.doc -197 - 1333489, the ammonia was removed under reduced pressure on a rotary evaporator. Diluted with aqueous hydrogen acid and residual ammonia to pH 7, diluted with EtOAc (200 mL), usually gradually, dehydrated (Na2S04), concentrated, and chromatographed on silica gel, using 33 to 100% CH2C12/ The title compound (3 7% yield) was obtained as white crystals. 1H NMR (3 00 megahertz, d6-DMSO) δ 1.35 (t, 3H), 4.35 (q, 2H), 7.00 (d, 1H), 7.53-7.60 (m, 2H), 7.84-7.91 (m, 2H) , 7.97 (d, 1H), 8.08 (dd, 1H), 10.55 (bs, 1H).

Example 143C ethyl 3-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-l-benzofuran-5-yl)benzoate as in Example 136C The title compound (52% yield) was obtained as a viscous dark brown oil. MS (ESI APCI) m/z 378 (M+H) + &lt;&quot;&gt;&gt;&gt; 144 3-(2-{2-[(2R)-2-mercapto-1-pyrrolidinyl]ethyl}-l-benzo Furan-5-yl)benzoic acid The product from Example 143C (755 mg, 2 mmol) was dissolved in ethanol (20 mL) and taken in 2M aqueous NaOH (2 mL). The mixture was heated to 55 ° C for 40 minutes, cooled to room temperature, concentrated, and partitioned between isopropyl alcohol and a mixture of aqueous potassium dihydrogen phosphate and brine. The liquid phase was separated and extracted with isopropyl alcohol&apos; and the mixed organic phase was washed with a mixture of a potassium phosphate buffer solution of pH 6 and brine. The liquid phase was separated and extracted with isopropanol and the combined organic phases were washed with brine. Separate the liquid phase again to isopropyl 98683.doc -198-1333489

The alcohol was extracted and the combined organic phases were diluted with EtOAc and filtered. The filtrate was dehydrated (Na 2 SO 4 ) and concentrated. The residue was chromatographed on silica gel eluting with 50% EtOAc / CH.sub.2Cl.sub.2. The title compound was obtained as a white powdery crystals eluted eluted eluted eluted MS (ESI APCI) m/z 350 (M+H)+; H NMR (300 MHz, CD3OD) 1.39 (s, 3H), 1.58-1.76 (m, 1H), 1.91-2.10 (m, 2H) ), 2.16-2.31 (m, 1H), 2.89-3.04 (m, 1H), 3.08-3.3 (m, 4H), 3.50-3.71 (m, 2H)} 6.70 (s, 1H)? 7.39-7.59 (m , 3H), 7.69 (d, 1H), 7.79 (s, 1H), 7.92 (d, 1H), 8.23 (s,. 1H). Example 145 N-Methoxy-N-methyl-3-(2-{2-[(2R)-2-fyl-1-pyrrolidinyl]ethyl}-benzofuran-5-yl) Benzoylamine The product from Example 144 was suspended in CH.sub.2Cl.sub.2 (25 mL) eluted with EtOAc (3.0 mL, EtOAc). After the foaming was receded, ν, Ν-dimethylcaraamine (3 〇〇 microliter) was slowly added over 15 minutes. After an additional 1 hour, more hydrazine, Ν-dimethylformamide (100 μl) was added. After a further 30 minutes, the mixture was concentrated and dissolved in CH2C12 (5 mL). Heat hydrazine, hydrazine-dimethylhydroxylamine hydrochloride (488 mg, 5.0 mmol) and pyridine (1 mL). The reaction flask was placed in a water bath, and the mixture was stirred overnight and concentrated to give EtOAc. Dichloroethane (5 ml) was diluted, heated to 85 ° C for 4 hours, concentrated, and partitioned between CH 2 Cl 2 and water. Saturated aqueous NaHC〇3 was added until the pH of the liquid phase exceeded 7.妷 98683.doc •199· 1333489 The liquid phase was separated and extracted with CH2C12. The mixed organic phase was washed with water and brine, dried (NazSO4), and purified eluting with EtOAc EtOAc EtOAc EtOAc ). 4 NMR (300 MHz, CD3〇D) 5 1.19 (s, 3H), 1.37-1.54 (m, 1H), 1.73-1.88 (m, 2H), 1.95-2.09 (m, 1H), 2.27-2.39 ( m, 1H), 2.45-2.64 (m, 2H), 2.95-3.17 (m, 2H), 3.20-3.3 (m, 2H), 3.39 (s, 3H), 3.63 (s, 3H), 6.62 (s, 1H), 7.46-7.83 (m, 4H), 7.73-7.81 (m, 2H), 7, 86 (s, 1H). Example 146 l-[3-(2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl b 1_ benzofurfuran-5-yl)phenyl]-1- Acetone The product from Example 145 (20 mg, 0.05 mmol) was dissolved in tetrahydrofuran (900 liters), cooled to 0 ° C, and taken in THF. Microliter, 150 micromole) treatment. The reaction mixture was then taken up at rt EtOAc (EtOAc)EtOAc. The liquid phase was separated and extracted with EtOAc, and the combined organic phases were washed successively with 0.5 hr of aqueous potassium dihydrogen phosphate and brine, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 Micron particle size), use 1 〇〇 / in 8 minutes. Gradient to 100% MeCN / 0.1% aqueous TF A (10 mins of execution time), purified at a flow rate of 40 ml / min to give the title compound (44% yield) ❶MS (ESI APCI) m/z 362 (M+ H)+; 4 NMR (300 dead Hz, CD3〇D) 1·ΐ8 (d, 3H), 1.21 (t, 3H), 1.39-1.53 (m, 1H), 1.74-1.87 (m, 2H), 1 -95-2.09 (m, 1H), 2.24-2.37 (m, 1H)S 2.42-2.61 (m, 2H), 98683.doc -200- 1333489 2.94-3.18 (m, 4H), 3.20-3.35 (m, 2H), 6.63 (s, 1H), 7.50-7.52 (m, 2H), 7.58 (dd, 1H), 7.77-7.79 (m, 1H), 7.87 (ddd, 1H), 7.96 (ddd, 1H), 8.22 (dd, 1H). Example 147 Cyclopropyl [3-(2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl bromide/benzopyran-5-yl)phenyl]methyl] The product from Example 145 and the deserted cyclopropyl magnesium' were obtained as described in Example 146 to give the title compound (48% yield). MS (ESI APCI) m/z 374 (M+H)+; hNMRQOO megahertz, CD3〇D)5 lom 22 (m, 7H), 1.39-1.53 (m, 1H), 1.73-1.86 (m, 2H) , 1.95-2.08 (m, 1H), 2.23-2.35 (m, 1H), 2.41-2.60 (m, 2H), 2.87-3.15 (m, 3H), 3.19-3.35 (m, 2H), 6.63 (s, 1H), 7.48-7.55 (m, 2H), 7.60 (dd, 1H), 7.78-7.81 (m, 1H), 7.89 (ddd, 1H), 8.02 (ddd, 1H), 8.25 (dd, 1H) ° Example 148 3-decyl-l-[3-(2-{2-[(2R)-2.methyl-14-rheptidyl]ethyl}p-benzopyran-5-yl)phenyl]-1 - Butanone The product from Example 145 and isobutylmagnesium chloride were treated as described in Example 146, except that after the reaction overnight, additional isobutylmagnesium chloride (400 mol%) was added and stirred. The reaction mixture was over 4 hours to give the title compound (19% yield). MS (ESI APCI) m/z 390 (M+H)+; 4 NMR (300 MHz, CD3OD) (5 1.01 (d, 6H), 1.17 (d, 3H), 1.37-1.53 (m, 1H), 173"86 (m,2H),194.2 〇7 (m,1H), 2H), 2.20-2.35 (mj 2H), 2.41-2.59 (m, 2H), 2.95 (d, 98683.doc -201 · 2 ο 5-3.14 (m} 2Η), 3.19-3.34 (m, 2Η), 6.62 (s, 1Η), *49-7.52 (m, 2H), 7.57 (dd, 1H), 7.77 (dd, 1H), 7.86 (ddd, lfi), 7.93 (ddd, ih), 8.19 (dd, 1H). Example 149 (2 {2-[(2R)-2 -methyl·ΐ-ρ比洛唉基]ethyl}-ΐ ·Benzammonium _5_ base) benzaldehyde

The product from Example 145 and the bromotetradecylcyclopentyl magnesium were treated as described in Example 146, except that after stirring the reaction overnight, additional brominated % mercapto magnesium (400 mol%) was added and After another 4 hours, the reaction mixture was stirred for an additional 3 days (1 6% yield) by adding (6 Torr). MS (ESI APCI) m/z 334 (M+H)+; NMR (300 MHz, CD3 〇D) 5 1.17 (d &gt; 3H), 1.38-1.53 (m, 1H), 1.77-1.86 (m, 2H) ), 1.94-2.08 (m, !Η), 2.23-2.34 (m, 1H), 2.40-2.59 (m, 2H), 2.94-3.15 (m, 2H), 3.19-3.34 (m, 2H), 6.63 ( d, 1H), 7.51-7.54 (m, 2H), 7-65 (dd, 1H), 7.80 (dd, 1H), 7.87 (ddd, 1H), 7.96 (ddd, 1H), 8.16 (dd, 1H) , 10.07 (s, 1H). Example 150 [3-(2-{2-[(2R)-2-methyl-1 - oxaridinyl]ethyl}-1 ·benzofuran·5-yl)phenyl](2-nonyl) The oxime ketone was treated as described in Example 146 to give the title compound (53% yield). MS (ESI APCI) m/z 416 (M+H)+; 1HNMR (3 00 MHz, CD3OD) δl.l8 (d, 3H), 1.38-1.53 (m, 1H), 1.73-1.86 (m, 2H) ), 1.95-2.08 (m, 1H), 2.24-2.36 (m, 1H), 2.42-2.61 (m5 2H), 2.95-3.15 (m, 2H), 98683.doc -202- 1333489 3.19-3.34 (m, 2H), 6.63 (d, 1H), 7.27 (d, 1H), 7.48-7.57 (m, 2H), 7.63 (dd, 1H), 7.76-7.84 (m, 3H), 7.90-7.98 (m, 2H) , 8.07 (dd, 1H) 〇 Example 15 1 (3-Fluorophenyl)[3-(2-{2-[(2R)-2-methyl-1 oxaridinyl]ethyl} benzofuran -5-yl)phenyl]methanone The product from Example 145 and the 3-bromo-bromo magnesium bromide were treated as described in Example 146 to the title compound (μ% yield). Ms (ESI APCI) m/z 428 (M+H)+ ; NMR (300 MHz, CD3OD) 5 1.17 (d, 3H), 1.36-1.53 (m, 1H), 1.72-1.86 (m, 2H), 1.94-2.07 (m, 1H), 2.22-2.33 (m, 1H), 2.39-2.58 (m, 2H), 2.93-3.14 (m, 2H), 3.18-3.3 (m, 2H), 6.62 (s, 1H ), 7.37-7.45 (m, 1H), 7.49-7.52 (m, 2H), 7.52-7.66 (m, 4H), 7.72 (ddd, 1H), 7.77 (dd, 1H), 7.94 (ddd, 1H), 8.02 (dd, 1H) 〇 Example 152 [3-(2-{2-[(2R)-2-indolyl-l-pyrrolidinyl]ethyl benzofuran·%)phenyl]methanol The product from Example 144 (167 mg, 0.48 mmol) was dissolved in EtOAc EtOAc (EtOAc m. Stop it and dilute with Et〇Ac. The organic phase was separated and washed successively with 0.5 Μ aqueous dipotassium hydrogen phosphate and brine, dehydrated (NajO4), concentrated, and passed through a short column of silica gel chromatography using 〇 to 5% MeOH/CHbCh gradient and passed Two short column gels, using a 0 to 5% MeCN/CKCh gradient, collecting and concentrating the mass of ions corresponding to the borane 98683.doc -203 - 1333489 complex. The residue was dissolved in methanol (15 ml) ), treated with 0.1 Μ aqueous hydrogen acid (0.3 ml), heated to 6 Torr for 3 hours, treated with more 0.1 hydrazine aqueous hydrochloric acid (〇.! mL), heated to ° ° 1 hour , concentrated, and passed through a short column of silica gel chromatography, using 2 to 1% of 2MNH3 (in MeOH/C^Ch) gradient to give a white powder.

Compound (13% yield). MS (ESI APCI) m/z 336 (M+H)+ ; lH NMR (300 MHz, CD3OD) c5 1.18 (s,3Η), 1.38-1.53 (m,1H), 1.73-1.87 (m, 2H) , 1.94-2.08 (m, 1H), 2.24-2.36 (m} 1H), φ 2.41-2.60 (m, 2H), 2.94-3.14 (m, 2H), 3.19-3.34 (m, 2H), 4.68 (s , 2H), 6.60 (s, 1H), 7.28-7.34 (m, 1H), 7.40 (dd, 1H), 7.46-7.49 (m, 2H), 7.52 (ddd, 1H), 7.62 (s, 1H), 7.73 (dd, 1H). Example 153 (2R)-l-[2-(5-Benzyl-l-benzofuran-2-yl)ethyl]_2_f-pyrrolidine

Example 153 A 4-Germanyl-2-Moth. ^ ^ 4-Benzol was treated as described in Example 143B except that no neutralization was carried out after completion of the reaction, and 25 to 33% of CH2C12/hexane was utilized. Chromatography was carried out to give the title compound (42% yield). 111^]^11 (300 MHz 'CDC13) &lt;5 3.88 (s, 2H), 5.13 (s, 1H), 6.90 (d, 1H), 7.05 (dd, 1H), 7.13 - 7.33 (m, 5H ), 7.47 (d, 1H).

Example 153B (2R)-l-[2-(5-Yoki-i-benzofuran-2-yl)ethyl]_2-methyl p-pyrrolidine was treated as described in Example 136C. The product, except 98683.doc • 204-1333489, was reacted at room temperature for 1 day 'then at 65. The mixture was taken overnight and gradually dried up as follows: the reaction mixture was taken to room temperature, concentrated, suspended in CH.sub.2Cl.sub.2 and mixed with 10% aqueous ammonia and filtered through Celite. The filtrate was diluted with water and the liquid phase was separated and extracted with CH2C12. The mixed organic phase was rinsed with 5% aqueous ammonia and then gradually completed, dehydrated (Na2S04), concentrated and chromatographed three times with MeOH/CH2Cl2 on silica gel. The appropriate fractions were concentrated and the residue obtained was dissolved in methanol and filtered. The filtrate was concentrated to give the title compound (yield: 3%). MS (ESI APCI) m/z 320 (M+H)+; 4 NMR (300 MHz, CD3OD) 5 1.18 (d,3H), 1.38-1.53 (m, 1H), 1.73-1.87 (m, 2H) , 1.95-2.09 (m, 1H), 2.26-2.39 (m, 1H), 2.45-2.61 (m, 2H), 2.90-3.11 (m, 2H), 3.18-3.3 (m, 2H), 4.01 (s, 2H), 6.47 (d, 1H), 7.05 (dd, 1H), 7.11-7.33 (m, 7H). Example 154 1 - (2- {2-[(2R)-2 -Methyl-1-p piroxy]ethyl}-l-benzopyrene _5_

Base)-1Η-imidazole Example 154A 4-(1Η-imidazol-1-yl)-2-iodophenol 4-Imidazolyl-1-ylphenol was treated as described in Example 143, except that it was removed under reduced pressure After ammonia, the mixture was diluted with brine and extracted with 33% isopropyl alcohol /EtOAc. The organic extract was concentrated and concentrated partially before flushing with saline. The brine phase was separated and extracted as before. The combined organic phase was then concentrated until some unisolated N,N-didecylamine and water remained and was left overnight. The crystals formed were collected by filtration and washed with EtOAc/ether of 98683.doc - 205 - 1333489 2:1. The filtrate was concentrated and diluted with brine. , 曰 ϋ, 吉 束 曰 沉淀 沉淀 沉淀 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰 曰

Filtered in MeOH/CHzCl2 and concentrated. A batch of the obtained flutes of Dings was mixed with the first batch to obtain the title compound (64% Yan) in the form of an off-white powder.

