TW200813011A - 3-azabicyclo [3.1.0] hexane vanilloid receptor ligands, pharmaceutical compositions containing them, and processes for their preparation - Google Patents

Abstract

The present invention relates to substituted 3-azabicyclo [3.1.0] hexane derivatives, which are useful as vanilloid receptor ligands, methods of treating diseases, conditions and/or disorders modulated by vanilloid receptors with them, and processes for preparing them.

Description

200813011 IX. INSTRUCTIONS: INSTRUCTIONS This application claims Indian Patent Application No. 1136/MUM/2〇〇6 and No. 381 5/MUM/ filed on July 17, 2006 and February 27, 2007. US Provisional Patent Application Nos. 60/835,560, 60/893,675, and 60/974,715, filed on August 3, 2006, March 8, 2007, and July 2007 All of these patent applications are incorporated herein by reference.

FIELD OF THE INVENTION The present invention relates to substituted 3-azabicyclo[3.1.0]hexane derivatives which can be used as ligands for vanillin receptors, and the use of these treatments for vanilla extracts And methods of modulating diseases, disorders, and/or disorders, and methods for their preparation. [Prior Art 3 15 Background] Pain is the most common symptom of a patient's consultation and treatment. The pain can be acute or chronic pain. Although acute pain is usually self-limiting, chronic pain can last for 3 months or longer and can lead to significant changes in patient personality, lifestyle, function, and overall quality of life (Κ·Μ· Foley, Pain, in Cedi 20) Textbook of Medicine 100-107, J. C. Bennett and F. Pium eds, 20th edition, 1996). Sensory neurons that can be painful by any physical or chemical stimuli and that mediate the response of these noxious stimuli are commonly referred to as "pain receptors." Pain receptors are primary sensory afferent (C and A5 fibers) neurons that are activated by a variety of noxious stimuli, including chemical, mechanical, thermal, and proton (pH <6) forms. Moreover, 'chronic pain can be classified as nociceptive or neurogenic pain. Nociceptive pain includes pain and inflammation induced by tissue damage, such as pain associated with arthritis. Neurogenic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by an abnormal somatosensory treatment procedure. There is considerable evidence for the activity of the vanilla extractor (VR1) on the pain management process (ν· Di Marzo et al.

Current Opinion in Neurobiology 22: 372-379, 2002). It is known that lipophilic vanilla extracts, Capsaicin (8-methyl-N-fragrant 10 turf-6-nonene amide; CAP), can be selected by specific cell surface capsaicin receptors. As a first vanilla extractor (VR1, now called TRPV1), it releases various sensory afferent neurotransmitters to stimulate pain pathways (Caterina MJ, et al., Science, Apr 14; 2M (5464): 306-13 , 2000). Capsaicin is the main spicy component of pepper. Traditionally, pepper has not only been used as a seasoning' but also as a traditional oral drug for treating stomach diseases, and can be administered locally to alleviate pain and inflammation. CAP has a broad-spectrum biological effect and not only has an effect on the cardiovascular and respiratory systems, but also induces pain and irritation once administered topically. However, after pain is induced, CAP can induce desensitization of CAP itself and other harmful stimuli, thereby relieving pain. CAP skin 20 is characterized by initial burning or thermal sensation, followed by long-term pain loss. It has been suggested that the analgesic component of VR1 receptor activation is mediated by the desensitization-induced desensitization of the main sensory afferent end. According to this property, CAP and its analogues are blocked, such as olvanil, nuranil, DA-5018, SDZ-249482, and resiniferat〇xin, 200813011. A therapeutic agent for use as an analgesic or for urinary incontinence or skin disease is used or is being developed (Wrigglesw〇rth and Walp〇le, Drugs 〇f the Future, 531-538, 1998). The VR1 line is widely expressed in non-neuronal tissues within various organ systems, and the goal is not to accurately understand the functional role of VR1 in these systems. More and more animal studies have shown that VR1 receptors may be involved in many conditions. Based on this poor news, VRi is the molecular target for various diseases such as migraine, joint pain, diabetic neuropathy, neurodegeneration, neurocutaneous skin disease, stroke, heartache caused by ischemic myocardium, and Huntington's (HuntinSton's disease), memory deficiency, restrictive brain function, lateral sclerosing muscular atrophy (ALS), dying, bladder allergy, urinary incontinence, chronic genital pain, pruritus (such as uremia pruritus), Colorectal irritation (IBS) (including gastroesophageal reflux disease (GERD), enteritis, ileitis, stomach, duodenal ulcer), inflammatory bowel disease (including Crohn's disease), milk 15 diarrhea and inflammation (such as pancreatitis), and respiratory disorders (such as allergic and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease), skin, eye or mucous membrane irritation, dermatitis, non-specific disorders, such as increased heat Retinopathy, muscle spasm, vomiting, difficulty in movement, and depression. Specifically, VR1 antagonist T is used in subtypes of genital pain, such as acute, chronic, neuropathic pain 2 or post-operative pain, and neuralgia (eg, post-therapy neuropathic pain, and trigeminal neuralgia) Pain caused, and pain, toothache and cancer pain caused by diabetic neuropathy. In addition, VR1 antagonists have also been shown to be useful in the treatment of inflammatory pain such as arthritis or osteoarthritis. In the treatment of diabetes, obesity, urticaria, keratosis, horny acanthoma, alopecia, Meniere's 7 200813011 disease, tinnitus, hyperesthesia and anxiety, vri antagonists have Potential advantage. A group of natural and synthetic compounds that can be modified with vanillin receptors (VR1) are characterized by vanillyl (4-hydroxy-3-decyloxybenzyl) or functionally equivalent groups and are characterized by extensive research and by Szallasi and Blumberg is widely commented in The Am. Soc. For Pharmacology and Experimental therapeutics, Vol. 51, No. 2 (1999). Various vanilla essence agonists and antagonists have been developed for the treatment of pain. These agonists act by desensitizing the receptor, while the antagonist blocks the stimulatory effect by a 10 (pathological) physiological ligand. The first antagonist, Capsizepine, was developed by Novartis. Additional VR1 antagonists currently used in preclinical evaluations are, for example, PAC-20030 from Amore Pacific, BCTC from Neurogen, A-425619 from Abbott, and AMG-9810 from Amgen. PCT Patent Publication No. WO 00/59510 (which is equivalent to U.S. Patent No. 6,414,149), No. WO 02/32411, No. WO 02/43762, and No. WO 2005/037284, which are incorporated herein by reference. Aminopyrimidines of dehydrogenase inhibitors and combinations thereof with statins, GABA agonists or hypertension agents. The PCT Patent Publication No. WO 02/34761 (U.S. Patent Publication No. 20/2002/0094989) discloses a pyrrole bite modulator of a CCR5 chemotactic hormone receptor. U.S. Patent Publication No. 2004/002504 describes substituted sulfonamides as NK-3 receptor inhibitors. Specific AKT protein kinase inhibitors are disclosed in PCT Patent Publication No. WO 2005/051304. The vanilla extractor-regulating compound is disclosed in the following patents: U.S. Patent No. 6,130,311, U.S. Patent No. 6,933,311, U.S. Patent No. 6, 939, 891, No. 7,037, 927, U.S. Patent Publication No. 2006/0100460, and PCT Patent Publication No. WO 02 /08221, 02/16317, 02/16318, 02Λ6319, 2004/103281, 2004/108133, 2004/111009 5, 2006/044527 and 2006/045498 . There is still a need for a safe and more effective vanilla extract regulator that can be used to treat diseases, conditions, and/or disorders modulated by vanilla extracts, including acute and chronic pain and neuropathic pain. I: SUMMARY OF THE INVENTION 3 ίο SUMMARY OF THE INVENTION The present invention relates to a VR1 receptor ligand of the formula (1):

Or a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide, a vinegar thereof, a pharmaceutically acceptable solvate thereof, a tautomer thereof, a stereoisomer thereof or X thereof is 0 or S; R1 Selected from

9 200813011

Ο DC , and R 1 thereof, are attached to the main structure via any carbon atom in the ring, and may be optionally substituted with one or more R groups; R and R 6 are independently selected from hydrogen and nitrate in each occurrence Base, cyano, formamidine 5, ethane group, halogen, 〇R7, -SR7, pendant oxy, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Substituted cycloalkenylalkyl, substituted or unsubstituted aryl 10, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl t-substituted or unsubstituted heteroaryl An alkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic group, _c(〇)R7,

And protecting groups; R and R are independently selected from the group consisting of hydrogen, nitro, dentate, cyano, -ORa, -SRa, pendant oxy, thio, substituted or unsubstituted alkyl. , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Take ring-shaped ring, (four) or unsubstituted ring-based base, substituted or unsubstituted aryl, silk or unsubstituted aryl, substituted or unrecorded heteroaryl, Substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, substituted 200813011 or unsubstituted heterocyclylalkyl, -C(〇)Ra, -C(〇)〇-Ra -C(〇)NRaRb, -S(〇)m-Ra, -S(0)m-NRaRb, -NRaRb, and a protecting group, or R7 and R8, when directly bonded to the same nitrogen atom, The attached nitrogen atoms together form a selectively substituted 3 to 7 member saturated or unsaturated 5 and ring ring 'which may optionally include one or more heteroatoms selected from the group consisting of ruthenium, NRa and S; R and R Independently selected at each occurrence From hydrogen, _, wall, cyano, methionyl, ethyl fluorenyl, pendant oxy, thio, _C(〇)_rc, -c(〇)〇_rc, -C(〇)NRcRd, - S(〇)m-Rc, _S(0)m-NRcRd, -NRcRd, -〇Rc, 10-SR, protecting group, substituted or unsubstituted alkyl group, substituted or unsubstituted dilute group , substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or not Substituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, 15 substituted or unsubstituted heteroaryl, substituted or unsubstituted a cyclic group, a substituted or unsubstituted heterocyclylalkyl group, and a substituted or unsubstituted heteroarylalkyl group; R & Rd is independently selected from hydrogen, substituted or unsubstituted at each occurrence Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, Substituted or unsubstituted Cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocycloalkane 11 200813011, substituted or unsubstituted heteroarylalkyl and protecting oxime, or R directly bonded to the same The nitrogen atom is entangled with the nitrogen atom to which they are attached to form a selectively substituted 3 to 7 membered saturated and unsaturated cyclocyclic ring which may optionally include one or more impurities selected from the group consisting of ruthenium and NR% ts. Atom; 5 ^ each: less pure _ independently selected from the nucleus or unsubstituted alkyl; m in each occurrence is independently 〇, 1 or 2; R and R are independently selected from 氲, light base And C16 alkyl; and R4 and R5 are independently selected from the group consisting of hydrogen, halogen, and alkyl at each occurrence, or when R4 and r5 are bonded to the same carbon atom, R4 and R5 together form a pendant oxy group. Or thio group. According to a preferred embodiment, the compound of formula (I) conforms to 1, 2 or all of the following characteristics: (a) R6 is not a substituted or unsubstituted pyrimidine, 15 (b) R0 is not substituted or unsubstituted Pyrrolidinyl, and (c) R1 is not a substituted or unsubstituted amine group. Another preferred embodiment is a compound of formula (I) wherein X is 0. Further, a compound of the formula (I) wherein R1 is an unsubstituted porphyrin, a porphyrinone, an isoindoline or an isoindolinone is preferred. Further preferred is a compound of the formula (1), wherein R1 is a substituted or unsubstituted porphyrin or isoporphyrin linked to a nitrogen at the 5th, 6th, 7th or 8th position.

Also preferred are compounds of formula (I) wherein R1 is w. 12 200813011

I

Further preferred is a compound of formula (I) wherein "is 〇0. Further preferred is a compound of formula (1) wherein R2, R3, R4 and R5 are each hydrogen. In the preferred embodiment, the ruler and the ruler 6 are each independently Is hydrogen, nitro, cyano, fluorenyl, ethinyl, i- or selected from alkyl, alkenyl, fast-radical, cycloalkyl, *alkyl, cycloalkenyl, aryl, aromatic a substituted or unsubstituted group of a heterofilament, a heteroarylalkyl group, a heterocyclic group or a heterocyclic group. Further preferred is a compound of the formula (I) wherein r6 is selected from a cycloalkyl group and a cycloalkyl group. a substituted or unsubstituted group of a fluorenyl group, a cycloalkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a heteroalkyl group, a hetero wire, and a heterocyclic group. Substituents (groups) are selected from the group consisting of a phenyl group, a thiol group, a schwitzyl group, a nitrogen group, a fluorenyl group, an ethyl fluorenyl group, a halogen group or a tri-alkyl group. Changping father 1 soil K, T, K are each independently hydrogen, nitrate a cyano group, a cyano group, a decyl group, an ethyl fluorenyl group, an im group or a substituted or unsubstituted nucleus, and 15 ^ from a weiji group, a hetero group, a cyclyl group, a ruthenium group, a branched group, a heteroaryl aryl group, Heterocyclic group, and heterocyclic group, substituted or ungrouped Wherein the substituent is a fine group (group) selected from the group consisting of an alkyl group, an I, a nitro group, a cyano group, a decyl group, an ethyl group, a decyl group or a tri-alkyl group. Further, a substituted or unsubstituted heteroaryl & is preferably a compound of the formula (I), wherein R6 is a 3-chloropyridinium-3-yl group. Further preferred is a compound of the formula (1) wherein 116 is 3_惫-earth milk 0 Further, a compound of the formula (I), wherein R6 is a #虱虱methylπ ratio, is a _2- group. Further preferably a compound of the formula (I), wherein R6 is 3 -z: Field * - murine methylpyridin-2-yl. Further preferred is a compound of formula (1) wherein the ratio is _2-based. 13 20 200813011 Further preferred is a compound of formula (I) wherein R6 is 4- Tris-butylbenzhydryl. According to a preferred embodiment, the VR1 acceptor ligand has the general formula (Ia) ··

Or a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, an ester thereof, a pharmaceutically acceptable solvate thereof, a tautomer thereof, a stereoisomer thereof or a polymorph thereof, wherein X is hydrazine Or -S-; R2, R3, R4 and R5 are hydrogen; R is a substituted or unsubstituted aryl group, a substituted or unsubstituted 10 aralkyl group, a substituted or unsubstituted heteroaryl group, C(0)R7, S(0)2R7 or COOR7; and R7 is a substituted or unsubstituted aryl group. A further preferred embodiment is a compound of formula (la) wherein r6 is methyl, isopropyl, tert-butyl, trifluoromethyl, bromo, chloro, fluoro, iodo, nitro, methoxy-15, Cyclopropylmethoxy, difluoromethoxy, trifluoromethoxy, etidinyl, trifluoroacetamido or methanesulfonylamino. Also preferred are compounds of formula (la) wherein R6 is substituted or unsubstituted aryl. Further preferred is a compound of the formula (la) wherein R6 is selected from the group consisting of a strepto group, a 2-fluorophenyl group, a 3-fluoro-based group, a 4-fluoro-based group, a 2,3-fluorophenyl group, a 2,4-di group. Fluorophenyl, 2,6-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorobenzene 14 200813011, 2,4,5_ Trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-methoxyphenyl, 4-decyloxyphenyl, 2-isopropylphenyl , 4-isopropylphenyl, 4-tri-butylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-di Fluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2-5 fluoro-5-methylphenyl, 2-cyclopropylmethoxyphenyl, 2-fluoro-3-trifluoromethyl Phenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro- 4-difluoromethoxyphenyl or 2-fluoro-4-methylphenyl. Also preferred are compounds of formula (la) wherein R6 is aralkyl. Further preferred is a compound of formula (la) wherein R6 is selected from the group consisting of benzyl, 4-abenzylbenzyl 10 and 4-trifluoromethylbenzyl. Also preferred is a compound of formula (la) wherein R6 is -S02R7. Further preferred is a compound of the formula (la) wherein R6 is selected from the group consisting of 4-phenylphenylsulfonyl, 4-trifluoromethylphenylsulfonyl, 4-fluorophenylsulfonyl, 2-6-di Phenylsulfonyl, 2,6-difluorophenylsulfonyl, 2,4-dibromophenylsulfonyl, 2,4-15 dichlorophenylsulfonyl, 2-trifluoromethyl Phenylsulfonyl, 2-fluorophenylsulfonyl, 2-chlorophenylsulfonyl, 2-bromophenylsulfonyl, phenylsulfonyl, 4-bromophenylsulfonyl, 4- Iodophenylsulfonyl or 4-methylphenylsulfonyl. Also preferred are compounds of formula (la) wherein R6 is -COR7. Further preferred is a compound of the formula (la) wherein R6 is selected from the group consisting of 4-bromobenzylidene, 20 4-chlorobenzylidene, 3-fluorobenzhydryl, 2-bromobenzylidene, 2- Fluorobenzylidene, 2-chlorobenzhydryl, 4-methylbenzhydryl, 2-trifluoromethylbenzhydryl, 4-trifluoromethylbenzimidyl or 4-benzylbenzene Hyperthyroidism. Also preferred are compounds of formula (la) wherein R6 is heteroaryl. Further preferred is a compound of the formula (la) wherein R6 is selected from the group consisting of 3-(ethenylamino) 15 200813011 mouth ratio 0-but-2-yl, 3-(diqi-ethylamino)pyrimidin-2- Base, 3-(methyl arylamino) u ratio σ -2- group, 3,5-two gas ton 11 -12, 3-> odor 0 ratio -2--2-yl or 5 - fluorenyl-σ ratio -2- group. Representative compounds of the present invention include the following compounds and prodrugs thereof, 5 pharmaceutically acceptable salts thereof, cerium-oxides, esters thereof, solvates thereof, and mutual Isomers, stereoisomers thereof and polymorphs thereof. The invention should not be construed as being limited to the following examples: 1 6Κ,5 〇!,6 ck -[6-(5-iso-junosyl-based amine group Brewing of amino)-3-(3-ethoxytosylpyridin-2-yl)]_3_azabicyclo[3.1.0]hexane (compound No. 1), 10 1 α, 5α, 6α - [6-(5-Isoindolinylaminocarboxylamido)-3-(3-trifluoroethylguanidinopyridine-2-yl)]-3-azabicyclo[3.1.0]hexane (No. 2 compound), 1 ύ!, 5 ύ;, 6ύ! - [6-(5-iso-quine-ylamino-based amide)-3-(3-carbofylaminopyridine-2 -yl)]-3-azabicyclo[3.1.0]hexane (compound No. 3), 1 α, 5α:, 6α - [6-(5-Isoindolinylaminocarboxylamido)-3-(3-(3,5-15 dichloro)pyridin-2-yl)]-3-azabicyclo[3.1.0] Hexane (Compound No. 4), 1 α,5 α,6 α -[6-(5-isoindolinylaminocarbamoylamino)-3-(3-bromopyridin-2-yl)]· 3-Azabicyclo[3.1.0]hexane (No. 5 compound), 1 ίϋ, 5 ο;, 6ύ! -[6-(5-iso-allinylamino-branched amine)-3-( 5-zolylpyridin-2-yl)]-3-azabicyclo[3.1.0]hexane (compound No. 6), 20 1 (2,5(2,6〇:-[6-(5- Isoindolinylamino 1 chloroamino)-3-(2-phenylphenyl)]-3-azabicyclo[3丄0]hexane (compound No. 7), 1 ck, 5 λ, 6 ϋ ϋ -[6-(5-isos-Chlorylamino-based arylamino)-3-(4-phenylphenyl)]-3-azabicyclo[3·1·0]hexane (No. 8 Compound), 1 ίϋ, 5 α, 6〇! -[6-(5-iso-n-aryl-aminoamine-branched amine)-3-(4·isopropyl 16 200813011 phenyl)]-3-aza Bicyclo[3.1.0]hexane (No. 9 compound), 1 α,5 α,6α -[6-(5-isoindolinylaminocarbamoylamino)-3-(2-decyloxybenzene) Base]]-3_azabicyclo[3.1.0]hexane (compound No. 10), 1 ο;, 5 ο;, 6ck -[6-(5-iso-σ-chalinylamine Brewing of amino)-3-(4-di-5-butylphenyl)]-3-azabicyclo[3丄0]hexane (No. 11 compound), 1«, 5〇:, 6〇 :-[6-(5-Isoindolinylaminocarboxylamido)-3-(2,4-dimethylphenyl)]-3-azabicyclo[3.1.0]hexane (12th No.), 1 〇!,5 ο;,6 λ -[6-(5-iso 1^ 奎°林基基基基胺胺)-3-(4-dimethylmethyl) phenyl]- 3-azabicyclo[3·1.0]hexane (compound No. 13), 10 1 α,5 α,6 α -[6-(5-isoindolylaminocarbamoylamino)-3-( (4-methoxy)phenyl)]-3-azabicyclo[3.1.0]hexane (Compound No. 14), 1 〇!, 5 ck, 6ck -[6-(5-iso σ 奎琳Aminoamino-branched amino)-3-(3,4,5-difluoro)phenyl]-3-azabicyclo[3·1·0]hexane (No. 15 compound), 1 〇!, 5 ck,6 ck -[6-(5-iso- cylinylamino-branched amine)-3-(2-di-hydrogen 15 methoxy)phenyl]-3-azabicyclo[3.1.0] Hexane (compound No. 16), 1«, 5〇:, 6〇;-[6-(5-isoindolinylaminocarboxylamido)-3-(3,4-difluoro)phenyl ]-3-Azabicyclo[3.1.0]hexane (No. 17 compound), 1〇!,5〇!,6〇!-[6-(5-iso-line Amino-based arylamino)-3-(2-a-5-methyl)phenyl]-3-azabicyclo[3.1.0]hexane (compound No. 18), 20 1ύ!, 5ύ!, 6ύ!-[6_(5·isoindolinylamino 竣S-amino)-3-(3- gas)phenyl]_3_azabicyclo[3.1.0]hexane (Compound No. 19), 1 ck,5 (2,6〇! -[6-(5-(iso- σ quinalylamino) arylamino)-3-(3- gas)phenyl]-3-azabicyclo[3.1.0 Hexane (Compound No. 20), 1 ck, 5 〇!, 6d -[6-(5•isoindole-based arylamine-based amine)_3_(2,4_二17 200813011 fluoro)phenyl ]-3-Azabicyclo[3·1·0]hexane (Compound No. 21), 1〇!,5〇!,6〇!-[6-(5-iso-p-guanylamine-based amine 3-(2,6-difluoro)phenyl]-3_azabicyclo[3.1.0]hexane (compound No. 22), 1 ,5 ύ!,6ίϊ -[6-(5- Iso-sigma-based amine-based amine 3-(2-a-3-trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (compound No. 23), 1 〇!,5,6〇; -[6-(5-isoindolinylguanidino)-3-(2-dimethoxymethoxy)phenyl]-3-azabicyclo[3· 1·0]hexane (No. 24 compound), 1 〇:, 5 λ,6 -[6-(5-iso-indolyl Amine-based amide amino)-3-(2-dimethylmethyl)phenyl]_3_azabicyclo[3·1·0]hexane (compound No. 25), 10 1 α,5 α,6 α: -{6-(5-isoindolylaminocarboxylamido)-3-[2-fluoro-(5-trifluoromethyl)phenyl]}-3-azabicyclo[3·1 ·0]hexane (compound No. 26), 1 α,5 α,6 α -{6-(5-isoindolylcarbamoylamino)-3·[2-fluoro-(4-di Fluoromethoxy)phenyl]}-3-azabicyclo[3·1·0]hexane (Compound No. 27), 1 α , 5 α, 6α: -[6-(5-isoindolyl Aminocarboxyamino)-3-(2,3,4-tri-15fluoro)phenyl]-3-azabicyclo[3·1·0]hexane (compound No. 28), 1 α, 5 α,6 α -[6-(5-isoindolylaminocarboxylamido)-3·(2,4,6-trifluoro)phenyl]-3-azabicyclo[3·1·0 Hexane (Compound No. 29), 1〇!, 5〇!, 6〇!-[6-(5_(Iso-aryl-amino-amino)-(2,3-difluoro) Phenyl]-3-azabicyclo[3.1.0]hexane (Compound No. 30), 20 Ick, 5 (2,6ck-[6_(5-iso 11-chalcarylamine-based amine)- 3-(2-Gaxo-4-indenylphenyl)phenyl]-3-azabicyclo[3.1.0]hexane (Compound No. 31), 1 Λ, 5 ο;, 6〇! 奎淋Amino-based arylamino)-3-(2-isopropyl)phenyl]-3-azabicyclo[3.1.0]hexane (compound No. 32), 1 α,5α,6α -[6- (5-Isoprolinylaminocarboxylamido)-3-(3,5-di 18 200813011 fluorophenyl)]-3-azabicyclo[3.1.0]hexane (Compound No. 33), 1 ,5 ck,6〇! -[6-(5-(inhomo-based arylamino)amino-3-(2,4,5-difluorophenyl)]-3-azabicyclo[3.1 .0]hexane (compound No. 34), 1 α,5 α,6 α -[6-(5-isoindolinylcarbamoylamino)-3-(2,4-difluoro 5 benzene Base]]-3-azabicyclo[3.1.0]hexane trifluoroacetate (compound No. 35), 1 ck,5 ο;,6λ -[6_(5-isolinylamine amide amine 3-(2,4-difluorophenyl)]-3-azabicyclo[3丄0]hexane trifluorodecane sulfonate (compound No. 36), 1 ύ!, 5 ο; ,6〇! -[6-(5-isoindolylamino-branched amine)-3-(2,4-di-10-fluorophenyl)]-3-azabicyclo[3丄0]hexane Hydrochloride (Compound No. 37), 1 α,5 α,6 α -[6-(5-isoindolylaminocarboxamido)-3-(2,4-difluorophenyl)] 3-Azabicyclo[3.1.0]hexanemethanesulfonate (Compound No. 38), 1 α ,5 α,6α -[6-(5-isoindolinylaminocarbamoylamino)-3-(4-chlorophenyl)sulfonyl]-3-azabicyclo[3丄0] Hexane (Compound No. 39), 15 1 α , 5 α,6 α -{6-(5-iso-4-linylaminocarbamoylamino)-3-[4-(trifluoromethyl)phenyl Sulfosyl}-3-azabicyclo[3.1.0]hexane (compound No. 40), 1 α,5 α,6 α -[6-(5-isoindolinylaminocarboxamide )-3-(4-fluorophenyl)sulfonyl]-3-azabicyclo[3.1.0]hexane (Compound No. 41), 1 α,5α,6α -[6-(5-isoindole) Lolinylaminocarboxylamido)-3-(2,6-di20 chlorophenyl)sulfonyl]-3-azabicyclo[3·1·0]hexane (Compound No. 42), 1 Ck,5 ck,6dz -[6-(5-iso-allinylamino 竣S basket amine)-3·(2,6-difluorophenyl)sulfonyl]-3-azabicyclo[3 ·1·0]hexane (No. 43 compound), 1 α,5α,6α-[6-(5-isoindolinylaminocarbamoylamino)-3-(2,4-dibromophenyl) ) sulfonyl]-3-azabicyclo[3.1.0]hexane (Compound No. 44), 25 1〇!, 561!, 661!-[6-(5-isoindolequinylamino) Acid amine)-3-(2,4 -di 19 200813011 chlorophenyl)sulfonyl]-3-azabicyclo[3.1.0] (Compound No. 45), 1 d, 5〇;, 6〇! -[6-(5-iso-phenyl-aminoamine-branched amino)-3-(2-disorganomethylphenyl)sulfonate Base]_3_azabicyclo[3.1.0]hexane (compound No. 46), 1 ck, 5〇!, 6ύ! -[6·(5-isoindolylamine-branched amine)_3- (2- disordered phenyl 5-yl)sulfonyl]-3-azabicyclo[3丄0]hexane (Compound No. 47), 1 α,5〇:,6α: -[6-(5-isoindole Lolinylaminocarboxylamido)-3-(2-chlorophenyl)sulfonyl]·3·azabicyclo[3.1.0]hexane (Compound No. 48), 1 α, 5 α, 6 Α-[6-(5-isoindolylaminocarboxylamido)-3-(2-bromophenyl)sulfonyl]-3-azabicyclo[3.1.0]hexane (No. 49) Compound), ίο 1 α,5α,6α -[6-(5-isoindolylaminocarbamoylamino)-3-(phenylsulfonyl)]-3-azabicyclo[3.1.0] Hexane (Compound No. 50), 1 0!, 5 〇:,6 _[6-(5-isoindolylamine amide amino)-3-(4-> odor phenyl) sulfonium sulfonate Base]-3-azabicyclo[3.1.0]hexane (No. 51 compound), 1 〇!, 5 Λ, 6ύ! - [6-(5-iso-junylamino decanoic acid amine)- 3-(4-Phenyl-15-yl)sulfonyl]-3-azabicyclo[3·1·0] Alkane (Compound No. 52), 1 ύ:,5 ύ!,6ύ! -[6-(5-iso-σ quinalylamino-brown amine)-3_(4-methylphenyl)sulfonyl ]-3-Azabicyclo[3.1.0]hexane (Compound No. 53), 1 〇!, 5 ck, 6ύϋ -^-^-iso 17 quinalylamino alanyl)-3-( 4 -> ointmentyl)]-3-azabicyclo[3.1.0]hexane (compound No. 54), 20 1 α,5α,6α-[6-(5-isoindolylamine Carboxylamido)-3-(4-chlorobenzylidenyl)]-3-azabicyclo[3.1.0]hexane (Compound No. 55), 1 6K, 5 λ, 6 ύ; -[ 6-(5-isoindolylaminoindolyl)-3-(3- benzylidene)--3-azabicyclo[3.1.0]hexane (Compound No. 56), 1 ύ ;,5 (2,6ύ! -[6-(5-iso-junylamino-based amide)-3-(2-> odor benzene 20 fluorenyl & ιβ gas heterobicyclo[3.1. 0] Hexane (Compound No. 57), m 5 α '6 α _[6·(5-iso-0-quinolinyl-propionylamino)-3-(2-fluorophenyl T-yl- ι Heterobicyclo[3.1.0]hexane (compound No. 58), 5 ^ '5 α,6 α _[6-(5-isoquinolinylaminocarboxamido)-3-(2-chlorophenyl) r醯)/ _heterobicyclo[3.1.0]hexane (No. 59) Compound), ^, α '6 α _[6_(5-isoindolinylcarbamoylamino)-3-(4-methylbenzamide, 1 2 ^ mouse heterobicyclo[3.1.0 Hexane (Compound No. 60), α '5 α,6 α _[6-(5-isoindolinylaminocarbamoylamino)-3-(2-trifluoro 10 thiol)_3-nitrogen Heterobicyclo[3丄〇]hexane (compound No. 61), methyl '5〇:, 6α-[6-(5-(isoindolinylaminocarbamoylamino)-3-(4-trifluoros) Benzoic acid group)>3-Azabicyclo[3.1.0]hexane (Compound No. 62), α '5 α,6 _[6-(5-isoquinolinylaminocarbamoylamino)- 3-(4-bromobenzoinyl)1 1 > indolebicyclo[3.1.0]hexane (compound No. 63), 15 ^ α,5α,6α -[6-(5-isoporphyrin Aminoaminocarboxylamido)-3-(4-benzylindole small 3-murine bicyclo[31〇]hexane (compound No. 64), 1 α,5 α,6α -[6·(5- Isoquinolinylaminocarboxylamido)-3-(4-chlorobenzyl^-azabicyclo[3.1.0]hexane (Compound No. 65), 1 α,5 α,6α -[6-( 5-I-quinolinylaminocarboxylamido)-3-(4-trifluoromethylbenzyl)]_3_azabicyclo[3.1.0]hexane (compound No. 66), 20 1 α, 5 α,6 α -[6-( 5-isoindolinylcarbamoylamino)-3-phenyl]-3-azabicyclo[3·1·〇]hexane (Compound No. 67), Ν·[3-(3-Fluorine Mercaptopyridin-2-yl)]-3-azabicyclo[3·1·〇]_hexyl-6-yl-indole-isotetralin-5-ylurea (compound No. 68), 1 α, 5α , 6α-[6-(5-isoindolinylaminocarbamoylamino)-3-(3-air ratio 21 200813011 pyridine-2-yl)]-3-azabicyclo[3·1·0] Hexane (Compound No. 69), 1 α, 5α, 6α _[6-(5-isoindolylaminocarbamoylamino)-3-(5-trifluoromethylpyridin-2-yl)] 3-Azabicyclo[3.1.0]hexane (Compound No. 70), 1 α,5 α,6 α -[6-(5-Iso-hydroxy-cylinyl-amino-indenyl)-3- (3-Ga-5-tris-5-fluoromethylpyridin-2-yl)]-3-azabicyclo[3·1·0]hexane (Compound No. 71), 1 α,5 α,6 α - [6-(5-isoindolinylcarbamoylamino)-3-(3-chloro-5-trifluoromethylpyridin-2-yl)]-3-azabicyclo[3丄0] Alkane (Compound No. 72), 1 α, 5α, 6α -[6-(5-isoindolylaminocarbamoylamino)-3-(3-nitropyridin-2-yl)]-3- Azabicyclo[3.1.0]hexane (No. 73 compound), 10 1 α,5 α ,6 α -[6_(5-isoindolylamine) Carboxylamido)-3-(4-tris-butylbenzylidene)]-3-azabicyclo[3.1.0]hexane (Compound No. 74), 1-[3-(2, 4-difluorophenyl)-3-azabicyclo[3.1.0]hex-6-yl]-3-(2-indolyl-1-yloxydihydroisoindoline-5-yl)-urea (No. 75 compound), Table 1

(R^R^R4^5^ X js 〇; » X is S) Compound code R° Compound code R° 1 2 P 3 4 α 5 BriN 6 N〇2 22 15 200813011 7 8 /χχ 9 10 OCHa 11 12 13 14 15 F 16 ochf2 "ό 17 'Ό:: 18 ch3 19 20 21 22 ίό 23 FU 24 25 π 26 cf3 27 28 ^ά: 29 30 23 200813011 31 32

33

34

35

.CFgCOOH 36

.cf3so3h 37

.HCI 38

.CH3SO3H 39

Ci 42

Cf3

Cl 43

44 .Br 45 Λ

a ci 46

Cf3 47

48

Cl 49

Br 50

51, xr 52

24 200813011 53 54 /yCT 0 55 ^Cra 0 56 'v^X 0 57 〇Br 58 〇F 59 0 Cl 60 ν〇^3 0 61 ° CF3 62 VX3 0 63 0 64 65 66 67 68* F3C^y 69 03⁄4 70 71 f3c' 72 73 02N 74 /Ύ°^ The present invention also provides a pharmaceutical composition comprising at least one compound of the invention and a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of the formula. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or diluent) or may be diluted or encapsulated in a carrier which may be in the form of a capsule, sachet, paper or other container. . The compounds and pharmaceutical compositions of the invention may be used to treat diseases, disorders and/or disorders mediated by vanilloid 25 200813011 class antagonists. The present invention further provides a method for treating a disease, a condition and/or a mites that is modulated by a vanillin class VIU receptor antagonist in a patient in need of the therapy, by administering to the patient a therapeutically effective amount of the invention Compound Ge 5 Pharmaceutical composition. The present invention further provides a method, a method, and/or a disorder for treating a patient in need of such therapy, wherein the vanillin VR1 is modulated by an II antagonist, by administering to the patient a therapeutically effective amount of a compound, Wherein R6 is a substituted, substituted or unsubstituted or substituted hydrazine methyl group or a pharmaceutical composition comprising at least one of the compounds of the formula τ and a pharmaceutically acceptable riding agent. According to a preferred embodiment, there is provided a method of preventing, ameliorating or treating a disease disorder or symptom which is mediated by vanilla extract, in particular for the vanilla extract, comprising the need for the therapy The patient is administered a therapeutically effective amount of a compound of formula I or la. According to a preferred embodiment, the disease, disorder or symptom is a pain or inflammatory disease, disorder or symptom that is mediated by the mediator. According to another preferred embodiment, the disease, disorder or symptom is selected from the group consisting of pain J, pain, nociceptive pain, neuropathic pain, post-operative pain, toothache, cancer pain, ischemic myocardium Heartache, migraine, pain caused by joint pain, joint pain, neuropathy, neuralgia, trigeminal neuralgia, nerve damage, diabetic neuropathy, neurodegeneration, retinopathy neuropathy, stroke, bladder allergy, Urinary incontinence, chronic vaginal pain, gastrointestinal disease (such as irritable bowel syndrome (IBS), gastroesophageal reflux disease 26 200813011 (RD), enteritis, ileitis, stomach. duodenal ulcer, inflammatory bowel disease, flu, milk Filling), inflammation (such as pancreatitis), respiratory disorders (such as sensitive and non-allergic rhinitis, asthma or chronic obstructive pulmonary disease), skin, ^ or mucous membrane irritation, skin syndrome, _ disease (such as uremia) ), body 5 rise, muscle spasm, feed vomiting, difficulty in movement, inhibition, Huntington's disease, brainless, limited cerebral atrophy (ALS), dementia, arthritis, Osteoarthritis, Diabetes, obesity, treatment # hemp, light ^ keratosis, keratinization acanthosis, filling fat, Mengni Ai's disease, tinnitus, hyperacusis, anxiety disorders and benign prostate hypertrophy. In another preferred embodiment, the disease, disorder or symptom is pain, acute pain, chronic pain or post-operative pain. In still another preferred embodiment the disease, disorder or condition is neuropathic pain. In yet another preferred embodiment, the disease, disorder or condition is urinary incontinence. In yet another preferred embodiment, the disease, disorder or condition is overactive bladder or benign prostate hypertrophy. In still another preferred embodiment, the disease, disorder or condition is ulcerative colitis. In yet another preferred embodiment, the disease, disorder or symptom is asthma. In yet another embodiment, the disease, disorder or symptom is inflammation. Also provided herein are methods for preparing compounds of formula (I) or (la). The present invention further provides an intermediate product which can be used to prepare a compound of the present invention having the following formula 26: 27 200813011

I «6 26 wherein R 4 and R 5 are hydrogen, and R 6 is selected from the group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4- Difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-three Fluorophenyl, 5 2,4,6-trifluoroiphenyl, 3,4,5-difluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-isopropylbenzene Base, 4-isopropylphenyl, 4-tri-butylphenyl, 2,4-dimethylphenyl, 2-dimethylphenyl, 4-dimethylphenyl, 2- Difluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2-fluoro-5-methylphenyl, 2-cyclopropylmethoxyphenyl, 2-fluoro-3-trifluoromethyl Phenyl, 2-trifluoromethoxy 10 phenyl, 2-gas-5-dimethylphenyl, 2-vapor-4-dimethoxymethylphenyl, 2-fluoro-4-methylphenyl , benzyl, 4-chlorobenzyl, 4-trifluoromethylbenzyl, 4-chlorophenylsulfonyl, 4-trifluoromethylphenylsulfonyl, 4-fluorophenylsulfonyl, 2 ,6-dichlorophenylsulfonyl, 2,6-difluorophenylsulfonyl, 2,4-dibromophenylsulfonyl, 2,4-dichlorophenylsulfonyl-2-tri Fluoromethylphenylsulfonyl, 2-fluorophenyl 15 sulfonyl, 2-chlorophenylsulfonyl, 2-bromophenylsulfonyl, phenylsulfonyl, 4-bromophenylsulfonyl, 4-iodophenylsulfonyl, 4-methylphenylsulfonate Base, 4-bromobenzylidene, 4-chlorobenzylidene, 3-fluorobenzhydryl, 2-bromobenzylidene, 2-fluorobenzhydryl, 2-chlorobenzylidene, 4-methylbenzhydryl, 2-trifluoromethylbenzimidyl 4-trifluoromethylbenzylidene, 4-pyrimidinyl, 3-(ethyl 20-bromoamino)^ Than sigma-2-yl, 3-(dihydroethylamino) guan-2-yl, 3-(methionine) 0 to 0-but-2-yl, 3,5-di Gas 11 is more than 唆_2_yl, 3-> odor-2-yl or 5-stone xiao 28 200813011 bispyridin-2-yl. The present invention further provides an intermediate product which can be used to prepare the compound of the present invention having the following formula 6a: PGHy

6 a 5 wherein R 4 , R 5 , and R 6 are as defined above for formula 26 and PG is an N — protecting group (also referred to as an amine protecting group) as defined below. The present invention further provides an intermediate product which can be used to prepare the compound of the present invention having the following formula: h2n

7 10 wherein R4, R5, and R6 are as defined in formula 26. I: Embodiment 3 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The term "alkyl" means that it consists solely of carbon and hydrogen atoms and is saturated with 15 substances, has from 1 to 8 carbon atoms and is a single bond. a linear or branched hydrocarbon group attached to the remainder of the molecule, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-decyl, and 1,1-dimethylethyl (t-butyl). The term "CK6 alkyl" refers to a 29200813011 alkyl chain having from 1 to 6 carbon atoms. The term "aminoalkyl" refers to an amine group bonded directly to an alkyl group as defined above. The amine group is substituted or unsubstituted. The amine alkyl group can be attached to any carbon atom within the alkyl group of the primary structure. 5 The term "alkenyl" refers to a straight or branched aliphatic hydrocarbon group containing carbon and carbon double bonds and which may have from 2 to about 10 carbon atoms, such as ethenyl, propylene, 2-propenyl (ene) Propyl), isopropenyl, 2-methylpropenyl, 1-butenyl, and 2-butenyl. The term "alkynyl" refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple chain and having from 2 to about 10 12 carbon atoms, preferably having from 2 to about 10 carbon atoms. For example, ethynyl, propynyl, and butynyl. The term "alkoxy" means an alkyl group attached to the remainder of the molecule by an oxygen bond. Representative examples of such groups are -OCH3 and -〇C2H5. The term "cycloalkyl," A non-aromatic 15 group mono- or polycyclic ring system having from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of poly-aminocycloalkyl groups include, but are not limited to, perhydronaphthyl, adamantyl and norbornyl, bridged or spirobicyclo, such as spiro(4,4)indol-2-yl. "Anything ring" refers to a ring-containing ring group having from 3 to about 8 anti-atoms directly attached to a group of 20. The cycloalkylalkyl group can be attached to the alkyl group of the main structure. Any carbon atom to produce a stable structure. Non-limiting examples of such groups include cyclopropyl fluorenyl, cyclobutyl ethyl, and cyclopentylethyl. The term "cycloalkenyl" means having 3 to about 8 carbon atoms and at least one carbon 30 200813011 t _ 5 - a carbon-containing double-chain ring-containing ring group, such as a cyclopropyl group, a cyclobutyl group, a pentenyl group. The term "aryl" refers to an aromatic group having 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, anthracene, and biphenyl. An alkyl group, as defined above, is directly bonded to a green as defined above, such as (10) and _c. / \ 10 -* The term "heterocyclic ring," means carbon Atom and a stable 3_ to 15_membered ring group consisting of (1) a hetero atom selected from the group consisting of nitrogen, decomposed, oxygen and sulfur. In the case of the present invention, the heterocyclic ring group may be a monocyclic, bicyclic or tricyclic ring system which may be a bridged, bridged or spiro ring system, and the heterocyclic ring group, The nitrogen, scale, carbon, oxygen or sulfur atoms therein can be selectively oxidized to various oxidation states. Further, the nitrogen atom may be selectively quaternized; and the ring group may be partially or fully saturated (i.e., a heterocyclic or heteroaryl group). Examples of such heterocyclic ring groups include, but are not limited to, nitrogen, tidinyl, decandyl, stupid and monooxy 15 £, l wuyuan, benzodipolar, benzopyran Base, ten-sitting base, sylvestre base, dioxinyl group called sputum base, naphthalene county, all hydrogen base, morphine, morphyl, thiophene, (iv), (iv), W base 1呤1, sedatives, peony, base, heterogeneous base, four silk, bite base, dihydrogeninyl, brittle base, base, 2_ side oxygen ryphthyl, 20 2- The side oxy group, the 2 _ side oxy group t each bite group, the 2 sided side oxy group 丫 丫 “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ “ 4- 4- 4- 4- 4- 。 。 。 。 。 Well base, spray bite base, 哒 基 base, material base, ten-bonded base, ten-line base, three money, silk, different ten bases, different. f (four) base, like, shot base, shoot base, sigh bite base, heterogeneous base, base, (four) silk, ah base, different (four) 31 200813011 base called 四 (four) base, different ah storage, human hydrogen base, Μ (4) 嗓 、, 氢 异 & 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎 奎Sodium, benzoxanthyl, fluorenyl, tetrahydrocarbyl, tetrachloropyranyl, porphinyl, benzoheptyl, thiomorphinyl thiophanazin, bowl 5 morpholine Base, dioxaPh〇spholanyl, oxadiazolyl, chromanyl, and heterochromyl. The heterocyclic ring group can be attached to any heteroatom or carbon atom of the main structure to give a stable structure. The term "heterocyclyl," refers to a heterocyclic ring group as defined above. The heterocyclyl ring group can be attached to any heteroatom of the main structure or a carbon atom = 10 to give a stable structure.环基基基, refers to a heterocyclic ring group bonded directly to a burnt group. The heterocyclyl group can be attached to any carbon atom in the courtyard of the primary structure to create a stable structure. The term "heteroaryl" refers to an aromatic heterocyclic ring group. The heteroaryl I5 ring group can be attached to any hetero atom or carbon of the main structure to produce a stable structure. A base group, which refers to a heteroaryl ring group bonded directly to a burnt group. The heteroarylalkyl group can be attached to any carbon atom within the alkyl group of the primary structure to create a stable structure. 20 Unless otherwise private, the term "substituted, as used herein, refers to a substitution with any of the following substituents - or any combination: via, dentate, Wei, cyano, nitro, side oxygen a thiol group, a thiol group (=s), a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted dilute group, a substituted or unsubstituted alkyne An aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or 5 unsubstituted Heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl group, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted anthracene, -COORx, _C(0)Rx, _C(S)RX, -C(0)NRxRy, -C(0)〇NRxRy, -NRxCONRyRz, -N(Rx)SORy, -N(Rx)S02Ry, -(=NN(Rx)Ry), -NRxC (0)0Ry, -NRxRy, -NR xC(0)Ry, 10 _NRxC(S)Ry, -NRxC(S)NRyRz, _CONRxRy, -S〇2NRxRy, -〇Rx, -0RxC(0)NRyRz, _〇RxC(0)ORy, _〇c( 〇) RX, -〇C(〇)NRxRy, _RxNRy(C(0)Rz, _Rx〇Ry, _Rxc(〇)〇Ry, -RxC(0)NRyRz,, _RX〇C(〇)Ry, _SRX, _s RX, _S〇2Rx, and -〇N〇2, wherein RX, Ry& RZ are independently selected from hydrogen, substituted 15 or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted Or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted amino group, substituted or unsubstituted heteroaryl group, substituted 2〇 heterocyclylalkyl ring, substituted or unsubstituted a heteroarylalkyl group, or a substituted or unsubstituted heterocyclic ring. According to one embodiment, the above "substituted, such substituents in the group are not substituted step by step. For example, when Substituting an alkyl group, the substituent on 'is a substituted aryl group', Then, the substituted aryl group, the substituent may not be a "substituted alkenyl group," 33 200813011 The term "protecting group," or "PG" means to block or protect a specific function. Other substituents on the compound that retain the reactive substituents, such as "amino protecting groups," are substituents attached to the amine group that can block or protect the amine functional properties of the compound. Suitable amine protecting group 5 groups include, but are not limited to, ethenyl, trifluoroethenyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-mercapto Alkyloxycarbonyl (Fmoc). By analogy, "radioprotective group" refers to a substituent of the hydroxy group which blocks or protects the hydroxy functional properties. Suitable hydroxy protecting groups include, but are not limited to, ethyl hydrazino, benzyl, tetrahydro σ The guaryl group and the methion group. The "wei 10 group protecting group" refers to a substituent of the thio group which blocks the carboxyl functional property. Suitable carboxy protecting groups include, but are not limited to: < Η 2 (: ϋ23Θ2Ρ1ι, gas-based ethyl, (diindolyl sulfonyl) ethyl, 2-(trimethylmethyl decyl) ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2 -(p-Nitrophenylphosphorus) ethyl, 2-(monophenylphosphino)-ethyl, and schiffylethyl. See TW Gfeene for a general description of the protecting group 15 and its use. ,Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. The term "prodrug" means the conversion in vivo to produce a compound of formula (I) or (la) or a pharmaceutically acceptable compound thereof. a compound of a salt, hydrate or solvate. It can be hydrolyzed by various means, such as in the blood. This conversion is discussed in the following reference: T· Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,'' Vol· 14 of the ACS Symposium Series, and in Bioreversible Carriers In Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 34 200813011 1987. The term "treatment" or "therapy" of a disease, condition, disorder or symptom includes: (1) avoidance or delay in the possibility The presence of clinical microbes that form a disease, condition, disorder, or symptom in a patient who has or is susceptible to a disease, condition, disorder, or condition but has not experienced or demonstrated clinical, or subclinical signs of the condition, disorder, or condition: 2) inhibiting the disease, condition, disorder or symptom, ie controlling or reducing the formation of the disease or at least one of its clinical or subclinical signs; or (3) dissolving the disease, ie causing the disease, condition, disorder or Symptom 10 or the regression of at least one of its clinical or subclinical signs. The benefit to the patient to be treated is statistically significant Or the patient or physician can perceive at least. The term "patient" includes mammals (especially humans) and other animals, such as poultry (eg household pets, including cats and dogs) and non-poultry (such 15 as wildlife). "Therapeutically effective amount" refers to the amount of a compound sufficient to effect the treatment when the patient is treated for a disease, condition, disorder or symptom. The "therapeutically effective amount" may vary depending on the compound, disease, condition, disorder or condition and its severity, and the age, weight, physical condition and anti-reactivity of the patient to be treated. The pharmaceutically acceptable salts forming part of the invention include salts derived from inorganic tests (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Μ), organic bases (such as N, N'- Salt of diethyl ethanediamine, reduced glucosamine, diethylamine, choline, hydroxide, dicyclohexylamine, metformin, amide, trialkylamine, 35 200813011 and thiamine Salts of bases such as alkylphenylamines, glycylamines, and stupid glycosaminols, natural amino acids such as glycine, alanine, valine, leucine, isoleucine, Leucine, tyrosine, cystine, cysteine, methionine, valine, hydroxyproline, histidine, ornithine, 5 lysine, arginine, and a salt of a serine, a salt of an unnatural amino acid such as a D_isomer or a substituted amino acid, a salt of hydrazine, a substituted hydrazine wherein the substituents are selected from the group consisting of a nitro group and an amine group , alkyl, alkenyl or alkynyl) salts, ammonium salts, substituted ammonium salts, and aluminum salts Other pharmaceutically acceptable salts include acid addition salts (if appropriate, such as sulfates, nitrates, phosphates, all Chlorate, Boron 10 acid salt, hydrohalide, acetate (such as trioxoacetate), tartrate 's-butenyl diacid salt, citrate, fubutenate, succinate, pamoate (palmoate), mesylate, benzoate, salicylate, benzoate, ascorbate, glyceryl, and glutaric acid. Further pharmaceutically acceptable salts include, but It is not limited to the quaternary ammonium salt of the compounds of the present invention having a burning base or sulfuric acid (such as MeI or MeJO4). Any of the conventional techniques known to the skilled artisan can be used, for example, Han (jb〇〇) k 〇f

Pharmaceutical Salts-Properties, Selection and Use5\ P.

The pharmaceutically acceptable salts of the present invention are prepared as described in Heinrich Stahl, Camille G. Wermuth [Eds.], VHCA and WILEY-VCH (2002). Pharmaceutically acceptable solvates include hydrates and other solvents which crystallization (such as alcohols). The compounds of the present invention can be formed into solvates having low molecular weight solvents by methods known in the art. Particular compounds of the invention may exist in stereoisomeric forms (e.g., diastereomeric 36 200813011 isomers and mirror image isomers) and the invention encompasses each such stereoisomeric form and mixtures thereof, including an arotor. The different stereoisomers may be separated from one another by known methods or any particular isomer may be obtained by stereospecific or asymmetric synthesis. The invention also encompasses any tautomeric form or a mixture thereof. For example, it encompasses two tautomeric forms having the following molecular groups:

Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise at least one compound of the invention and a pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention (group). The compounds of the present invention may be associated with or conjugated to a pharmaceutically acceptable excipient (such as a carrier or diluent) in a carrier which may be in the form of a capsule, sachet, paper or other container. Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, 15 polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, white earth, sucrose, dextrin, carbonated, Sugar, soil dextrin, direct bond powder, magnesium stearate, talc, agar, pectin, acacia, stearic acid or low-alkyl ether of cellulose, tannic acid, fatty acid, fatty acid amine, fatty acid Monoglycerides and diglycerides, isoamyl alcohol fatty acid esters, polyethylene oxide, 20 hydroxymethyl cellulose, and polyvinyl pyrrolidone. The carrier or diluent may include a sustained release material such as monostearyl 37 200813011 acid, glyceride or glyceryl distearate, either alone or in admixture with a wax. The pharmaceutical composition may also include one or more pharmaceutically acceptable adjuvants, wetting agents, emulsifiers, suspending agents, preservatives, salts for affecting osmotic pressure, buffers, sweeteners, flavoring agents, coloring agents Or any combination of the foregoing. The pharmaceutical composition of the present invention can be formulated to rapidly, continuously or delay release of the active ingredient after administration to a patient by procedures known in the art. The pharmaceutical compositions of the present invention can be prepared by conventional techniques, for example, as described in Remington: The Sdenre pmH Practice of Pharmacy, 20th Edition, 2003 (LiPPinc〇tt Williams & Wilkins). For example, the 10 active compound may be mixed with the carrier or may be diluted by the carrier or enclosed in a carrier which may be in the form of an ampule, capsule, sachet, paper or other container. When the container is used as a diluent, it may be a solid, semi-solid or liquid substance as a vehicle, excipient or medium for the active compound. The active compound can be adsorbed onto a granular solid container. 15 The pharmaceutical compositions may be in a conventional form such as a capsule, a lozenge, an aerosol, a solution, a suspension liquid or a product for topical administration. The mode of administration may be any means effective to deliver the active compound of the invention to a suitable or desired site of action. Suitable administration methods include, but are not limited to, oral, nasal administration, pulmonary administration, buccal administration, subcutaneous administration, intradermal administration, transdermal administration, parenteral administration, rectal administration, storage administration, intravenous administration, intraurethral administration. Intramuscular administration, intranasal administration, ocular administration (such as the use of eye drops) or topical administration (such as the use of topical ointments). Solid oral formulations include, but are not limited to, lozenges, capsules (soft or hard gelatin), dragee pills (containing active ingredients in powder or granule form), mouth containing 38 200813011 red and s tablets. I-formulations, dragees or capsules having talc and/or carbohydrate carriers or binders are particularly suitable for oral administration. Preferred carriers for lozenges, dragees or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in the example of using a sweetening vehicle. 5 A general lozenge which can be prepared by the conventional tablet technology may contain: (1) a core active compound (in the form of a free compound or a salt thereof), 250 mg of acerium dioxide (Aersil®), 1.5 Mg of microcrystalline cellulose (Avicel®), 70 grams of modified cellulose gum (Ac-Di_Sol®), and 7.5 mg of magnesium stearate; (2) coating: HPMC, about 9 mg Mywacett 9-40T and about 0.9 mg of deuterated single 10 glycerol. Liquid formulations include, but are not limited to, syrups, lotions, soft gelatin, and sterile injectable solutions such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral administration, it is especially suitable as an injectable solution or suspension' preferably an aqueous solution having the active compound 15 which has been dissolved in the polyhydroxylated castor oil. Methods of Treatment The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, disorders, and/or disorders modulated by vanillin-type V R receptor antagonists. The present invention further provides a method of treating a disease, disorder, and/or disorder modulated by a fragrant 20 grass essence receptor antagonist in a patient in need of the therapy by administering to the patient a therapeutically effective amount of the present invention a compound or pharmaceutical composition. This method is particularly useful for treating diseases, conditions, and/or disorders modulated by VR1 receptor antagonists. The diseases, disorders, and/or disorders modulated by the vanilla extractor 39 200813011 antagonists include, but are not limited to, migraine, joint pain, diabetic neuropathy, Neurodegeneration, neuropathic skin disease, stroke, heartache caused by ischemic myocardium, Hunting^ disease, memory deficiency, restrictive brain function, lateral cord hard 5-muscular atrophy (ALS), Dysentery, bladder allergy, urinary incontinence, chronic pubic pain H (such as uremia syndrome), large intestine irritation (muscle) (including gastroesophageal reflux disease (GERD), enteritis, ileitis , stomach, duodenal ulcer), inflammatory bowel disease (including Crohn's disease), milky shore and inflammation (such as adrenitis), and respiratory disorders (such as allergic and non-over-sex) sensitive rhinitis , asthmatic obstructive pulmonary disease), skin, eye or mucous membrane irritating skin people # special disorders, such as increased heat, retinopathy, muscle spasm, dyspnea, difficulty in movement and inhibition. The pain regulated by the vanilla extract is not limited (4) including acute pain, chronic pain, U original! · Pain, postoperative pain, neuralgia (eg 15 neuralgia or trigeminal after band treatment) Pain caused by neuralgia), pain, pain and cancer caused by diabetic neuropathy. Other diseases, disorders, and/or disorders modulated by vanilla extract receptors include, but are not limited to, inflammatory pain (eg, arthritis and osteoarthritis), diabetes, obesity, urticaria, Actinic keratosis, horny acanthoma, hair filling, Meniere's disease, tinnitus, hypersensitivity 20 and anxiety. A further embodiment is a method of treating or preventing a disease or disorder in which a patient (eg, a mammal or a human) in need of the therapy is mediated or associated with the activity of the vanilla extractor. A therapeutically effective compound or pharmaceutical composition of the invention is administered. These diseases and disorders 40 200813011 : Not limited to: disorders such as pain, chronic pain, neurogenic = post-pain, rheumatoid arthritis pain, osteoarthritis pain, monthly pain, visceral pain, cancer pain, pain Jindou L Zhimin, neuralgia, migraine, neuropathy, diabetic neuropathy, sitting brother "7C< 丄月 neuralgia, HIV-associated neuropathy==2nd post-secret neuralgia, fibromyalgia, Nerve injury, ischemia, nerves, stroke, post-stroke pain, multiple sclerosis, respiratory disease, qi%, coffee D, inflammation, esophagitis, gastroesophageal reflux disease (GERD), (4) irritability (IBS) , inflammatory bowel disease, pelvic allergy, urinary incontinence, cystitis, burns, bovine secret 1 spit, stomach. Duodenal ulcer and pain. 1〇 ^ An embodiment is a method of treating or preventing pain in a patient in need of such therapy by administering a therapeutically effective amount of a compound or pharmaceutical composition of the present invention. The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt, in the preparation of a disease or disorder associated with or associated with the activity of treating or preventing the activity of the vanilla extractor 15 The use of the drug.