ν ϊ)° *H NMR (300 MHz 'CD3OD) (J 6.93 (d, 1H), 7.10 (d, m) 7 37 (dd 1H), 7.43 (dd, 1H), 7.86 (d, 1H), 7.97 (d, 1H). '

Example 154B l-(2-{2-[(2R)-2-Methyl-1-pyrrolidinyl]ethyl hydrazone b. benzofuran _5. yl)-1 Η-methanol as in Example 136C The process of treating the product from Example ι 54 ,, except that the reaction was carried out at 80 ° C for 6 hours, adding an additional acetylene solution 〇〇 mol %) and after an additional 2.3 hours, the reaction was returned to room temperature. Concentrate and chromatograph through a short column of silica gel (coated with a layer of diatomaceous earth) using a gradient of M to 1% of 2 MNH3 (in MeOH/CH2Cl2). The appropriate fractions were combined, concentrated&apos; and chromatographed twice with celite, using 67% CHzCl2/hexanes followed by a 0 to 10% MeOH/CHAh gradient. Mix the appropriate fractions, dilute with CH2C12, rinse with 10% aqueous NaOH, dehydrate (Na2S04), concentrate, and again pass through a short column of silica gel chromatography, using a MeOH/CH2Cl2 gradient from 〇 to 20 °/〇. 'The title compound was obtained (58% yield). MS (ESI APCI) m/z 296 (M+H)+; 4 NMR (300 MHz, CD3OD) 5 1.17 (d,3H),1.37-1.52 (m,1H),1.72-1.86 (m, 2H) , 1.92-2.08 (m, 1H), 2.22-2.34 (m, 1H), 2.40-2.59 (m, 2H), 2.95-3.16 (m, 2H), 3.18-3.34 (m, 2H), 6.65 (s, 1H), 7.14 (s, 1H), 7.39 (dd, 1H), 7.51-7.58 (m, 2H), 7.68 (d, 1H), 98683.doc -206- 1333489 8.06 (s, 1H) 〇Example 155 4 -(3-bromo-2-{2-[(2R)-2-methyl_i_pyrrolidinyl]ethyldimethanebenzofuran-5-yl)-2-methylbenzonitrile according to the example The title compound (18% yield) (ESI) m/z 423/425 (M+H)+; i NMR (300 megabytes) of the brownish orange gum was obtained as described in 101. Hertz, CD3OD) (5 1.39 (d, 3H), 1.60-1.77 (m, 1H), 1.96-2.12 (m, 2H), 2.20-2.33 (m, 1H), 2.61 (s, 3H), 2.9-3.5 (m, 5H), 3.52-3.76 (m, 2H), 7.60-7.77 (m, 6H).

Example 156A 4-(3-Gas-2-{2-[(2R)-2-methyl-l-pyrrolidinyl]ethylb benzofuran

嗔-5-based) gambling and example 156B 4-(3,6-diox-2-{2-[(2R)-2-methyl-1-indolyl) ethyl bup benzofuran -5-yl)benzonitrile The mono-(L)-tartrate salt of the product of Example 1D (120 mg, 0.25 mmol) was suspended in trifluoroacetic acid' with N-chloroammonium imine (53 mg, 〇.4〇 millimolar), and stirred for 2 days. The reaction mixture was poured into aqueous NazS 3 to give aqueous NazCO; to be made basic and extracted with CH.sub.2Cl.sub.2. The combined organic phases were washed with brine, dehydrated (Najoj, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (40 mm χ 100 mm, 6 micron particle size), using 1% to 1 12 in 12 minutes) 〇% MeCN/0.1% aqueous TFΑ gradient (15 min execution time), purified at 7 〇 ml 98683.doc -207- 1333489 /min] to give the title of brown gum (57% yield) And dichloro (12% yield) compound. 156A MS (ESI) m/z 365/367 (M+H)+; NMR (300 MHz, CD3OD) 5 1.48 (d, 3H), 1.67- 1.83 (m, 1H), 1.99-2.24 (m, 2H), 2.30-2.44 (m, 1H), 3.21- 3.63 (m, 5H), 3.72-3.92 (m, 2H), 7.65 (d, 1H), 7.73 (dd, 1H), 7.80-7.89 (m, 5H). 156B MS (ESI) m/z 399/401/403 (M+H)+; NMR (300 MHz, CD3OD) 5 1.48 (d, 3H), 1.67- 1.83 (m, 1H), 2.00-2.25 (m, 2H), 2.27-2.45 (m, 1H), spring 3.21 - 3.64 (m, 5H), 3.72-3.92 (m, 2H), 7.57 (s, 1H) , 7.63 (d, 2H), 7.80 (s, 1H), 7.84 (d, 2H). Example 157 4-(3iodo-2-{2-[(2R)-2-methyl-1-pyrrolidinyl) [Ethylbenzofuran-5-yl)benzonitrile as described in Example 156 Treatment of the mono-(L)-tartrate and N-Mothimide of the product of Example id, except that a large excess of N-moth amber imine (2.4 molar equivalent) was used to give a yellow-brown gelatinous title Compound _ (18% yield) MS (ESI) m/z 457 (M+H)+; 4 NMR (300 MHz ^ » CD3OD) 5 1.49 (d, 3H), 1.67-1.84 (m, 1H) , 00.25 (m, 2H) ), 7.80-7.89 (m, 4H) « Example 158 4-(2-{2-[(2R)-2-methyl-5-oxo-1-pyrrolidinyl]ethyl bromide·benzoc喃-5-yl)carbonitrile The mono-(L)-tartrate salt of the product of Example 1D (96 mg, 〇 2 〇 millimoles) 98683.doc • 208- 1333489 was suspended in acetone (10 ml) and It was treated with a solution of ΚΜ04 (158 mg '1 〇 millimolar) and Mgs 〇4 (120 mg, 1. 〇 millimol) in water (5 ml) in 3 min. After the disappearance of the purple color, the solid β was filtered off, the filtrate was diluted with EtOAc, washed with aqueous sodium dihydrogen phosphate, concentrated and taken by HPlc [\\^6^:^£^3-?31^1111 (:18 column) (25 mm 乂 100 mm, 0 μm particle size) 'Use a gradient of 1〇% to 1〇0% MeCN/0.1% aqueous TFA in 8 minutes (1 执行 minute execution time) to 40 ml/min flow Obtained to give the title compound (2% yield). MS (ESI APCI) m/z 345 (M+H)+; [H NMR (300 MHz, CD3OD) of 1·22 (d, 3H), 1.55 -1.64 (m, 1H), 2.15-2.32 (m, 2H), 2.34-2.42 (m, 1H), 2.99-3.13 (m, 2H), 3.39-3.46 (m, 1H), 3.68-3.76 (m, (H, 1H) {2-[(2R)-2-Methyl-1-p piroxime] ethyl ι·benzo scent. South-5-yl)+ guess the product of Example 1D (330 mg ' 1.0 mmol) The ear was dissolved in ch2C12 (500 μl) and cooled to 〇°c. Add B-brew (140 μl, 2.0 mmol) and 1 M SnCl4 in CH2C12 (1.5 mL, i.5 mmol) Ear) and allow the reaction to warm up to the chamber Warm and stir overnight. Dissolve the mixture between 20% EtOAc/CHzCl2 and 0.5 liter of aqueous dipotassium hydrogen hydride. Separate the liquid phase and solid, extract with CH/h, and mix the organic phase, usually gradually Finished 'but rinsed with aqueous dipotassium hydrogen carbonate, dehydrated (Na2s〇4) and concentrated. The residue was then re-accepted to the same reaction conditions as previously used except 98683.doc -209-1333489 for additional CH2C12 ( The mixture was stirred for 5 days and treated as before. The residue obtained by EtOAc (EtOAc/EtOAc/CH.sub.2).

The mixture (260 mg) and (4-t-butylphenyl)-hydrazine hydrochloride (201 mg, 1.0 mmol) were dissolved in methanol (2 mL) and treated with &lt . The mixture is stirred overnight, concentrated, and partitioned between M. 5 M dipotassium hydrogen phosphate and CHiCl 2 , usually gradually, dehydrated (Na 2 S 〇 4), concentrated, and passed through a silica gel chromatography using 0.5 to 4%. MeOH gradient (in 20% MeCN/CPhCh). The appropriate fractions were concentrated and appeared to cleave after a few days, some of which were the desired ketones. The residue was again passed through a short column of silica gel chromatography using a gradient of 0 to 4% MeOH/CH 2 CI 2 followed by HPLC

[Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 μm particle size), using a 10% to 100% MeCN/0.1% aqueous TFA gradient (15 minutes of execution time) to 70 ml in 12 minutes Purification at a flow rate of /min to give the title compound (4% yield). MS (ESI APCI) m/z 373 (M+H)+; 4 NMR (300 MHz, CD3OD) &lt;5 1.49 (d,3H), 1.68-1.84 (m, 1H), 2.01-2.25 (m, 2H), 2.31-2.46 (m, 1H), 2.80 (s, 3H), 3.3-3.71 (m, 5H), 3.76-3.92 (m, 2H), 7.69-7.76 (m, 2H), 7.84 (d, 2H), 7.89 (d, 2H), 8.20-8.22 (m, ih). Example 160 Cyclopropyl [4_(2_{2-[(2R)-2-indolyl-1-pyrrolidinyl]ethyl}_ι·benzofuran-5-yl)phenyl] fluorenone will be obtained from an example The product of 1D (330 mg, 1. mM mil) was dissolved in tetrahydrofuran (1 mL) to give bromopropyl bromo bromo br. ML, approximately 1.4 mM) and copper iodide (1) (millions of milligrams) were treated and heated to 45 ° C for 1 day, and 60 ° C for 2 days. The reaction was returned to room temperature and quenched with EtOAc (EtOAc) (EtOAc) Rinse the organic phase with 〇.5 Μ aqueous dipotassium hydrogen phosphate and brine, dehydrate (Na2S〇4) 'concentrate' and use the book 1^[%^6^1^〇乂&amp;-?31&lt;:1111 €18 column (40 mm X 100 mm '6 μm particle size), using a gradient of 1〇% to ι〇〇〇/0 MeCN/0.1% aqueous TFA in 12 minutes (15 minutes of execution time) to 7〇 Purification at a flow rate of cc/min gave the title compound (44% yield) as a powder. MS (ESI APCI) m/z 374 (M+H)+ ; 4 NMR (300 MHz, CD3〇D) 5 1.06-1.21 (m, 7H), 1.38-1.53 (m, 1H), 1.73-1.86 ( m, 2H), 1.94-2.08 (m, 1H), 2.23-2.34 (m, 1H), 2.40-2.59 (m, 2H), 2.83-3.15 (m, 3H), 3.19-3.34 (m, 2H), 6.62 (s, 1H), 7.51 (d, 1H), 7.56 (dd, 1H), 7.76-7.85 (m, 3H), 8.12 (d, 2H) 〇 Example 161 3,5-dimercapto-4-( 2-{2-[(2 ft)-2-methyl-1-? ratio 1» each bite base] ethyl}_1_

Benzophenone 11 South-5-yl) Heteroquinone Example 161A 2-[5-(3,5-Dimethyl-isoxazol-4-yl)-benzofuran-2-yl]-ethanol 10 5% isopropanol and 10 ml of water were added to the product from Example 1128 (1.446 g, 6.00 mmol) in 3 indole (20 mL), 3,5-dimethyliso-s-s--4-butyric acid (2.09 g, 6.6 mmol) (Frontier Scientific, Chemical Abstract No. 16114-47-9), palladium acetate (11) (0.07 g, 0.3 mmol) and bis--2-yldicyclohexylphosphine ( 0·15 g '0.6 mmol> of a thoroughly stirred suspension. The reaction was heated to 60 ° C for 36 hours, then cooled and poured into ethyl acetate 98683.doc • 211 - 1333489 ester (50 ml) and Rinse with water (100 ml). After dehydration over sodium sulfate, the organic layer was concentrated in vacuo and purified by flash chromatography eluting with 1:1:4 ethyl acetate/hexane/di-methane The title compound (97% yield) was obtained as a yellow brown oil. MS (DCI) m/z 258.2 (Μ+Η)+; NMR (300 MHz, CDC13), 1,74 (s,1 Η), 2.24 (s, 3Η), 2,40 (s, 3H), 3.05 (t, 2H, J = 6.0 Hz), 4.02 ( t, 2H, J = 6.0 Hz), 7.08 (dd, 1H, J = 9.0, 2_1 Hz), 7.34 (d, 1H, J = 2.1 Hz), 6.54 (s, 1H), 7.46 (d, 1H, 9.0) hertz).

Example 161B 2-[5-(3,5-Dimercapto 4-isoxazolyl)-1-indolofuran-2-yl]ethylmethanesulfonate 0.53 mL (3.75 mmol) Triethylamine was slowly added to the mixture of the product from Example 161A (643 mg, 2.5 mmol) and methanesulfonic acid anhydride (522 mg, 3 mmol) in 3 mL of dichloromethane. In the solution. Allow the reaction to warm to 23 ° C, and pour into a gas - burned _, then rinse with aqueous sodium citrate (buffered to pH 8), desiccate with sodium sulfate, and then concentrate in vacuo to give an oil The title compound.

Example 161C 3,5-dimercapto-4-(2-{2-[(2R)-2-methyl-Ι-t» ratio α each bite base] ethyl b 1· 本弁?夫喃-5 -Based on a 3.3 ml (1 mmol) aliquot of the product from Example 161B in 8.33 mL of acetonitrile was transferred to a separate flask. Converting (R)-2-methylpyrrolidine mono-(L)-tartrate into a free test by shaking with i ml of toluene, 5 ml of 50% w/v sodium hydroxide and 2 ml of brine . After separation 98683.doc • 212· 1333489, the toluene layer was removed by pipette and added to a 3.3 ml aliquot of the product from Example 161. After stirring at room temperature for 1 week, the reaction was poured into di-methane methane and washed with aqueous ammonia, dehydrated with sodium sulfate, and purified by flash chromatography to give a methylene chloride/f alcohol of 97:3. / 〇_ι% Νη3 eluted to give 225 mg (69%) Ms (DCI) m/z 325.2 (M+H)+ ; ^NMR (300 MHz, CDC13) (5 1.18 (d, 1H, J = 6.3 Hz), 2.24 (s, 3H), 2.40 (s, 3H) ), 1.5-2.0 (m, 6H), 2·5 (m, 1H), 3.02 (t, 2H, J = 7.5 Hz), 3.23 (m, 2H), 6.48 (s, 1H), 7.08 (dd, 1H, J=9.0, 2.1 Hz), 7.34 (d, 1H, J=2.1 Hz), 7.44 (d, 1H, 9.0 Hz) Example 162

4-[2-(2-Aminoethyl)-pobenzopyranyl)benzonitrile Example 162 A 4-[2-(2-azidoethyl)-1-benzopyranyl]-carbonitrile Methanesulfonic acid (1 〇 9 mg, 0.32 mmol) was stirred in DMF, obtained from the product of Example 1C and sodium azide (83 mg, 1.28 mmol, and then poured into di-methane). The title compound (65 mg, 71%) was obtained.