The compounds of the present invention have potent analgesic and anti-inflammatory activities, and thus the pharmaceutical compositions of the present invention can be used to alleviate or alleviate acute, chronic or inflammatory pain, inhibit inflammation or treat urge incontinence. The compounds of the invention may be used alone or in combination with other pharmaceutically active compounds. The compounds and pharmaceutical compositions of this invention may be used alone or in combination with other pharmaceutically active compounds to prepare a medicament for use in the therapeutic use described herein. Preparation

The compound of formula (1) can be synthesized as shown in Scheme la below, wherein R3 is oxime, X 200813011 is 0, and R1, R2, R4, R5, and R6 are as defined in the general description. According to one embodiment, R4 and R5 are deuterium or, when R4 and R5 are attached to the same carbon atom, form a pendant oxy or thio group. Graphic la

As shown in the scheme la, it is preferred to formulate a compound of the formula 7 with a compound of the formula 8a (wherein L is a leaving group such as a halo group, an aryloxy group, an alkoxy group, a microphone) in the presence of a test such as triethylamine or hydrazine. The reaction is carried out to obtain a compound of the formula (I) by a reaction of a sulfhydryl group, a benzopyranyl group, a tetrasyl group, a benzotetradecyl group, an amber quinone imine group. The R3 group in the compound of formula (I) by the formation of the formula la can be converted to a different R3 group, such as an alkyl or aryl group, a benzamidine group, by methods known in the art. In another embodiment, the compound of formula (I) can be synthesized as illustrated by lb, wherein R2 and R3 represent oxime and X, R1, R4, R5 and R6 are as defined in general description 15. Graphic lb

42 200813011 As shown in Figure lb, the compound of formula 7 is reacted with a compound of formula 8 in the presence of a test such as triethylamine or σ 唆 to obtain a compound of formula (I). According to a preferred embodiment of the drawings la and lb, R1 is selected from

¢0 OCX

R

A, B

According to another preferred embodiment of the drawings la and lb, R1 is selected from the group consisting of Formulas A and D. In one embodiment, the intermediate of formula 7 is synthesized as illustrated in Scheme Ila, wherein R4 and R5 represent oxime and R6 is as defined above in the general description. Methods for the synthesis of compounds of formula 7 are described below in Ila to Ilg 10. In each of the methods, R6 may be a protecting group. Graphic Ila

43 200813011 In the above-mentioned general scheme IIa, for example, in the presence of a test (such as carbonic acid clock, sodium carbonate or quaternary ammonium) and a solvent (such as dimercaptocarhamamine), the compound of formula 2 and the actress The reaction is carried out to convert the compound of the formula 2 into the intermediate product 2a. The compound of formula 3 can be reduced by reacting, for example, a (iv) prodrug (such as hydrogenation, magnetic, shed 5 sodium hydride, BF3 (e.g., Bf3.0Et2) or a mixture thereof) to form a compound of formula 3. The compound of formula 3 is reduced, for example, using a reducing condition such as hydrogenation in the presence of (e.g., Pd/C), Raney, iron/hydrochloric acid, or Raney nickel/rhodium to obtain a compound of formula 4. The support group is then preferably subjected to a suitable solvent such as methanol, methylene chloride, chloroform or ethyl acetate in the presence of a test such as triethylamine, sodium carbonate, carbonic acid or sodium oxynitride, such as The third · butoxy lin (B 〇 c), the protection of the amine in the compound of formula 4 is carried out to obtain the compound of formula 5. For example, under acidic conditions, such as in an appropriate solvent (such as ethyl acetate 'methanol or: gas hospital) using anhydrous hydrochloric acid or trifluoroacetic acid, the compound of formula 5 is removed in 15 lines (ie, selective shifting) In addition to the protecting group, a compound of formula 6 (in the form of its free base or acid addition salt) is preferred. It is preferably in the presence of a base such as triethylamine or potassium carbonate, or under metal catalysis, such as in steel or In the presence of a compound of formula 6 and a suitably substituted aryl/heteroaryl, aryl-based/heteroaryl halide (mainly with the desired r6 substituent) to give a compound of formula 6a, for example The compound of formula 6a is deprotected (ie, the protecting group pG is removed) under acidic conditions, such as anhydrous hydrochloric acid or trifluoroacetic acid, in a suitable solvent such as ethyl acetate, methanol or dichloromethane. To obtain a compound of formula 7. 44 200813011 Alternatively, directly in the absence of protection group chemistry, preferably in the presence of, for example, triethylamine or potassium carbonate, or under metal catalysis, such as in copper or palladium In the presence of The compound is reacted with a suitably substituted aryl/heteroaryl, aralkyl/heteroaralkyl group to give a compound of formula 7. In yet another embodiment 4, a compound of formula 7 is synthesized as illustrated in lib, wherein R4 and R5 represent H and R6 is as defined in the general description.

7 The compound of formula 9 is reacted with a compound of formula 1 which is suitably substituted with H), for example, in the presence or absence of an acid such as acetic acid to form a towel. The compound of formula 12 is obtained, for example, by using a dehydrating agent, an o-acetate needle or dicyclohexylcarbodiimide (DCC), and cyclizing the intermediate (10). For example, it is preferred to compare the compound of the formula U to a compound of the formula 3 in the presence of a reaction such as carbonic acid dehydration, sodium carbonate or quaternary salt, in order to prepare a compound of formula 7, 15 of which R4 and R5 are present. Starting from the formation of a pendant oxy group, for example, using a reducing condition such as hydrogenation in the presence of palladium, Raney nickel, iron/hydrochloric acid, or Raney nickel/ruthenium, the compound of formula 13 is reduced to obtain a compound of formula 7. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; Compounds to give compounds of formula 14. The compounds of formula 14 are then reduced, for example, using reducing conditions such as hydrogenation in the presence of palladium, Raney nickel, iron/hydrochloric acid, or Raney nickel/niobium to obtain a compound of formula 7 In yet another embodiment, the compound of formula 7 is synthesized as illustrated in Figure lie.

6a R4

The compound of formula 7 can be prepared using the conditions provided by the formula or the like, wherein R4 and R5 are hydrogen or together form a pendant oxy group, as indicated by the above diagram lie. (Tamim F. Braish et al., Synlett: September 1996, 11〇〇·11〇2 and Catherine E. Brighty et al., Synlett 46 200813011

September 1996, 1097-1099) In yet another embodiment, a compound of formula 7 is synthesized as illustrated in lib, wherein R4 and R5 represent oxime and R6 is as defined in the general description. Graphic lid

For example, in the presence of Τί(〇ρή4, MeMgCl, and/or cyclohexylmagnesium bromide, in a suitable solvent such as tetrahydrofuran, dimethoxyethane or dioxane, by the formula 19N-benzylpyrroline compound Reacting with N,N-dibenzylformamide to obtain a compound of formula 21. For example, hydrogenation is carried out using reducing conditions such as in the presence of 10 Raney nickel, iron/hydrochloric acid, or Raney nickel/rhodium. The compound of formula 21 is subjected to thorough debenzylation to give a compound of formula 4 (Chem. Eur. J. 8 (16), 3789-3801, 2002). Preferably, in the presence of, for example, triethylamine or potassium carbonate, or The compound of formula 4 is reacted with a suitably substituted aryl/heteroaryl 'aralkyl/hetero15 aralkyl i under metal catalyzed conditions, such as in the presence of copper or palladium, to give a compound of formula 7. In another method, a compound of formula 7 is synthesized as illustrated in the scheme, wherein R4 and R5 represent oxime and R6 is as defined in the general description.

Uille

15 (external) For example, in a suitable solvent (such as stupid, toluene, dioxin or acetone), N-nodal-butenyldienimide and formula (2) 禹5-pole (ylide) The reaction is carried out to obtain a mixture of the internal isomer (15a) and the external isomer (15) of the compound of the formula 23. For example, the internal isomer and the external isomer are separated by column chromatography. The compounds of formulae 15 and 15a are then converted to the compounds of formula 7 and 7a, respectively, using, for example, the procedure described in Scheme lie. Yet another method of preparing a compound of formula 7 wherein R4 and R5 together form a pendant oxy group and R6 is as defined in the general description herein is shown below in Scheme Ilf. Graphical Ilf

R6 R6 13 7 48 200813011 For example, the hydrogenation reaction is carried out using reducing conditions, such as in the presence of palladium or Raney nickel, iron/hydrochloric acid, or Raney nickel/rhodium, to form an amine compound of formula 7 by reduction of the hydrazine 3 nitro compound. Yet another method of the compound of Formula 7 wherein R4 and R5 represent oxime and R6 is as defined in the general description is shown below in Scheme Ilg. MJillg

Ph Ph. Face ΊΓ

26 7 In the presence or absence of a test, such as triethylamine or carbonic acid, in the presence of a compound of the formula 24 (where l is a de-hybrid) such as halogen, toluene, or sulphur The compound of formula 25 is synthesized by reacting a mesylate with a compound of the formula R6-NH2, preferably in the presence of titanium isopropoxide, methylmagnesium chloride, methylmagnesium bromide, cyclohexylmagnesium bromide or cyclohexylmagnesium chloride. The compound of formula 25 is reacted with N,N-dibenzylformamide in a solvent such as tetrahydrofuran, dimethoxyethane or dioxane to obtain a compound of formula 26. For example, a reducing strip 15 is used. A compound such as palladium, platinum or Raney nickel is subjected to a hydrogenation reaction to subject the compound of formula 26 to a complete debenzylation reaction to give a compound of formula 7 (Chem. J. 8 (16), 3789-3801, 2002). 49 20 200813011

Illustration III

X, Ar 37 The compound of formula 37 can be prepared using the procedure described in Scheme III above, to give a compound of formula 33 wherein PG is a oxime-protecting group [for example, but not limited to: 5 tert-butoxycarbonyl, Benzyl urethane (such as benzyl benzoate), 9-fluorenyl carbazate (such as 9-fluorenyl chloroformate), and vinyl urethane (such as vinyl chloroformate), A compound of formula 34, wherein l is as defined above, is reacted to obtain a compound of formula 35. Preferably in one or more assays, such as triethylamine, pyridine, sodium carbonate, potassium carbonate or lithium carbonate, in the presence of one or more than one solvent (eg, an aprotic polar solvent (eg, dimethyl hydrazine, dimethyl The reaction is carried out in carbamide, acetonitrile, a chlorinated solvent (for example dichloromethane, dichloroethane, gas imitation) or a mixture of them or a mixture thereof. For example, the compound of formula 35 can be removed by reacting a compound of formula 35 with a deprotecting agent such as p-toluene, cereanoic acid, brittle bite, monochloroacetic acid or triduronic acid to remove the compound of formula 35. To form a compound of formula 36. In the presence of one or more bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate, in one or more 50 200813011 aprotic polar solvents such as tetrahydrofuran, diethyl ether or a mixture thereof The deprotection of the compound of formula 35 is carried out. In the presence of one or more bases, such as triethylamine, tonate, sodium carbonate, carbonic acid or carbonic acid, in one or more aprotic polar solvents such as tetrahydrofuran, diethyl ether or a mixture of 5 The compound of formula 36 is reacted with an aromatic sulfonium halide, an arylcarbonyl halide or an arylalkyl halide to form a compound of formula 37.

Graphic IV

Step I

10 m

4 38 39

51 15 200813011

Step II a) 『

40a Compounds of formula 43 and 44 can be prepared by the reaction schemes shown above. The compound of formula 4 is reacted with a compound of formula 38 in a polar aprotic solvent such as 5 dimethyl hydrazine or dimethylformamide in the presence of a base such as triethylamine or pyridine to form a compound of formula 39 . The compound of formula 39 is reacted with a protecting agent wherein PG is as defined above to form a compound of formula 4. The compound of formula 43 is prepared as follows: for example, in the presence of a catalytic reducing agent (for example, 1% by weight of palladium on carbon or platinum and hydrogen in carbon) or a metal reducing agent (for example, zinc/acetic acid biting 10 Fe/HCl) in polar protonicity. The compound of formula 40 (wherein R' is N〇2 and R, is hydrazine) is reduced in the presence of a solvent such as methanol, ethanol, isopropanol or water to give an amine of formula 4. The amine of the compound of formula 41 is reacted with sulfonium chloride or trifluoroacetic anhydride or acetic anhydride to form a compound of formula 42 (wherein W is C〇 or S〇2 and R is CH3 or CF3 and PG is as previously defined) For example, by removing the protective agent (for example, p-toluenesulfonic acid, methanesulfonic acid, piperidine, dichloroacetic acid or trifluoroacetic acid) to remove the protective effect of the compound of formula 42 to form a compound of formula 42a. For example, in the presence of a reagent such as triethylamine, the compound of the formula 5 42a and the heterogeneous _5-aminocarbamic acid are subjected to a polar aprotic solvent such as dimethyl ferrous or dimethyl urethane. The reaction is intended to form a compound of formula 43.

10

The compound of formula 44 is prepared by, for example, removing the protective effect by removing the protective agent (for example, p-toluene, methyl hydrazine, _, di-acetic acid or trifluoroacetic acid) to cleave the compound of formula 4). To form a compound of the formula 4Ga. In the presence of a reagent such as triethylamine, the compound of formulae 40a and 42a and the heterogeneous _5-aminocarbamic acid benzoate are incorporated in a polar aprotic solvent such as dimethyl sulfoxide or dimethyl hydrazine J. Reacting to form a compound of formula 44. These examples are for illustrative purposes only. In the following examples, the invention is used in the context of the invention, and therefore should not be considered as an intermediate product within the scope of the invention.

Process for the preparation of intermediates 1 · 1 α , 5 α ·6 ry - 丄 3 salt 1 ·· 2-Phase-4-Mothylhexahydrocyclopropane [cM_13_Two methods of preparation under 30 C to 25 C - Anhydrous carbonic acid was added in portions (7, 53.4 mmol) to Ν· 基 顺 顺 稀 dibutyl imidate (10) g, 26 7 Å), nitromethane (7.48 g, 52 4 mmol) ), Celite (5. G grams), and 4 angstroms (Α) 5 5g) in: methyl ketone (5 〇. 〇 ml) in the charge (10) mixed suspension Stir for 3 to 4 hours. Add 53 200813011 (500 ml) to the reaction mixture and acidify to Ph5-6 via 1% HCl in water. Ethyl acetate (1 mL) was added and the mixture was filtered through a pad of Celite. The layers were separated and washed with EtOAc EtOAc m. The crude product is then purified by a ruthenium gel column using ethyl acetate:: petroleum ether (2:8) to give the product as a pale yellow product. IR (KBr): 3086, 1789, 1707, 1560, 1433, 1405, 1360, 1173, 1017, 833 cm]. b-NMROOOMHz, DMSO-d6): 5 3.74 (s, 2H), 4.40 (s, 2H), 5.57 (s, 1H), 7.23 - 7.35 (m, 5H). 10Step 2: 1 a, 5 a, 6a-(6-Amino-3-benzyl)-3-azabicyclo[3·1·0] hexane method of adding sodium borohydride at -20 ° C (〇·92 g, 24.36 mmol) to 2-pyristyl-4-nitrohexahydrocyclopropane [c]azole _i,3_dione (2·〇g, 8.12 mmol) in anhydrous THF (20.0 ml) was thoroughly stirred in the suspension. Then, BF3 · Et2O (3.0 ml, 24.36 mmol) was slowly added at the same temperature of 15. The reaction mixture was then stirred at rt EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to give 1.7 g of product as a white solid, which was purified from ethyl acetate and ethyl acetate. IR (KBi〇: 3076, 1782, 1717, 1562, 1442, 14 (H, 1363, 1178, 1017, 883 cm 1. i-NMR pOO MHz, DMSO-d6): 5 2.91 (s, 2H), 3.42 (s, 4H), 4.34 (s, 2H), 5.37 (s, 1H), 7.43-7.62 (m, 5H). Step 3 ·· la,5a,6a-6-amino-3-azabicyclo[3.1·0 ]Heil production method 54 200813011

................ and remove the catalyst. The solvent is removed under actual conditions to give the product as a fine sm. One . In vacuum step 4: 1 a, 5 a, 6 a - butoxy-based] - 3 - azabicyclo[3d Q] calcined

The solvent was removed to give 280 mg of product as a pale yellow solid. A-[heart (t-butoxyamine-mercapto- 3_(third) A-NMRpOOMHz, CDC13): 3 i.42 (s, 9H), 1.44 (s, 9H), 1.56 (s, 2H) 2.28 (s, lH), 3.32-3.40 (m, 2H), 3.64 - 3.67 (m, 2H), 4.75 (s 1H). 15 Step 5 ·· la,5a,6a-6Amino-3-azabicyclo[3·1·0]hexane hydrochloride is stirred at room temperature 1 α,5 α,6 α -[6-( Third)·Butoxyaminecarbamyl_3_(Third)-butoxycarbonyl]_3·azabicyclo[3·1·0]hexane (280 mg) and ethyl acetate saturated with HC1 ( A solution of 5.0 ml) takes 5 to 6 hours. The residue obtained after removing the solvent was washed with anhydrous ether to give a product of 180 mg of 20 as white solid. Α-ΝΜΙΐρΟΟΜΗζ, CD3OD): 5 231 (s, 2H), 2.82 (s, 1H), 3.57 (s, 4H). - intermediate product 2: 3-(3-Shishouji p out t? setting)-3 - Milky double soil Γ3·1 ·01 hex-6-amine method of adding 2-chloro-3-nitropyridine (1.05 g) , 6.52 millimolar) to 1 α,5〇:,6 55 200813011 α Aminoazabicyclo[3·1·0]hexane hydrochloride (400 mg, 408 mmol) and triethylamine ( 2·〇 ml) in a solution of dimethyl hydrazine (5.0 ml) and stirred at room temperature for 15 to 16 hours. The reaction mixture was diluted with water (1 mL) andEtOAc. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the residue obtained after solvent removal was purified by using a hydrazine gel column using a solution of 10% methanol in the solvent as a solvent to obtain 300 mg. The product of brown oil. 1H-NMR (300MHz, DMSO-d6): (5 1.73 (brs, 3H), 2.17 (s, 1H), 3.52 (d, 2H, J = 10.2 Hz), 3.70 (d, 2H, J = l〇. 2 Hz), 7.32 (d, 1H, J = 9.3 Hz), 10 7.60 (d, 1H, J = 8.7 Hz), 8.28 (s, 1H). Intermediate 3: 3-(3-nitropyridine-2- Addition of a solution of Boc-anhydride in methanol to a solution of 3-(3-nitropyridin-2-yl) at room temperature with a heterobicyclic "3.1.01 hex-6-amino phthalic acid tert-butyl ester" a mixture of 3-azabicyclo[3.1.0]hex-6-amine (1 mmol) and triethylamine (1.5 15 mmol) in methanol. The reaction mass is heated up to The reflux temperature, which took 3 to 4 hours, allowed the distillation product methanol and the reaction mass to be dissolved in ethyl acetate and extracted with water. The compound was purified by column chromatography. 1H-NMR (DMSO-d6): 5 1.43 ( 9H, s); 1.82 (2H, s); 2.16 (lH, s); 3·60 (2Η, d); 3·82 (2Η, d); 4·70 (1Η, s); 6·66 ( 1Η,m); 20 7·99(1Η,d) ; 8·28(1Η,d).IR(KBr)(cm-1): 2984, 1759, 1622, 1450, 1200, 1095, 709. MS ( M++1) : 321 Intermediate 4 : 3-(3-Aminopyridin-2-yl)H heterobicyclic π.ι.〇ihex-6-nonylamine Process for the preparation of tert-butyl carboxylic acid 56 200813011 Hydrogenation of 3-(3_nitropyridin-2-yl)_3_azabicyclo[3·1·0]hex-6-ylamino group in Pan: apparatus Formic acid third _ Dingku and i〇% carbon-loaded pd suspension liquid 'takes 8 to 10 hours. The catalyst is removed by filtration, and the obtained sputum is concentrated to obtain the product. 5 Soil-intermediate product 5 · - A酹(^ is ^^^^^^^^^^^^^^^^^^^^^

Add a mixture of cis-butanediol (ι〇·5 ml, 0·127 mol) and triethylamine (84 ml, 〇6〇4 mol) to the stone in a nitrogen atmosphere under a nitrogen atmosphere. Chloric acid chloride (40 ml, 〇·527 mol) was placed in a solution of 3 ml of anhydrous dichloromethane and mixed for 30 to 40 minutes. The mixture was stirred for a further 3 minutes and then transferred to a separating funnel and washed successively with 2 mL of cold water, 1% HCI, saturated sodium bicarbonate solution and saturated sodium chloride solution. The methylene chloride layer was separated and dried over sodium sulfate. The solvent was removed in vacuo to give a yellow powder (1 g). IR (KBr) 2929, 1624, 1319, 1173, 1144, 1056, 1018, 934, 795 cm 1. h-NMRpOOMHz, CDC13): 5 5.90 (m, 2H), 15 4.80 (d, 4H), 3.03 (s, 6H). Process for the production of soil I do not θ : N_3-azaindoleisoline-5-ylurea Step 1: 6-{[(isoporphyrin-5-ylamino)carbonyl]amino}_3-aza Bicyclo[3 j 0] hexane--3-carboxylic acid tert-butyl vinegar was stirred at room temperature with iso-phenyl phenyl phenyl ester (1 mmol) and 6-amino-3-nitrogen. Heterobicyclo[3·1〇]hexane-3-carboxylic acid tert-butyl ester (1 mmol) and diethylamine (23⁄4 mol) in DMSO took 5 to 7 hours. Add a few drops of water to the reaction mixture. The precipitated solid was filtered, washed with water and dried. 57 200813011 IR (KBr) (cm-1): 3355, 3214, 2973, 1693, 1648, 1554, 1368, 1266, 1116. WnMR^CDCU): 5 1.39(9H, s); 1.70-1.76(2H?m); 2.26-2.32(lH?m); 3.28-3.40(2H, m); 3.53(2H,d,J=11.2Hz ; 6.85(1H,m) ; 7·56-7·65(1Η,m); 5 7·76(1Η,d,J=7.2Hz) ; 7·84·7·90(1Η,s), 8·20-8·27(1Η,m); 8·53(1Η,d,J=4.8Hz); 8.16(1H,s) ; 9.27(1H,s). Step 2: N-3-azabicyclo[3丄0]hex-6-yl-N,-isoindoline-5-ylurea was added to a solution of p-toluenesulfonic acid (3.0 mmol) at room temperature. 6-{[(isoindolino-5-ylamino)carbonyl]amino}_3_azabicyclo[3_1.0]hexane-3-carboxylic acid 10 tert-butyl ester (1.0 mmol) In a solution of tetrahydrofuran. The reaction mixture was stirred at the same temperature for 6 to 7 hours. Excess solvent was evaporated under vacuum. The residue is treated with an aqueous NaOH solution to give the desired compound as a white solid. 1H_NMR(CDC13): 5 1·50-1·57(2Η,m); 2·26·2·32(1Η, m); 3·15(2Η,d,J=9.3Hz); 3·70( 2Η,d,J=10.2Hz); 7·57(1Η, 15d, J=7.2Hz); 7·68(1Η,d,J=7.2Hz); 7·96(1Η,s); 8· 22·8·34(3Η, m) ; 8·44-8·50(1Η,m) ; 9·22(1Η,s); 9·62(1Η,s). IR (KBr) (cm _1): 3434, 1640, 1545, 1429, 1406, 645. MS (M+-1): 267.26 soil product 7 : 1α.5α,6 a-"6-amino-3(3-pyridin-2-yl)1-3-aza20bicyclo"3·1·〇 1 hexane method was added to the compound 2,3-dichloropyridine (720 mg, 4.98 mmol) to intermediate 1 (400 mg, 4.08 mmol) and triethylamine (2.0 ml) in dimethyl Stir in a solution of hydrazine (5.0 mL) at 85 to 90 ° C for 15 to 16 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and EtOAc EtOAc. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the residue obtained after solvent removal was purified by using a hydrazine gel column using a solution of 10% methanol in a solvent. The product of 〇mg such as brown oil. 1H-NMR (300MHz, DMSO-d6): 5 5 1.60 (s? 2H) ^ 1.67 (bs? 2H) ^ 2.62 (s? 1H) &gt; 3.56-3.69 (m? 2H ); 4.07-4.20 (m, 2H), 6.59 (m, 1H), 7.46 (m, 1H), 8. 〇 5 (m, ih).

J7·inter-product 8 · 1 〇; , 5 〇;, 6 a _ "6-amino group _3-(5 three gas ^ 咐 _2 _2 _ base) 1-3 - aza complex ring "3. i. The oi hexane method is added to the compound, 2-chloro-5-trifluoromethyl. ratio. Set (1. 2 grams, 6.63 millimoles) 10 to intermediate product 1 (500 mg, 5. 1 mM) and triethylamine (2 〇 ml) in dimethyl hydrazine (5. Stir in the solution in 0 ml) and stir at room temperature for 15 to 16 hours. The reaction mixture was diluted with water (100 mL) andEtOAc. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the residue obtained after removing the solvent was purified by using a 10% methanol in a solution of hydrazine as a dissolving agent to produce 300 mg. Such as the product of brown oil. h-NMROOOMHz, DMSO-d6)·· 51. 73 (brs, 3h), 2 17 (s 1Η), 3. 52 (d, 2 Η, Μ〇 · 2 Ηζ), 3. 70 (d, 2 Η, J = l〇. 2Hz), 6 31(d, 1H, J=9. 3HZ), 7. 58 (d, 1H, J = 8. 7Hz), 8. 35 (s, 1H). ‘ Middle ϋ, 6 α - 『6: Amino winter (3-three ^ ^ 20 base) 1_3H double ring 丨 3. 1. 〇1 hexane recovery! Add 2-gas-3·trifluoromethylpyridine (1.44 g, 6 95 mmol) to intermediate 1 (600 mg, 6.12 mmol) and triethylamine (2 mL) in two Methyl sulfoxide (5. In a solution of 0 ml), and stirred at room temperature for an hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 mL). The layer was dried over anhydrous sodium sulfate, and the residue obtained after solvent removal was purified by using a solution of 10% methanol in hexanes as a solvent to obtain 300 mg of product as brown oil. 1H-NMR (300MHz, DMS〇-d6): (n. 73 (brS, 3H), 2. 17(s, 5 1H), 3. 52 (d, 2H, :=10·2Ηζ), 3. 70(d, 2H, &gt;1〇·2Ηζ), 7”2(d, 1H, J=9. 3HZ), 7. 60 (d, 1H, J = 8. 7Hz), 8. 24(s, 1H). ' 土盟立物 10 : methylpyridin-2-yl) 1_3_azaindole V1 〇1?', the method of adding 2,3-digas-5-trifluoromethylpyridine (14〇 Gram, 6. 52 millimoles) to 10 intermediates 1 (400 mg, 4·08 mmol) and triethylamine (2. 0 ml) in dimethyl hydrazine (5. Stir in the solution in 0 ml) and stir at room temperature for 15 to 16 hours. The reaction mixture was diluted with water (100 ml) and evaporatedEtOAc. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and purified by using a 10% methanol in a solution of the solvent as a solvent to dissolve the residue obtained after removing the solvent to obtain 300 mg. The product of brown oil. 1H-NMR (300MHz, DMSO-d6): 5 1. 73 (brs, 3 Η), 2. 17(s, 1H), 3. 52 (d, 2H, J = 10. 2Hz), 3. 70 (d, 2H, J = l〇. 2Hz), 7. 60 (m, 1H), 8. 22 (d, 1H, J = 7. 2Hz). a product of soil H α,5 α,6 a -"6-mercapto-3-(3-nitrogen pyridine_2_2 〇 〇 双 坏 坏 π · · · 添加 添加 添加 添加 添加 添加 添加 添加 添加 添加 添加 添加Pyridine (1. 05 g, 6. 52 mmoles to intermediate 1 (400 mg, 4. 08 millimoles) and diethylamine (2. 0 ml) in dimethyl hydrazine (5. The solution in 0 ml) was stirred at room temperature for 15 to 16 hours. The reaction mixture was diluted with water (100 mL) 200813011 The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the residue obtained after removal of solvent was purified by using a 10% methanol in chloroform as a solvent. The product of oil. 1H-NMR (300MHz, DMSO-d6): 5 1. 73 (brs, 3H), 2. 17(s, 5 1H), 3. 52 (d, 2H, J == 10. 2Hz), 3. 70 (d, 2H, J = 10. 2Hz), 7. 32 (d, 1H, J = 9_3Hz), 7. 60 (d, 1H, J = 8. 7Hz), 8. 28(s, 1H). Between the soil and the product Π : ΐ a, 6α _ Γ 6_ (the third y butyl carbamide, a gas 塍 double ring "3. 1. Method for the treatment of 01 alkane Slowly add di-tertiary-butyl ester at 0 to 5 ° C (ι·33 g, 6. 12 10 millimoles) solution to intermediate 1 (400 mg, 4. 08 mM) and triethylamine (〇·4 ml) in methanol (5. Stir the solution thoroughly in 0 ml) and stir for 15 to 16 hours at room temperature. The reaction mixture was diluted with water (1 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the residue obtained after solvent removal was purified by using a hydrazine 15 gel column using a solution of 2% methanol in the solvent as a solvent to obtain 200 mg. The product of yellow oil. 1H-NMR (300MHz, DMSO-d6): (n. 42(s, 9H), 1. 48(s, 2H), 2. 10(s, 1H), 3. 33 (m, 2H), 3. 48 (m, 2H). , 5α, 6α _『6·(5·Iso-I: Lin-Amino-Carboxyl-Fluorine, Its Ethylpyridin-2-yl-V3-Azabicyclo[3 · 1. 01 hexane (竿1 compound, 20 Step 1 · Aminoformic acid [3-(ethylideneamino) σ than 嚏-2-yl] azabicyclo[3丄〇]hex-6-yl ester The process is slowly added with acetic anhydride under stirring (1. 1 mM) to 3_(3_amino 0 to 0-but-2-yl)-3-azabicyclo[3丄0]hex-6-ylaminocarbamic acid tert-butyl ester (1 mmol 61 200813011 Ears and diethylamine (23⁄4 mol) in a cold solution in gas, ρ-rolled methane (DCM). At room temperature, it should be monitored, (iv) out (four). The reaction mixture is cooled and the organic layer is separated, and then the desired compound is obtained by column chromatography purification. Heart delete (four): Chuan ah... Township (four) hit, S) - 2. 27(1H, m) ; 3. 43(3H, m) ; 3. 76(2H, d); 6. 68(1H, m); top OH, s); 7. 33(1H,d) ; 7 96(lH, s) ; 9 35(ih,s); MS(M++1):333. 27 Step 2 · 1 a,5 a,6 a_[6-(5-isoindolinylamino amide)_3♦(ethinylamino)% bit-2-yl)-3-aza Double-ring [31〇] hexane method 1 〇 至 至 至 至 至 至 至 至 至 至 至 至 授 授 授 授 授 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ J azabicyclo ring is called _3-yl) 咐^疋-3-yl]-2,2,2_acetamide (1 〇 millimolar) and triethylamine (15 mM) in dimethyl In a stirred solution of hydrazine (DMSO). The reaction mixture is then stirred at room temperature for 2 to 5 hours. The reaction mixture was inverted into cold water. The separated solid was filtered and dried to give a crude product. Purified by column chromatography to yield to the pure product. ^-NMRCDMSO-^): ά 1. 80 (2H? s); 2. 04(3H9 s); 3. 46(2H9 d) ; 3_88(2H,d) ; 99(1H,m) ; 6·83(1Η,m) ; 7·36(1Η,dd); 7·61(1Η,m) ; 7·75(1Η,dd) ; 7·89(1Η,d ); 7·99(1Η,d); 20 8. 24 (1H, dd); 8. 54(1H,m) ; 9·27(1Η,s); 9. 39(1H, s); IR(KBr)(cm': 3271, 1638, 1533, 1451, 1242, 758; MS(M++1): 403. 25. Example 2: 1〇;,5〇;,6〇;-[6-(5-isoquinolineamine,carboxylamido)-3-(3彳di-fluoroethinylamino)Hhidine-2 - Some) 1-3 - Miscellaneous Interpretation "3. 1. 01 hexane (di.  62 200813011 制备) Method 1 · 3-{3-[(Difluoroethyl)amino]pyridyl}s_azabicyclo[3·1·0]hex-6-ylaminocarbamic acid Preparation of the third-butyl ester slowly adding trifluoroacetic anhydride (L1 mmol) to 3-(3-amino-5t-but-2-yl) azabicyclo[31〇]hexylamino group with stirring Formic acid tert-butyl vinegar (1 house Mohr) and triethylamine (2 mmol) in a cold solution in DCM. The reaction mixture was allowed to stand at room temperature for 3 to 4 hours. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated and purified by column chromatography to give the desired compound. 10 ^-NMRCDMSO^): ^ 1. 38 (9H? s); 2. 17(1H? s); 3. 16(1H? s) ’ 3·45(2Η,d),3·75(2Η,d); 73 (1H, m); 7. 101 (1H, s); 7. 43 (lH, d); 8. 09(lH,d); 11. 06 (1 people 8). Claw (broken) (cm-1): 3273, 1671, 1509, 1332, 1287, 1113, 823; MS (M++1): 387. 19. \5Step 2 · 1 a,5 a,6a-[6-(5·isoindolylaminocarbamoylamino)_3_(3_(trimethylacetamidoamine)% bit I))_3_ Azabicyclo[3丨〇]hexadol is prepared by adding a solution of isoporphyrin phenyl-5-ylaminocarbamate (丨·mole) in DMSO to N_[2|amino group under stirring at a temperature. Winter azabicyclo[3 1 〇] hex-3-yl)t-3-yl]-2,2,2-trifluoroacetamide 毫·mole) and triethylamine 2 〇 (1. 5 millimoles) in a stirred solution in DMSO. Monitoring the reaction at room temperature takes 2 to 5 hours. The reaction mass is added to cold water to obtain the desired product and zinc is purified by column chromatography and purified. ^. NMRiDMSO^): ^ 1. 85 (2H5 s); 2. 〇 4 (3H5 s); 3. 51(2H?d), 3. 86(2H,d),6·47(1Η,m) ; 6·84(1Η,s) ; 7·44(1Η,dd); 63 200813011 7·59(1Η,t) ’ 7. 74( 1H,d); 7. 86( 1H,d) ; 8. 10( 1H,d); 8. 24 ( 1H, dd), 8. 52 (1H, d); 8. 61 (1H, s); 9·27 (1Η, s); 〇9 (ih, m); IR (KBr) (cm 3 : 3374, 1638, 1717, 1594, 1550, 1459, 1225, 1157, 757; MS (M++1): 457. 3 卜 5 宜例3 · l. p;,5α,6α _"6-(5-isoindylamine) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Step 1 of the compound No. 3) ··· 3-{3-[(oxasulfonyl)amino]pyridine_2_ylbu 3_azabicyclo[3"〇]hex-6-ylamino Process for the preparation of tert-butyl formate 1〇 Slowly add a sulphur (11 mmol) to 3_(3_Amino- acridine-2-yl)-3-azabicyclo[3丄〇] _6_ylaminocarbamic acid tert-butyl ester (1 Torr) and diethylamine (2 mM) in a cold solution in Dcm. The reaction mixture was stirred at room temperature for 3 to 4 hours. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated and purified by column chromatography to give the desired compound. H-NMR (DMSO_d6): (5l. 38(9H,s) ; 1·70(2Η, s) ; 2·17(1Η, s), 3. 16 (lH, s); 3. 12 (3H, S); 3. 45 (2H, d); 3. 75(2H,d);6. 73(lH, m), 7·10(1Η, s); 7. 43(1H,d) ; 8·09(1Η,d) ; 06 (1H, s); IR (KBr) (cm): 3289, 1668, 156, 1345, 1293, 1119, 20 823; MS (M++1): 369. twenty four. Example 2 · 1 a,5 a,6a-[6-(5-isoindolinylaminocarboxylamidocarbamidyl)pyridin-2-yl)]_3_azabicyclop丨〇] Adding benzene of isoquinolin-5-ylaminocarbamate (1·mole) solution in DMSO to the base of 3_{3 heptaphyllum) at room temperature with stirring比〇64 200813011 基}-3-气杂双衣 [3. 1. 〇] hex-6-ylaminocarbamic acid third _ vinegar (1 mmol) and diethylamine (1. 5 millimoles) in the turbid solution in DMSO. The reaction was monitored at room temperature and took 2 to 5 hours. The reaction mass is added to cold water to give the desired product and is purified and purified by column chromatography. 5 also Li R (DMSO-d6): 5 1. 89(2H, s); 2. 54(1H, s) ; 2·64(1Η, s); 3. 38 (3H, s); 3. 58 (lH, d); 4. 00 (lH, d); 5. 75 (lH, s); 6. 77 (lH, m); 6. 85 (1H, s); 6. 77 (1H, m); 6. 85 (1H, s); 7·70 (3Η, dd); 7·90 (1Η, m); 8. 23(2H,m) ; 8. 53(1H,m) ; 8·62(1Η,s); 9. 27(1H, s) ; IR(KBr)(cm-1): 3403, 165〇, 1555, 1461, 10 1364, 1159, 762 ; MS(M++1) : 439. 25. 1_Example 4 · 1 αα, 6 a 4 4 某 胺 胺 -3- -3- -3- -3- -3- -3- -3- -3- 比 比 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 . 1. 〇1匕 (No. 4 compound) 刍 method step 1 ··· 3-(3,5-di-pyridin-2-yl)-3-azabicyclo[3丄〇]hex-6-amine 15 The compound was added, 2,3,5-trichloropyridine (74 mg, 4. 98 mM) to 1 α,5α,6α-6·amino-3-azabicyclo[31〇]hexane hydrochloride (4 〇〇 milligrams, 4. 083⁄4 mol) and triethylamine (2·ml) in a solution of dimethyl sulfoxide (5 mL) and stirred at 85 to 9 (TC for 15 to 16 hours. Allow the reaction mixture 20 to cool to It was diluted with water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was used as a dissolving agent by using 10% methanol in air. The residue obtained after removing the solvent was purified by a silica gel column to give a product of 2 mg of a crude oil, for example, brown oil. 65 200813011 iH_NMR (DMSO-d6): (n. 56(2H, s) ; 1·18(1Η, s) ; 1·19(1Η, s) ; 3·86(2Η, bs, D20 can be exchanged); 3·46(3Η,m) ; 6·78 (1Η, s); 8·13(1Η, s) ; IR(KBr)(cm': 3281, 163, 1562, 13H, 1299, 1102, 826; MS(M++1): 243. 03. 5Step 2: 1 a,5 a,6 a -[6-(5-(I-oxalinylaminocarboxamide))-3-(3-(3,5-^一气)ϋ ratio) -3-Azabicyclo[3·1·〇]Hangyuan method is stirred at room temperature 1 α,5α,6α -[6·amino-3-(3,5·dichloropyridin-2-yl) ]-3-Azabicyclo[3·1·〇]hexane (1 〇〇 mg, 0·40 mmol), phenyl isoindoline-5-ylcarbamate (127 mg, 0. 5116 millimoles) A solution in dimethyl sapphire 10 (5·0 house liter), which takes 12 to 13 hours. The reaction mixture was diluted with water (5 mL) andEtOAcEtOAc The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removing the solvent was purified by using a hydrazine gel column of 2% methanol in chloroform &lt; 15 b-NMR pMSO-A): 5 h86 (2H, s); 2 55 (m, m); 3 6 〇 (2Η, d); 1〇(2H9 d) ; 86 (1H5 s); 7. 60 (1H5 m); 7. 75 (1H? d); 7. 87 (2H5 dd), 8. 15 (lH? d); 8. 23 (lH5 dd); 8. 53 (lH5 d); 8. 60 (lH5 s), 8.27 (1 Η, s); IR (KBr) (cm-i): 327, 1638, 1533, 1451, 1242, 758; MS (M++1): 418 32.查 啉 胺 基 篡彳 篡彳 篡彳 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The compound is added by the method of winter toluene, 3|2_chlorine (783 mg, money millimolar) to 1〇:,5〇!, 6-core 6-amino 1azabicyclo[310]hexahydrochloride hydrochloride (side milli 66 200813011 grams ' 4. 08 mmol) and diethylamine (2·ml) in a solution of DMS® (5 mL) at 85 to 90X; (4) 15 to 16 hours. The reaction mixture was cooled to room temperature, diluted with water (100 ml) The organic layer was washed with water and dried over anhydrous sodium sulfate; and the residue obtained after solvent removal was purified by using a solution of 5 with 10% methanol in chloroform as a solvent. 〇 mg of product such as brown oil. 'H-NMRC DMSO-^): (5 1. 56(2H? s); 1. 18(1H9 s); 1. 19(1H, s) ’ 3. 47(2H,brs) ; 3·46(3Η,m) ; 6·54(1Η,m) ; 6·67(1Η,d); 8·00(1Η5 d) ; IR(KBr)(cm' : 3265, 1601, 15M, 1459, 10 1246, 756; MS (M++1): 255. 28. Step 2: 1 a,5 a,6 α·[6-(5-(indolylaminocarbamoylamino) bromide) 唆··2_yl]-3-azabicyclo[3·1·〇 The method of hexane is used to scramble 1 α,5 α,6 α -[6-amino-3-(3- σ 比 比 -2--2-yl)] azabicyclo[3·1· 0] Hexane (1 〇〇 mg, 〇·4 〇 millimolar), isoporphyrin _5_ 15 phenylamino decanoic acid phenyl ester (127 mg, 0. A solution of 5116 millimoles in dimethyl hydrazine (5_0 milliliters) takes 12 to 13 hours. The reaction mixture was diluted with EtOAc (EtOAc) The combined organic layers were washed with water and dried over anhydrous sodium sulfate. Via use 2. The residue obtained after removing the solvent was purified by removing the solvent from a solution of 0% decyl alcohol in a solvent as a solvent to obtain a product of 50 2 毫克 mg as a nearly pure white solid. 1H-NMR (DMSO-d6): 5 1. 82 (2H? s); 2. 55 (1H? m); 3. 54(2H?d) ; 4·14(2Η,d) ; 6·72(1Η,m) ; 7·84(1Η,s) ; 7·60(1Η,t); 74 (1H, d); 7_87 (2H, dd); 8. 15 (lH, d); 8. 22 (lH, d); 8. 53(lH, d); 8. 60(1H, s); 9·27(1Η, s); IR(KBr)(cm-1): 327b 1638, 67 200813011 1533, 1451, 1242, 758; MS(M++1) : 425. 40. Example 6: 1α·5π·6π-|~6__〇isoporphyrinamine A borrowing face 篡)-3-(3-(5-Nan-shame is more than 唆-2-yl) 1 each heterocyclic ring Process for the preparation of "3丄01 hexane (Compound No. 6) 1 · 3- 3-(5-nitropyridin-2-yl)-nazabicyclo[3丄〇]hex-6-amine 5 2 ϋ nitro. Compared with ° (1 · 〇 5 grams, 6. 52 millimolar) to 1 α,5α,6 «-6-amino-3-azabicyclo[3. 1. 0] hexane hydrochloride (4 〇〇 mg, 4. 08 millimoles) and ethylamine (2. 03⁄4 liters) in the monomethyl slate wind (5. Stir in the solution in 0 liters and stir at room temperature for 15 to 16 hours. The reaction mixture was diluted with water (1 mL) andEtOAc. The combined organic layers were washed with water and dried over anhydrous sodium sulfate 10, and the residue obtained after solvent removal was purified by using a hydrazine gel column using a solution of 10% methanol in the solvent as a solvent to obtain 3 〇〇. The product of milligrams such as brown oil. H-NMR (DMSO-d6): (n. 56(2H, s); 1. 18(1H,s) ; 1·19(1Η, s) ; 3·47(2Η,brs) ; 3·46(3Η,m) ; 54(1H, m) ; 6·67(1Η,d); 15 8·〇〇(1Η,d);called leg)(cm force··3289, 1638, 1568, 1345, 1299, 1109, 823; MS (M++1) : 221. 32. Step 2: la,5a,6a-[6-(5-iso-4-linylamine-based amine) winter (3_(5 "Schottyl)pyridinyl)]-3-azabicyclo[3丨〇] The method of preparing hexane is mixed at room temperature. 1 α,5 α,6 α _[6_Amino_3_(5_nitro.bybiting the base)]-3-Azabicyclo[3丄〇]烧烧_mg, 〇4〇 mmol, 喧 喧 喧 胺 27 27 27 mg, 0. A solution of 5116 millimoles in dimethyl acetaminophen (four) milliliters&apos; takes 12 to 13 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removing the solvent was purified by using a solution of 2% methanol in chloroform as a hydr. 'H. NMRCDMSO·^): ^ 1. 99(2H5 s); 2. 41 (1H? m); 3. 69 (2H? d); 3. 99(2H,d);6. 62 (lH, d); 6. 92 (lH, s); 7. 61 (lH, t); 7. 77 (lH, 5 d); 7. 87 (1H, dd); 8. 22(2H,d) ; 8·54(1Η,d) ; 8·98(1Η,s); 8·60(1Η,s); 27(1H, s) ; IR(KBr)(cm-1) : 3294, 1633, 1572, 1327, 1293, 1117, 820 ; MS(M++1) : 391. 2 〇Example 7 : 1〇;,5〇;,6〇!-"6-(5-isoindolylamine a certain amine) _3_(2-xiao|| base) 1-3-azabicyclo "3丄01 Hexane (Compound No. 7) Process 10 Step 1 · 1-(2-F-Phenylphenyl)_2,5-dichlorobenzene Method Add 2-Fluoroaniline (30) at room temperature under nitrogen . 0 millimolar) to dimethyllithic acid (2Ζ)-butyl-2-diamond-1,4-diyl vinegar (2. 44 grams, 10 millimoles) in a solution of 5 milliliters of anhydrous dichloromethane. The resulting solution was stirred for a night and then with 50 cc of water. The organic layer was separated and dried over sodium sulfate. After removing the solvent, the residue was purified in pet ether (EtOAc): ethyl acetate (1%) to give the product. IR (KBr): 3055, 2892, 2848, 1596, 1530, 1475, 1372, 1341, 1275, 1160, 1014, 1075, 1027, 906, 815 cm-1; iH_NMR (300 MHz, CDC13): ". L〇(s,4H), 5 98(s,2H), 20 7. 01-7. 05(m, 2H), 7. 32-7. 42 (m, 2H). Step 2: 1〇;,5〇!,6〇^凡沁Dibenzyl-3-(2-fluorophenyl)_3_azabicyclo[3·1·0]hexylamine Magnesium (3 Μ in THF, 1 〇. 〇1m) treatment of 1_(2_fluorophenyl)-2,5-dihydro-1H-pyrrole (1〇·〇 millimole) and tetrapropylene titanium oxide (1〇〇米69 200813011 Moer) THF (5. A mixture of 0 ml) was then added in portions to a solution of N,N-dibasic chitosan (10 mmol) in the pass. Add cyclohexylmagnesium bromide (20_0 mmol, 2M in 2) at ambient temperature and heat the reaction mixture under reflux for 15 minutes to release the reaction mixture 5 ml of salt solution. Transitional sedimentation of inorganic salts. The organic layer was dried over sodium sulfate and concentrated. After removal of the solvent, the residue was purified in EtOAc (EtOAc) (EtOAc) Step 3: [3-(2-Fluorophenyl)_3_azabicyclo[3 i 〇]hexanyl]carbamic acid 1 a,5 a,6 a-tri-butyl ester 10 method at room temperature Hydrogenation of 1 a,5 a,6 α -N,N-dibenzyl-3-(2-fluorophenyl)-3-azabicyclo[3丄0]hex-6-amine in a Pettin hydrogenation unit The suspension in methanol (2 ml) and 10% Pd/C (50% w/w) took 2 to 12 hours. The process of monitoring is monitored by TLC. The reaction mixture was filtered through a Celite bed. B〇C2〇 (20 mmol) was added to the filtrate and spoiled at room temperature for 2 hours. The reaction mixture was purified by a hydrazine gel column using a mixture of petroleum ether and ethyl acetate as a solvent to afford a product as a white solid. IR (KBr) · 3334, 3155, 2829, 2845, 1631, 1575, 1523, 1488, 1370, 1329, 1269, 1144, 1110, 1054, 1022, 916, 855 cm 1 ; h-NMR GOO MHz, DMSO-d6): 5 1. 45(s,9H), 20 1. 76(s? 2H) &gt; 2. 58(s? 1H) ^ 3. 29(d? 2H? J=9. 0Hz) ^ 3. 80 (d5 2H? J=9. 0Hz), 6. 61 (m, 2H), 6. 