Example 162B 4-[2-(2-Aminoethyl)-1-benzopyran-5-yl)phthalonitrile The product from Example 162A was dissolved in 3 mL of THF and Treatment with triphenylphosphine (262 mg, 1 mmol). After 3 days, the reaction was poured into a gas purge and rinsed with aqueous ammonia. The title compound was obtained as a white powder. Melting point 118-120 °C; MS (DCI) m/z 263.0 (M+H)+; NMR (300 Hz, CD3OD) d 3.00 (m, 2H), 3.08 (m, 2H), 6.64 (s, 1H ), 7.56 (m, 2H), 7_82 (m, 5H) 〇 Example 163 4-(2-{2-[(2R)-2-ethyl- Ι-p ratio b each bite] ethyl}-l - benzopyrano-5-yl) gambling According to the description in Example 1D, the product from Example 1C was treated and (2R)-ethyl p was bitten (Andres, Jose M_; Herraiz-Sierra, Ignacio Pedrosa, Rafael; Perez-Encabo, Alfonso; Eur. J. Org. Chem.; Vol. 9; 2000; pp. 1719-1726; Chemical Abstract No. 123168-37-6 Hydrochloride) 'Get the title compound, except The carbonic acid was replaced by sodium carbonate, and the reaction was carried out at 60 C, and then treated by pouring into benzene. The organic phase was extracted with 7:2:1 water/N-methylpyrrolidone/10% aqueous methanesulfonic acid, then the liquid phase was covered with isopropyl acetate and adjusted to pH 50 with 50% aqueous NaOH. After shaking and separating the layers, the isopropanol extract is retained and then mixed with the isopropanol extract of the second liquid layer. The combined isopropanol extract was washed three times with 5% aqueous NaHc(R) 3 and water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown oil. The free base is converted to the monotartrate by adding one equivalent of tartaric acid to the free base in ethanol. The mixture was heated to 7 Torr. 〇, and allowed to cool, precipitated a gray-white solid. The isopropyl acetate was used to form a slurry&apos; and the solid was collected by filtration to give the title compound as the tartrate salt. Melting point 147t; MS m/z (M+H) + 98683.doc m 345. 345.1333489 Example 164 4-(2-{2-[(2S)-2-(fluoromethyl)_ι·pyrrolidinyl]ethyl}-l-benzofuran

-5-yl)benzonitrile Example 164 A (2S)-2-{[methylsulfonyl)oxy]methylpyridinium-pyrrolidinecarboxylic acid tert-butyl ester was treated with 4.04 g of triethylamine. N-Boc-(2S)-dehydrazide (6.04 g) in 100 ml of dichloromethane was cooled to EtOAc and was slowly treated with decanesulfonium (4-0 g). After stirring for 3 minutes at 〇 °c, the reaction was allowed to warm to EtOAc EtOAc (EtOAc) Gram).

Example 164B (2S)-2-(fluoromethyl)_1-pyrrolidinecarboxylic acid, the third butyl ester was obtained from 100 ml of THF and tetrabutyl fluoride (42 ml of 1 M solution in THF t). The product of 164A (7 g) was heated to reflux for 17 h, cooled, concentrated to dryness, diluted with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The filtrate was concentrated to give an oil. The oil was evaporated in vacuo (50 ° C, m.

Example 164C (2S)-2-(Fluoromethyl)pyrrolidine The product of Example 164B (4.4 g) was taken from EtOAc EtOAc (EtOAc) The solution was stirred overnight, and 98683.doc -215 - 1333489 of an additional 5 ml of 4N HCl in the ι,4- 2 yard was added and the slurry was stirred for an additional 24 hours. The off-white solid was collected by EtOAc (EtOAc) elute elute 13C NMR (DMSO) 6 81.6 (JCF = 167 Hz), 58.1 (JCF = 18 Hz), 45.0, 25.2 (JCF = 6 Hz), 23.3.

Example 164D 4-(2-{2-[(2S)-2-(Fluoromethyl)-indolylpyrrolidinyl]ethylbububenzofuran-5-yl)benzonitrile as described in Example 1D The product from Example 1C and the product from Example 164C were obtained to give the title compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was carried out at 60 ° C for 3 days, and then treated by pouring into toluene. The organic phase was extracted with 7:2:1 water/N-methylpyrrolidone/1% aqueous methanesulfonic acid&apos; and the liquid phase was then covered with isopropyl acetate and adjusted to pH 11 with 5% aqueous NaOH. After shaking and separating the layers, the isopropanol extract was retained and then mixed with the isopropanol extract of the second liquid layer. The mixed isopropanol extract was washed 3 times with 5 〇 / 〇 water containing NaHCCh, water, dehydrated with magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. The free base is converted to mono-L-tartrate by adding 1 equivalent of L-tartaric acid to the free base in ethanol. Two hours after removal of some of the ethanol under vacuum, the mixture precipitated an off-white solid. The solid was collected by filtration and dried <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -5-Dibubenzonitrile tartrate, melting point 156.3. 〇MS m/z (M+H)+ 349 ; 13c NMR (DMSO) 5 158.6, 154.2, 145.2, 133.2 132.7, 129.4, 127.7, 122.8, 1 19.2, 1 18.9, 98683.doc -216- 1333489 111.2, 109.4 , 103.0, 85.6 and 84.3, 72.1, 62.8, 53.5, 52.3 27 2 26.4, 22.7 ° Example 165 4-(2-{2-[(2R)-2-methyl-indole-p-pyridyl)ethyl }_ι·Benzene? Fu 0 South·5_ base) 芊carbonitrile Example 165Α 1-Bromo-4-[(2,2-diethoxyethyl)thio] stupid in Banfield et al; J. Chem. Soc . 1956; 2603-2607 and in the description of Amin et al; J. Chem. Soe. Perkin Trans. 2; 1982; 1489-1492 'Preparation of 1-bromo-4-[(2·2-diethoxyB) Base) thiol] This (Chemical Abstract No. 96804-05-6). Treatment of 4% bromine in ethanol (80 ml) with 21% by weight of sodium ethoxide (36 g, 1.05 eq.) in ethanol (20 g, 95% octadecide the solution to 55^30 min, and Bromoacetaldehyde diethyl acetal (22.56 g, 1.05 eq.) was added. The mixture was heated to reflux for 10 s. &lt;&quot;&quot;&quot;&quot;&quot; The product was extracted with an ester. The combined ethyl acetate layer was washed with 2 X 40 mL of 1 5% NaCI and concentrated to a brown oil (32············ The product was further purified by column chromatography (gelatin, 5:95 EtOAc:hexanes). </RTI> </RTI> </RTI> </RTI> </RTI> 5-bromo-1-benzo </RTI> </ RTI> in Banfield et al.; J. Chem. Soc.; 2603-2607 and preparation of 5-bromobenzo[b]thiophene as described in Seed, Alexander J. et al; J. Mater. Chem.; vol. 2; 2069-2080 (Chemical Abstract No. 98683.doc) -217- 1333489 4923-87-9). Heat a mixture of phosphonic acid (218 g) and chlorobenzene (2 liters) to

130 C, then using a syringe pump within 2 hours, was treated with the product from Example 165A (107.0 g). The mixture was heated to 13 Torr. [15 hours. The Dean-Stark trap was used at the beginning of the reflux to remove moisture from the mixture. The mixture was allowed to cool to room temperature, and the liquid layer at the bottom was extracted with 200 ml of a gas chamber with 4 ml of water. The combined organic layers were washed with 2 mL of 1N/EtOAc NazCOa and concentrated to a brown oil (129 g). The crude oil was dissolved in 1 liter of 1 〇:9 EtOAc: hexanes, filtered, EtOAc EtOAc (EtOAc) Further purification was carried out by column chromatography (Shi Xixi, 5:95 EtOAc:hexane).

Example 165C 2-(5-Bromo-benzobenzophen-2-yl)ethanol at -55 ° C 'with lithium diisopropylamide (2.4 mL, previously cooled to -50 to -55 ° C, The product from Example 165B (43 g) was taken in THF (10 mL) to afford a reddish brown. The mixture was warmed to -25 ° C and treated with EtOAc (0.96 g &lt;RTI ID=0.0&gt;&gt; The mixture was warmed to 45 C ' and was searched for 3 hours. The mixture was acidified with 2N EtOAc (EtOAc) (EtOAc) elute (〇62 g). 4 NMR (CDC13, (5) 1.6 (broad s, 1H), 3·17 (t, 2H), 3.93 (m, 2H), 7.02 (s, 1H), 7·35 ( d,1H), 7.61 (d,1H), 7.80 (s,1H).MS (m/z): 274, 276 (M+NH4) 98683.doc -218· 1333489

Example 165D 4-(5-bromo-1-benzo-p-phen-2-yl)acetic acid 4- fluoromethane (10 mL) mp. Add to triethylamine (0.3 g, 1.5 eq.) followed by toluenesulfonate (〇.37 g, 1.0 eq.). The solution was stirred at room temperature overnight and rinsed with 3 x 20 mL of water. The methylene chloride layer was concentrated to a viscous oil (0.98 g, 68.1% potency, 83.5% yield). The crude product was purified by crystallization from 20:80 EtOAc (hexane: hexane). NMR (CDC13, δ) 2.38 (s, 3H), 3.21. 2H), 4.30 (t, 2H), 6.87 (s, 1H), 7.18 (d, 2H), 7.36 (d, 1H), 7.55 (d, 1H), 7.63 (d, 2H), 7.75 (d , 1H). MS (m/z): 428, 430 (M+NH4).

Example 165E (2R)-l-[2-(5-Bromo-1-benzothiophen-2-yl)ethyl]-2-methylpyrrolidine using (2R)-2-mercaptopyrrole in acetonitrile A solution of the pyridine (11.1 g, 12.6 mg/g solution, 1.5 eq.) was treated with benzene benzene sulfonic acid, product from </ RTI> </ RTI> </ RTI> (0.45 g) and K.sub.2CO3 (0.23 g, 1.5 eq.). The mixture was heated to 55 ° C for 24 hours, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was taken up in EtOAc EtOAc (EtOAc m. , 73.3%). *H NMR (CDC13j δ ) 1.1〇(d, 3Η), 1.4-2.0 (m, 4H), 2.20 (q&gt; 1H), 2.30-2.50 (m, 2H), 3.00-3.23 (m, 4H), 6.97 (s, 1H), 7.33 (d, 1H of d), 7.60 (d, 1H), 7.78 (d, 1H). MS (m/z): 324, 326 (M+H)+. 98683.doc • 219· 1333489

Example 165F 4_(242-[(2R)-2-methyl-i-pyrrolidinyl]ethyl}_丨_benzofuran·5-yl)benzonitrile as potassium phosphate (0.52 g, in 8 liters of water, 2 equivalents) of the product from Example 165E (0.4 g), 4-cyanophenyl succinic acid (0.45 g '2.5 equivalents), triphenylphosphine (65 mg, 〇.2) in isopropanol (8 mL) Equivalent) and di-p-triphenylphosphine palladium (87 mg '01 equivalent). The mixture was heated to 65 C for 25 hours under nitrogen to allow cooling to room temperature and was treated with H.sub.2:NMP:MeS03H (70:20:10&apos; The mixture was extracted with toluene (2 χ 1 mL) and the acidic liquid phase was basified to pH 1 〇 using 50 〇 / 〇 NaOH. The alkaline solution was extracted with a methane (10 mL), washed with water (2 X 1 mL) and concentrated to a brown oil. The brown oil was dissolved in EtOAc (20 mL)EtOAcEtOAcEtOAc The residue was purified by EtOAc EtOAcjjjjjjjj Ms (m/z) 347 (M+H)+. The free base was dissolved in 5 mL MeOH and added to EtOAc (EtOAc &lt The mixture was concentrated to dryness and crystallised from EtOAc/EtOAc to afforded tart. lH NMR (DMSO-d6) (5 1.17 (doublet), 1.414.49 (multiple peak), 1.74-1.82 (multiple peak), 1.97-2.03 (multiple peak), 2.55-2.59 (multiple peak), 2.80 ( Multiple peaks), 3.12-3.37 (multiple peaks), 4.11 (single peak), 7.33 (single peak), 7.66 (doublet), 7.93 (single peak), 8.02 (doublet), 8.13 (double) Example 166 4-(2-{2-[(2S)-2-methylpyrrolidinyl]ethyl}-1_ benzofuran _5-yl) 98683.doc • 220· 1333489 芊carbonitrile Example 166 A (2S)-2-methylpyrrolidine can be used in Nijhuis, Walter HN et al, J. Org. Chem.; 54; 1; (1989) pp. 209-216; or Kim, Mahn-Joo et al. (2S)-2-Mercaptopyrrolidine hydrobromide, Bioorg. Med. Chem. Lett.; Volume 6; 1; (1996) Procedures described on pages 71-76.

Example 166B 4-(2-{2-[(2S)-2-methylpyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile can be treated as described in Example 1D ( 2S)-2-Methylpyrrolidine hydrobromide and the product from Example 1C gave the title compound. Example 167 (2R)-2-methylpyrrolidine was prepared using the procedure described in Elworthy, Todd R.; Meyers, AI., Tetrahedron, Vol. 50, 20, (1994) pp. 6089-6096, (2R) -2-Methyl p is a bite, or used in Karrer, Ehrhardt, Helv. Chim. Acta, Vol. 34, (1951) No. 2202, 2208; Gaffield, William, Lundin, Robert E., Keefer, Larry K Tetrahedron, 37; 1981; 1861-1869; Yamada et al., Tetrahedron Lett. (1973) p. 381; or Andres, Jose M., Heraiz-Sierra, Ignacio, Pedrosa,

Rafael, Perez-Encabo, Alfonso, Eur. J. Org. Chem., 9; (2000) pp. 1719-1726, to prepare (2R)-2-methylpyrrolidine. Example 168 (2R)-2-Methyl-l-[2-(5-phenoxy-1-benzofuran-2-yl)ethyl]p pyrrole 98683.doc -221 - 1333489 唆2-iodine 4-Phenoxy-the title compound was prepared by treating 4-phenoxyphenol (Aldrich, catalog No. 83 1-82-3) as described in Example 143A. (2R)-2-Methyl-l-[2-(5-phenoxy-1-benzopyran-2-yl)ethyl]pyrrolidine was treated as described in Example 136C. The product, (R)-l-but-3-ynyl-2-methylpyrrolidine, gave the title compound. Example 169 (2R)-1 -(2-{5-[(3-fluorophenyl)thio]·ι_benzopyran-2-yl)ethyl)-2-methyl ρ Treatment at -78 ° C in 2 molar equivalents of tri-butyllithium and bis(3-fluorophenyl) disulfide (Lancaster synthesis Ltd., chemical abstract number 63930-17-6) in tetrahydrofuran (2R)-l-[2-(5-Bromo-1-benzofuran-2-yl)ethyl]-2-methylpyrrolidine' gave the title compound. Example 170 3-(2-{3-[(2R)-2-indolyl-1-pyrrolidinyl]propylbububenzofuran_5_

Example 芊carbonitrile Example 170A 3-(5-bromo-l-benzofuran-2-ylpyridinol) The product from Example J12 and 4-pentyne-1 were treated as described in Example 112. The title compound was obtained as the alcohol. Example 170 Β 3-[2-(3-Hydroxypropyl). "benzofuran-5-yl]phthalonitrile The product from Example η was obtained as described in Example 112C ( 193 mg '0.80 mmol" and 3-cyanophenylboronic acid gave the title compound. 98683.doc •222- 1333489

Example 170C 3_[5-(3-Cyanophenyl)-1-benzofuran-2-yl]propylmethanesulfonate The product from Example 170B was treated as described in Example 112D. Gas, the title compound was obtained.