91 (m, 2H). Step 4 ···1 a,5 α,6α-(6·(5-isoindolylaminocarbamoylamino)-(2-fluorophenyl)azabicyclo[3丄〇]hexane Add a saturated solution of HC1/ethyl acetate to [3-(2-fluorophenyl)_3_aza 70 200813011 bicyclo[3·1·〇]hex-6-yl]carbamic acid 1 α,5α,6α - The third-butyl ester is stirred in a solution of ethyl acetate for 2 to 3 hours. The residue obtained after removing the solvent is dissolved in dimethyl hydrazine and first added with hydrazine (20 mmol) and 5-Aminoisoindoline phenyl carbazide (1 mM millimolar then stirred at room temperature to mix the mixture, which took 2 to 3 hours. The reaction mixture was poured onto ice-cold water. The solid precipitate was filtered off and Dilute in methanol to give pure product. IR (KBr) · 3300, 3127, 2894, 2850, 1631, 1597, 1531, 1477, 1371, 1336, 1270, 1161, 1114, 1071, 1027, 906, 815 cm 1 ; h-NMROOOMHz, DMSO-d6): 5 1. 84(s, 2H), 10 2. 6〇(s,1H), 3. 37(d, 2H, J=9. 0Hz), 3. 72 (d, 2H, J = 9. 0Hz), 6. 73 (d, 2H, J = 8. 1Hz), 6. 86(s, 1H), 7. 02 (m, 2H), 7. 60(t, 1H), 7. 75 (d, 1H); 7. 90 (d, 1H); 8. 23(d,1H); 8. 53(d,1H); 8. 61(s, 1H), 9. 27 (s, 1H); the refining point is 225 to 227 ° C. Example 8: 1〇?,5«,6〇;-"6-(5-isoindolinylamine carboxycarbamoylamino)-3彳4-fluorophenyl-15-yl)1-3_azabicyclo"3 . 1. 01 hexane (No. 8 compound) method step 1 · 1-(4-fluorophenyl)-2,5-dihydro-1H-pyrrole by the same method as described in step 1 of Example 7. The present compound was prepared from the intermediate product 5 and 4-fluoroaniline. IR (KBr): 3098, 2817, 2807, 1545, 1531, 1470, 1346, 20 1261, 1161, 1154, 1071, 1017, 915, 806 cm -1 ; ^-NMRCSOOMHz, CDC13): 5 4. 14(s? 4H)&gt;5. 96(s? 2H)'6. 51 (d? 2H, J=8. 4Hz), 7. 45 (d, 2H, J = 8. 7Hz). Step 2 ··· 1 a,5 a,6 a-N,N-dibenzyl-3-(4-fluorophenyl)-3-azabicyclo[3. 1. 0] Process for the preparation of hexa-6-amine 25, such as the one described in Step 2 of Example 7, but from 1α, 5α, 6α 71 200813011 -1-(4-fluorophenyl)-2,5-dihydro-1H - Pyrrole and N,N-dibenzylformamide are made into the present compound. IR (KBr): 3055, 2939, 2914, 1540, 1477, 1453, 1370, 1355, 1270, 1242, 1155, 1120, 1099, 967, 811 cm-1; 5 h-NMRpOOMHz, DMSO-d6): (5 1. 56(s, 2H), 1. 73(s, 1H), 3. 05 (d, 2H, J = 9_0Hz), 3. 30 (d, 2H, J = 9. 0Hz), 3. 57(s, 4H), 6. 39 (m, 2H), 6. 89 (m, 2H), 7. 26-7. 31 (m, 10H). Step 3: [3-(4-Fluorophenyl)-3-azabicyclo[3. 1. 0]H-6-yl]carbamic acid 1 a,5 a,6a-tributyl butyl ester 10 by the same method as described in Step 3 of Example 7 from N,N-dibenzyl- 3-(4-fluorophenyl)-3-azabicyclo[3. 1. 0] Hex-6-amine is made into the present compound. IR (KBr): 3300, 3127, 2844, 2831, 1635, 1590, 1529, 1473, 1344, 1333, 1243, 1159, 1114, 1069, 1026, 916, 875 cm-1; h-NMR pOOMHz, DMSO-d6) :(5 1. 46(s, 9H), 15 1. 77(s, 2H), 2. 60 (s, 1H), 3. 25(d, 2H, J=9. 0Hz), 3. 75(d, 2H, J=9. 0Hz), 6. 65 (d, 2H, J = 9. 0Hz), 6. 95 (d, 2H, J = 9. 0Hz). Step 4 · 1 〇;, 5 o;, 6 ex-[6-(5-iso-v-quine-ylamine apolipodo)-3-(4-phenylphenyl)]-3-azabicyclo[ 3丄0] hexane was prepared by the same method as described in Step 4 of Example 7 from [3-(4-fluorophenyl-2-indenyl)-3-azabicyclo[3·1·0]- 6-Aminoformic acid 1 α,5α,6α -T-butyl ester and phenyl-(isoindoline-5-yl)carbamic acid phenyl ester to prepare the present compound IR (KBi〇: 3378, 3145, 2899, 2850, 1645, 1598, 1535, 1489, 1378, 1334, 1299, 1133, 1134, 107, 1027, 956, 810 cm-1; W-NMR pOOMHz, DMSO-d6): 52. 50 (m, 2H), 72 200813011 2. 62(s, 1H), 3. 23(d, 2H, J=9. 0Hz), 3. 76(d, 2H, J=9. 0Hz), 6. 40 (d, 2H, J = 8. 1Hz), 6. 55(t, 2H), 7. 64-7. 91 (m, 4H), 8. 33(s, 1H), 8. 53 (d, 1H), 9. 31 (s, 1H); melting point 226 to 228 ° C. Example 9: 1 α,5α,6α-|~6-(5-isoindolylaminocarbamoylamino)·344-isopropyl 5-ylphenyl)1-3-azabicyclo”3. 1. Process for the preparation of 01 hexane (compound No. 9) 1 · 1-(4-isopropylphenyl)-2,5-dihydro-1H-pyrrole is prepared as described in Step 1 of Example 7. The present compound was prepared in the same manner from Intermediate 5 and 4-isopropylaniline. IR (KBr): 3027, 2894, 2850, 1593, 1531, 1477, 1371, 10 1335, 1269, 1165, 1124, 1075, 1027, 909, 817 cm -1 ; b-NMRpOOMHz, CDC13): 6 1. 14(s,6H), 4. 00 (s, 4H), 6. 02(s, 2H), 6. 42 (d, 2H, J = 8. 4Hz), 7. 04(d, 2H, J=8. 7Hz). Step 2: 1 a, 5 a, 6 aN, N-dibenzyl-3-(4-isopropylphenyl)-3-azabicyclo[3·1·0]hex-6-amine Prepared from 1-(4-isopropylphenyl)-2,5-dihydro-1indole-pyrrole and indole-indole-dibenzylformamide by the same method as described in Step 2 of Example 7. Compound. IR (KBr): 3044, 2976, 2914, 1530, 1477, 1450, 1377, 1355, 1249, 1242, 1190, 1120, 1088, 945, 810 cm -1; h-NMRQOOMHz, DMSO-d6): 5 1. 27(s,6H), 1. 20(s, 2H), 20 1. 30 (s, 1H), 2. 99 (d, 2H, J = 9. 0Hz), 3. 34(d, 2H, J=9. 0Hz), 3. 57(s, 4H), 6. 37 (m, 2H), 7. 12 (m, 2H), 7. 26-7. 31 (m, 10H). Step 3: [3-(4-Isopropylphenyl)-3-azabicyclo[3丄0]hex-6-yl]amino decanoic acid 1 a, 5 a, 6a-tri-butyl ester The method was carried out by the same method as described in Step 3 of Example 7 from 1α,5α,6α 73 200813011 -Ν,Ν-dibenzyl-3-(4-isopropylphenyl)-3-azabicyclo[ 3. 1. 0] hex-6-amine is made into the present compound. IR (KBr): 3332, 3178, 2894, 2855, 1640, 1543, 153 1476, 1370, 1339, 1279, 1165, 1114, 1065, 1033, 917, 5 865 cm-1; i-NMR pOOMHz, DMSO-d6 ): 5 1. 24(s,9H), 1. 33(s,6H), 1. 97(s, 2H), 2. 17(s,lH), 3. 13(d, 2H, J=9. 0Hz), 3. 49 (d, 2H, J = 9. 0Hz), 6. 45 (d, 2H, J = 9. 0Hz), 7. 15(d, 2H, J=9. 0Hz). Step 4: 1 a,5 a,6a-[6-(5-isoindolylaminocarbamoylamino)-3-(4-isopropyl10-phenyl)-3-azabicyclo[3· 1. 0] hexane was prepared by the same method as described in Step 4 of Example 7 from [3-(4-isopropylphenyl)-3-azabicyclo[3. 1. 0]Hex-6-yl]carbamic acid 1 〇:,5〇:,6〇:-tri-butyl ester and N-(isoindoline-5-yl)carbamic acid phenyl ester were prepared into the present compound. IR (KBr): 3296, 3093, 2956, 2864, 1649, 1568, 1519, 15 1483, 1360, 1336, 1265, 1248, 1169, 11CH, 1027, 966, 827 cm 1 ; h-NMR pOOMHz, DMSO-d6) :5 1. 13(d, 6H, J=7. 0Hz), 1. 86 (m, 2H), 2. 73(s, 1H), 3. 16(d, 2H, J=9. 0Hz), 3. 58 (d, 2H, J = 9. 0Hz), 6. 49 (d, 2H, J = 9. 0Hz), 6. 88 (s, 1 Hz), 7. 02(d, 2H), 7. 58(t, 1H), 7. 75 (d, 1H), 7. 88 (d, 1H), 8. 24(d, 20 1H), 8. 54 (d, 1H), 8. 62(s, 1H), 9. 28 (s, 1H); melting point 236 to 237 〇C. Example 10: 1〇!,5〇;,6〇;-"6-(5-iso-4-oxanylaminocarbamoylamino)-3-(2-methylphenyl)1-3-azabicyclo "3. 1. Process for the preparation of 01 hexane (compound No. 10) 1 1. Process for the preparation of 1-(2-methoxyphenyl)-2,5-dihydro-1H-pyrrole 74 200813011 By the method described in step 1 of Example 7. In the same manner, the present compound was prepared from the intermediate product 5 and 2-methoxyaniline. IR (KBr): 3044, 2855, 2847, 1593, 1520, 1475, 1368, 132, 1270, 116, 1114, 107, 1027, 906, 815 cm-1; 5 iH-NMRpOOMHz, CDC13): 5 3. 81 (d, 3H), 4. 26(s, 4H), 5. 89(s, 2H), 6. 98 (m, 2H), 7. 25-7. 30 (m, 2H). Step 2: 1 a, 5 a, 6a-N, N-dibenzyl-3-(2-methoxyphenyl)-3-azabicyclo[3·1·0]hex-6-amine The compound was prepared from 1-(2-methoxybenzo-10-yl)-2,5-dihydro-1H-pyrrole and N,N-dibenzylformamide according to the same procedure as described in Step 2 of Example 7. . IR (KBr): 3037, 289 Bu 2844, 1597, 153 Bu 1466, 1370, 1327, 1234, 1154, 1109, 1000, 906, 815 cm. 1 ; h-NMROOOMHz, DMSO-d6): (5 1. 49(s, 2H), 1. 63(s, 1H), 3. 32(s, 3H), 2. 92(d, 2H, J=9. 0Hz), 3. 28(d, 2H, J=9. 0Hz), 15 3. 63(s, 4H), 6. 39(d, 2H), 6. 73(d, 2H), 7. 26-7. 38 (m, 10H). Step 3 ··[3-(2-Methoxyphenyl)-n-hebibicyclo[3·1·0]hex-6-yl]carbamic acid 1 α,5 α,6α-T-butyl ester By the same method as described in Step 3 of Example 7, from 1 α,5 α,6 α -Ν,Ν-dibenzyl-3-(2-methoxyphenyl)-3-azabicyclo[3 . 1. 0] hex-6-amine is made into the compound of the present invention. IR (KBr): 3331, 3156, 2878, 2850, 1644, 1578, 1543, 1465, 1323, 1390, 1254, 1198, 1123, 1078, 1032, 909, 878 cm 1 ; W-NMR pOOMHz, DMSO_d6): (n . 38(s, 9H), 1. 70(s, 2H), 2. 20(s, 1H), 2. 99 (d, 2H, J = 9. 0Hz), 3. 67(d,2H, 75 200813011 J=9. 0Hz), 3. 74(s, 3H), 6. 65(d, 2H), 6. 78 (m, 2H). Step 4 ···1〇;,5〇;,6〇!-[6-(5-isoindolinylaminocarboxylamido)-3-(2-methoxycarbonyl)] ML heterobicyclo[ 3·1·〇] The method of burning has been carried out by the same method as described in Step 4 of Example 7 from [3-(2-methoxyphenyl 5yl)_3_azabicyclo[3丄〇]hex-6- The present invention is prepared from benzyl hydroxyglycolic acid and phenyl N-(isoindolyl) carbamic acid. IR (KBr): 3354, 3127, 2894, 2850, 1631, 1597, 1531, 1477, 137 Bu 1336, 1270, 116 Bu 1114, l (m, 1027, 906, 815 cm. 1 ; iH-NMRGOOMHz, DMSO-d6): 5 1. 75 (m, 2H), 10 2. 70 (s, 1H), 3. 07(d, 2H, J=9. 0Hz), 3. 76(s,3H), 3. 81 (d, 2H, J = 9. 0Hz), 6. 69-6. 88 (m, 4H), 7. 60(t,1H), 7. 74(d,lH)7. 89(d, 1H), 8. 25 (d, 1H), 8. 53 (d, 1H), 8. 60 (s, 1H), 9. 27 (s, 1H); melting point 189 to 191 ° C. _Example 11 : 1〇^,5〇;,6〇;-『6-(5-isoindolinylaminocarboxamide, a private 3-(4-third 15 oximeylphenyl) 1-3 - azabicyclo β·1. 01 hexane (Compound No. 11 compound k, method step 1 · 1-(4-t-butylphenyl)-2,5-dihydro-1H) is prepared by the method of step 1 in Example 7 The same method was used to prepare the present compound from the intermediate product 4 and 4-tris-butyl amide. IR (KBr): 3047, 2945, 2829, 2809, 1500, 1475, 1380, 20 1362, 1282, 1181. 1042, 1007, 943, 815 cm _1 ; b-NMR pOOMHz, CDCl3): (n. 29(s,9H), 4. 1〇(s,4H), 5. 93(s, 2H), 6. 48(d, 2H, J=9. 0Hz), 7. 25(d, 2H, J=9. 〇Hz). Step 2: 1 a, 5 a, 6 aN, N-dibenzyl-3-(4-t-butylphenyl) azabicyclo[3·1·0]hex-6-amine method 76 200813011 From the same method as described in Step 2 of Example 7, from 1-(4-t-butylphenyl)-2,5-dihydro-1H-pyrrole and N,N•dibenzylformamide The cost of the compound. IR (KBr): 3010, 2947, 2900, 2893, 2876, 1576, 1544, 1480, 1388, 1336, 1289, 1156, 1114, 1074, 1027, 911, 5 803 cm 1 ; Α-ΝΜΚ^ΟΟΜΗζ, DMSO- D6): 5 1. 20(s, 9H), 1. 27(s, 2H), 1. 50 (s, 1H), 3. 08 (d, 2H, J = 9. 0Hz), 3. 34(d, 2H, J=9. 0Hz), 3. 66(s, 4H), 6. 39(d, 2H), 6. 73(d, 2H), 7. 21-7. 36 (m, 10H). Step 3: [3-(4_Terti-butylphenyl)_3_azabicyclohexyl-6-yl]amino 10carboxylic acid 1 a,5 a,6 a-third-butyl ester The same procedure as described in Step 3 of Example 7 was carried out from N,N-dibenzyl-3-(4-t-butylphenyl)-3-azabicyclo[3丄〇]hex-6-amine The cost of the compound. IR (KBr): 3331, 3156, 2878, 2850, 1644, 1578, 1543, 1465, 1323, 1390, 1254, 1198, 1123, 1078, 1032, 909, 15 878 cm -1 ; W-NMR POO MHz, DMSO-d6 ): 5 1. 38(s, 9H), 1. 70(s, 2H), 2. 20(s, 1H), 2. 99 (d, 2H, J = 9_0Hz), 3. 67(d, 2H, J=9. 0Hz), 3. 74(s, 3H), 6. 65(d, 2H), 6. 78 (m, 2H). Step 4: 1 a, 5 a, 6a-[6-(5-isoindolylaminocarbamoylamino) each (4_t-butylphenyl)]-3-azabicyclo[3丄〇]The method of decocting is carried out by the same method as described in the step 4 of Example 7 from [3-(4-t-butylphenyl)-3-azabicyclo[3丄〇]hex-6 The present invention is prepared from amino-based phthalic acid 1 α,5α,6α_tri-butyl ester and phenyl-(isoindoline-5-yl)carbamic acid phenyl ester. IR (KBr): 3314, 3042, 2958, 2828, 1633, 1582, 1520, 1478, 1362, 1268, 1248, 1164, 1030, 966, 813 cm-1; 77 200813011 W-NMRPOOMHz, DMSO_d6): (51. 22(s,9H), 1. 88 (m, 2H), 2. 51(s, 1H), 3. 17(d, 2H, J=9. 0Hz), 3. 58 (d, 2H, J = 9. 〇Hz), 3. 66(s, 3H), 6. 49 (d, 2H, J = 9. 0Hz), 6. 89 (s, 1 Hz), 7. I6(d, 2H), 7. 61(t,1H), 7. 75 (d, 1 Hz), 7. 89 (d, 1H), 8. 24(d,1H), 5 8. 54 (d, lH), 8. 62(s,lH), 9. 28 (s, 1H); melting point 218 to 220 ° C. Example 12: Ια,5 α,6α 46-(5-iso π 啾 胺 胺 醯 某 某 某 甲基 1-3 1-3 1-3 1-3 1-3 1-3 ( ( ( ( ( ( ( The method of the first step is to prepare the method of 1-(2,4-dimethylphenyl)-2,5-dihydro-1?-pyrrole by the same method as described in the step 1 of Example 7 from the intermediate product 5 10 and 2,4-T-dimercaptoaniline were prepared into the present compound. IR (KBr): 3037, 2948, 2920, 1505, 1473, 1403, 1351, 1324, 1234, 1163, 1110, 1015, 941, 807 cm-1; W-NMR POOMHz, CDC13): (5 2. 17(d,3H), 2. 26(d,3H), 4. 04(s, 4H), 5. 95(s, 2H), 6. 18(s,1H), 6. 86 (m, 3H). 15 Step 2: 1 a,5 〇;,6〇;-Fan 1 dibenzyl-3-[(2,4-dimethyl)phenyl)-3-azabicyclo[3·1·0] The -6-amine was prepared by the same method as described in the procedure of Example 7 from ΐ-[(2,4-dimethyl)phenyl]·2,5·dihydro-lH-u piroxime and hydrazine. , Ν-dibenzylcarbamide is made into the present compound. 20 IR (KBr): 3055, 2890, 2850, 1589, 1527, 1460, 1344, 1336, 1269, 1154, 1114, 1092, 1000, 905, 815 cm-1; i-NMROOOMHz, DMSO-d6): (n . 37(s, 2H), 1. 50 (s, 1H), 2. 11-2. 16 (m, 6H), 2. 73 (d, 2H, J = 9. 0Hz), 3. 13(d, 2H, J=9. 0Hz), 3. 61(s, 4H), 6. 74(d, 2H), 6. 87 (d, 2H), 7. 31-7. 36 (m, 78 200813011 10H). Step 3 ··[3-(2,4-Dimethyl)phenyl]-3-azabicyclo[3·1·0]hex-6-yl]carbamic acid 1 α,5 α,6α- The tri-butyl ester was prepared by the same method as described in Step 3 of Example 7, Ν-dibenzyl 5 -3-(2,4-dimethylphenyl)-3-azabicyclo [3. 1. 0] Hex-6-amine is made into the present compound. IR (KBr): 3356, 3124, 2812, 2878, 1645, 1592, 1544, 1470, 1370, 1336, 1290, 1162, 1117, 1078, 1027, 934, 876 cm 1 ; i-NMROOOMHz, DMSO-D: 5L25 (s, 9H), 10 1. 37(s, 2H), 1. 50 (s, 1H), 2. 11-2. 16 (m, 6H), 2. 83(d, 2H, J=9. 0Hz), 3. 23 (d, 2H, J two 9. 0Hz), 3. 64 (s, 4H), 6. 74(s, 1H), 7. 05 (d, 2H). Step 4: 1 a,5 a,6a-[6-(5-isoindolinylaminocarbamoylamino)-3-(2,4-dimethylphenyl)] azabicyclo[3· 1·0] Method for the preparation of hexane 15 by the same method as described in Step 4 of Example 7 from [3-(2,4-dimethyl)phenyl)_3_azabicyclo[3丄0] -6-yl]aminocarbamic acid 1α,5α:,6α-tributyl butyl ester and phenyl-(isoquinolin-5-yl)carbamic acid phenyl ester were prepared into the present compound. IR (KBr): 3332, 3056, 2958, 2816, 1644, 1558, 1502, 1370, 1326, 1265, 1242, 1116, 1017, 86 821 cm. 1 ; 20 W-NMR pOOMHz, DMSO-d6): 51·72 (ιη, 2H), 2. 19(d,6H), 2. 37(s, 1H), 2. 50 (d, 2H, J = 9. 0Hz), 3. 04(d, 2H, J=9. 0Hz), 6. 80-6. 92 (m, 4H), 7. 60(t,1H), 7. 74 (d, 1H), 7. 90 (d, 1H), 8. 25 (d, 1H), 8. 53-8. 59 (m, 2H), 9. 27(s,1H); melting point i9〇 to 192〇C. 79 200813011 实-例ϋ_: 1 〇:,5〇:,6〇;46-(5-Muline porphyrin amine carboxy 醯 醯 ))_3_(4_二举甲I遂基1-3-aza Double ring [3·1. 01 Κ (Compound No. 13) excimer step 1 : 1_[(4_trifluoromethyl)phenyl]_25_dihydropyrrole is produced by the same method as described in Step 1 of Example 7. The intermediate product 5 5 and 4-(trifluoromethyl)aniline were prepared as the present compound. IR (KBr): 3087, 2945, 2998, 1512, 1487, 1498, 1355, 1324, 1234, 1164, 1114, 1015, 941, 805 cm _1 ; W-NMR pOOMHz, CDC13): 5 4. 06(s, 4H), 5. 99(s, 2H), 6. 56(d, 2H, J=9. 0Hz), 6. 76(d, 2H, J=9. 0Hz). 10 Step 2: 1 a,5 a,6a_N,N-dibenzyl-3-[(4-trifluoromethyl)phenyl)-3-azabicyclo[3. L0]H-6-amine was prepared from 1-[(4-trifluoromethyl)phenyl]-2,5-dihydro-1H-pyrrole by the same method as described in Step 2 of Example 7. N,N-dibenzylformamide is used to prepare the present compound. 15 IR (KBr): 3098, 2834, 2867, 1543, 1556, 1460, 1321, 1131, 1267, 1190, 1114, 1045, 1012, 945, 867 cm-1; iH-NMRpOOMHz, DMSO-d6): (5 1. 42(s, 2H), 1. 52(s, 1H), 2. 81 (d, 2H, J = 9. 0Hz), 3. 18(d, 2H, J=9. 0Hz), 3. 63(s, 4H), 6. 76 (m, 2H), 6. 91 (m, 2H), 6. 91 (m, 2H), 7. 33-7. 39 (m, 10H). 20 Step 3 ··[3-(4-Trifluoromethyl)phenyl]-3-azabicyclo[3·1·0]hex-6-yl]carbamic acid 1 α,5 α,6α- The tri-butyl ester was prepared by the same method as described in Step 3 of Example 7, Ν-dibenzyl-3-[(4-trifluoromethyl)phenyl]-3-azabicyclo[ 3·1·0]hex-6-amine is made into the present compound. 80 200813011 IR (KBr): 3312, 3178, 2856, 2843, 1676, 1591, 1578, 1423, 1344, 1336, 1255, 1156, 1198, 1034, 1019, 909, 823 cm 1 ; W-NMROOOMHz, DMSO-d6 ):5 1. 34(s, 9H), 2. 20(s, 2H), 2. 50 (s, 1H), 3. 27 (d, 2H, J = 9_0Hz), 3. 72(d, 2H, 5 J=9. 0Hz), 6. 68 (d, 2H), 7. 43 (d, 2H). Step 4 ··· 1 a,5 a,6 a-[6-(5-isoindolylaminocarbamoylamino)-3-(4-trifluoromethyl)phenyl]-3-azabicyclo [3·1·0] hexane was prepared by the same method as described in Step 4 of Example 7 from [3-(4-trifluoromethyl)phenyl)-3-azabicyclo[3. 1. 0]hex-6-yl]aminocarboxylic acid 1 α , 5 α , 6 α l〇 -tri-butyl ester and phenyl-(isoindoline-5-yl)carbamic acid phenyl ester were prepared into the present compound. IR (KBr): 3356, 3078, 2989, 2834, 1678, 1545, 1502, 1378, 132, 1267, 1244, 1118, 1055, 855, 809 cm-1; iH-NMRpOOMHz, DMSO-d6): 51. 95 (m, 2H), 2. 27(s,1H), 2. 50 (d, 2H, J = 9. 0Hz), 3. 63 (d, 2H, J = 9. 0Hz), 6. 65(d, 2H, 15 J=9. 0Hz), 6. 90 (s, 1H), 7. 44 (d, 1H, J = 9. 0Hz), 7. 60(t,1H), 7. 75 (d, 1H, J = 9. 0Hz), 7. 88 (d, 1H, J = 9. 0Hz), 8. 21 (d, 1H, J = 9. 0Hz), 8. 53 (d, 1H, J = 9. 0Hz), 8. 62(s, 1H), 9. 27 (s, 1H); melting point 247 to 249 ° C. Example 14: 1〇;,5〇;,6〇;-"6_(5-Momo-4-phenylaminocarbamoylamino)-3-((4-methyl20oxy)phenyl)-3-nitrogen Miscellaneous double ring Process for the preparation of 01 hexane (Compound No. 14) 1 · · 1_(4-methoxyphenyl)-2,5-dihydro-1H-pyrrole is produced by the same method as described in Step 1 of Example 7. The present compound was prepared from the intermediate product 5 and 4-methylamine. IR (KBr): 3043, 2942, 2919, 1500, 1474, 1413, 1344, 81 200813011 1328, 1328, 1232, 1160, 1111, 1012, 945, 807 cm. 1 ; W-NMRpOOMHz, CDC13): 6 3. 36(s,3H), 4. 06(s, 4H), 5. 97(s, 2H), 6. 22(d, 2H), 7. 12 (d, 2H). Step 2: 1〇;,5〇:,6〇;- Team of dibenzyl-3-[(4-methoxyphenyl)azabicyclo-5[3·1·0]hex-6-amine The method was prepared from 1-(4-methoxy)phenyl-2,5-dihydro-imba and N,N-di-decylcarbamidine by the same method as described in Step 2 of Example 7. Compound. IR (KBr): 3043, 2944, 2911, 2841, 2875, 1514, 1483, 1358, 1244, 116, 1037, 962, 815 cm '111 small]^11(300]^1^, 10 DMSO-d6): 5 1. 49(s, 2H), 1. 63(s, 1H), 2. 50 (s, 3H), 2. 92(d, 2H, J=9. 0Hz), 3. 28(d, 2H, J=9. 0Hz), 3. 63(s, 4H), 6. 39(d, 2H), 6. 73(d, 2H), 7. 26-7. 38 (m, 10H). Step 3: Preparation of [3-(4-methoxy)phenyl]azabicyclo[3丄0]hex-6-yl]carbamic acid 1 a,5 a,6 a-third-butyl ester 15 By the same method as described in Step 3 of Example 7, from N,N-dibenzyl-3-[(4.nonyloxy)phenyl]-3-azabicyclo[3. 1. 0] Hex-6-amine is made into the present compound. IR (KBr): 3356, 3156, 2878, 2834, 1645, 1567, 1523, 1467, 1334, 1323, 1245, 1189, 1198, 1037, 1056, 934, 867 cm-1; 1H-NMR (300 MHz, DMSO- D6): 5 1. 36(s, 9H), 20 2. 21(s, 2H), 2. 50 (s, 3H), 2. 53(s, 1H), 3. 24(d, 2H, J=9. 0Hz), 3. 69 (d, 2H, J = 9. 0Hz), 6. 75(d, 2H), 7. 75 (d, 2H). Step 4 ···1 a,5 a,6a-[6-(5-isoindolylaminocarbamoylamino)-3-((4-methoxy)phenyl)-3-azabicyclo[ 3·1·0] hexane was prepared by the same method as described in Step 4 of Example 7 from [3-(4-methoxy 82 200813011 phenyl)phenyl)-3-azabicyclo[3. 1. 0]hex-6-yl]aminocarbamic acid 1 α,5α,6α-third-butyr and Ν-(isoindoline-5-yl)carbamic acid benzene S are prepared to give the present compound. IR (KBr): 3329, 3127, 2894, 2850, 1631, 1597, 1531, 1477, 1371, 1336, 1270, 1161, 1114, 1071, 1027, 906, 5 815 cm 1 ; W-NMR pOOMHz, DMSO-d6) j 1. 87 (m, 2H), 2. 51(s, 1H), 3. 11 (d, 2H, J = 9. 0Hz), 3. 57 (d, 2H, J = 9. 0Hz), 3. 66(s, 3H), 6. 52 (d, 2H, J = 9. 0Hz), 6. 78(d, 2H, J=9. 0Hz), 6. 86(s, 1H), 7. 58(t, 1H), 7. 75 (d, 1H), 7. 89 (d, 1H), 8. 23(d, 1H), 8. 53 (d, 1H), 8. 60 (d, 1H), 9. 28 (s·1H); melting point 226 10 to 228 °C. Example 15: lα,5α,6α-“6-(5-isoindolinylaminocarboxylamido V3-(3A5-trifluoro)]phenyl-1-3 azabicyclo f3. 1. 01 hexane (No. 15 compound) hydrazine step 1 : l-(3,4,5·trifluorophenyl)-2,5-dihydro-1H-pyrrole is produced in the first step of Example 7 The present compound was prepared in the same manner from the intermediate product and 15 3,4,5-trifluoroaniline. IR (KBr〇cm-1: 3044, 2989, 2898, 2866, 1658, 1545, 1599, 1434, 132, 1244, 1265, 1120, 1044, 1078, 995, 827 cm 1 ; ^-NMRPOOMHz, CDC13): δ 4. 27(s, 4H), 5. 88(s, 2H), 6. 77-6. 89 (m, 2H). 2〇Step 2: 1 a, 5a, 6a-N, N-di-benzyl-3-[(3,4,5-trifluorophenyl)-3-azabi-[3·1·〇] The -6-amine was prepared by the same method as described in Step 2 of Example 7 from 1-(3,4,5-trifluorophenyl)-2,5-dihydro-1H-pyrrole and N, N-dibenzylformamide is made into the present compound. 83 200813011 IR(KBf) : 3098, 2867, 2855, 1540, 1593, 142, 1370, 1254, 1121, 1165, 1056, 1034, 986, 878 cm _1 ; Α-ΝΜΡ^ΟΟΜΗζ, DMSO-d6): ( 5 1. 45(s, 2H), 1. 68(s, 1H), 3. 12(d, 2H, J=9. 0Hz), 3. 44 (d, 2H, J = 9. 0Hz), 3. 63(s, 4H), 5 6. 51 (m, 1H), 7. 27 (m, 1H), 7. 27-7. 38 (m, 10H). Step 3: [3-(3,4,5-Trifluorophenyl]-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 a,5 a,6a-tri-butyl ester was prepared by the same method as described in Step 3 of Example 7, from 1,5 α,6 α -Ν, Ν_Bisary-3-[(3,4,5-trifluorophenyl]-3-azabicyclo[3. 1. 〇] _6-amine 10 cost compound. IR (KBr): 3332, 3126, 2898, 2845, 1677, 1599, 1533, 1456, 1366, 1332, 1256, 1166, 1078, 1021, 909, 867 cm 1 ; W-NMROOOMHz, DMSO-d6): 51. 42(s, 9H), 1. 69(s, 2H), 2. 55(s, 1H), 3. 32 (d, 2H, J = 9. 0Hz), 3. 45(d, 2H, 15 J=9. 0Hz), 6. 95-7. 10 (m, 2H). Step 4: 1 a,5 a,6a-[6-(5-isoindolinylaminocarboxylamido)-3-(3,4,5-trifluoro)phenyl]-3-azabicyclo [3. 1. 0] Method for the preparation of hexane from 3-(3,4,5-trifluorophenyl)-3-azabicyclo[3.] by the same procedure as described in Step 4 of Example 7. 1. 0] Hex-6-ylaminocarbamic acid 1 α,5 ο:,6α- 2nd 〇-butyl ester isoindolin-5-ylcarbamic acid phenyl ester was prepared as the present compound. IR (KBr) · · 3291, 3109, 3055, 298, 2863, 1650, 1613, 1580, 1517, 1484, 1387, 1254, 121, 1176, 1111, 1025, 916, 841, 828, 791 cm-1; H-NMRGOOMHz, DMSO-d6): δ 1. 92(s, 2H), 2. 42(s,lH), 3. 35 (d, 2H, J = 9. 0Hz), 3. 55(d, 2H, 84 200813011 J=9. 0Hz), 6. 45 (m, 2H), 6. 89(s, 1H), 7. 61(t,1H), 7. 75(d, 1H), 7. 90 (d, 1H), 8. 22 (d, 1H), 8. 54 (d, 1H), 8. 62(s, 1H), 9. 28 (s, 1H); the marriage point is 211 ° C. Example 16: la,5a,6a-J^-(5-isoindolylaminocarbamoylamino)-3-(2-difluoro-5 1oxy) phenyl 1-1-3 azabicyclo"3 . 1. Process for the preparation of 01 hexane (Compound No. 16) Step 1: The method for preparing 1-(2-difluoromethoxyphenyl)-2,5-dihydro-1H-pyrrole is as described in Step 1 of Example 7. The present compound was prepared in the same manner from the intermediate product 5 and 2-difluoromethoxyaniline. TR(KRr): 3039, 2939, 2840, 2847, 1620, 1537, 1522, 10 1477, 1306, 1352, 1270, 1184, 1035, 1009, 975, 825 cm 1 ; W-NMR pOOMHz, CDC13): (5 4 . 22(s, 4H), 5. 89(s, 2H), 6. 98 (m, 2H), 7. 1 (s, 1H, J = 72. 0Hz), 7. 30 (m, 2H). Step 2: 1 a,5 a,6a-N,N-dibenzyl-3-[(2-difluoromethoxyphenyl)-3-azabicyclo[3. Process for the preparation of L6]hex-6-amine 15 from 1-(2-difluoromethoxy)phenyl-2,5-dihydro-1H-pyrrole and the same procedure as described in Step 2 of Example 7. Ν,Ν·Dibenzylcarbamide is made into the present compound. IR (KBr): 3032, 2878, 2887, 1534, 152, 1489, 1367, 1334, 1232, 1178, 1154, 1067, 965, 817 cm; 20 iH-NMR pOOMHz, DMSO-d6): 5 1. 44(s, 2H), 1. 66(s, 1H), 3. 18(d, 2H, J=9. 0Hz), 3. 40 (d, 2H, J = 9. 0Hz), 3. 61(s, 4H), 6. 77(d, 2H), 7. 01(t, 1H, J=9. 0Hz), 7. 10(d, 2H), 7. 22-7. 35 (m, 10H). Step 3: [3-(2-Difluoromethoxy)phenyl]-3-azabicyclo[3·1·0]hex-6-yl]amine 85 200813011 carboxylic acid 1 a,5 a,6a- The third butyl ester was prepared by the same method as described in Step 3 of Example 7 from 1 α,5 α,6 α -Ν,Ν-dibenzyl-3-(2-difluoromethoxyphenyl) ]-3-Azabicyclo[3. 1. 0] hex-6-amine manufactured by cost compound. 5 IR (KBi〇: 3330, 3123, 2857, 2845, 1640, 1589, 1525, 1498, 1352, 1367, 1234, 1178, 1049, 1001, 915, 823 cm); i-NMRpOOMI^DMSOOjlWb^H), 1 . 74(s, 2H), 2. 24(s,1H), 2. 87 (d, 2H, J = 9. 0Hz), 3. 54 (d, 2H, J = 9. 0Hz), 6. 68 (d, 2H), 6. 80 (t, 1H, J = 72. 0Hz), 6. 98 (m, 2H). 10 Step 4: 1 a,5 a,6a-[6-(5-isoindolinylaminocarboxylamido)-3-(2-difluoromethoxy)phenyl]-3-azabicyclo [3. 1. 0] Method for the preparation of hexane from 3-(2·difluoromethoxy)phenyl)-3-azapine soil by the same method as described in Step 4 of Example 7. [3. 1. 0]hex-6-yl]carbamic acid 1 〇!, 5 (2,6 〇: -tri-butyl ester and N-(isoindoline-5-yl)carbamic acid phenyl ester to prepare the present compound. IR (KBr): 3369, 3270, 1667, 1643, 1578, 1523, 1465, 1423, 1321, 1267, 1221, 1189, 1132, 1078, 967, 823 cm -1 ; ^-NMRGOOMHz, DMSO-d6): 51 . 82(s, 2H), 2. 63(s, 1H), 3. 27(d, 2H, J=9. 0Hz), 3. 27(d, 2H, J=9. 〇Hz), 6. 76-7. 25 (m, 5H), 7. 60(t,1H), 7. 74 (d, 1H), 7. 90 (d, 1H), 20 8. 24(d,1H), 8. 53 (d, 1H), 8. 60 (s, 1H), 9. 27 (s, 1H); melting point 170 to 172 ° C. Example 17 ··· 1 α ,5 α,6α-『6-(5-Iso-mouth beer, some amines, a few face-faced sheep) _3_(3,4_difluoro)phenyl 1-3·azabicyclo”3 ·1·01 惊惊▲ (No. 17 compound) 夕Step 1 ·· 1-(3,4-difluorophenyl)-15-dihydro-1H-pyrrole 86 Method 8610113011 By Step 1 of Example 7 The present compound was prepared from the intermediate product 5 and 3,4-difluoroaniline in the same manner as described above. IR (KBr): 3035, 2949, 2855, 2849, 1607, 1555, 1523, 1470, 1316, 1355, 1279, 1155, 1036, 1019, 966, 827 5 cm 1 ; iH-NMRpOOMHz, CDC13): δ 4. 10(s, 4H), 5. 98(s, 2H), 6. 80 (m, 1H), 7. 1(s, 1H), 7. 32 (m, 1H). Step 2: 1 a,5 a,6a-N,N-dibenzyl-3-[(3,4-difluorophenyl)-3-azabicyclo[3·1·0]hex-6-amine The preparation method is the same as the method described in the step 2 of Example 7, from 1 -(3,4-difluoro) 10 phenyl-2,5-dihydro-1 Η-pyrrole and hydrazine, fluorene-dibenzyl hydrazine. The amine is made into the present compound. IR (KBr): 3067, 2887, 2867, 1578, 1516, 1489, 1345, 1336, 1290, 1189, 1156, 1098, 1010, 967, 819 cm -1; W-NMRpOOMHz, DMSO-d6): (5 1 . 43(s, 2H), 1. 74(s, 1H), 3. 05 (d, 2H, J = 9_0Hz), 3. 39(d, 2H, J=9. 0Hz), 3. 63(s, 4H), 15 6. 66 (m, 1H), 6. 87 (m, 1H), 7. 07 (m, 1H), 7. 24-7. 35 (m, 10H). Step 3: [3-(3,4-Difluoro)phenyl]-3-azabicyclo[3·1·0]hex-6-yl]carbamic acid 1 α,5 α,6α-third- The butyl ester was prepared by the same method as described in Step 3 of Example 7 from 1 α,5 α,6 α -Ν,Ν-dibenzyl-3-(3,4-difluorophenyl)-3. - azabicyclo[3. 1. 0] hex-6-amine was made into 20 compounds. IR (KBr): 3390, 3134, 2856, 2812, 1645, 1567, 1523, 1412, 1378, 1332, 1278, 1101, 1049, 1021, 934, 801 cm 1 ; h-NMROOOMHz, DMSO-d6): 5 1 . 35(s, 9H), 2. 23(s, 2H), 2. 52(s, 1H), 3. 25(d, 2H, J=9. 0Hz), 3. 63(d,2H, 87 200813011 J=9. 0Hz), 6. 85 (m, 1H), 7. 21(s, 1H), 7. 34 (s, 1H). Step 4: 1 a,5 a,6a-[6-(5-isoindolinylaminocarboxylamido)_3_(3,4-difluoro)phenyl]-3-azabicyclo[3·1 · 〇] hexane was prepared by the same method as described in Step 4 of Example 7 from 3-(3,4-difluoro) 5 phenyl)-3-azabicyclo[3丄0]hex-6 -Alkylcarbamic acid 1 hydrazine;,5 〇:,6 〇;-T-butyl acrylate and iso-porphyrin-5-ylaminocarbamate phenyl ester to prepare the present compound. IR (KBr): 3345, 3288, 1649, 1632, 1599, 1534, 1478, 1432, 1376, 1256, 1254, 1198, 1176, 1024, 978, 816 cm -1 ; &quot;H-NMROOOMHz, DMSO-d6) : 5 1. 90(s, 2H), 2. 50(s, 10 1H), 3. 20 (d, 2H, J = 9. 0Hz), 3. 56(d, 2H, J=9. 0Hz), 6. 31(d, 1H), 6. 56(d,1H), 6. 88(s,1H), 7. 18 (m, 1H), 7. 60(t,1H), 7. 75 (d, 1H), 7. 88 (d, 1H), 8. 22 (d, 1H), 8. 53 (d, 1H), 8. 61(s, 1H), 8. 27 (s, 1H); melting point 208 to 210 ° C. Example 18: 1 α , 5α , 6α 46-(5-isodecylaminocarboxamido)-3_(2-a-5-15 methyl)phenyl 1-3-azabicyclo "3. 1. 01 hexane (No. 18 compound) method step 1 · 1-(2-Fluoro-5-methylphenyl)-2,5-dihydro-1H-pyrrole is produced in the first step of Example 7 The present compound was prepared from the intermediate product 5 and 2-fluoro-5-methylaniline in the same manner as described above. IR (KBr) · · 3056, 2943, 2858, 2823, 1612, 1578, 1545, 20 1467, 1316, 1399, 1276, 1200, 1159, 1022, 1019, 960, 816 cm 1 ; W-NMR pOOMHz, CDC13): 6 2. 22(s,3H), 4. 19(s, 2H), 5. 95(s, 2H), 6. 27(s,1H), 6. 48 (m, 1H), 7. 29 (m, 1H). Step 2 ··· 1 a,5 a,6a-N,N-dibenzyl-3-(2 gas-5-methylphenyl) azabicyclo[3. 1. 0] Method for the preparation of hexa-6-amine 88 200813011 From 1-(2-fluoro-5-methylphenyl)-2,5-dihydro-1H- by the same method as described in Step 2 of Example 7. The present compound is prepared from pyrrole and N,N-dibenzylformamide. IR (KBr): 3055, 2890, 2850, 1589, 1527, 1460, 1344, 5 1336, 1269, 1154, 1114, 1092, 1000, 905, 815 cm -1 ; W-NMR pOOMHz, DMSO-d6): 5 1 . 48(s, 2H), 1. 67(s, 1H), 2. 50 (s, 3H), 3. 22 (d, 2H, J = 9. 0Hz), 3. 51 (d, 2H, J = 9. 0Hz), 3. 64 (s, 4H), 6. 82 (d, 1H), 7_29-7. 35 (m, 12H). Step 3 ···"3-(2-Fluoro-5-methyl)methyl 1-3-azabicyclo "3丄01 hex-6-yl 1 Amino — - y · - -μ - - λ - w — ^ — ίο Formic acid 1 a,5 a,6a-tri-butyl ester by the same method as described in Step 3 of Example 7 from 1 α,5 α,6 α -Ν,Ν-dibenzyl- 3-(2-Fluoro-5-methylphenyl)-3_azabicyclo[3. 1. 0] Hex-6-amine is a cost compound. IR (KBr): 3345, 3167, 2843, 2823, 1665, 1565, 1520, 15 1414, 1375, 1332, 1254, 1145, 1012, 1098, 912, 856 cm-1; i-NMRpOOMHz, DMSO-d6): 51. 23(s,9H), 2. 25(s, 2H), 2. 56(s,1H), 2. 78(s,3H), 3. 33(d, 2H, J=9. 0Hz), 3. 70(d, 2H, J=9. 0Hz), 6. 91(s, 1H), 7. 42-7. 56 (m, 2H). Step 4: 1 a,5 a,6 a-[6-(5-isoindolinylaminocarbamoylamino)-3-(2-fluoro-5-20 methyl)phenyl]-3-nitrogen The method of the miscellaneous double [3·1·〇] hexane was prepared by the same method as described in the step 4 of Example 7 from 3-(2-fluoro-5-methyl)phenyl]-3-azabicyclo[ 3. 1. 0]Hex-6-yl]carbamic acid 1 〇:, 5 〇:, 6 〇: -T-butyl ester and phenyl isoindoline-5-ylaminocarbamate to prepare the present compound. IR (KBr): 3361, 3290, 1650, 1613, 158, 1517, 1484, 89 200813011 1459, 1359, 1264, 1254, 1176, 1154, 1024, 981, 829 cm -1 ; W-NMRQOOMHz, DMSO-d6) : 51. 29(s,3H), 2. 20(s, 2H), 2. 70 (s, 1H), 3. 15(d, 2H, J=9. 0Hz), 3. 34(d, 2H, J=9. 0Hz), 6. 53 (m, 2H), 6. 88 (m, 1H), 7. 64 (d, 1H), 7. 78(d, 5 lH), 7. 83 (m, 2H), 8. 33(s,lH), 8. 51 (d, 1H, J = 9. 0Hz), 9. 30 (s, 1H); melting point 218 to 219 ° C. Example 19: 1 J,5,6 ck-"6-(5-isosex 17-linylamino decanoic acid amine)-3-(3-gas) 笑一1-3-azabicyclo" 1. Process for the preparation of 01 hexane (compound No. 19) Step 1: 1-(3-carbophenyl)-2,5-diphos-1Η-σ piroxime 10 As described in Step 1 of Example 7 The present compound was prepared in the same manner from Intermediate 5 and 3-fluoroaniline. IR (KBr): 3032, 2945, 2858, 2878, 1612, 1573, 1522, 1410, 1314, 1333, 1274, 1208, 1160, 1028, 1012, 965, 819 cm 1 ; W-NMR pOOMHz, CDC13): 5 4 . 26(s, 4H), 6. 01(s, 15 2H), 6. 98 (m, 2H), 7. 25(s,1H), 7. 30 (d, 1H). Step 2: 1 a, 5 a, 6 aN, N-dibenzyl-3-(3-fluorophenyl)-3-azabicyclo[3丄0]hexylamine is prepared by the step 2 of Example 7 The present compound is prepared from 1-(3-fluorophenyl)-2,5-dihydro-1H-pyrrole and N,N-dibenzylformamide in the same manner as described above. 20 IR (KBr): 3032, 2945, 2858, 2878, 1612, 1573, 1522, 1410, 1314, 1333, 1274, 1208, 1160, 1028, 1012, 965, 819 cm _1 ; h-NMR pOOMHz, CDC13): 5 4. 26(s, 4H), 6. 01(s, 2H), 6. 98 (m, 2H), 7. 25(s,1H), 7. 30 (d, 1H). Step 3 ··[3-(3-Fluoro)phenyl]-3-azabicyclo[3·1·0]hex-6-yl]carbamic acid 90 200813011 1 a,5 a,6 a-third - butyl ester was prepared by the same method as described in Step 3 of Example 7 from 1 〇:,5 α,6 Λ -Ν,Ν·Dibenzyl-3-(3-fluorophenyl)-3- Azabicyclo[3. 1. 0] Hexylamine is made into the present compound. 5 IR(KBr): 3332, 3121, 2843, 2854, 162, 1565, 152, 1416, 1356, 1332, 1298, 1178, 1043, 1021, 916, 887 cm 1 ; h-NMRQOOMHz, DMSO-d6)jl. 24(s,9H), 1. 74(s, 2H), 2. 22(s,1H), 3. 35 (d, 2H, J = 9. 0Hz), 3. 65(d, 2H, J=9. 0Hz), 6. 95(s, 1H), 7. 12 (m, 1H), 7. 42-7. 56 (m, 2H). 10 Step 4: la,5a,6a-[6-(5-isoindolinylaminocarbamoylamino)-3-(3-fluoro)phenyl]azabicyclo[3丄0]hexane The method was the same as described in the step 4 of Example 7, and was carried out from 3·(3-fluoro)phenyl]-3-azabicyclo[3·1·0]hex-6-yl]carbamic acid 1 hydrazine. :,5〇:,6〇:-Third-'butyl ester and isoporphyrin_5_ylaminocarbamic acid phenyl ester to prepare the present compound. 15 IR(KBr): 3355, 3039, 2923, 2844, 1679, 1556, 1544, 1513, 1509, 1345, 1278, 1023, 1016, 829 cm-1; i: • W-NMRpOOMHz, DMSO-d6): 5 2. 26(s, 2H), 2. 75(s,1H), , 2. 95 (d, 2H, J = 9. 0Hz), 3. 73 (d, 2H, J = 9. 0Hz), 6. 31 (m, 3H), 7. 14 (m, 1H), 7. 28(d,1H), 7. 64 (d, 1H), 7. 79·7·98(πι,3H), 20 8. 42 (s, 1H), 8. 54 (d, 1H, J = 9. 0Hz), 9. 31 (s, 1H); the grafting point is 126 to 127 °C. Example 20: 1^5〇;,6〇!-[6-(5-iso-4-linylamine carboxycarbamoylamino)-3-(3 difluoro) stupyl l-3-i shy ring [3 . 1. Process for the preparation of 01 hexane hurricane compound No. 20) 1. Preparation method of 1-[2-(cyclopropylmethoxy)phenyl]-2,5-dihydro-1 fluorene-pyrrole 91 200813011 By example 7 The present compound was prepared from the intermediate product 5 and 2-(cyclopropylmethoxy)aniline in the same manner as described in the step 1. IR (KBr): 3021, 2940, 2845, 2898, 1605, 1521, 1509, 1465, 1332, 1398, 1243, 1209, 1145, 1026, 1〇η, 969, 5 813 cm-1; iH-NMRpOOMHz, CDC13 ): 5 0. 35(d, 2H), 0. 51(d, 2H), 1. 29 (m, 1H), 1. 79(s, 2H), 4. 17(s, 4H), 5. 90(s, 2H), 6. 98 (m, 2H), 7. 25-7. 30(m,2H) 〇Step 2 ·· 1 a,5 a,6a-N,N-dibenzyl-3-[2-(cyclopropylmethoxy)phenyl]-3-azabicyclo[ 3. 1·0] Process for the preparation of hexa-6-amine 10 from 1-[2-(cyclopropylmethoxy)phenyl]-2,5-dihydrogen by the same method as described in Step 2 of Example 7. -1 Η-pyrrole and hydrazine, hydrazine-dibenzylcarbamide are used to prepare the present compound. IR (KBi〇: 3078, 2899, 2833, 1650, 1578, 1489, 1378, 1344, 1278, 1145, 1132, 102, 1009, 935, 823 cm-1; 15 h-NMRpOOMHz, DMSO-d6) 5 0. 36(d, 2H), 0. 50(d, 2H), 1. 28 (m, 1H), 1. 40(s, 2H), 1. 64 (s, 1H), 1. 81(s, 2H), 3. 09(d, 2H, J=9. 0Hz), 3. 40 (d, 2H, J = 9. 0Hz), 3. 64 (s, 4H), 6. 49 (m, 2H), 6. 59 (m, 2H), 7. 30-7. 41 (m, 10H). Step 3: 3-[2,4-Difluorophenyl]-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 20 1 a,5 a,6a-tri-butyl ester was prepared by the same method as described in Step 3 of Example 7 from 1 α, 5 α, 6 α - Ν,Ν·Dibenzyl each [2-(cyclopropylmethoxy)phenyl]-3_azabicyclo[3. 1. 0] Hex-6-amine is made into the present compound. IR (KBr〇: 3378, 3199, 2832, 2843, 1678, 1589, 1509, 92 200813011 1443, 1387, 1332, 122, 1167, 1054, 1021, 967, 832 cm-1; iH-NMRpOOMHz, DMSO-d6) : 5 〇. 36(d, 2H), 0. 50(d, 2H), 1. 24(s,9H), 1. 28 (m, 1H), 1. 74(s, 2H), 1. 91(s, 2H), 2. 26(s,1H), 3. 23(d, 2H, J=9. 0Hz), 3. 45 (d, 2H, J = 9. 0Hz), 5 7. 11 (m, 2H), 7. 23 (m, 2H). Step 4: 1 a, 5 a, 6 a-[6-(5-isoindolylaminocarbamoylamino) phenyl] method for the preparation of each azabicyclo[3·1·0] hexane The same procedure as described in Step 4 of Example 7 was carried out from 3-[2,4-trifluorophenyl]-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 α,5〇: ,6 α-third-10 butyl ester and phenyl isoindoline-5-ylaminocarbamate were prepared into the present compound. IR (KBr): 3346, 3046, 2900, 2856, 1639, 1589, 156, 1514, 1505, 1328, 1231, 1007, 1020, 825 cm _1 ; i-NMR GOO MHz, DMSO-d6): 5 0. 34(d, 2H), 0. 57(d, 2H), 1. 25 (m, 1H), 1. 77(s, 2H), 2. 70 (s, 1H), 3. 12(d, 2H, 15 J=9. 0Hz), 3. 77(d, 2H, J=9. 0Hz), 3. 87 (d, 2H, J = 9. 0Hz), 6. 66-6. 85 (m, 5H), 7. 60(t,1H), 7. 74 (d, 1H), 7. 89 (d, 1H), 8. 24(d,1H), 8. 53 (d, 1H), 8. 58(s, 1H), 9. 27 (s, 1H); melting point 152 to 154 °C. Example 21 · 1 , 5 , 6 isoindolinylaminolanyl)-3-(2,4-di 20 Jl)phenyl1-3-azabicyclo π. 1. Process for the preparation of 01 hexane (compound No. 21) Step 1: The method for preparing 1-(2,4-difluorophenyl)-2,5-dihydro-1H-pyrrole is as described in Step 1 of Example 7. The present compound was prepared in the same manner from Intermediate 1 and 2,4-monoaniline. IR (KBr): 3028, 2987, 2894, 2856, 1600, 1525, 1548, 93 200813011 1463, 1330, 1394, 1243, 1219, 1156, 1045, 1019, 934, 810 cm 1 ; iH-NMR pOOMHz, CDC13): (5 4. 17(s, 4H), 5. 98(s, 2H), 6. 64 (m, 1H), 6. 89 (m, 1H), 7. 11 (s, 1H). Step 2 ···1〇;,5〇;,6 core team of dibenzyl-3-(2,4-difluorophenyl)-3-azabicyclo-5[3Λ·0]hex-6-amine The process was carried out by the same method as described in Step 2 of Example 7 from 1-(2,4-difluorophenyl)-2,5-dihydro-1?-pyrrole and hydrazine, hydrazine-dibenzylformamide. The cost of the compound. IR (KBr): 3056, 2866, 2832, 1698, 1555, 1478, 1378, 1332, 1256, 1189, 1122, 1067, 1011, 937, 829 cm "; 10 W-NMR pOO MHz, DMSO-d6): 51. 43(s, 2H), 1. 74(s, 1H), 3. 04(d, 2H, J=9. 0Hz), 3. 43(d, 2H, J=9. 0Hz), 3. 63(s, 4H), 6. 67 (m, lH), 6. 87 (m, lH), 7. 08 (m, lH), 7. 26-7. 35 (m, 10H). Step 3: 3-[2,4-Difluorophenyl]-3-azabicyclo[3. 1. 0] hexa-6-ylaminocarbamic acid 1 a,5 a,6a-third-butyl ester method 15 by the same method as described in step 3 of Example 7 from 1 α, 5 α, 6 α - Ν,Ν-dibenzyl-3-(2,4-difluorophenyl)-3-azabicyclo[3. 1. 0] hex-6-amine is made into the present compound. IR (KBr): 3356, 3132, 2854, 2832, 1625, 152, 1502, 1467, 1343, 1356, 1232, 1167, 1099, 1021, 909, 843 20 cm "; iH-NMRpOOMHz, DMSO-d6): 5 1. 32(s, 9H), 1. 68(s, 2H), 2. 42 (s, 1H), 3. 18(d, 2H, J=9. 0Hz), 3. 52 (d, 2H, J = 9. 0Hz), 6. 92 (m, 1H), 7. 24(s,1H), 7. 44 (s, 1H). Step 4: 1 a,5 a,6a-[6-(5-isoindolinylaminocarbamoylamino)-3-(2,4-difluoro)phenyl]-3-azabicyclo[3 . 1. 0] Method for the preparation of hexane 94 200813011 By the same procedure as described in Step 4 of Example 7, from 3-[2,4-difluorophenyl]-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 〇:, 5 〇:, 6 〇?-T-butyl acrylate was made into the present compound. IR (KBr): 3292, 3103, 2978, 2852, 1651, 1579, 1516, 5 1483, 1387, 1327, 1360, 1269, 1252, 1135, 1100, 948, 845 cm 1 ; W-NMROOOMHz, DMSO-d6) :5 1. 83(s, 2H), 2. 