Example 170D 3-(2-{3-[(2R)-2-indolyl-1-pyrrolidinyl]propyl)benzofuran_5_yl)

The product from Example 17A was treated as described in Example 112E and (2R)-2-methyl. Example 171 3-(2-{[(2R)-2-methyl-1-pyrrolidinyl]methyl benzofuran-5-yl)carbonitrile was treated as described in Example 112B-E. 2-propyne-1 · alcohol and the product from Example 112 A gave the title compound. Example 172

3-(2-{4-[(2R)-2-methyl-1-pyrrolidinyl;j butyl benzofuran-5-yl)carbonitrile was treated as described in Example 112B-E. The product was obtained from the product from Example 112A to give the title compound. Example 173 4-(4-{2-[2-(2S)-Methyl-1-pyrrolidinyl)ethyl]- benzofuran·% phenyl] oxalyl) morpholine as in Example 1D Description, treatment of (2S)_2_methylpyrrolidine hydrobromide and the product from Example 23D (2_{5·[4_(4-morpholinecarbonyl) stupyl/丨'benzene 98683.doc-223- and The title compound was obtained as the title compound. Example 174 4-{4-methyl-2-oxo-3-[2-(2S)-methyl-1·pyrrolidine The base ethyl 2··2Η·bitite-6-yl} word was judged to treat (2S)-2-methylpyrrolidine hydrobromide and the product from Example 41C (2-{5) as described in Example 1D. -[4-(4-morpholinecarbonyl)phenyl]-1-benzopyran-2-yl}ethylmethyl decanoate) gave the title compound. Example 175 4-{4-methyl-2 -Oxo-3-[2-(2R)-methyl_ι-pyrrolidinylethyl]_2H_ 咬-6-yl} It is assumed that (2R)_2-methyl is treated as described in Example 1D. Pyrrolidine Hydrogen Desertification and the product from Example 41C (2-{5-[4-(4-morpholinecarbonyl)phenyl]-indole-benzocyano-2-yl}ethylmethyl decanoate ), the title compound was obtained. Example 176 4-{[6-(2-{2-[(2S)·Methylpyrrole (2)-2-methylpyrrolidine hydrobromide and obtained from the examples as described in Example 1D, ethyl bromide benzofuran _5-yl)-3-pyridyl]carbonyl}morpholine The product of 44E (2-{5-[4-(4- morpholinecarbonyl) phenyl) and the title compound. {2-[(2R)-Mercaptopyrrolidinyl]ethyl b 2,3-dihydrobenzofuran-5-yl)carbonitrile The (2S)_2-methyl was treated as described in Example 1D. The pyrrolidine hydrobromide and the product from Example 67D afforded the title compound. 98683.doc -224 - 1333489 Example 178 4-(2-{2-[(2S)-2-methyl-1-pyrrolidinyl] Ethyl}·1-benzofuran-Nan-4_yl)carbonitrile The (2S)-2-methylpyrrolidine gas-filled product and the product from Example 85E were treated as described in Example 1D to give the title compound. Example 179 4-{2-[2-(2(S)-indolyl-pyrrolidin-1-yl)-ethyl]-benzofuran. South_6•benbbenzonitrile

The (2S)-2-methylpyrrolidinium hydrobromide and the product from Example 86E were worked up to give the title compound as described in Example 1D. Example 180 3-(2-{2_[(2S)-2-Methyl-1-pyrrolidinyl]ethyl benzofuran d-yl)benzonitrile was treated as described in Example 1D (2S). - decylpyrrolidinium hydrobromide and the product from Example 112D gave the title compound. Example 181-202

Examples 181-220 are compounds of formula (50) which are aryl or heterocyclic. These compounds can be prepared according to the procedures set forth in Schemes 13 and 14 below.

Plan 13

% (50) 1 = aryl:, heterocycle 9NA-casnBU3 986S3.doc -225 - 1333489 treated as a third-butyllithium and tributyltin alkyl gas at -78 °C as shown in Scheme 13. (2R)-l-[2-(5-Bromo-1-benzofuran-2-yl)ethyl]2_methyl heart bite 'obtains (2R)_2_f base]P [5_(tributyltinyl) Benzofuran-2-yl]ethyl}pyrrolidine. In the presence of a palladium catalyst such as palladium acetate (1) and a divalent phosphine such as tris(2-furyl)phosphine in an organic solvent such as dimercaptoamine at 25 ° C to 12 ((2R)_2_Methyl small {2-[5-(tributylstannyl)) is treated with a suitable starting material, such as an aryl dentate, an aryl trifluoro sulfonate or a heterocyclic compound. A compound of the formula (5A) is obtained by a method known to the art. For example, a compound of the formula (50) can be isolated and purified. The compound of the formula ($ 〇) can be partitioned between the gas and the water, the organic phase is concentrated, and the residue is purified by chromatography on silica gel.

As shown in Plan 14, at _78. (:, in tetrahydrofuran, treated with a third-butyl clock and a borate ester such as tri-isopropoxy borane (2R)-l-[2-(5·bromo-indole-benzofuran) -2·yl)ethyl]_2-methylpyrrolidine gives 2-{2-[(2R)-2.methyl-1-pyrrolidinyl]ethyl}·ι_ benzofuran-5-yl Diisopropyl isopropylate. Treatment of 2-{2-[(2R)-2-mercapto-1-pyrrolidinyl]ethyl}-1 -benzofuran-5-yl acid diisopropylate with water , get _ acid or phthalate, 98683.doc • 226· 1333489 used directly in the Suzuki coupling reaction. In palladium catalysts, such as palladium acetate and trivalent phosphine, such as biphenyl 2-based bicyclic In the presence of hexylphosphine, and in the presence of aqueous sodium carbonate or potassium hydride, in an organic solvent such as ethanol or tetrahydrofuran at 25 ° C to 120 ° C with a suitable starting material such as aryl halide An aryl difluoro acid ester or a heterocyclic compound, which is treated with a sun acid or an acid ester to give a compound of the formula (50). The compound of the formula (50) can be isolated and purified by a method known to the art. For example, a compound of the formula (5〇) can be partitioned between dioxane and water, and the organic phase is concentrated. Purification of the residue by chromatography on silica gel. Examples of compounds can be prepared according to the procedures described in Schemes 13 and 14, and starting materials suitable for the preparation of such compounds are provided in Table 2 below. Table 2 Example No. Compound Starting Material Chemical Abstract No. 181 3,5-Dimercapto-4-{2-[2-(2R)-methyl-pyrrolidin-1-yl·ethyl]_ benzoquinone bite 11 Nanji}-Different π σ sit 4-iodo-3,5-dimethyl-iso-4 saliva_ 10557-85-4 182 5-{2-l2-(2R)-methyl-oxime -1-yl-ethyl]-benzofuran_ 5-yl}-2-phenyl number. Sit 5-independent-2-phenyl number. Sit 92629-11-3 183 2-{2-[2- (2R)-mercapto-t-bite-1 -yl-ethyl]-stupid bite 11 south _ 5-base}-carbazole 2-di., 嗓 3034-53-5 184 "4-{2 -[2_(2R)-Methylpyrrolidino-1-ylethyl]-benzopyrene·5-yl b 1H-pyrazole "4-Moth-11^°°°3469-69-0 185 4-{2-[2-(2R)-indolyl-pyrrole 1-ocyl-ethyl]-stupidyl 5-yl}-1-indolyl-lH-p than saliva 4-iodo-1 - Stupid-1Η-ρ than saliva 23889-85-0 98683.doc -227- 1333489 186 methyl-4-{2-[(2R)-(2-methyl-? Bilo bite *1-yl)- Ethyl]-benzofuran-5· }}-1Η-imidazole 4-bromo-1-methyl-1Η-α rice bran 25676-75-9 187 4-{2-[2-(2R)-methyl-pyrrolidone-1-yl-ethyl ]-Benzene 弁 _ _ 5-基}-远°坐四漠-ρ塞峻34259-99-9 188 2-{2-[2-(2R)-Methyl-pyrrole_1-yl- Ethyl]•benzoquinone-5-yl}-1沁imidazole 2-A-1Η-imidol 3034-62-6 189 4-{2-[2-(2R)-methyl-pyrrole-1 -yl-ethyl]-benzoquinone-5-yl}-1Η-benzimidazole 4-bromo-1Η-benzimidazole 83741-35-9 190 3-methyl-6-{(2R)-[ 2-(2-methylpyrrolidin-1-yl)-ethyl]·benzoquinone bite Nan-5-yl}-tower 13 well 3-chloro-6-methyl-tower tilling 1121-79-5 191 2-{2-[2-(2R)-Methyl-pyrrolidin-1-yl-ethyl]-benzoquinone-n--5-ylpyrazine 2-硖-ρ ratio tillage 32111-21- 0 192 5-{2-[2-(2R)-Methyl-pyrrole0-l-yl-ethyl]-benzoquinone-5-yl}-pyrimidine 5----bite 4595-59- 9 193 5-{2-[2-(2R)-Methyl-pyrrolidone-1-yl-ethyl]-benzoquinone-Ban-5-kib-indole-4-ylamine 5--gt;塔ρ井-4-ylamine 55928-90-0 194 5-{2-[2-(2R)-fluorenyl-pyrrolidine-1-yl-ethyl]-benzoin-5-yl}- Nicotine phthalonitrile 5-bromo-nicotine phthalonitrile 35590-37-5 195 4-{2-[2-(2R)-methyl-pyrrole -1-yl-ethyl]benzoquinone-5-yl}-1Η-吲哚4-bromo-1Η-吲哚52488-36-5 196 4-{2-[2-(2R)-fluorenyl -pyrrole bite-I-yl-ethyl]-benzoquinone-n--5-yl-p-phthalonitrile-brown-o-phthalaldehyde nitrile 69518-17-8 197 5-{2-[2-( 2R)-fluorenyl-pyro-bito-l-yl-ethyl]-benzoquinone-5-yl}-murine-1-嗣5-bromo-hydropurin-1-one 34598-49-7 98683 .doc -228- 1333489 198 1 - {2-[5·(5,6-Diazin-2H-*7-n-butyl-3-yl)-benzofuran-2-yl]-ethyl}-(2R )-Methyl ratio σ each bite 5-bromo-3,6-dihydro-2H-pyran 100130-39-0 199 1-[2-(5-cyclohept-1-enyl-benzofuran-2 -yl)-ethyl]-(2R)-methyl-ρ ratio β each 1-fill-cycloheptene 49565-03-9 200 (2R)·methyl-1-(2-{5-[2 -(11Η-10-vio-dibenzo[a,d]cyclohexade-5-yl)-ethyl]•benzoxan-2-yl}-ethyl)-p ratio §·bit Dilute 5-(2-bromo-extended ethyl)-5,ll-dihydro-10-1I-dibenzo[a, d]cycloheptene 112930-54-8 201 4-{2-[2-( 2R)-Methyl-P ratio leptin-1-yl-ethyl]-benzocarbamate-5-yl}-leafidine 4-bromopyridine hydrochloride 1952-06-2 202 4-{2 -[2-(2R)-indolyl-pyrrolidone-1-yl-ethyl]-stupid and gnash-5-yl}·!1 than bite 2-desert Bite 109-04-6 --- Example 203-224 Compound of formula (51) Examples 203-224 are compounds of formula (51) wherein 1 is aryl or heterocyclic. These compounds can be prepared according to the procedure shown in 51&quot;15 below. Program 15

R〇=aryl or heterocyclic ring 98683.doc -229· 1333489 As shown in Scheme 15, at 〇 ° C, in CH 2 C 12, with methane sulfonate and triethylamine treatment herein in accordance with Example 85 2-(2-Hydroxyethyl)-1-benzofuran-4-yltrifluorofluorene sulfonate prepared as described in A_85C to give 2-{2-[(sulfonyl)oxy]B Benzofuran-4 M-trifluoromethane acid ester. At about 35 ° C in 'MeCN, with (2R)-methyl p piroxime- (1 〇-tartrate and € 32 (: 〇 3 treatment 2-{2-[(methylsulfonyl)) Oxy]ethyl}-1-indene and ketone-4-yltrifluorodecanoate for 1 to 4 days to give 2-{2-[(2R)-2-mercapto-purin-p bilo Bite base] Ethyl}·ι· Stupid and 7 D South _4_Base three said A burnt acid ester. According to Murata et al., Journal of Organic

Chemistry (2000) 65· 164-168, treatment of 2_{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-l- benzofuran-4-yltrifluoromethane The acid ester gives (2R)-2-methyl-l-{2-[4-(4,4,5,5-tetramethyl-i,3,2-diindole-5-yl) )-1-benzopyrimidin-2-yl]ethyl is slightly bitten. For example, at 25 ec 'in 1,4-dioxane, palladium acetate or [ι,ι, bis(biphenylphosphino)ferrocene] dipalladium (PdChdppf), 3 equivalents of triethylamine and Treatment of 1 equivalent of 2-{2-[(2R)-2-methyl-1-pyrrolidine]ethyl} with 1.5 equivalents of 2,3-didecyl-2,3-butanediol (pinacol) borane 1-benzofuran-4-yltrifluoromethanesulfonate for several hours or until the reaction is judged complete by TLC. In an organic solvent such as ethanol or tetrahydrogen yttrium, at 25 to 120 ° C, with a suitable starting material, such as a square halide, a square disulfide ® or a hetero-halide, catalyst , such as palladium (II) acetate, trivalent phosphines like biphenyl-2-yl-dicyclohexyl scales, and aqueous sodium carbonate or potassium phosphate treatment (2R)-2·methyl 丨5 5-tetra A compound of the formula (51) is obtained by the group -1,3,2-disylborolan-2-yl)-1 -benzofuran-2-yl]ethyl}anthrolidine. Compounds of formula (51) can be isolated and purified by methods known to those skilled in the art, 98683.doc -230- 1333489. For example, a compound of the formula (5丨) can be partitioned between a gas and a water, the organic phase is concentrated, and the residue is purified by chromatography on a gel. Examples of compounds can be prepared according to the procedures described in Scheme 15, and starting materials suitable for the preparation of such compounds are provided in Table 3 below. Table 3 Example No. Compound Starting material f Chemical Abstract 203 3,5, dimethyl·4·{2-[2-(2ΙΙ)-methyl·ρ比洛 bit-1-yl-ethyl]_ Bite -4-yl}-iso 17 ί sit 4-^-3,5-dimethyl 'different' saliva — _ 10557-85-4 204 5-{2-[2-(2R)- Methyl-p-pyrrolidin-1-yl-ethyl]-benzo-p-flavor-4-yl}-2-phenyl-s-oxazol-5-indi--2-phenyl-salt 92629-11-3 205 2-{2-[2-(2R)-methyl-indolyl-1-yl-ethyl]-benzop-butan-4-yl}-ff sputum 2-indigenous sputum 3034- 53-5 206 _4-{2-[2_(2R)-fluorenyl-indolyl-1 -yl-ethyl]-benzop-propanyl-4--4-yl}-11^ than salivary 4-moth 1 Η·ρ比嗤3469-69-0 207 4-{2-[2-(2R)-Methyl-pyrrolidine•1-yl-ethyl]benzo-kick-4-yl} _ 1 -benzene -1-1 H-叶匕σ sit 4-峨-1 -phenyl-1Η·p ratio Jun 2889-85-0 208 1-mercapto-4-{2-[(2R)-(2-methyl ratio洛唆-1 -yl)-ethyl]-benzofuran-4-yl}-1 沁imidazole 4·;? 臭-1-曱基-1Η_味唾25676-75-9 209 4-{2-[ 2-(2R)-Methyl-oxaridin-1-yl-ethyl]-benzoxan-4-yl}-oxime. Sit 4-bromine plug. Sitting 34259-99-9 210 2-{2-[2-(2R)-methyl-indolyl-1-yl-ethyl]-benzofuran-4-yl}-1 oxime imidazole 2-broken -1Η-咪唾3034-62-6 211 4-{2-[2-(2R)-Methyl-pyrrolidin-1-yl-ethyl]-benzoheptan-4-yl}-1Η·benzene Imidazole 4-bromo-1Η-benzimidazole-1 83741-35-9 98683.doc -231 - 1333489 212 3_ Methyl-6-{(2R)-[2-(2·methyl-p 洛洛 bite -1-yl)-ethyl]-benzoquinone bite-4-yl}-σ荅33-rat-6-曱 base preparation 1121-79-5 213 2-{2-[2-(2R) -Methyl-pyrrolidin-1-yl-ethyl]-benzoquinone p-propan-4-yl}-say tillage 2-峨-ν»比耕32111-21-0 214 5-{2-[2- (2R)-Mercapto-pyrrolidin-1-yl-ethyl]-benzoxan-4-ylpyrimidine 5-bromo-bite 4595-59-9 215 5-{2-[2-(2R )-Methyl-pyrrolidinyl 1-yl-ethyl]-benzopyrano-4-yl}indole-4-ylamine 5-bromo-indole-4-ylamine 55928-90-0 216 5- {2-[2-(2R)-Methyl-pyrrolidin-1-yl-ethyl]-benzoquinone bite South-4_ kibnicotinonitrile nitrile 5-bromo-nicotinonitrile nitrile 35590-37-5 217 4-{2-[2-(2R)-Methyl-pyrrolidin-1-ylethyl]-benzoquinone p-propan-4-yl}-1Η-蜊哚4-bromo-1Η-吲哚52488-36-5 218 4-{2-[2-(2R)-indolyl-pyrrolidine-1·yl-B ]-Phenylhydrazone p-Phenyl-4-yl}-phthalic acid nitrile 4-iodo-o-phthalonitrile 9925-17-8 219 5-{2-[2-(2R)-methyl-pyrrolidine -1-yl-ethyl]-benzobenzopyrim-4-yl}-nitrogen-I-嗣5->odor-nitrogen imprint-1-嗣34598-49-7 220 1-{2-[4- (5,6-Dihydro-2H-pyran-3-yl)-benzoquinone-2-yl]-ethyl}-(2R)-indolyl-pyrrolidine 5-bromo-3,6-di Hydrogen-2Η-pyran 100130-39-0 221 1 -(2-(4-3⁄4hept-1 -carbo-benzoquinone-2-yl)-ethyl]-(2R)-methyl-p Bilolide 1-Moth-Cycloheptane 49565-03-9 222 (2R)-Methyl-1-(2-{4-[2-(11Η-10-thia-dibenzo[a,d]] ring庚hepthen-5-yl)-ethyl]-benzoheptan-2-yl}-ethyl)-external b each 5-(2-bromo-extended ethyl)-5,ll-dihydrogen Benzene-dibenzo[a,d]cycloheptene 112930-54-8 223 4-{2-[2-(2R)-methyl-pyrrolidin-1.yl-ethyl]-benzoquinone喃-4-yl}-17 than bite 4-mute ρ than bite 19524-06-2 98683.doc -232- 1333489 Compound of formula (52) Example 225-246 is a compound of formula (52), wherein I is aryl The base or heterocycle can be prepared according to the procedure shown in Scheme 16 below:

224 4-{2-[2-(2R)-indolylpyrrolidin-1-yl-ethyl]-benzopyrene-4_ 2-bromop ratio bite~-kibbi bite__ Example 225- 246 R7 = aryl or heterocycle As shown in Scheme 16, according to the procedure described for Schemes 203-224 shown in Scheme 15, the treatment was carried out as described in Example 86a. Ethyl H. stupid and succinyl 6-fluorotrifluoroacetate is used to obtain a compound of the formula (9). The compound of the formula (52) can be isolated and purified by a method known in the art. An example of a compound can be prepared by dissolving a compound of the formula (52) between a gas and a water to "concentrate the organic phase, and purifying the residue by chromatography on (4)", the initiation of such a compound. Substance. May be prepared according to the procedure described in Program 16 and in Table 4 below for the preparation of 98683.doc-233. Table 4 Example No. Compound Starting Material Chemical Abstract Number 225 3,5-Dimethyl-4- {2-[2-(2R)-Methyl-p ratio each 1-yl-1-yl]-ethyl]-benzofuran-6-yl}_isoxazole 4-iodo-3,5-dimethyl - Iso-rrazole 10557-85-4 226 5-{2-[2-(2(R)-methyl-pyrrole bite- 1-yl)-ethyl]-benzoquinone pfluran-6-yl}-2-phenyl-oxazole 5-bromo-2-phenyl-sodium oxazoline 92629-11-3 227 2-{2-[ 2-(2(R)-Methyl-pyrrole-l-yl)·Ethyl]-benzo benzophenan-6-yl}-spirit spit 2-moly-soul. Sit 3034-53-5 228 4- {2-[2-(2(R)-Methyl-pyrrole-1-yl)-ethyl]-benzo-bite. Nan-6-yl}-111-pyrazole 4-break-lH-p ratio Saliva 3469-69-0 229 4-{2-[2-(2(R)-Methyl-pyrrole-1-yl)-ethyl]-benzoquinone bite. South-6-yl b-1-phenyl ·1Η·pyrazole 4-iodo-1-phenyl-1H-P ratio σ sitting 23889-85-0 230 1-methyl-4-{2-[2(R)-(2-methyl bilo 11 Ding-1-yl)-ethyl]-benzofuran-6-yl}·1Η·imidazole 4-bromo-1-indenyl-1Η-°m° sitting 25676-75-9 231 4-{2-[ 2-(2(R)-methyl-oral ratio l-butyl-1-yl)-ethyl]-benzoquinone-n--6-yl}-^ 塞 吐 4-漠-viors 34259-99-9 232 2-{2-[2-(2(R)-methyl-pyrrole-1-yl)-ethyl]-benzoquinone pfluran-6-kib 1H-imidazole 2-iodo-1Η- 3034-62-6 233 4-{2-[2-(2(R)-Methylpyrrole-1-yl)-ethyl]-benzobenzoin-6-yl}-111-benzimidazole 4 -Bromo-1Η-benzimidazole 83741-35-9 234 3-Methyl-6-{2(R)-[2-(2-methyl-p ratio:-1-yl)-ethyl]- Benzoquinone bite 6-yl} -.荅p well 3-chloro-6-methyl-indole 1121-179-5 235 2-{2-[2-(2(R)-fluorenyl-pyrrolidine-1-yl)-ethyl]-benzene And biting each base}-^17 well 2-峨-峨耕32111-21-0 236 5-{2-[2-(2(R)-fluorenyl-pyrrolidone-1·yl)·ethyl] -Benzobenzoate 5-bromo-pyrimidine 4595-59-9 98683.doc -234· -6-ylpyrimidine 237 5-{2-[2-(2(R)-methyl-pyrrole bite-1- ))-ethyl]-benzoquinone p-fu-stone-based}-^17 well-4-ylamine odor-σ荅呼-4-ylamine 55928-90-0 238 5-{2-[2- (2(R)-fluorenyl-pyrrole-1-yl)-ethyl]-stupid and -6-yl}•---------- 5-bromo-nicotinyl nitrile 35590-37-5 239 4-{2-[2-(2(R)-indolyl-pyrrole-1-yl)-ethyl]-benzo-bite-6-yl}-1Η-吲哚4-bromo-1Η-啕哚52488-36-5 240 4-{2-[2-(2(R)-indolyl-pyrrole-1-yl)-ethyl]-benzoquinone-6-yl}-o-phenylene Nitrile 4-iodo-phthalonitrile 69518-17-8 241 5-{2-[2-(2(R)-indolyl-pyrrolidone-1-yl)-ethyl]-benzopyrene- 6-yl}-hydroquinone-1-one 5-a-gas-printed-1-steel 34598-49-7 242 1-{2-[6-(5,6-dihydro-2H-pyran-3- ))-benzoquinone-2-yl]-ethyl}-2(R)-fluorenyl-biloxi-5-bromo-3,6-dihydro-2Η-pyran 100130-39-0 2 43 1-[2-(6-Cyclohept-1-enyl-benzobenzo-2-yl)-ethyl]-2 (R)-methyl-p pirate 1-iodo-cycloheptene 49565-03-9 244 2(R)-mercapto-1-(2-{6-[2-(11Η-10-喽-dibenzo[a,d]cyclodextrin-5-yl)- Ethyl]-benzobenzopyran-2-ylethyl)-ρ piroxime 5-(2-"odor-extension ethyl)·5,11-diqi-10· s-dibenzo[a, d] cycloheptene 112930-54-8 245 4-{2-[2-(2(R)-fluorenyl-pyrrole-l-yl)-ethyl]-benzobenzoin-6-yl}- P-precipitate 4-bromopyridine 19524-06-2 246 4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzop-pentan-6- } 匕 匕 2- 漠 漠 漠 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 -04 。 98683.doc -235 - 1333489 Preparation of such compounds according to the procedure shown in Scheme 17 below

/ *· R5 = aryl or heterocyclic ring as shown in Scheme 17, treated with dichlorodi-triphenyl scales, moth copper, triethylamine and 3-butyne small alcohol 3_演-1,2 - Benzenediol, and heated to 4 (TC to 8 〇. = several hours, or until τιχ (thin layer chromatography) indicates that the reaction is completed until 2-(2-ethylidene) benzophenone is given _7_Alcohol. Then according to the procedure described in Scheme i5 for the example 2G3_224, Μ·ethyl) benzofuran-7-ol was treated to give 2_{2_[(2R) winter methyl small Pyrrolidinyl]ethylidene 1 - benzofuryl trifluoromethanesulfonate, treated as described in Murata et al, Journal 〇f 〇rganic Chemistry (2〇〇〇) 65, i64 i68, followed by In an organic solvent such as ethanol or tetrahydrop-pentane, at 25 ° C to 12 ° t, with a suitable starting material, such as an aryl halide, an aryl trifluorosulfonate or a heterocyclic halide, A palladium catalyst such as palladium(II) acetate, a trivalent phosphine such as biphenyl-2-dicyclohexylphosphine, and aqueous sodium or potassium phosphate are treated to give a compound of formula (53). The compound of formula (53) can be isolated and purified by methods known to those skilled in the art. For example, a compound of the formula can be partitioned between dichlorof-alkane and water, the organic phase is concentrated, and the residue is purified on silica gel by chromatography. An example of a compound can be prepared according to the procedure described in Scheme 17A, 98683.doc • 236 1333489 and the starting materials suitable for the preparation of such compounds are provided in Table 5 below. Table 5 Example No. Compound Starting Material Chemical Abstract No. 247 3,5-Dimethyl-4-{2-[2-(2-(2R)-methyl-pyrrolidin-1-yl)-ethyl]- Benzo-^fufu-7-yl}-iso, oxazole 4-iodo-3,5-dimethyl-iso-α 嗤10557-85-4 248 5-{2-[2-(2(R )-Methyl-pyrrole-1-yl)-ethyl]-benzoquinone-7-yl}-2-phenyl-oxazole 5 -> odor-2-phenyl^ olfactory 92629-11- 3 249 2-{2-[2-(2(R)-Methyl-pyrrole-1-yl)-ethyl]-benzoate. South-7-yl]'-p-Sev 2- 2-bromo-thiazole 3034-53-5 250 4-{2-[2-(2(R)-indolyl-pyrrolidine-1-yl)-ethyl] - benzoquinone -7-kib 1H-pyrazole 4-moth-lH-p ratio. Sitting 3469-69-0 251 4-{2-[2-(2(R)-methyl-pyrrolidin-1 -yl)-ethyl]-benzop-amino-7-yl}-1- Phenyl-1H-pyrazole 4-moth-1-phenyl-1Η-ρ ratio 88923889-85-0 252 1_ methyl_4-{2-[2(R)-(2-methyl-p ratio洛11-1-yl)-ethyl]-benzofuran-7-yl}-1 Η-imidazole 4-bromo-1-methyl-1 Η-mi. Sitting 25676-75-9 53 4-{2-[2-(2(R)-methyl-yttrium-decyl-1-yl)-ethyl]•benzopyran--7-ylexazole 4 - 塞塞吐34259-99-9 254 2-{2-[2-(2(R)-Methyl-pyrrolidine-1 -yl)-ethyl]-benzobenzoin-7-yl}-111 - Imidazole 2-峨-1Η-11 m. Sitting 3034-62-6 255 4-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzoquinone-n--7-yl}-1Η-benzo Imidazole 4-bromo-1Η-benzimidazole 83741-35-9 256 3-methyl-6-{2(R)-[2-(2-methyl-P than each bit-1-yl)-B Benzo]-benzofuran-7-yl}-indole 3-chloro-6-methyl-indole 1121-79-5 257 2-{2-[2-(2(R)-fluorenyl-pyrrole -I-yl)-ethyl]-benzo-p-pentan-2-base-ρ ratio 11 well 32111-21-0 98683,doc 237 - 1333489 -7-base}-0 to 17 well 258 5-{2- [2-(2(R)-Methyl-pyrrole-1-yl)-ethyl]-benzoquinone bite-7-yl}-mouth bite 5-bromo-pyrimidine 4595-59-9 259 5-{ 2-[2-(2(R)-methyl-pyrrole-1-yl)-ethyl]-benzoquinone bite ~N-7-yl}-嗒耕-4-ylamine 5-bromo-嗒4-ylamine 55928-90-0 260 5-{2-[2-(2(R)-methyl-pyrrolidone-1-yl)-ethyl]-benzobenzoin-7-yl} In the test of S basket wax 5-bromo-nicotinyl nitrile 35590-37-5 261 4-{2-[2-(2(R)-methyl-pyrrolidine-1-yl)-ethyl]-benzo Bite °N-7-yl}-1Η-啕哚4-bromo-1H-吲哚52488-36-5 262 4-{2-[2-(2(R)-methyl-pyrrolidone-1-yl )-ethyl]-benzoquinone-n--7-yl}-phthalic acid nitrile 4-moth-phthalonitrile 69518-17-8 263 5-{2-[2-( 2(R)-fluorenyl-pyrrole bit-1-yl)-ethyl]-benzo-bist-7-yl}murine-1-嗣5-moly-hydrogen莽-1-嗣34598-49-7 264 1-{2-[7-(5,6-Dihydro-2H-piperazin-3-yl)- awkward bite 17 Nan-2-yl]-ethyl b 2(R)-methyl-pyrrole Acridine 5-&gt; odor-3,6-dihydro^ 2H- shouting 100130-39-0 265 1 -[2-(7- gheptane-1 - fryyl-benzo-butan-2-yl)_ Ethyl]-2(R)-fluorenyl-batch 0 each bite 1-iodo-cycloheptene 49565-03-9 266 2(R)-methyl-1-(2-{7-[2-(11Η -10-thia-dibenzo[a,d]cyclohexadelidene-5-yl)-ethyl]•benzobis-n-yl-2-yl}-ethyl)-p 2-&gt;Smelly-extended ethyl)-5,11-two-rat-10-0 stopper·Benzene[a,d]cycloheptene 112930-54-8 267 4-{2-[2-(2(R )-Methyl-pyrrole-1-yl)-ethyl]benzoin-7-yl}-bite 4-bromopyridine hydrochloride 19524-06-2 268 4-{2-[2-( 2(R)-fluorenyl-yttrium-yttrium-l-yl)-ethyl]• stupid and pf-am-7-yl}-? 比淀2-indifferent bite 109-04-6 Example 269-283 98683.doc •238 · 1333489 Compound of formula (54)