63(s, 1H), 3. 22 (d, 2H, J = 9. 0Hz), 3. 67(d, 2H, J=9. 0Hz), 6. 79_6. 92 (m, 3H), 7. 08(t, 1H), 7. 58(t, 1H), 7. 74(d,1H), 7. 90 (d, 1H), 8. 22 (d, 1H), 8. 53(d, 1H), 8. 60 (s, 1H), 9. 27 (s, 10 1H); melting point 207 to 209 ° C. Example 22: Ια, 5α. 6 α-"6-(5-isodecylaminocarbamoylamino)-3-(2,6-diaza)phenyl U-azabicyclo"3. 1. Process for the preparation of 01 hexane (Compound No. 22) Step 1: The method for preparing 1_(2,6-difluorophenyl)-2,5-dihydro-1H-pyrrole is the same as described in Step 1 of Example 7. The present invention is prepared from the intermediates 5 15 and 2,6-difluoroaniline. IR (KBr): 3078, 2970, 2890, 2834, 1615, 1527, 1545, 1460, 1323, 1378, 1223, 1210, 1178, 1044, 1023, 987, 817 cm -1 ; h-NMRGOOMHz, CDC13): 5 4. 42(s, 4H), 5. 98(s, 2H), 6. 93-7. 10 (m, 3H). 20 Step 2 ·· 1 〇^,5〇^,6〇^Team Dibenzyl-3-(2,6-difluorophenyl)-3-azabicyclo[3·1·0]hex-6 - Amine is produced by the same method as described in Step 2 of Example 7 from 1-(2,6-difluorophenyl)-2,5-dihydro-1H-pyrrole and indole, indole-dibenzyl Formamide is made into the present compound. IR (KBr): 3012, 3008, 2876, 2850, 1588, 1555, 1498, 95 200813011 1364, 1336, 1243, 1161, 1114, 1071, 1027, 906, 815 cm 1 ; iH-NMR pOOMHz, DMSO-d6): δ 1. 37(s, 2H), 1. 79(s, 1Η), 3·20-3·34(πι, 8H), 3. 62(s, 2H), 3. 61(s, 4H), 6. 90-6. 95 (m, 1H), 7. 30-7. 34 (m, 12H). 5 Step 3 ··3-[2,6-Difluorophenyl]-3-azabicyclo[3丄0]hex-6-ylaminocarbamic acid 1 a,5 a,6a-tri-butyl ester The process was carried out by the same method as described in Step 3 of Example 7 from 1α,5α,6α-Ν,Ν_dibenzyl-3-(2,6-difluorophenyl)-3-azabicyclo[3 . 1. 0] hex-6-amine is made into the present compound. 10 IR (KBr): 3334, 3178, 2854, 2832, 1665, 1554, 1521, 1414, 1387, 1343, 1276, 1178, 1098, 1045, 909, 857 cm; iH-NMR pOOMHz, DMSO-d6): 5 1 . 38(s, 9H), 1. 68(s, 2H), 2. 50 (s, 1H), 3. 18(d, 2H, J=9. 0Hz), 3. 55 (d, 2H, J = 9. 0Hz), 6. 74 (m, 1H), 6. 90 (s, 1H), 7. 09 (m, 1H). 15 Step 4 ···1〇;,5〇;,6〇:-[6-(5-isoindolylaminocarbamoylamino)-3-(2,6-difluoro)phenyl H-nitrogen Heterobicyclo[3. 1. 0] Method for the preparation of hexane from 3-[2,6.difluorophenyl]-3-azabicyclo[3.] by the same procedure as described in Step 4 of Example 7. 1. 0] _6_ylaminocarbamic acid 1 α,5 α,6 α -t-butyl ester was prepared into the present compound. 20 IR(KBr): 3291, 3106, 3063, 2856, 1645, 1542, 1484, 1470, 1359, 1254, 1158, 1138, 1033, 973, 828 cm-1; W-NMRQOOMHz, DMSO-d6): 5 1 . 76(s, 2H), 2. 70(s, 1H), 3. 51 (d, 2H, J = 9. 0Hz), 3. 60 (d, 2H, J = 9. 0Hz), 6. 82-7. 00 (m, 4H), 7. 60(t,1H), 7. 74 (d, 1H), 7. 88 (d, 1H), 8. 24(d,1H), 96 200813011 8. 53 (d, lH), 8. 55(s,lH), 9. 27 (s, 1H); melting point 201 to 203 ° C. Example 23: 1 αα . 6 a 46-(5-isoquinoline amine, carboxy oxime amino)-3-(2-fluoro-3ditrifluoromethyl) phenyl 1-3-indole bicyclic "3. 1. Process for the preparation of 01 hexane (Compound No. 23) Step 1: Method for preparing 1-(2-fluoro-3-trifluoromethylphenyl)-2,5-dioxin-1H-pyrrole 5 By the procedure of Example 7 The present compound was prepared from the intermediate product 5 and 2-fluoro-3-(trimethylhydrazino)aniline in the same manner as described in 1. IR (KBr) cm -1 : 3034, 2974, 2843, 2890, 1610, 1512, 1523, 1445, 1387, 1323, 1290, 1210, 1155, 1078, 1045, 998, 815 cm -1 ; ^-NMROOOMHz. CDCh): accounted for 4. 28(s, 4H), 10 6. 00(s, 2H), 6. 93_7. 01 (m, 3H). Step 2: 1〇;,5〇;,6〇;-team&amp;dibenzyl-3-(2-dun-3-trifluoromethylphenyl)-3-azabicyclo[3丄0] The -6-amine was prepared by the same method as described in Step 2 of Example 7 from 1-(2-fluoro-3-trifluoromethylphenyl)-2,5-dihydro-1H.pyrrole and N. N-dibenzylcarbamide was used to prepare 15 compounds. IR (KBr): 3076, 2843, 2821, 1576, 1511, 1490, 1356, 1322, 1265, 1143, 1115, 1092, 1056, 905, 844; iH-NMRpOOMHz, DMSO-d6): 5 1. 48(s, 2H), 1. 66(s, 1H), 3. 21 (d, 2H, J = 9. 0Hz), 3. 50 (d, 2H, J = 9. 0Hz), 3. 63(s, 4H), 20 6. 73(s, 1H), 6. 91 (d, 1H), 7. 24-7. 33(m,12H) 〇Step 3 ··3-[2-Fluoro-3-trifluoromethylphenyl]-3-azabicyclo[3·1·0]hex-6-ylamino decanoic acid 1 α,5 α,6α_T-butyl ester was prepared by the same method as described in Step 3 of Example 7 from 1,6α-Ν,Ν-dibenzyl_3·(2-fluoro-3- Trifluoromethylphenyl)oxazabicyclo[3丄0]hex 97 200813011 -6-amine was prepared as the present compound. IR (KBr) · · 3344, 3134, 2854, 2821, 1602, 1566, 1544, 1498, 1376, 1332, 1235, 1101, 1043, 1026, 910, 885 cm -1 ; W-NMRPOOMHz, DMSO-d6): δ 1. 34(s, 9H), 1. 65(s, 5 2H), 2. 52(s, 1H), 3. 16(d, 2H, J=9. 0Hz), 3. 54 (d, 2H, J = 9-0Hz), 6. 78 (m, 1H), 6. 92(s, 1H), 7. 19 (m, 1H). Step 4 · 1 cn,5 〇!,6 ca-[6-(5-Iso-u- cylinyl-amino-propylamino)-3-(2-trifluoromethyl)phenyl] azabicyclo [3·1·0] hexane was prepared by the same method as described in Step 4 of Example 7 from 3-[2-fluoro-3-10-trifluoromethylphenyl]-3.azabicyclo[ 3. 1. 0] Hex-6-ylaminocarbamic acid 1 α,5 α,6α-tris-butyl ester was prepared into the present compound. IR (KBi〇: 3430, 3299, 3059, 2948, 2838, 1644, 1586, 1494, 1478, 1362, 1320, 1250, 1226, 1169, 119, 995, 827 cm 1 ; W-NMR pOOMHz, DMSO-d6): (n. 89(s, 2H), 15 2. 50 (s, 1H), 3. 54 (d, 2H, J = 9. 0Hz), 3. 77(d, 2H, J=9. 0Hz), 6. 88(s,1H), 7. 01 (m, 2H), 7. 20 (d, 1H), 7. 61(t,1H), 7. 75(d, lH), 7. 90 (d, lH), 8. 22 (d, lH), 8. 53(d,1H) 8. 62(s,lH), 9. 27 (s, 1H); melting point 224 to 226 ° C. Example 24: 1 ο; 5 α . 6 a Isoquinoline, an amine, a carboxamide, a -3-(2-trifluoro 20 fluorene), a 1-3-azaindole ring, "3. 1. 01 hexane (Compound No. 24) &amp; Step 1 · 1-(2-Trifluoropyridylphenyl)-2,5-dihydro-1H-pyrrole was prepared as in Step 1 of Example 7. The present compound was prepared from the intermediate product 5 and 2-trifluoromethoxyaniline in the same manner as described above. IR (KBi〇: 3034, 2974, 2843, 2890, 1610, 1512, 1523, 98 200813011 1445, 1387, 1323, 1290, 1210, 1155, 1078, 1045, 998, 815 cm-1; Α-ΝΜΚ^ΟΟΜΗζ, CDC13): (5 4. 21(s, 4H), 6. 00(s, 2H), 6. 70 (t, 1H, J = 6. 0Hz), 6. 79 (d, 1H), 7. 19-7. 21 (m, 2H). Step 2 ··· 1 a,5 a,6 aN,N-dibenzyl-3-(2-trifluoromethoxyphenyl)oxazapine 5 ring [3丄0]hex-6-amine The compound was prepared from 1-(2-trifluoromethoxyphenyl)-2,5-dihydro-1H-pyrrole and N,N-dibenzylformamide according to the same procedure as described in Step 2 of Example 7. . IR (KBr): 3044, 2898, 2832, 1566, 1503, 1478, 1354, 132, 1292, 1148, 1ΗΠ, 1055, 1021, 965, 822 cm _1 ; 10 W. NMR pOOMHz, DMSO-d6): 51. 45(s, 2H), 1. 67(s,1H), 3. 08 (d, 2H, J = 9. 0Hz), 3. 46(d, 2H, J=9. 0Hz), 3. 63(s, 4H), 6. 79 (d, 1H), 7. 15-7. 30 (m, 13H). Step 3 ·· 3-[2-Fluoro-3-trifluoromethoxyphenyl] each azabicyclo[3. 1. 0] hexa-6-ylaminocarbamic acid 1 a,5 a,6a-third butyl ester method 15 by the same method as described in step 3 of Example 7 from 1 α, 5 α, 6 α - Ν,Ν-Bisary-3-(2-trifluoromethoxyphenyl)-3-azabicyclo[3. 1. 0] Hex-6-amine is a cost compound. IR (KBr) · · 3332, 3144, 2887, 2854, 1643, 1527, 1521, 1498, 1355, 1333, 1295, 1176, 1034, 1021, 916, 833 20 cm 1 ; i-NMRGOOMHz, DMSO-d6) · δ 1. 36(s,9H), 1. 73(s, 2H), 2. 23(s, 1H), 2. 88(d, 2H, J=9. 0Hz), 3. 52 (d, 2H, J = 9. 0Hz), 6. 68 (d, 2H), 6. 98(m,2H) 〇Step 4:1 a,5 a,6 a-[6-(5-(I-oxalinylaminocarboxylamido)-3-(2-trifluoromethoxy)phenyl ]-3-Azabicyclo[3. 1. 0] Method for the preparation of hexane 99 200813011 From the same method as described in Step 4 of Example 7, from 3-[2-trifluoromethoxyphenyl]-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1α,5α,6α-tris-butyl ester was prepared into the present compound. IR (KBr): 3313, 3066, 2960, 2905, 2845, 1650, 1567, 5 1607, 15CU, 1479, 1359, 1260, 1205, 1156, 1107, 1056, 1020, 921, 826 cm YH-NMRpOOMHz, DMSO- D6): 6 1. 86(s, 2H), 2. 50 (s, 1H), 3. 34(d, 2H, J=9. 0Hz), 3. 71 (d, 2H, J = 9. 0Hz), 6. 85-6. 91(s, 3H), 7. 20 (d, 2H), 7. 60(t,1H), 7. 74(d, lH), 7. 90 (d, lH), 8. 23(d,lH), 8. 53 (d, lH), 8. 61(s,lH)9. 27(s, 10 1H); melting point 182 to 184 °C. Example 25: 1〇;,5〇;,6〇;-"6-(5-isoindolylaminocarbamoylamino)-3-(2-trifluoromethyl)phenyl1-3-nitrogen Miscellaneous double ring "3. 1. 01 hexane (No. 25 compound) floc step 1 · 1-(2-trifluoromethoxyphenyl)-2,5-dihydro-1H-pyrrole is prepared as in step 1 of Example 7. The present compound was prepared in the same manner from the intermediates 5 15 and 2-(trifluoromethyl)aniline. IR (KBr): 3067, 2998, 2847, 2832, 1667, 1532, 1587, 1432, 1343, 1398, 122, 1287, 1143, 1089, 1054, 997, 821 cm-1; h-NMRGOOMHz, CDC13): 5 4. 16(s, 4H), 5. 98(s, 2H), 6. 93(t,1H), 7. 09(d,1H), 7. 47(t,1H), 7. 58 (d, 1H). 20 Step 2: 1 a,5 a,6 a-N,N-dibenzyl-3-(2-trifluoromethylphenyl)-3-azabicyclo[3. L0]H-6-amine is prepared by the same method as described in Step 2 of Example 7 from 1-(2-trifluoromethylphenyl)-2,5-dihydro-1H-pyrrole and N, N-dibenzylformamide is used to prepare the present compound. IR (KBr): 3078, 2865, 2834, 1598, 1532, 1456, 1378, 100 200813011 1320, 1232, 1189, 1132, 1079, 102 906, 803 cm; W-NMR GOOMHz, DMSO-d6): 5 1. 41(s, 2H), 1. 96(s, 1H), 3. 05(d, 2H, J=9. 0Hz), 3. 17(d, 2H, J=9. 0Hz), 3. 61(s, 4H), 7. 12 (m, 1H), 7. 27-7. 34 (m, 11H), 7. 52 (m, 2H). 5 Step 3 ·· 3-[2-Trifluoromethylphenyl]-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 a,5 a,6a-third butyl ester was prepared by the same method as described in Step 3 of Example 7 from 1 α, 5 α, 6 α -Ν , Ν-di-benzyl-3-(2-trifluoromethylphenyl)-3-azabicyclo[3. 1. 0] Hex-6-amine is a cost compound. 10 IR(KBr): 3335, 3198, 2833, 2866, 1654, 1577, 1522, 1455, 1373, 1332, 1212, 1193, 1016, 1021, 916, 821 cm-1; iH-NMRpOOMI^DMSO-dAinJSb^H ),1. 75(s, 2H), 2. 25(s,1H), 2. 90 (d, 2H, J = 9. 0Hz), 3. 54 (d, 2H, J = 9. 0Hz), 6. 70 (d, 2H), 6. 99 (m, 2H). 15 Step 4 ··· 1 a,5a,6a-[6-(5-isoindolinylaminocarboxylamido)-3-(2-trifluoromethyl)phenyl]azabicyclo[3. L0]Hexane was prepared from 3-[2-trifluoromethylphenyl]-3-azabicyclo[3.] by the same procedure as described in Step 4 of Example 7. 1. 0] Hex-6-ylaminocarbamic acid 1 〇:, 5«, 6^:-tri-butyl ester and phenyl isoindoline-5-ylaminocarbamate were prepared into the present compound. 20 IR(KBr): 3358, 3264, 1650, 1604, 1556, 1496, 1476, 1496, 1357, 1239, 1210, 1138, 1097, 1033, 962, 826 cm 1 ; ^-NMRPOOMHz, DMSO-d6): δ 1. 77(s, 2H), 2. 81(s, 1H), 3. 26(d, 2H, J=9. 0Hz), 3. 35 (d, 2H, J = 9. 0Hz), 6. 80 (m, 1H), 7. 21(t, 2H), 7. 41 (d, 1H), 7. 60 (m, 3H), 7. 74(d,1H), 101 200813011 7. 89 (d, 1H), 8. 25 (d, 1H), 8. 53 (d, 1H), 8. 59(s,1H), 9. 27(s, 1H); melting point 165 to 167 °C. Example 26: 1α,5α,6α·丨6-(5-iso-4-linylamine, a carboxy fluorene face, a certain fluorine-(5-trifluoromethyl) phenyl 1丨-3-azaindene "3. 1. 01 hexane (compound No. 26) 5 Process step 1 · 1-[2-type-(5-trifluoromethyl)phenyl]-2,5-dihydro-1H-pyrrole The present compound was prepared from Intermediate 5 and 2-fluoro-5-(trifluoromethyl)aniline by the same procedure as described in Step 1 of 7. IR (KBr): 3021, 2987, 2898, 2843, 1632, 1576, 1545, 10 1436, 1333, 1345, 1230, 1257, 1167, 1060, 1053, 996, 820 cm 1 ; b-NMR pOOMHz, CDC13): ( 5 4. 28(s, 4H), 6. 33(s, 2H), 6. 84 (d, 2H, J = 9. 0Hz), 6. 97 (d, 1H, J = 9. 0Hz), 7. 68 (s, 1H). Step 2 · Ί a, 5 a, 6 aN, N-dibenzyl-3-[2-fluoro-(5-trifluoromethyl)phenyl]-3-azabicyclo[3·1·0] Process for the preparation of -6-amine 15 by the same procedure as described in Step 2 of Example 7 from 1-[2-fluoro-(5-trifluoromethyl)phenyl]-2,5-dihydro-1?- Pyrrole and hydrazine, hydrazine dibenzylcarbamide are used to prepare the present compound. IR (KBr): 3098, 2834, 2878, 1545, 1520, 1460, 1319, 1302, 1205, 1145, 119, 1058, 1048, 929, 840 cm -1 ; 20 W-NMR 44(s, 2H), 1. 65(s, 1H), 3. 07(d, 2H, J=9. 〇Hz), 3. 41 (d, 2H, J = 9. 0Hz), 3. 62(s, 4H), 6. 45 (m, 2H), 6. 88 (m, 1H), 7. 26-7. 35 (m, 10H). Step 3 ·· 3-[2-Fluoro-(5-trifluoromethyl)phenyl]-3-azabicyclo[3. 1. 0] Process for the preparation of 1 a, 5 a, 6 a-tri-butyl ester of hex-6-ylaminocarbamate 102 200813011 From 1α, 5α, 6α -Ν by the same method as described in Step 3 of Example 7. , Ν_dibenzylfluoro-(5-trifluoromethyl)phenyl]-3-azabicyclo[3. 1. 0] -6-amine is made into the present compound. IR (KBr) · · 3334, 3178, 2843, 2856, 1639, 1565, 1520, 5 1416, 1354, 1332, 1296, 1186, 1043, 1021, 916, 842 cm "; 1H-NMR (300MHz, DMSO-d6 ): 51. 23(s,9H), 2. 27(s, 2H), 2. 58(s, 1H), 3. 36(d, 2H, J=9. 0Hz), 3. 77(d, 2H, J=9. 0Hz), 6. 95(s, 1H), 7. 44-7. 58 (m, 2H). Step 4 ··· 1 a,5 a,6a-{6-(5-isoindolylaminocarbamoylamino)-3-[2-fluoro-(5-1-trifluoromethyl)phenyl] }_3·Azabicyclo[3,1·0]hexane was prepared from 3-[2-fluoro-(5-trifluoromethyl)phenyl] by the same method as described in Step 4 of Example 7. -3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 〇:, 5 〇!, 6 〇: -T-butyl ester and phenyl isoindoline-5-ylaminocarbamate were prepared into the present compound. IR (KBr): 3365, 3291, 1650, 1579, 1523, 1483, 1437, 15 1360, 1292, 1253, 1211, 1112, 1082, 992, 816 cm-1; b-NMRGOOMHz, DMSO-d6): ά 1 . 88(s, 2H), 2. 56(s, 1H), 3. 40 (d, 2H, J = 9. 0Hz), 3. 78(d, 2H, J=9. 0Hz), 6. 87-6. 95 (m, 2H), 7. 05(d, 1H), 7. 24 (m, 1H), 7. 60(t,1H), 7. 75 (d, 1H), 7. 88 (d, 1H), 8. 22 (d, 1H), 8. 53 (d, 1H), 8. 60 (s, 1H), 9. 27 (s, 20 1H); melting point 230 to 232 ° C. Example 27: 1 〇;,5〇;,6〇;-丨6-(5-isoquinolinylaminocarboxamido)-3-"2-1-(4-trifluoromethyl)benzene Base 1丨-3-azaindole ring "3. 1. Process for the preparation of 01 hexane (No. 27) 1. Preparation method of 1-[2-fluoro-4-difluoromethoxyphenyl]-2,5-dihydro-1H-pyrrole 103 200813011 By example 7 The present compound was prepared from the intermediate product 5 and 2-fluoro-4-(difluoromethoxy)aniline in the same manner as described in the step 1. IR (KBr): 3034, 2955, 2878, 2889, 1634, 1567, 1523, 1467, 1334, 1398, 1254, 1267, 1109, 1007, 1045, 997, 5 818 cm -1 ; i-NMR pOOMHz, CDC13): 5 4. 26(s, 4H), 6. 29(s, 2H), 6. 84 (m, lH), 6. 97 (m, lH), 7. 1 (t, 1H, J = 72Hz), 7. 68 (s, 1H). Step 2: 1 a,5 〇^,6〇;-:^,:^-dibenzyl-3-[2-fluoro-4-(difluorodecyloxy)phenyl]oxazabicyclo[3· 1. 0] Hex-6-amine was prepared by the same method as described in Step 2 of Example 7 from 1-(2-fluoro-4-10-difluoromethoxyphenyl]-2,5-dihydro-1H. - Pyrrole and N,N-dibenzylformamide to prepare the compound. IR (KBr): 3058, 2821, 2865, 1543, 1510, 1443, 1313, 1204, 112, 1104, 1078, 102, 909, 850 cm -1 ; W-NMR 1. 44(s, 2H), 1. 65(s, 1H), 3. 05(d, 2H, J=9. 0Hz), 3. 44(d, 2H, 15 J=9. 0Hz), 3. 63(s, 4H), 6. 48 (m, 2H), 6. 59 (m, lH), 7. 11 (t, 1H, J = 72Hz), 7. 28-7. 37 (m, 10H). Step 3 ·· 3-[2-Fluoro-4-(difluoromethoxy)phenyl]-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 a,5 a,6 a-third-butyl ester was prepared by the same method as described in Step 3 of Example 7 from Ια, 5α, 6α 20 -Ν, Ν-Dibenzyl-3_[2-fluoro-4-(difluoromethoxy)phenyl]-3-azabicyclo[3. 1. 0] Hex-6-amine is made into the present compound. IR (KBr): 3334, 3125, 2843, 2855, 1623, 1566, 1522, 1417, 1358, 1333, 1296, 1172, 1047, 10232, 917, 889 cm 1 ; W-NMR pOOMHz, DMSO-d6): 5 1 . 25(s,9H), 2. 28(s, 104 200813011 2H), 2. 54(s, 1H), 3. 37(d, 2H, J=9. 0Hz), 3. 78(d, 2H, J=9. 0Hz), 6. 88(s,1H), 7. 10(t, 1H, J=72. 0Hz), 7. 45-7. 59 (m, 2H). Step 4: 1 a,5 a,6 a-{6-(5-isoindolylaminocarbamoylamino)-3-[2-fluoro-(4-difluoromethoxy)phenyl]} -3-azabicyclo[3·1. 0] Method for the preparation of hexane 5 from 3-[2-fluoro-4-(difluoromethoxy)phenyl]-3-azabicyclo[3.] in the same manner as described in Step 4 of Example 7. 1. 0] Hex-6-ylaminocarbamic acid 1 α,5 α,6 α-tris-butyl ester and phenyl isoindoline-5-ylaminocarbamate were prepared into the present compound. IR (KBr〇: 3364, 3292, 3108, 2978, 2958, 2910, 2856, 1650, 1579, 1518, 1482, 1387, 1360, 1327, 1252, 1224, 10 1135, 1100, 1062, 976, 828 cm -1 ; W-NMRpOOMHz, DMSO-d6): δ 1. 84(s? 2H), 2. 60 (s, 1H), 3. 53(d, 2H, J=9. 0Hz), 3. 69 (d, 2H, J = 9. 0Hz), 6. 75-6. 87 (m, 3H), 7. 02(t, 1H, J=72. 0Hz), 7. 08(s, 1H), 7. 60(t,1H), 7. 75 (d, 1H), 7. 90 (d, 1H), 8. 23 (d, 1H), 8. 55 (d, 1H), 8. 61(s, 1H), 9. 27(s,1H); 15 Melting point is 201 to 203 °C. Example 28: Ιο; . 5α. 6 α iso 4 oxo, amino-aminocarboxylamido)-3-(2,3,4-trifluoro) phenyl 1-1-3 azabicycloindole 3. 1. Process for the preparation of 01 hexane (compound No. 28) 1 · 1-(2,3,4-trifluorophenyl)-2,5-dihydro-1H-pyrrole is produced in the first step of Example 7 The present compound was prepared in the same manner from the intermediate product 5 20 and 2,3,4-trifluoroaniline. IR (KBr): 3045, 2978, 2899, 2886, 1675, 1532, 1578, 1445, 1399, 1223, 1267, 1123, 1045, 1078, 999, 823 cm 1 ; W-NMR pOOMHz, CDC13): 4. 24(s,4H), 5. 91(s, 2H), 6. 17 (m, 1H), 6. 75 (m, 1H). 105 200813011 Step 2: 1 a,5 a,6a-N,N-dibenzyl-3-(2,3,4-trifluorophenyl)-3-azabicyclo[3. 1. 0] Hex-6-amine was prepared by the same method as described in Step 2 of Example 7 from 1-(2,3,4-trifluorophenyl)-2,5-dihydrololine and N,N. - Dibenzylcarbamide is made into the present compound. 5 IR (KBr): 3089, 2876, 2843, 1592, 1518, 1445, 1319, 1204, 1178, 1144, 1010, 1008, 949, 812 cm-1; iH-NMR (300 MHz, DMSO_d6): 5 1. 46(s, 2H), 1. 69(s, 1H), 3. 12(d, 2H, J=9. 0Hz), 3. 42 (d, 2H, J = 9. 0Hz), 3. 63(s, 4H), 6. 45 (m, 1H), 7. 05 (m, 1H), 7. 27-7. 38 (m, 10H). 10Step 3: 3-(2,3-Trifluorophenyl)-3-azabicyclo[3·1·0]hex-6-ylaminocarboxylic acid 1 α,5 α,6α-T-butyl ester The preparation method is the same as the method described in the step 3 of Example 7 from 1α, 5α, 6α -Ν, Ν-dibenzyl_3-(2,3,4-trifluorophenyl)·3_aza Double loop [3. 1. 0] hex-6-amine manufactured by cost compound. 15 IR(KBr): 3334, 3187, 2840, 2833, 1671, 1546, 1589, 1435, 1389, 1332, 1227, 1178, 1043, 1021, 967, 832 cm-1; iH-NMRGOOMHz'DMSO-dAdlJSCs^H ),1. 62(s, 2H), 2. 50 (s, 1H), 3. 37(d, 2H, J=9. 0Hz), 3_45 (d, 2H, J=9. 0Hz), 6. 95-7. 06 (m, 2H). 20Step 4: 1α,5α,6α·[6-(5-isoindolinylaminocarbamoylamino)-3-(2,3,4-dimer)phenyl]-3-azabicyclo[ 3丄〇]Hexane was prepared from 3-(2,3,4-trifluorophenyl)-3-azabicyclo[3丄〇]hexylamine by the same method as described in Step 4 of Example 7. The present compound is prepared from carboxylic acid 1 ^, 5 α, 6 α -tri-butyl ester and isoporphyrin _5-ylamino decanoic acid phenyl ester. 106 200813011 IR (KBr): 3292, 2869, 1650, 1519, 158 Bu 1496, 1363, 1284, 1253, 1187, 1154, 1048, 1008, 827 cm. 1 ; iH-NMRpOOMHz, DMSO-d6): 5 1. 86(s, 2H), 2. 57(s, 1H), 3. 34(d, 2H, J=9. 0Hz), 3. 70 (d, 2H, J = 9. 0Hz), 6. 56 (m, 1H), 5 6. 86(s, 1H), 7. 11 (m, 1H), 7. 58(t, 1H), 7. 75 (d, 1H), 7. 88(d, 1H), 8. 22 (d, 1H), 8. 53 (d, 1H), 8. 61(s, 1H), 9. 27 (s, 1H); melting point 207 ° C.