Examples 269-283 are compounds of formula (54) wherein 116 is selected from the group consisting of imidazolyl, benzoxepylene, 3H-imidazo[4,5-c]p than bite, ratio η and p a heterocyclic ring, and wherein the heterocyclic ring may be 1, 2 or 3 selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkane Isosulfonyl, alkylsulfonyl, alkylthio, aralkyl, carboxyl, carboxyalkyl, cyano, cyano, base, _, halooxy, halogen Substituting a substituent of a carbonyl group, a hydroxyl group, a hydroxyalkyl group, a decyl group, a nitro group, an oxo group, a -NRARB, a (NRARB) alkyl group, a (NRaRb)carbonyl group, and a (nrarb)sulfonyl group; and RA*RB is in the formula (1) The definition in . Such compounds can be prepared according to the procedure shown in Schedule 18 below: Program 1 8

As shown in Scheme 18, 'in an organic solvent such as toluene, at 60 C to 140 ° C' is a palladium source, such as acetic acid (η), trivalent phosphine, like 疋1,1 -1 (biphenylphosphine) ferrocene, test, like CszC〇3, metal oxide oxide 'like third sodium butoxide, and appropriate starting materials like imidazolyl, stupid imidazolyl, 3H -Imidazo[4,5-c]pyridyl, pyrrolyl and pyrazolyl, treating (2R)-l-[2-(5-bromo-indolebenzoxan-2-yl)ethyl]_2_ Methylpyrrole' gives a compound of formula (54). The compound of formula (54) can be isolated and purified by methods known to those skilled in the art. For example, a compound of the formula (54) can be partitioned between dioxane and water, the organic phase is concentrated, and the residue is purified on a silica gel by chromatography. 98683.doc .239. 1333489 It is also possible to use a copper source, such as a stupid compound of copper trifluoromethanesulfonate (1), in an organic solvent such as xylene, at 100 ° C to 1501. A ligand, such as 1,10-phenanthrene-inorganic, trans, trans-di-n-butyl acetonide, is Cs2C〇3, and a suitable starting material, such as imidazolyl, benzimidazolyl , 3H-Mi. Sit and [4,5-c] P is more specific than sulfhydryl, P-bi-haki and p-saltyl, and (2R)-l-[2-(5-bromo-1-benzo ol. Ethyl]-2-indenyl p is a bite to prepare a compound of formula (54). Examples of compounds can be prepared according to the procedures described in Scheme 18, and starting materials suitable for the preparation of such compounds are provided in Table 6 below. Table 6 Example No. Compound Starting Material Chemical Abstract No. 269 l-{2-[2-(2(R)-Methylpyrrole-1-yl)-ethyl]-benzofuran-5-yl}-111 -Milybdenum-4,5-Deember 1H-imidazole-4,5-dicarbonitrile 1122-28-7 270 4,5-digas-l-{2-[2-(2(R)-methyl Bilo-1-yl)-ethyl]·benzofuran-5-yl}-1 imidazole 4,5-diqi-1H- miso 15965-30-7 271 l-{2-[2- (2(R)-Methyl p-Bistidin-1-yl)-ethyl]-benzofuran-5-yl}-11·!-Benzo-Stymidine 1H-Benzimidine η Sit 51-17 -2 272 3-{2-(;2-(2(Κ·)-methylρ than each bit-1-yl)-ethyl]-benzopyran-5-yl}-]!!-11 Rice saliva[4,5-c] ρ than bite 3H-imidazo[4,5-c] p bite 272-97-9 273 •&quot;sn λ (5-methyl-3-{2- [2-(2(R)-Mercaptopyrrolidin-1-yl)-ethyl] _ benzofuran-5-yl}-311-imidol-4-yl)-nonanol (5-hydroxyl) -3-3H-imidazol-4-yl)methanol 33457-48-6 Ζ/4 l-{2-[2-(2(k_)-fluorenyl p piroxicam-1-yl)-ethyl]- stupid And p. South_5-base}-111-叶匕'» each 1Η-ρ ratio.------ 109-97-9 98683.doc •240· 1333489 275 l-(l-{2 -[2-(2(R)-methylpyrrolidinyl-1-yl)-ethyl]-benzo-Binding 3-yl)-acetamidine 1-(1H-pyrrol-3-yl)-ethanone 1072-82-8 276 3-methyl-l-{2-[2-(2(R)-methyl? Bilolide-1-yl)-ethyl]-benzofuran-5-yl}-1Η-pyrrole 3-methyl-1H-pyrrole 616-43-3 277 l-{2-[2-(2( R)-Methylpyrrolidin-1-yl)-ethyl]-benzoquinone bite. South-5-yl}-3,4-di-tris-methyl-lH-p bilo 3,4-di- Dioxomethyl-lH-ρBilo 82912-41-2 278 l-{2-[2-(2(R)-methylpyrrole-1-yl)-ethyl]-benzo-bend-5 -基}-1Η-pyrazol-ρΛ0^ 288-13-1 279 4-methyl-l-{2-[2-(2(R)-methylρ比洛唆-1-yl)-B ]]-benzopyran-5-yl}-1Η-ρ than 嗤4-methyl-1Η-pyrazole 7554-65-6 280 l-{2-[2-(2(R)-methylpyrrole Ethyl-1-yl)-ethyl]-benzo 17-amino-5-yl}-1-pyrazole-4-carboxylate ethyl ester 1-pyrazole-4-carboxylic acid ethyl ester 37622-90-5 281 L-{2-[2-(2(R)-Methylpyrrolidine-1-yl)-ethyl]-benzobenzoin-5-yl} 1 Η-ρΛ 〇坐-4-月青11^ ratio. Sodium-4-nitrile 31108-57-3 282 4-gas-l-{2-[2-(2(R)-methyl? than each bit-1-yl)-ethyl]-benzofuran-5 -yl}-1Η-pyrazole 4-ox-1Η-pyrazole 15878-00-9 283 3,5-dimethyl-l-{2-[2-(2(R)-methylpyrrolidine-1 -yl)-ethyl]-benzofuran-5-ylindole-indole-pyrazole 3,5-dimethyl-1 fluorene-pyridyl ratio β sitting 67-51-6 Example 284-287 Compound of formula (55) Examples 284-287 are compounds of formula (55) wherein RA*R2() is as defined in formula (I). Such compounds can be prepared according to the procedure shown in Scheme 19: 98683.doc Program 19

1333489 As shown in Scheme 19, in an organic solvent such as F stupid, at 60 C to 140 C, palladium source, such as palladium acetate (π), palladium activated ligand, like l , r_bis(biphenylphosphine)ferrocene, tri-tert-butylphosphine, BINAP or 2-(di-tertiary-butylphosphine)·〇-biphenyl, or μ•diisopropyl Phenyl)-4,5-dihydroexazolidin-2-yl base, such as CS2C〇3' metal alkoxide, such as sodium tributoxide, and suitable starting materials such as or aryl a group, or a cycloalkyl group, wherein the heterocyclic, aryl or cycloalkane group has a -nhra substituent 'treated (211) small [2_(5-bromobenzophenan-2-yl) Ethyl]-2-methylindole is bitten to give a compound of formula (55). The compound of formula (55) can be isolated and purified by methods known to those skilled in the art: for example, a compound of formula (55) can be partitioned between a gas and a water, and the organic phase is concentrated and borrowed. The residue was purified by chromatography on silica gel. Examples of compounds can be prepared according to the procedures described in Scheme 19, and starting materials suitable for the preparation of such compounds are provided in Table 7 below. Example No. Compound Starting Material Chemical Abstract 284 (4_decyloxy-phenyl)-fluorenyl-{2-[2-(2(R)-fluorenyl-P-rhosinyl)-ethyl]- Benzobenzopyran-5-yl}-amine oxime methyl-p-amine 5961-59-1 285 stupid [i,3]-dioxapentan-5-yl-fluorenyl-{2-[2- (2-indolyl-pyrrolidin-1-yl)-ethyl]- benzofuran-5-ylbumine oxime [1,3] dioxapenta-5-yl-ethyl-amine 32953-14-3 286 cyclohexylmethyl-{2-[2-(2(R)-methyl-pyrrolidin-1-yl)-ethyl; 1-benzidine °N-5-yl}- Aminomethylcyclohexylamine 100-60-7 98683.doc •242. 1333489 287 ~ {2-[2-(2(R)-methyl-ϋ ratio η each bit _ 1-yl)-ethyl]- Benzopyrene peak _5-yl}-(tetrahydro-pyran-4-yl)-amine tetrahydro-piperidin-4-ylamine 38041-19-9 The compound of the present invention can exist as a stereoisomer There are asymmetric or chiral centers. These stereoisomers are &quot;R&quot; or &quot;s, depending on the configuration of the substituents around the anti-atomic hand of the hand. The terms &quot;r&quot; and &quot;S&quot; used in this article are followed. & meaning in IUPac 1974 Rec〇mmendati〇ns ~^Η〇η E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45. 13-30. The invention expects various &amp;isomers and mixtures thereof ' And is specifically included within the scope of the invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers which can be synthesized, from commercially available asymmetric or The starting material of the chiral center is used to prepare individual stereoisomers of the compounds of the invention, or by the preparation of racemic mixtures, followed by the dissociation well known to those skilled in the art. These examples are (1) mixtures of enantiomers. Attached to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography, and releasing an optically pure product from the adjuvant, or (2) in a chiral layer Direct separation of the mixture of optical enantiomers on the column. As used herein, "in a pharmaceutically acceptable carrier," - meaning non-toxic, inert solid, semi-solid or liquid filler, diluent two' material or any form of formulation aid. Some examples of materials for pharmaceutically acceptable carriers are sugars such as lactose, glucose and lactic sugars; temple powders, such as U rice powder and potato starch; cellulose and derivatives, such as a few Qian Weiqi, ethyl fiber and fiber (4) material of Huangqi knee; malt; gelatin; talc, · excipients, 98683.doc • 243 · 1333489 suppository 躐; oil, like peanut oil, cottonseed oil, Safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as hydroxide locks and hydrogen Oxidation; alginic acid; water without _ pyrogen; isotonic saline; Ringer's solution; ethanol and phosphate buffer solution, and other non-toxic compatible lubricants like dodecane Sodium sulphate and magnesium stearate, as well as coloring agents, release agents, Coating agents, sweeteners, flavorings and fragrances, antiseptic

Agents and antioxidants may also be present in the compositions, as judged by the skilled artisan. The invention provides pharmaceutical compositions comprising a compound of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical composition can be formulated into a solid or liquid form for oral administration, parenteral injection or rectal administration. It is also within the scope of the present invention to include a pharmaceutical composition comprising one or more compounds of formula lvh and is pharmaceutically compatible with - or a plurality of non-toxicities.

= Mixed mixing. The pharmaceutical composition can be formulated into a solid or liquid form for oral administration, parenteral injection or direct administration. The pharmaceutical composition of the present invention can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally (such as by powder, ointment or syrup), buccal, or by oral or thin: spray Objects are cast on humans and milk. As used herein, "parenteral, a method of administration, including intravenous, intramuscular, intraperitoneal, intrasternal, intradermal, dermal, and infusion. Gasoline injection: including pharmaceutically acceptable in the present invention Enteral pharmaceutical compositions 98683.doc -244- 1333489 Acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution in sterile injectable solutions or dispersions. Examples of non-aqueous carriers, dilutions, solvents or vehicles, including water, ethanol, more than 7 L of alcohol (propylene glycol, polyethylene glycol, glycerol, etc.), a suitable mixture, vegetable oil (like (iv) oil) and injectable Organic lining, such as oleic acid vinegar. For example, by using a coating such as a printing disc grease, in the case of dispersion, by maintaining the required particle size and by using a surfactant Appropriate fluidity. The compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. By means of various antibacterial and antifungal agents, for example, parabens, gas Alcohol, expectant, sorbic acid, etc., to ensure inhibition of micro-organism activity. It may also be desirable to include isotonic agents, such as sugars, sodium vaporized, etc. By using a delayed absorption preparation, such as monostearic acid Ming and gelatin, resulting in prolonged absorption of injectable pharmaceutical formulations. In some cases, in order to prolong the effect of the drug, it is usually desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be poorly water soluble by using it. A liquid suspension of crystalline or amorphous material is achieved. The rate of drug absorption will depend on the rate at which it is dissolved, depending on the crystal size and the crystal form, or by dissolving or suspending the drug in oily form. Delayed absorption of the parenterally administered drug form in the vehicle. In addition to the active compound, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and Sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof. ' 98683.doc -245- 1333489 If needed, and for more Effectively distributed, the compounds of the invention can be incorporated into slow-release or targeting-delivery systems, such as polymer matrices, vesicles, and centrosomes. For example, by filtering through a filter paper that leaves bacteria, ' It is sterilized by combining it with a human sterilizing agent in the form of a solid composition without g, which is dissolved in sterile water, or some other sterile injectable medium, before use.

The active compound may also be in the form of micro-encapsulated, if appropriate, one or more of the above-mentioned excipients. The use of coatings or shells, such as casings, controlled release coatings, and other coatings well known in the art of pharmacy, can be used to prepare keying agents, dragees, capsules, pills, and granules (4) in such solid dosage forms. 'The active compound can be mixed with at least one inert diluent such as a sugar, lactose or a powder. In normal practice, such dosage forms may also include other materials than inert diluents, such as ingot lubricants and other substances that help form lozenges, such as stearic acid green and

(d) In the case of capsules _ and pills, the dosage form may also include a buffer. It may optionally contain an opacifying agent and may also delay the release of the active ingredient (5) in such a portion of the intestinal tract only or preferentially. Examples of useful compositions for burying humans include polymeric substances and soils by biodegradable granules, such as polylactide-polyglycolide-type microencapsulated drugs. Medium to create a storage form that can be &amp; The rate at which the drug is released can be based on the ratio of the drug to the polymer and the nature of the particular polymer used in the application. And Xiandou private π μ Α , an example of his biodegradable polymer encapsulation (orthoester) and poly (anhydride). It is also possible to prepare a storage injectable preparation by allowing the substance to enter into a liposome or microemulsion of body composition 98683.doc * 246 - 1333489. : For example, by transitioning through the paper leaving the bacteria, or by taking the form of the solid composition in the form of a solid composition (4), the formulation of the main shot is smashed and dissolved or divided before use. Fresh knives are scattered in sterile water or other innocent injection media. According to known techniques, sowing pain a. ^ Use suitable dispersing or wetting agents and suspending dips to formulate injectables such as sterile aqueous or oily-injected solutions for injection. The preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic, parenteral or solvent, in 1,3-butanol. In acceptable vehicles and solvents Medium's use of water, Ringer's solution, usp and isotonic chlorinated steel solutions. In addition, 'sterilized S] oil is traditionally used as a solvent or suspension medium. For this purpose, any non-irritating fixation can be used. Oils include synthetic mono- or diglycerols. In addition, fatty acids such as oleic acid may be used in the preparation of injectable preparations. Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms, the active compound is combined with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or acid, and/or a) filler or extender. Like starch, lactose, Yan , glucose, mannitol and salicylic acid; b) binders, such as ketone cellulose, alginate, gelatin, polymethylene (four) (four), (four) and gum arabic 'c) moist, I, like glycerin; d) Disintegration, such as cyclolipid-cyclolip, calcium carbonate, potato or tapioca starch, alginic acid, certain citrates and sodium carbonate; e) solution blockers, like paraffin; f) absorption accelerators, like Is a quaternary ammonium compound 98683.doc -247- 1333489; g) a humectant, such as a whale licking stupid B Guzheng 4·1 hard moon 醆 醆 monoglyceride; 匕) absorbent, like 疋同岭土And bentonite clay; calcium acid, hui (four) money and 0 lubricant 'like talc, stearin, magnesium stearate, solid poly-r-compound, 曰8... 12-sodium sulfate and its mixture ^ In the case of 柙乐丸, the dosage form may also include a buffering agent. It may also be in a soft and hard filling sac of lactose or lactose and a high molecular weight polyethylene glycol as an excipient. Solids as a filler. ' Available in paints or shells, like the county wax ^ # 保疋 casings and other in the pharmaceutical blending skills The well-known coatings are used to prepare tablets, tablets, capsules, granules and granules in the form of solid bismuth. It can be used as a total amount of opaque agent, and can also be delayed in the way of 'fourth' The substance is only released or preferentially released in certain parts of the intestinal tract. The examples which can be used for embedding the composition include polymeric substances and waxes. Compositions for rectal or vaginal administration are the most Preferably, a suppository can be formulated by mixing a compound of the present invention with a suitable non-irritating fumigant @ or a carrier, such as cocoa butter, "b: alcohol or suppository", which is solid at ambient temperature. However, it is liquid at body temperature and thus melts in the rectum or vaginal cavity to release the active compound. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, suspensions, suspensions, syrups Harbin agent. In addition to the active compound, liquid dosage forms may contain inert diluents which are often employed in the art such as, for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, acetic acid Ethyl ester, benzofuranol, benzoic acid ester, 98683.doc * 248 - 1333489 Propylene glycol, 13 3 butyl alcohol, dimethyl ketone amine, oil (especially cottonseed oil, :, rice) Oil, germ oil, olive oil, pen sesame oil and sesame oil), mixed with Gan: The fatty acid esters of furam methanol, polyethylene glycol and sorbitan, and the inert diluents may also include agents, emulsifiers and suspending agents, sweeteners, flavoring agents and perfumes.疋』 Ben:: The dosage of the compound or percutaneous administration of the compound =: arsenic rj, gel, powder, solution, spray, and the sputum of the squid (,, under the conditions of the bacteria, the active component and Pharmaceutically acceptable: human and any necessary preservatives or buffers that may be required: 2 also attempts to include ophthalmic formulations, eye drops, eye drops and body washes within the scope of the present invention. In addition to ointment, ointments, ointments, creams and gels can also be used as excipients like animal and vegetable fats, oils, soils, stone soils, temple powders, sputum gums, cellulose derivatives, poly Ethylene glycol, anthrone, sulphate, citric acid, talc, and zinc oxide, or a mixture thereof. In addition to the compound of the present invention, the powder and the spray may also contain a shaped d-like sugar, talc, and oxalic acid. , gas oxidation, oxalic acid and polystyrene powder 'or mixture of some substances. Spray may additionally contain traditional propellant 'like gas-containing fluorocarbons. Can also be administered in the form of micro-lipids (4) a compound of the formula. As is known in the art, microlipids are usually derived from (4) His lipid substance. Disperses the microfilaments formed by mono-d hydrated liquid crystals in aqueous capsules. Any non-toxicity capable of forming vesicles can be used, physiologically 98683.doc -249-1333489 is acceptable and Metabolizable lipids. The compositions of the invention in the form of vesicles may contain, in addition to a compound of the invention, stabilizers, preservatives, excipients, etc. Preferred lipids are natural and synthetic, separately or together. Phospholipids and phospholipids Choline (lecithin). Methods of forming vesicles are known in the art. See, for example,

Prescott, eds., Methods in Cell Biology, Book xiv, Academic

Press, New York, N.Y., (1976), page 33 below. The term "learnably acceptable salts, vinegars, and amines" as used herein means a carboxylate, an amino acid addition salt, a zwitterion, an ester of a compound of formula I-VII. And guanamines, which are suitable for contact with human and lower animal tissues in sound medical judgment, without undue toxicity, irritation, allergic reactions, etc., in accordance with reasonable benefits/risk ratios, and for It is effective for the intended use. The compound of the present invention can be used to form a pharmaceutically acceptable salt derived from an inorganic or organic acid. In a pharmaceutically acceptable salt, it means a sound medical judgment. Within the scope of 'is suitable for contact with human or lower animal tissues, without undue toxicity, irritation, allergic reactions, etc., and in accordance with reasonable benefits/risk ratios. This is the pharmaceutically acceptable salt. It is well known in the art. For example, SM Berge et al., J. Pharmaceutical Sciences, 1977, 66: 1 below, describe pharmaceutically acceptable salts in detail. During the final isolation and purification of the compounds of the invention, Salts are prepared or prepared by reacting a free base function with a suitable organic acid, respectively. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citric acid Salt, aspartate, benzoate, benzene 98683.doc -250-1333489 Continuous acid salt, hydrogen sulphate, butyrate, camphorate, camphor sulfonate, digluconate, glycerol phosphate Salt, hemi sulphate, heptanoate, hexanoate, methacrylate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate Salt), lactate, maleate, methanesulfonate, nicotinate, 2-anthracene sulfonate, oxalate, hydroxamate, pectate ester, peroxoic acid Salt, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p- Toluene sulfonate and undecanoate. Also useful are, for example, lower alkyl alkyl carbides such as decyl, ethyl, propyl and butyl, bromine and iodine; dialkyl sulfates, Is dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides like sulfhydryl, lauryl, broth and stearyl sulfonate, bromine and moth; aryl Halides, such as benzyl and phenethyl bromide, and other preparations, record the nitrogen-containing groups in a four-stage manner, thereby obtaining a product soluble in water or oil, or dispersible. Examples of pharmaceutically acceptable acid addition salt acids include inorganic acids such as hydrogen acid, hydrogen desert acid, sulfuric acid, and dish acid, and such as oxalic acid, cis-succinic acid, succinic acid, and citric acid. The organic acid can be prepared in situ during the final isolation and purification of the compound of the invention by reacting the carboxylic acid-containing moiety with a suitable base, such as a pharmaceutically acceptable metal cation. Hydroxide, carbonate or bicarbonate, or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal based cations such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like, and non-toxic tertiary amines and amines. Cation, including Syria, Sijiaxu, Siyilu, A 98683.doc -251-1333489 Amine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines which can be used to form base addition salts include ethylenediamine, ethanolamine, diethanolamine, hexahydropyridine, hexahydropyridinium and the like. Preferred salts of the compounds of the invention include phosphates, tris(hydroxymethyl)aminodecane and acetate. The term &quot;in pharmaceutically acceptable ester&quot; as used herein, means an ester of a compound of the invention which hydrolyzes in vivo and rapidly disintegrates in the human body, leaving the parent compound or a salt thereof. Examples of pharmaceutically acceptable non-toxic esters of the present invention include C!-to-C6 alkyl esters, and C5_ to _c7 cycloalkyl vinegars, although c 1 · to -C 4 alkanes are preferred. Base ester. The g-type of the compound of the formula I-VII can be prepared according to a conventional method. The term "pharmaceutically acceptable indoleamine" as used herein means the invention derived from ammonia, a primary Ci- to -C6 alkylamine, and a secondary C,- to -C6 dialkylamine. Non-toxic guanamine. In the case of a secondary amine, the amine may be in the form of a 5- or 6-membered heterocyclic ring containing i nitrogen atoms. Amine derived from ammonia, to a -C3 alkyl primary guanamine And (^- to ^2 dialkyl secondary decylamine is preferred. The guanamine of the compound of the formula ΙνΐΙ can be prepared according to a conventional method. The "pharmaceutically acceptable prodrug" as used herein or "Prodrug, a medicinal, means a prodrug of a compound of the invention, within the scope of sound medical judgment, suitable for contact with tissues of humans and lower animals, without undue toxicity, irritation, allergic reaction." Etc., in accordance with a reasonable benefit/risk ratio, and is effective for its intended use. The prodrugs of the present invention can be rapidly converted in vivo to the parent compound of formula I-VII, for example by blood. Hydrolysis. At T. Higuchi and V Stella, pr〇drugs as N〇vel

Delivery Systems, Volume 14 of the A.C.S. Symposium Series, and 98683.doc -252· 1333489 Edited by Edward B. Roche, Bi〇reversible Carriers in Drug

A detailed discussion is provided in Design, American Pharmaceutical Association and Pergamon Press (l 987), which is incorporated herein by reference. Dosage forms for topical administration of a compound of the invention, including powders, mouth sprays, ointments and inhalants, under sterile conditions, the active compound with pharmaceutically acceptable carriers, and any necessary preservatives, buffers The solution, or a mixture of propellants that may be needed. It is also intended to include ophthalmic formulations, eye ointments, powders and solutions, within the scope of the invention. The actual dosage of the active ingredient in the pharmaceutical compositions of the present invention can be varied to provide an effective amount of active compound(s) effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration. The amount of the agent selected will depend on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the medical history of the patient to be treated. However, it is within the skill of the art to start at a lower dose of the compound than is required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The pharmaceutically active compounds contemplated by the present invention are chemically synthesized or formed by biotransformation into a compound of the formula in vivo. The compounds of the invention, including but not limited to those specified in the examples, have an affinity for histamine. As a histamine-3 receptor complex, the compounds of the present invention are useful for treating and preventing diseases or conditions such as acute myocardial infarction, Alzheimer's syndrome, over-reaction hyperactivity disorder, bipolar disorder, Cognitive improvement, cognitive deficits in mental disorders, 98683.doc -253 - 1333489 Drug abuse, memory and learning deficits, jet lag, Parkinson's disease, epilepsy, schizophrenia, dementia, depression, skin cancer, moderate Cognitive impairment, medullary thyroid cancer, melanoma, allergic rhinitis, asthma, narcolepsy, mood and attentional changes, ear vertigo, gastrointestinal disorders, inflammatory response, migraine, motion sickness, neurogenic Sexual inflammation, obsessive-compulsive disorder, Duruit's syndrome, obesity, pain's onset, septic shock, dizziness, and insomnia.

By Imamura et al, Circ. Res., (1996) 78, 475-481; Imamura et al, Circ. Res., (1996) 78, 863-869; R. Levi and NCE Smith, &quot; histamine H3-receptors: A new frontier in myocardial ischemia&quot;, J. Pharm. Exp. Ther., 292:825-830, (2000); and Hatta, E., K Yasuda and R. Levi, "Activation of histamine H3 receptor, inhibits vector-regulated norepinephrine release in a human model of prolonged myocardial ischemia (Activation of histamine H3 receptors inhibits carrier -mediated norepinephrine release in a human model of protracted myocardial ischemia)&quot;, J. Pharm. Exp. Ther., 283:494-500, (1997), demonstrating compounds of the invention, including but not limited to those specified in the examples Those who are capable of treating septic shock and cardiovascular disorders, particularly acute myocardial infarction. By Lin et al, Brain Res. (1990) 523, 325-330; Monti et al, Neuropsychopharmacology (1996) 15, 31-35 ; Sakai et al., Life Sci. (1991) 48, 2 397-2404; Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67,75-78; 98683.doc -254- 1333489

Panula, P. et al., Neuroscience (1998) 44, 465-481; Wada et al, Trends in Neuroscience (1991) 14, 415; and Monti et al, Eur. J. Pharmacol. (1991) 205, 283, confirmed Compounds of the invention, including but not limited to those specified in Example 10, are capable of treating sleep disorders, particularly narcolepsy.

By Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78; Panula, Ρ· et al, Neuroscience (1997) vol. 82, 993-997; Haas et al., Behav Brain Res. (1995) 66, 41-44; De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986) 283, 193-198; Kamei et al.

Psychopharmacology (1990) 102, 312-318; and Kamei and Sakata, Jpn. J. Pharmacol. (1991) 57, 437-482; Schwartz et al, Psychopharmacology; The fourth Generation of Progress. Bloom and Kupfer (ed.) Raven Press , New York, (1995) 397; and Wada et al, Trends in Neurosci., (1991) 14, 415, demonstrating compounds of the invention, including but not limited to those specified in the examples, in the treatment of cognitive and memory dysfunction Ability on the ground. By Shaywitz et al., Psychopharmacology (1984) 82, 73-77; Dumery and Blozovski, Exp. Brain Res. (1987) 67, 61-69; Tedford et al., J. Pharmacol. Exp. Ther. (1995) 275, 598-604; and Tedford et al, Soc. Neurosci. Abstr. (1996) 22, 22, demonstrating compounds of the invention, including but not limited to those specified in the examples, in the treatment of over-reaction with attention deficit Ability on the disease (ADHD). 98683.doc • 255- 1333489 by Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129; Yokoyama and Iinuma, CNS Drugs (1996) 5, 321; Onodera et al., Prog. Neurobiol (1994) 42 685; R. Leurs, RC Vollinga and H. Timmerman, &quot;Therapeutic potential of the ligands of histamine H3 receptors (The medicinal chemistry and therapeutic)

Potentials of ligand of the histamine H3 receptor)&quot;, Progress in Drug Research 45:170-165, (1995); Leurs and Timmerman, Prog. Drug Res. (1992) 39, 127; The Histamine H3 Receptor, Leurs and Timmerman (ed.), Elsevier Science, Amsterdam, The Netherlands (1998); H. Yokoyama and K. Iinuma, "Histamine and Seizures: Implications for the treatment of epilepsy", CNS Drugs, 5(5); 321-330, (1995); and K. Hurukami, H. Yokoyama, K. Onodera, K. Iinuma and T. Watanabe, AQ-0145, &quot; Recently developed histamine H3 antagonists A newly developed histamine H3 antagonist, decreased seizure susceptibility of electrically induced convulsions in mice&quot;, Meth. Find. Exp. Clin. Pharmacol., 17(C) :70-73 (1995), demonstrates the ability of the compounds of the invention, including but not limited to those specified in the examples, to treat episodes, particularly epilepsy. By Onodara et al., Prog. Neurobi Ol. (1994) 42,685; Leurs and Timmerman, Prog. Drug Res. (1992) 39,127; and Histamine H3 Receptor, Leurs and Timmerman (ed.), Elsevier Science, Amsterdam, The Netherlands (1998), 98683.doc -256- 1333489 demonstrates the ability of the compounds of the invention, including but not limited to those specified in the examples, to treat motion sickness, Alzheimer's syndrome, and Parkinson's disease. By R. Leurs, RC Vollinga and H. Timmerman, "The medicinal chemistry and therapeutic potentials of ligand of the histamine H3 receptor", Progress in Drug Research 45: 170-165, (1995); Histamine H3 Receptor, Leurs and Timmerman (eds.), Elsevier Science, Amsterdam,

The Netherlands (1998) ; and Perez-Garcia C, et al., Laboratory of Pharmacology,

University of San Pablo CEU, Madrid, Spain, Psychopharmacology (Berl) (1999) Feb., 142 (2): 215-20, demonstrating compounds of the invention, including but not limited to those specified in the examples, in the treatment of episodes Ability to sleep, schizophrenia, depression and dementia.

The compounds of the invention, including but not limited to those specified in the examples, can be demonstrated by (Schwartz, Physiol. Review (1991) 71, pp. 1-51) in the treatment of insomnia, cognitive improvement, mood and attentional changes , dizziness and motion sickness, and the ability to treat cognitive deficits in mental disorders. By (CE Tedford, "The Histamine H3 Receptor: a target for new drugs" &quot; Ί 7, the Pharmacochemistry Library, Vol. 30 (1998), R. Leurs And H. Timmerman, Elsevier (New York), page 269, and incorporated herein by reference, for the purposes of the present disclosure, the disclosure of which is incorporated herein by reference in its entirety, in Moderate cognitive impairment, memory deficits, learning deficits, and dementia abilities. By Leurs et al., Trends in Pharm. Sci. (1998) 19, 177-183; Itoh. E., Fujimiay, M., and Inui, A., thioperamide, a histamine H3 receptor antagonist, potently suppresses peptide YY-induced food intake in rats (Thioperamide, A histamine H3 receptor)

Antagonist, powerfully suppresses peptide YY-induced fodd intake in rats), Biol. Psych. 45(4): 475-481 (1999); Yates SI·, Pawlowski, GP, Antal, JM, Ali, SM, Jiang, J. , and Brunden, KR, a novel histamine H3 receptor antagonist, GT-2394, in Sprague-Dawley rats, Effects on a novel histamine H3 receptor antagonist (GT-2394, On food intake and weight gain in Sprague-Dawley rats), Abstracts, Society for Neuroscience, 102.10, page 219, November, (2000); and Bjenning, C., Johannesson, U., Juul, AG., Lange, KZ, and Rimvall, K., peripherally administered ciprofloxacin, elevated the hypothalamic histamine content in Sprague Dawley rats and effectively reduced the food intake (Peripherally administered ciproxifan elevates hypothalamic histamine levels and Potently reduces food intake in the Sprague Dawley rat.), Abstracts, International Sendai Histamine Symposium, Sendai, Japan, November, 2000, #P 39, confirming the compound of the present invention, package These include, but are not limited to, those specified in the examples, the ability to treat obesity. By Phillips et al., Annual Reports in Medicinal 98683.doc -258- 1333489

Chemistry (1998) 33, 3 1-40, demonstrates the ability of the compounds of the invention, including but not limited to those specified in the examples, to treat inflammatory responses and pain. The medicinal chemistry and therapeutic potential of the ligands of histamine H3 receptor by R. Leurs, R_C. V oiling a and H. Timmerman, &quot;The medicinal

Chemistry and therapeutic potentials of ligand of the histamine H3 receptor)&quot;, Progress in Drug Research 45:170-165 (1995); and Matsubara et al, Eur. J. Pharmacol. (1992) 224,145; and Rouleau et al. J. Pharmacol. Exp. Ther. (1997) 281, 1085, demonstrates the ability of the compounds of the invention, including but not limited to those specified in the examples, to treat migraine.

By the role of Polish Med. Sci. Mon., (1998), Vol. 4, No. 5, 747; Adam Szelag, &quot;Histamine H3-receptor in the proliferation of neoplastic cells in vitro (Role of Histamine H3-receptors in the proliferation of neoplastic cells in vitro)&quot;, Med. Sci. Monit., 4(5): 747-755, (1998); and Fitzsimons, C., H. Duran, F.

Labombarda, B. Molinari and E. Rivera, &quot;Histamine receptors signalling in epidermal tumor cell lines with H-ras gene alterations&quot;, Inflammation Res., 47 (Appendix 1): S50-S51, (1998), demonstrating compounds of the invention, including but not limited to those specified in the Examples, in the treatment of cancer, particularly melanoma, skin cancer and medullary thyroid The ability to cancer. The medicinal chemistry and therapeutic potentials of ligands of R. Leurs, RC Vo 11 inga and H. Timmerman, &quot;histamine 98683.doc •259-1333489 H3 receptors The histamine H3 receptor)&quot;, Progress in Drug Research 45: 170-165, (1995), demonstrating compounds of the invention, including but not limited to those specified in the examples, in the treatment of vestibular dysfunction, particularly otic vertigo The ability to be sick. Delaunois A., Gustin P., Garbarg M., and Ansay M., "In the isolated lungs of rabbits, the effects of acetylcholine, capsaicin and substance P are regulated by histamine H3 receptors ( Modulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungs)&quot;, European Journal of Pharmacology 277 (2-3): 243-50, (1995); and Dimitriadou et al., "in rats In the lungs and spleen, regulated by histamine H3-receptors, demonstrating a functional relationship between mast cells and C-sensitive nerve fibers

(Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen) 1', Clinical Science, 87(2): 151-63, (1994), confirming the compound of the present invention, These include, but are not limited to, those specified in the examples, the ability to treat asthma. The ability of the compounds of the invention, including but not limited to those specified in the examples, to treat allergic rhinitis can be demonstrated by McLeod et al, Progress in Resp. Research 31, 133 (2001). The aqueous liquid composition of the present invention is particularly suitable for the treatment and prevention of asthma, epilepsy, Raynaud's syndrome, male sexual dysfunction, 98683.doc - 260 - female land steepness, this disorder, migraine, pain, eating Disorders, urinary incontinence, functional bowel disorders, neurodegeneration, and bursts. When used in the above or other treatments, the field may be used in a pure form or in the form of a salt, an anthraquinone, a guanamine or a prodrug in the form of a drug, which is therapeutically effective. a compound of the invention. Alternatively, the compound can be administered in the form of a pharmaceutical composition of interest mixed with a pharmaceutically acceptable excipient. The term &quot;content effective for mu treatment&quot; of the compounds of the invention means a compound that is sufficient to treat the disorder at a reasonable benefit/risk ratio applicable to any medical treatment. However, it will be understood that the clinical care will be taken care of. Physicians, within the scope of sound medical judgment, determine the total daily usage of the compounds and compositions of the present invention. The therapeutically effective dosage levels specified for any particular patient will depend on a variety of factors including the disorder to be treated. And the severity of the disorder; the activity of the indicated compound used; the specified composition used; the age, weight, general health, sex and diet of the patient; the time of administration, the route of administration, and the designation used. The rate of excretion of the compound; the period of treatment; the drug used in conjunction with or concurrent with the specified compound used; and such factors well known in the medical arts, for example, at lower doses required to achieve the desired therapeutic effect. The starting dose of the compound, and gradually increase the dose until the desired effect is achieved, is in this skill The total daily dose of the compound of the invention administered to humans or lower animals may range from about 0.003 to about 30 mg/kg/day. For oral administration, the preferred dosage may range from about 0.1 to about In the range of 1 5 mg / kg / day. If necessary, 98683.doc -26! - 1333489 can be divided into several doses for effective daily dose; therefore, a single dose of the composition can contain such a content, Or a fraction thereof, in order to constitute each dose. Of course, the foregoing detailed description and accompanying examples are intended to be illustrative, and are not intended to limit the scope of the invention It is to be understood that various changes and modifications of the specific embodiments disclosed herein will be apparent to those skilled in the art. Chemicals, Substituents, Derivatives, Intermediates, Synthesis, Formulation, and/or Formulations: 2. All references cited herein are incorporated into the text. In contradictory cases 'This disclosure Content, including the definition of a dominant Let dagger Hu Cloth and righteousness will 98683.doc

Claims (1)

1333489 No. TM Patent Application, Chinese Application Specific Miscellaneous (%Ά1 &amp; Jcj * Patent Application Range: i—— 1. A Compound of Formula (I) Rer7 or a pharmaceutically acceptable salt, ester, guanamine or prodrug thereof, wherein A is a covalent bond; D is hydrazine; L is selected from the group consisting of a lower alkyl alkyl group, a fluoroalkyl group, and a hydroxyalkylene group. P and Q together form a covalent bond or both are hydrogen; R1 and Κ·2 are respectively selected from the group consisting of an alkyl group, an aryl group, an aryl group, a cycloalkyl group, a cycloalkyl group, a heterocyclic ring, a heterocycloalkyl, hydroxyalkyl, alkenyl and alkynyl group; or 1 and r2 together with a nitrogen atom attached thereto form a heterocyclic ring; R3 is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, Alkylcarbonyl, pyrenyloxy, alkyl sulfhydryl, alkyl, thiol, aryl, sulfhydryl, slow-burning, cyano, cyanogen, formazan, halogen, Haloalkoxy, _alkyl, heterocyclic, hydroxy, hydroxyalkyl, decyl, nitro, -NRaRb, (nrarb)alkyl, (NRARB)carbonyl and (NRARB)sulfonyl; R4, R5, ruler 6 And 117 are respectively selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxyl, Carboxyalkyl, cyano, cyanoalkyl, ring Alkyl, fluorenyl, halogen, haloalkoxy, haloalkyl, heterocyclic, hydroxy, hydroxyalkyl, decyl, nitro, -nrarb, (nrarb)alkyl, (nrarb) 98683-990723.doc 1333489 Thus, (NRaRb) continuation base, · LaRzc) and -R2 () L3R22; 1 L2 is selected from the group consisting of S, s(o), s(o)2, c(=o), c=(NOR21) and N(RA); w L3 is selected from the group consisting of a covalent bond, an alkylene group, an alkenyl group, an anthracene, an s, a c-diazine, N(=〇R2i), and N(RA); And a heterocyclic ring and a cycloalkyl group; R21 is selected from the group consisting of hydrogen and alkyl; R22 is selected from the group consisting of an aryl group, a heterocyclic ring and a cycloalkyl group; φ Ra*Rb is respectively selected from the group consisting of an alkylcarbonyl group and a carbenyl group; At least one of R4, R5, R6 and L is -L2R2〇. 2. The compound according to claim 1, wherein one of the substituents R4, R5, 1 and 7 is _L2r2〇; and the other substituents of R5, R6 and I are respectively selected from the group consisting of Hydrogen and alkyl. 3. The compound according to claim 3, wherein R4, R5, 1 and 117 are respectively selected from the group consisting of hydrogen, alkyl, heterocycle, _L2R2〇 and -R20L3R22. From 4. According to the scope of the patent application! a compound selected from the group consisting of (3 phenyl) (2-{2-[(2R)_2-methyl oxime oxime] ethyl H-benzo benzo-5-yl) Ketone; (2-fluorophenyl) (2-{2_[(2R)_2-methyl each octa] ethyl} small benzofuran-5-yl) fluorenone; (3-phenylphenyl) ( 2-{2.[(2R)_2_Methyl small ^ each base] ethyl}-1 benzopyran-5-yl)methanone; ('chlorophenyl) (M2-[(2R)- 2-methyl-1-pyrrolidinyl]ethyl}-1 -benzene 98683-990723.doc 1333489 and furan-5-yl)fluorenone; (4-methoxyphenyl) (2-{2-[( 2R)-2-methyl-1-pyridinyl]ethyl}small benzofuran-5-yl)anthone; (4-fluoro-3-indolyl) (2-{2-[(2R) -2-methyl small, pyridyl]ethyl}-1-benzopyran-5-yl)anthone; (4-chloro-3-indolyl) (2-{2-[( 2R)-2-methyl·bu,pyrrolidyl]ethyl}-1-benzofuran-5-yl)anthone; (2-{2-[(2R)-2-mercapto-1- Pyrrolidinyl]ethylbub benzofuran·5-yl)[4-(methylthio)phenyl]anthone; [4-(didecylamino)phenyl](2_{2_[(2R)_2 _Methylpyrrolidinyl]ethyl}-1-benzopyran-5-yl)methanone; (4-tolyl)(2-{2-[(2R)-2-mercapto-1-pyrrole) Pyridyl Ethyl i benzofuran-5-yl) fluorenone; (3,5-difluorophenyl)(2-{2-[(2R)-2-methyl-;;·, pyrrolidinyl) Ethyl}-1-benzofuran-5-yl)methanone; (2-methoxyphenyl) 2-(2-[(2R)-2-ylindolylpyrrolidyl]ethyl }Small benzofuran-5-yl)fluorenone; (3-_2-((2R)-2-methyl-p-pyrrolidyl)ethyl}-benzopyrene喃-5-yl)曱_ ; and (2-{2-[(2R)-2-fluorenyl············· - A pharmaceutical composition for selectively modulating histamine-3 receptor in a mammal comprising a therapeutically effective amount of a compound of the scope of claim ii, and a pharmaceutically acceptable carrier. 98683- 990723.doc 1333489 • The use of a compound according to claim 1 in the manufacture of a medicament for the selective modulation of the effects of histamine-3 receptor in a mammal. The use of a compound of the first item for the manufacture of a medicament for use in a mammal to modulate a histamine-3 receptor to ameliorate a condition. The use of item 7, wherein the condition is selected from the group consisting of acute myocardial infarction, asthma, bipolar disorder, cognitive improvement, cognitive deficit in mental disorders, skin cancer, drug abuse, depression, gastrointestinal disorders, inflammatory response, Jet lag, medullary squamous cell carcinoma, melanoma, allergic rhinitis, ear vertigo, migraine, mood and attention changes, motion sickness, neurogenic inflammation, obsessive-compulsive disorder, pain, Parkinson Disease, schizophrenia, seizures, septic shock, Duruit's syndrome, dizziness and insomnia. 98683-990723.doc