Example 29: 1 〇;, 5 〇;, 6 〇; - "6-(5-iso-n-hydroxyl-ylaminocarboxamide)&gt;)-3-(^4,6·trifluoro) awkward 1 -3-氤 譬 ring [3. 1. 01 hexane (No. 29 compound 彳 _ method 10 step 1 · l-(2,4,6-di-phenyl)-2,5-diazepine is produced as described in step 1 of Example 7. In the same manner, the present compound was prepared from the intermediate product 5 and 2,4,6-trifluoroaniline. IR (KBr): 3056, 2977, 2856, 2870, 1634, 1544, 1590, 1434, 1356, 1278, 1234, 1120 , 1078, 1034, 990, 825 15 cm "; b-NMRpOOMHz, CDC13): 5 4. 28(s, 4H), 5. 87(s, 2H), 6. 59_6. 65 (m, 2H). Step 2: 1〇:,5〇;,6〇;-沁沁Benzyl-3-(2,4,6-trifluorophenyl)-3-azabicyclo[3·1·0]- The 6-amine was prepared by the same method as described in Step 2 of Example 7 from 1-(2,4,6·trifluoro 20 phenyl)-2,5-dihydro-1 Η-pyrrole and hydrazine, hydrazine. - Dibenzylcarbamide is made into the present compound. IR (KBr): 3055, 2893, 2821, 1554, 1518, 1389, 1278, 1121, 1146, 1099, 1034, 956, 810 cm "; Α-ΝΜΚ^ΟΟΜΗζ, DMSO-d6): 5 1. 45 (s? 2H), 1. 68(s, 1H), 3. 11 (d, 2H, J = 9. 0Hz), 3. 42 (d, 2H, J = 9. 0Hz), 3. 62(s, 4H), 6. 48 (m, 1H), 107 200813011 7_07 (m, 1H), 7. 28-7. 39 (m, 10H). Step 3: 3-(2,4,6-trifluorophenyl)-3-azabicyclo[3. 1. 0] hexa-6-ylaminocarbamic acid 1 a,5 a,6 a-third-butyl ester was prepared by the same method as described in Step 3 of Example 7 from 1α, 5α, 6α 5 -Ν, Ν-dibenzyl each (2,3,4-trifluorophenyl)-3-azabicyclo[3. 1. 0] hex-6-amine manufactured by cost compound. IR (KBr): 3332, 312, 2856, 2824, 1679, 1565, 1523, 1416, 1357, 1333, 1298, 1177, 1042, 1026, 919, 883 cm 1 ; iH-NMR (300 MHz, DMSO-d6): δ 1. 39(s, 9H), 1. 65(s, 10 2H), 2. 53(s,lH), 3. 39(d, 2H, J=9. 0Hz), 3. 46(d, 2H, J=9. 0Hz), 6. 97-7. 05 (m, 2H). Step 4: 1 a,5 a,6a-[6-(5-isoindolinylaminocarboxylamido)-3-(2,4,6-trifluoro)phenyl]-3-azabicyclo [3·1·〇] hexane was prepared by the same method as described in Step 4 of Example 7 from 3·(2,4,6-trifluoro15phenyl)·3·azabicyclo[3丄0] hex-6-ylaminocarbamic acid 1 hydrazine; 561:, 6 fluorene: -tris-butyl ester and phenyl isoindoline-5-ylaminocarbamate were prepared as the present compound. IR (KBr): 3364, 3297, 3122, 3067, 2914, 2855, 1650, 1586, 1517, 1484, 1387, 1346, 1329, 1358, 1254, 1211, 1176, 1025, 916, 828 cm 1 ; ^ΟΟΜΗζ, DMSO-d6): 20 5 1. 76(s, 2H), 2. 72(s,lH), 3. 16(d, 2H, J=9. 0Hz), 3. 44(d, 2H, J=9. 0Hz), 6. 81 (m, 2H), 7. 13(t, 2H), 7. 60(t,1H), 7. 74(d, 1H), 7. 88 (d, 1H), 8. 23 (d, 1H), 8. 53 (d, 1H), 8. 60 (s, 1H), 9. 27 (s, 1H); melting point I79 °c. Example 30: Ια,5 αisomorpholinylcarbamoylamino)-3-(2,3-di 108 200813011 1)phenyl 1-3-azabicyclo "3. 1. Process for the preparation of 01 hexane (No. 30) Step 1 · 1-(2,3-Trifluorophenyl)-2,5-dihydro-1H-pyrrole is prepared as described in Step 1 of Example 7. In the same manner, the present compound was prepared from the intermediate product 5 and 2,3-trifluoroaniline. 5 IR (KBr): 3066, 2978, 2889, 2856, 1689, 1544, 1590, 1434, 1329, 1249, 1269, 1127, 1044, 1078, 995, 827 cm 1 ; iH-NMR GOOMHz, CDC13) J4. 21(s, 4H), 5. 90(s, 2H), 6. 72 (m, 1H), 6. 78-6. 92 (m, 2H). Step 2: 1 a. 5 a,6a-N,N-dibenzyl-3-(2. 3-Trifluorophenyl)-3-azabicyclo 10 [3·1·0]hex-6-amine was prepared by the same method as described in Step 2 of Example 7 from 1-(2,3-di) The present compound is prepared from fluorophenyl)-2,5-dihydro-1H-pyrrole and N,N-dibenzylformamide. IR (KBr): 3077, 2889, 2832, 1678, 1555, 1467, 1373, 1331, 1256, 1183, 1125, 1060, 10H, 945, 822 cm-1; 15 i-NMRpOOMHz, DMSO-d6): 5 1 . 42(s, 2H), 1. 75(s, 1H), 3. 07(d, 2H, J=9. 0Hz), 3. 44 (d, 2H, J = 9. 0Hz), 3. 63(s, 4H), 6. 68 (m, lH), 6. 89 (m, lH), 7. 09 (m, lH), 7. 28-7. 36 (m, 10H). Step 3: 3-(2,3-Difluorophenyl)-3-azabicyclo[3. 1. 0] hexa-6-ylaminocarbamic acid 1 a,5 a,6a-tri-butyl ester 20 by the same method as described in step 3 of Example 7 from 1 α, 5 α, 6 α - Ν,Ν-dibenzyl-3-(2,3-difluorophenyl)-3-azabicyclo[3. 1. 0] hex-6-amine is made into the present compound. IR (KBr): 3356, 3134, 2867, 2823, 1698, 1545, 1534, 1478, 1335, 1367, 1265, 1134, 1056, 1067, 989, 808 109 200813011 cm 1 ; iH-NMR pOOMHz, DMSO-d6): 5 1. 34(s, 9H), 1. 66(s, 2H), 2. 43(s,lH), 3. 16(d, 2H, J=9. 0Hz), 3. 53 (d, 2H, J = 9. 0Hz), 6. 96 (m, 1H), 7. 27(s,1H), 7. 47 (s, 1H). Step 4: la,5a,6a-[6-(5-isoindolinylaminocarbamoylamino)-3-(2,3-di-5fluoro)phenyl]-3.azabicyclo[3· 1. 0] hexane was prepared by the same method as described in Step 4 of Example 7 from 3-(2,3-difluorophenyl)-3.azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 〇:, 56^, 6〇:-tri-butyl ester and iso-porphyrin-5-ylamino decanoic acid phenyl ester were prepared into the present compound. IR (KBr): 3296, 3066, 2965, 2870, 1640, 1582, 1512, 10 1475, 1463, 1363, 1327, 1259, 1187, 1073, 910, 822 cm 1 ; h-NMRpOOMHz, DMSO-d6): 51 . 87(s, 2H), 2. 27(s, 1H), 3. 29(d, 2H, J=9. 0Hz), 3. 74 (d, 2H, J = 9. 0Hz), 6. 56(t, 1H), 6. 68(t,1H), 6. 87(s, 1H), 6. 97 (m, 1H), 7. 58(t,1H), 7. 75 (d, 1H), 7. 88 (d, 1H), 8. 22 (d, 1H), 8. 53 (d, 1H), 8. 62(s, 15 1H), 9. 28 (s, 1H); melting point 212 ° C. Example 31: 1α, 5α. 6α J6_(5-isoindolinylamine, a certain carboxyamino)-3-(2-fluoro-4-methylphenyl)-3-indole ring "3. 1. Process for the preparation of 01 hexane (compound No. 31) Step 1 · 1-(2-Ga-4-methylphenyl)-2,5-dihydro-1H-pyrrole is produced in the first step of Example 7 The present compound was prepared in the same manner from the intermediate product 5 20 and 2-fluoro-4-methylaniline. IR (KBr) cm -1 : 3034, 2999, 2845, 2878, 1645, 1578, 1532, 1412, 1334, 1255, 1236, 1123, 1067, 1035, 992, 816 cm 1 ; h-NMROOOMHz, CDC13): 2 . 20(s,3H), 4. 20(s, 4H), 5. 95(s, 2H), 6. 70 (m, 1H), 6. 78(s,1H), 6. 98 (m, 1H). 110 200813011 Step 2 · · 1 a, 5 a, 6a-N, N-dibenzyl-3-(2-fluoro-4-methylphenyl) azabicyclo[3. 1. 0] hex-6-amine was prepared by the same method as described in Step 2 of Example 7 from 1-(2-fluoro-4-methylphenyl)-2,5-dihydro-1H-pyrrole and N,N-dibenzylformamide is made into the present compound. IR (KBr): 3076, 2883, 2812, 1677, 1532, 1456, 1378, 1323, 1265, 1134, 1165, 1069, 1056, 944, 826 cm-1; h-NMRpOOMHz, DMSO-d6): (51. 42(s, 2H), 1. 72(s, 1H), 2. 17(s, 3H), 3. 10(d, 2H, J=9. 0Hz), 3. 52(d, 2H, J=9. 0Hz), 10 3. 63(s, 4H), 6. 46 (d, 1H), 7. 27-7. 38 (m, 12H). Step 3: 3-(2-Fluoro-4-indolylphenyl)-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 a,5 a,6 a-third-buty_ is produced by the same method as described in Step 3 of Example 7 from Ια, 5α, 6α -Ν, Ν -Bisyl-3(2-carb-4-methylphenyl)-3-azabicyclo[3. 1. 0] Hex-6-amine 15 is a cost compound. IR (KBr): 3378, 3156, 2889, 2867, 1645, 1578, 1534, 1478, 1334, 1378, 1278, 1145, 1067, 1067, 934, 832 cm "; i-NMR pOOMHz, DMSO-d6): 6 1 . 24(s,9H), 2. 27(s, 2H), 2. 58(s,1H), 2. 67(s,3H), 3. 34(d, 2H, J=9. 0Hz), 3. 69(d, 20 2H, J=9. 0Hz), 6. 95(s, 1H), 7. 44-7. 58 (m, 2H). Step 4 ···1 a,5 a,6a-[6-(5-isoindolinylaminocarbamoylamino)-3-(2-fluoro-4-methylphenyl)phenyl] aza The bicyclo[3·1·0] calcined process was carried out by the same method as described in Step 4 of Example 7 from 3-(2-fluoro-4-methylphenyl)-3-azabicyclo[3丄0 Benzene-6-ylaminocarbamic acid 1 〇;, 5 (2,6 〇:-third 111 200813011 - butyl ester and phenyl isoindoline-5-ylaminocarbamate to prepare the present compound. IR (KBr): 329 335 234 3107, 2916, 2858, 1649, 158, 1519, 1483, 1359, 1327, 1253, 1140, 1170, 1117, 1033, 1061, 967, 854 cm Ά-ΝΜΙΐρΟΟΜΗζ, DMSO-d6): 5 1. 81(s, 5 2H), 2. 19(s,3H), 2. 63(s, 1H), 3. 20 (d, 2H, J = 9. 0Hz), 3. 67(d, 2H, J=9. 0Hz), 6. 65(t, 1H), 6. 84-6. 91 (m, 3H), 7. 60(t,1H), 7. 74 (d, 1H), 7. 88 (d, 1H), 8. 22 (d, 1H), 8. 53 (d, 1H), 8. 59(s, 1H), 9. 27 (s, 1H); melting point 218 ° C. Example 32 : 1 a . 5 a , 6 a isoquinolinylaminocarboxylamido)-3-(2-isopropyl 10 -yl)phenyl 1-3_indole bicyclic "3. 1. Process for the preparation of 01 hexane (Compound No. 32) Step 1: The method of 1-(2-isopropyl)-2,5-dihydro-1H-pyrrole is carried out by the same method as described in Step 1 of Example 7. The present compound was prepared from the intermediate product 5 and 2-isopropylaniline. IR (KBr) · · 3025, 2899, 2854, 1598, 1535, 1477, 1374, 15 1338, 1269, 1163, 1075, 1027, 919, 817 cm -1 ; h-NMRpOOMHz, CDC13): 5 1. 21(s,6H), 2. 83 (m, lH), 4. 09(s, 4H), 5. 94(s, 4H), 6. 48(d, 2H, J=9. 0Hz), 7. 04(d, 2H, J=8. 7 Hz) 〇 Step 2: 1 a, 5 a, 6 a-N, N-dibenzyl-3-(2-isopropylphenyl)-3-azabicyclo 20 [3. 1. 0] hex-6-amine was prepared by the same method as described in Step 2 of Example 7, from 1-(2-isopropyl)-2,5-dihydro-111-0 ratio and N, The N-dibasic base amine is used to prepare the present compound. IR (KBr): 3055, 2890, 2850, 1589, 1527, 1460, 1344, 1336, 1269, 1154, 1114, 1092, 1000, 905, 815 cm -1 ; 112 200813011 i-NMRpOOMHz, DMSO-d6"5 1 . 29(s,6H), 1. 42 (s, 1H), 1. 50(s, 2H), 1. 70 (s, 1H), 3. 08 (d, 2H, J = 9. 0Hz), 3. 34(d, 2H, J=9. 0Hz), 3. 66(s, 4H), 6. 43(d, 2H), 7. 2-7. 36 (m, 12H). 'Step 3: 3-(2-isopropylphenyl)-3-azabicyclo[3丄0]hex-6-ylaminocarbamic acid 5 1 a,5 a,6 a-third-butyl ester By the same method as described in Step 3 of Example 7, from 1 α,5 α,6 α -Ν,Ν-dibenzyl-3-(2-isopropylphenyl)-3-azabicyclo[ 3. 1. 0] The amine is made into the present compound. '' IR (KBi〇: 3377, 3177, 2887, 2843, 1665, 1578, 1523, 10 1454, 132, 131, 1256, 1198, 1132, 1054, 102, 902, 809 cm 1 ; W-NMR pOOMHz, DMSO- D6): 5 1. 29(s,6H), 1. 37(s,9H), 1. 42(s,lH), 2. 24(s, 2H), 2. 54(s,lH), 3. 25(d, 2H, J=9. 0Hz), 3. 69 (d, 2H, J = 9. 0Hz), 6. 66 (m, 2H), 7. 24 (m, 2H). Step 4: 1 a,5 a,6a-[6-(5-isoindolinylaminocarbamoylamino)-3-(2-isopropyl15-yl)phenyl]-norazabicyclo[3·1 The process of hexane was prepared from 3-(2-isopropyl V 1 phenyl)·3-azabicyclo[3.] by the same method as described in Step 4 of Example 7. 1. 0] Hex-6-ylaminocarbamic acid 1 α,5 α,6 α -Terti-, D-S and 异: Lin-5-ylamino phenyl vinegar to prepare the present compound. IR (KBr): 3345, 3265, 1689, 1634, 1580, 1534, 1478, 20 1456, 1345, 1290, 1227, 1134, 1167, 1045, 966, 827 cm-1; iH-NMRpOOMHz, DMSO-d6): (H. 09 (m, 1H), 1. 15(d, 6H, J=6. 6Hz), 1. 73(s, 2H), 2. 97(s,1H), 3. 10(d, 2H, J=9. 0Hz), 3. 24(d, 2H, J=9. 0Hz), 6. 08(s, 1H), 7. 04-7. 13 (m, 3H), 7. 22 (d, 2H, J = 8. 1Hz), 7. 57(t, 1H, J=9. 0Hz), 7. 74(d,1H, 113 200813011 J=9. 0Hz), 7. 89 (d, 1H, J = 9. 0Hz), 8. 25 (d, 1H, J = 9. 0Hz), 8. 53(d, 2H, J=9. 0Hz), 8. 60 (s, 1H), 9. 27 (s, 1H); melting point 195 ° C. Example 33: la,5 a,6 a 46-(5-iso-4-oxanylaminocarbamoylamino)-3-(3. 5-Di-I pen base) 1 method for preparing each doped bicyclo "3·1·01 hexane [Compound No. 33] 5 Step 1 ·· 1-(3,5-difluorophenyl)-2,5- The present invention was prepared from the intermediate product 5 and 3,5-difluoroaniline by the same procedure as described in Step 1 of Example 7. IR (KBr) (cm - 1): 3361, 1673, 1525, 1166, 948, 843; ^-NMRCCDCls): δ 4. 06(4H? s); 5. 94 (2H? s); 5. 92-6. 20 (2H, 10 m); 6·96-7·20 (1Η, m). Step 2 ··· 1 a,5 a,6 aN,N-dibenzyl-3_(3,5-difluorophenyl)oxazabicyclo[3·1·0]hex-6-amine is produced by The compound was prepared from i. (3,5-difluorophenyl)-2,5-dihydro-1H-pyrrole and N,N-dibenzylformamide according to the same procedure as described in Step 2 of Example 7. . 15 1h_NMR(CDC13): 5 1·40-1·44(2Η,m) ; 1·88-1·92(1Η, m); 3·08(2Η,d,J=9. 3Hz) ; 3·48(2Η,d,J=9. 0Hz) ; 3·67(4Η, s); 5·92-6·20(2Η,m); 96-7·20 (1Η, m); 7·20-7·30 (10Η, m). Step 3 · 3-(3,5-Difluorophenyl)_3-azabicyclo[3·1·0]hexylaminocarbamic acid 1 α,5 α,6α-T-butyl ester 2 By the same method as described in Step 3 of Example 7, from 1 a, 5 a, 6 a -N,N-dibenzyl-3·(3,5-dioxyphenyl)-3-nitrogen This compound is prepared from heterobicyclo[3·1·〇]hex-6-amine. IR (KBr) (cm-1): 3361, 1673, 1525, 1166, 948, 843; 'H-NMRCCDCls): 5 1. 46(9H? s); 1·84-1·90(2Η,m); 114 200813011 2·38·2·41(1Η,m) ; 3·30(2Η,d,J=8. 1Hz) ; 3·54(2Η,d, J=9. 1 Hz); 4·70-4·80 (1Η, m); 6·08·6·20 (1Η, m); 7·24-7·44 (2Η, m). Step 4: 1〇:,5〇;,6〇:-[6-(5-isoindolylaminocarbamoylamino)-3-(3,5-di-5fluorophenyl)] aza Double loop [3. 1. 0] The method of burning was carried out by the same method as described in Step 4 of Example 7 from 3-(3,5-difluorophenyl)-3-azabicyclo[3. 1. 0] Hex-6-ylaminocarbamic acid 1 α , 5 α, 6 «-tris-butyl ester and phenyl isoindoline-5-ylaminocarbamate were prepared into the present compound. IR (KBr) (/l m-1): 3308, 1638, 1578, 1567, 1211, 811; 10 ^-NMRCSOOMHz, DMSO-d6): δ 1. 90-1. 98 (2H5 m); 2. 40-2·48(1Η,m) ; 3·28-3·40(2Η,m) ; 3·58(2Η,d,J=9. 0Hz); 6·18-6·40(3Η,m); 6·90(1Η,s); 7·61(1Η,t,J=7. 5Hz); 7·77(1Η, d, J=7. 8Hz) ; 7·90(1Η,d,J=5. 7Hz) ; 8·23(1Η,d,J=7. 8Hz); 8. 54(1H,d,J=6. 0Hz) ; 8·63(1Η, s) ; 28(1H,s) ; m/z(M++l): 15 381. 36; melting point of 206 to 208 ° C. Example 34: 1 〇;, 5 〇;, 6 〇; - "6-(5-isoindolyl 铋8 gas face base) _3-(2 children 5-trifluorophenyl) 1-3 noisy Double-ring "3·1·01 hexane (No. 34 hydrazine) less y 氺 Step 1: 1-(2,4,5-trifluorophenyl)-2,5-dihydro-1H-pyrrole The compound was prepared from the intermediate 5 20 and 2,4,5-trifluoroaniline by the same procedure as described in Step 1 of Example 7. IR (KBr) (cm -1): 3361, 1673, 1525, 1166 , 948, 843; lU^MR(COCh): 6 4. 23(4U, s); 5. 90 (2H? s); 6. 30-6. 42 (1Η? m); 6·80-6·92 (1Η, m). Step 2 ··· 1 a,5 α,6α-Ν,Ν·dibenzyl-3-(2,4,5-trifluorophenyl)ungazinium double 115 200813011 Ring [3丄〇]hex-6- The amine was prepared by the same method as described in Step 2 of Example 7 from 1-(2,4,5-trifluorophenyl)-2,5-dihydro-1H-pyrrole and N,N-dibenzyl. Formamide is made into the present compound. ^-NMRCCDCls): 5 1. 40-1. 44(2H5 m) ; 1. 88-1. 92(1H5 m); 5 3·08(2Η,d,J=9. 3Hz) ; 3·48(2Η,d,J=9. 0Hz) ; 3·67(4Η, s); 6·30-6·42(1Η,m) ; 6·80·7·92(1Η,m) ; 7·20·7·30(10Η,m) . Step 3: 3-(2,4,5-trifluorophenyl) azabicyclo[3丄0]hex-6-ylaminocarbamic acid 1 a,5 a,6a-third-butyl ester The same procedure as described in Step 3 of Example 7 was carried out from 1α,5α,6α 10 -Ν,Ν-dibenzyl-3-(2,4,5-trioxyphenyl)-3-azabicyclo[ 3·1·0]hex-6-amine is made into the present compound. IR (KBr) (cm force: 3364, 1672, 1528, 1245, 118, 1163, 870; ^-NMRCCDCls): (5 1. 46(9H, s); 1. 72-1. 82(2H5 m); 2·52-2·61(1Η,m) ; 3·25(2Η, d, J=9. 0Hz) ; 3·73(2Η,d, 15 J=8. 7Hz); 4. 72 (1H? S); 6. 32-6. 48 (lH? m); 7. 78-6. 92(1H, m) 〇Step 4: la,5a,6a-[6-(5-isoindolylaminocarbamoylamino)-3-(2,4,5-trifluorophenyl)] winter The azabicyclo[3·1·0]hexane was prepared by the same method as described in Step 4 of Example 7 from 3-(2,4,5-trifluorophenyl)-3-azabicyclo[ 3·1·0]hex-6-ylaminocarboxylic acid 1 〇:,5〇:,6〇:-third-2 butyl butyl ester and phenyl isoquinolin-5-ylaminocarbamate are prepared into the present compound. ^-NMRiBOOMHz, DMSO-d6): δ 1. 82-1. 90 (2H? m); 2. 55-2·61(1Η,m) ; 3·30(2Η,d,J=8. 4Hz) ; 3·70(2Η,d,J=7. 8Hz); 6·78·6·90(1Η,m) ; 6·86(1Η,s); 7. 34-7. 48(lH,m) ; 7·61(1Η,t, J=7. 5Hz) ; 7·76(1Η,d,J=7. 8Hz) ; 7·90(1Η,d,J=6. 0Hz); 116 200813011 8·24(1Η,d,J=7. 5Hz) ; 8·54(1Η,d,J=6. 3Hz) ; 8·62(1Η, s); 9·28(1Η, s) ; IR(KBr)(cm_1) : 3306, 1635, 1589, 1528, 1178, 822 ; m/z (M++ l) : 399. 31; melting point 227 to 229 ° C. Example 35: 1 α,5α,6α·“6_(5·isoindolylamine carboxycarboximine)-3-(2. 4-二 5 fluorophenyl)1-3-azabicyclo "3. 1 · 〇1 hexane trifluoroacetate f箆35 compound, the method of adding trifluoroacetic acid (1 mmol) to 1 α,5 α,6 α -[6·(5-iso) at 0 °C Quinolinylaminocarboxylamido)-3-(2,4-didenyl)phenyl]_3-azabicyclo[3. 1. Hexane (1 mmol) (Example 21) was stirred well in dichloromethane (10 mL) and stirred at room temperature for 12 hr. The residue obtained after removing the solvent was wet-milled with diethyl ether and dried to give the product. IR (KBr) 3380, 1646, 1579, 1515, 1202, 118, 1122, 796 2. 63-2. 68 (m, 1H), 3. 25(d, 2H, J=9. 0Hz), 3. 69(d, 2H, 15 J=9. 0Hz) ^ 6. 74-6. 86(m9 1H) ^ 6. 88-6. 98(m5 2H) ^ 7. 09-7. 20(t? 1H, J=7. 8Hz), 7. 92 (d, 1H, J = 8. 4Hz), 8. 09 (d, 1H, J = 6. 3Hz), 8. 35 (d, 1H, J = 7. 5Hz), 8. 61 (d, 2H, J = 6. 3Hz), 8. 77(s 1H), 9. 49 (s, 1H); melting point 147 to 149 °C. : 1 α·5α,6α-"6-(5•isoindolyl carbaryl fluorenyl)-3-(2,4-di^ 20 氲1 stupyl 1-3-azabicyclo"3丄〇1 hexane trifluorodecane sulfonic acid _ (% 也 il il) method of adding trifluoromethanesulfonic acid (1 mmol) to 1α, 5α, 6α-[6-(5_) at 0 ° C Isoprolinylaminocarboxylamido)-3-(2,4-difluoro)phenyl]-3-azabicyclo[3. l. o] Hexane (1 mmol) (Example 21) was stirred well in dichloromethane (10 mL) 117 200813011 and stirred at room temperature for 10 to 12 hours. The residue obtained after removing the solvent was wet-milled with diethyl ether and dried to give the product. IR (KBr) 3357, 3293, 307 Bu 3055, 1694, 1559, 1274, 1226, 1026 cm _1. 5 W-NMR pOOMHz, DMSO-d6): δ 1. 84-1. 90 (m, 2H), 2. 62-2. 70 (m, 1H), 3_25 (d, 2H, J = 8. 4Hz), 3. 70 (d, 2H, J = 8. 7Hz), 6. 74-6. 86 (m, 1H), 6. 88-6. 98 (m, 2H), 7·08-7·20 (ιη, 1H), 7. 94-8. 04 (m, 1H), 8. 17-8. 24 (m, 1H), 8. 42_8. 50 (m, 1H), 8. 50-8. 60 (m 1H), 8. 72-8. 78 (m, 1H), 8. 98(s 1H), 9. 89 (s 10 1H); melting point 216 to 218 ° C. Example 37: 1〇;,5〇;,6〇;-"6-(5-isoquinoline, amidinoyl)-3-(2,4-difluoro)phenyl1-3-nitrogen Miscellaneous double ring "3. 1. 01 hexane salt 酴gjr πth compound) Method of adding 10% HCl solution in ethyl acetate to 1 α,5α,6 α-[6-(5-isoindolylamino group) at 〇 ° C Carboxylamido)-3-(2,4-difluoro)phenyl]-3-azapine 15 ring [3丄0] hexane (1 mmol) (Example 21) in ethyl acetate (1) Stir the solution thoroughly in 〇 ml) and stir at room temperature for 10 to 12 hours. The residue obtained after removing the solvent was wet-milled with diethyl ether and dried to give the product. IR (KBr) 3420, 3290, 2618, 1706, 1552, 1246, 1274, 820 cm 1 ; b-NMROOOMHz. DMSOO. S 1. 78-1. 86 (m, 2H), 20 2. 60-2. 68 (m, 1H), 3. 25(d, 2H, J=9. 0Hz), 3. 68(d, 2H, J=8. 7Hz), 6. 74-6. 84 (m, 1H), 6. 88-6. 98 (m, 2H), 7. 06-7. 20 (m, 1H), 7. 70-7. 78 (m, 1H), 7. 96(t, 1H, J=7. 5Hz), 8. 15(d,1H, J=8. 4Hz), 8. 64-8. 74 (m, 2H), 8. 91-8. 98 (m, 1H), 9. 73(s 1H), 9. 88 (s 1H); melting point &gt; 250 ° C. 118 200813011 Column 38: 1〇;,5〇;,6〇;-"645_iso4 porphyrin a face 篡 醯 amine)-3-(2,4-di A) stupid 1-3_aza镂 ring "3丄〇1 hexane methane sulfonate (compound No. 38) is prepared by adding hydrazine sulfonic acid (1 mmol) to α, 5 α, 6 α _[6·( 5-isoindole 5-phenylaminocarbamoylamino)-3-(2,4-difluoro)phenyl]-3-azabicyclo[3. 1. 0] hexane (1 mmol) (Example 21) was stirred in a stirred solution of di-methane (1 mL) and stirred at room temperature for 10 to 12 hours. The residue obtained after removing the solvent was wet-milled with diethyl ether and dried to give the product. IR (KBr) 342 Bu 3282, 3052, 1695, 1557, 1274, 1208, 1192, 10 1044 cm -1 ; h-NMRpOOMHz, DMSO-d6): 3 1·83-1·89 (ηι, 2Η), 2 . 33(s,1Η), 2. 62-2. 68 (m, 1 Η), 3. 24(d, 2Η, J=9. 3Hz), 3. 30-3. 80 (m, 2H), 6. 74-6. 84 (m, 1H), 6. 88-7. 0 (m, 2H), 7. 10-7. 20 (m, 1H), 7. 92-8. 0 (m, 1H), 8. 16(d, 2H, J=6. 0Hz), 8. 40-8. 46 (m, 1H), 8. 50-8. 57 (m, 1H), 8. 72 (d, 1H, J = 6. 0Hz), 15 8. 99(s,1H), 9. 83 (s, 1H); melting point 176 to 178 °C. Example 39: 1〇;,5〇;,6〇;-|&quot;6-(5-isoindolinylaminocarboxamide)-3-(4_aero-mosyl)sulfonyl 1-3 -Azabicyclo"3. 1. 01 hexane (No. 39 厶h U U 沬 添加 added triethylamine (8 mmol) to N-3-azabicyclo[3. 1. 0] A solution of hex-6-yl-indole-isoindoline-5-ylurea (1 mmol) in anhydrous THF. A solution of 4-chlorobenzene oxime (1 mmol) in anhydrous thf was slowly added to the reaction mixture at 〇 °C. The reaction mixture was stirred at RT and took 15 hours. Excess solvent was evaporated under vacuum. The reaction mixture was diluted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The crude product is purified by column to give the desired product as a white solid. 25 'H-NMRC DMSO-^): 5 1. 71-1. 79 (2H? m); 2. 39-2. 46(lH, m); 119 200813011 3·11(2Η,d,J=9. 0Hz) ; 3·53(2Η,d,J=9. 0Hz) ; 6·81(1Η, s); 7. 60 (1H, t, J = 8. 4Hz) ; 7·70·7·90 (6Η, m); 8. 19(1H,d, J=7. 5Hz); 8. 54(1H, s) ; 8·61(1Η, s) ; 9·28(1Η, s) ; IR(KBr)(cm-1): 3304,1643, 1580, 1345, 1162, 1089, 630; MS (M++1): 5 443. 30; melting point 204 ° C. Example 40: 1α, 5α. 6α-(6-(5-isoquinolylaminocarbamoylamino)-344-(trifluoroindolyl) stupyl 1 碏醯 a 丨-3-氤hebicyclo ring "3. 1. 01 hexane (Compound No. 40) was prepared by the same method as described in Example 39 from Ν·3·azabicyclo[3. 1. 0] 10 hex-6-yl-indole'-isoindoline-5-ylurea and 4-(trifluoromethyl)benzenesulfonium oxime to prepare the present compound. ^-NMRCDMSO-^): 5 1. 71-1. 79 (2H? m); 2. 39-2. 45(lH5 m); 3·14(2Η,d,J=9. 3Hz) ; 3·56(2Η,d,J=9. 6Hz); 6·98(1Η, s); 7. 59(1H,t,J=7. 8Hz); 7. 75(1H,d,J=8. 1Hz) ; 7·88-7·98(1Η, 15 m) ; 8·00-8·10(4Η,m) ; 8·20(1Η, d, J=7. 5Hz) ; 8·51(1Η,d, J=6. 0Hz) ; 8·68·8·78(1Η,m) ; 26(1H,s) ; IR(KBr)(cm. 1): 3346, 165 Bu 1550, 1328, 1160, 613; MS (M++1): 475. 33 ; melting point 209 ° C. Example 41 · 1 α,5 α isodecylaminotrans group fluorinated fluorobenzene 20 yl) sulfonyl benzene 3-retanning bicyclo "3 丄 01 hexane (the compound) by the method of Example 39 Said the same method and from N_3_azabicyclo[3. 1. 本] _6_ yl-N'-isoporphyrin _5-based urea and 4-fluoro sulfonium sulfonate are used to prepare the present compound.丽R(DMS〇-d6): (51·71·1·78(2Η,m); 2·37-2·43(1Η,m); 3·09(2Η,d,J=8. 4Hz) ; 3·52(2Η,d,J=9. 6Hz); 6·79(1Η, s); 120 200813011 7·46-7·56(2Η,m) ; 57-7. 63(1H,m) ; 7·76(1Η,d,J=7. 8Hz); 7·72-7·93 (3Η, m); 8. 19(1H,d,J=6. 6Hz) ; 8·52(1Η,d, J=5. 7Hz) ; 8·59(1Η, s) ; 9·27(1Η, s); IR(KBi〇(cm-1): 3296, 1645, 1579, 1569, 1345, 1157, 621 ; MS(M++ 1) : 427. 45 ; 5 Melting point 197 ° C. Example 42: 1〇;,5〇;,6〇;-"6-(5-isoindolinylaminocarboxylamido)-3彳2_6_dioxolyl) fluorenyl 1-3-nitrogen Miscellaneous double ring "3. 1. M method of 01 hexane (Compound No. 42) by the same method as described in Example 39 from hydrazine-3-azabicyclo[3. 1. 0] Hex-6-yl-indole'-isoindoline-5-ylurea and 2,6-dioxasulfonyl oxime are used to prepare the present compound. 10 ^-NMRC DMSO-^): δ 1. 71-1. 77(2H, m) ; 2. 42-2. 47(lH? m); 3. 48(2H? m5 J=9. 0Hz); 3. 64(2H? m9 J=9. 3Hz); 6. 83(1H? s); 7·56-7·78(5Η,m); 7. 86 (1H, d, J = 5. 4Hz); 8. 20(1H, d, J=6. 6Hz); 8. 53 (1H, d, J = 5. 4Hz) ; 8·62(1Η, s) ; 9·27(1Η, s); IR(KBr)(cm-1) : 3370, 1657, 1556, 1426, 1346, 1176, 15 617 ; MS(M+ +1) : 477. 46; melting point 190 ° C. Example 43: 1〇;. 5〇!. 6〇!彳6-(5-Isoprolinylaminocarboxylamido)-3-(^6-difluorophenyl)碏醯1-3-indole bicyclic "3. 1. 01 hexane (Compound No. 43) oxime by the same method as described in Example 39 from N-3-azabicyclo[3. 1. 0] Hexyl-indole-isoindoline-5-ylurea and 2,6-difluorobenzenesulfonate are used to prepare the present compound. 20 1H-NMR (DMSO-d6): δ 1. 74-1. 82 (2H5 m); 2. 34-2. 40(lH5 m); 3·30-3_68(4Η,m); 7·32·7·41(2Η, m) ; 7·52-7·62(1Η,m); 66-7. 74 (lH, m); 7. 75-7. 84 (lH, m); 7. 94-8. 00 (lH, m); 8·28-8·39 (2Η, m); 8. 44(1H,s) ; 9·23(1Η,s) ; 9·40(1Η,s); IR(KBr)(cm. 1): 3321, 1644, 1611, 1579, 1465, 1167, 121 200813011 793, 536; MS (M++1): 443. 33; melting point 233. (:. Example 44: 1α,5α,6α-Γ6·ί5-isoprostol to guanylaminocarboxylamido)-3-(2,4-dibromo-phenyl)sulfonyl 1-1-3-nitrogen The method for the preparation of "3丄〇1 decane (Compound No. 44) was carried out by the same method as described in Example 39 from N-3-azabicyclo[3. 1. 0] 5 hex-6-yl-indole'-isoindolin-5-ylurea and 2,4-dioxabenzene continue to chlorinate to prepare the present compound. 1H-NMR (DMSO-d6): 5 1. 80-1. 86 (2H? m); 2. 44-2. 56(1H? m); 3·43(2Η,d,J=10. 5Hz) ; 3·56(2Η,d,J=9. 6Hz) ; 6·84(1Η, s); 7·59(1Η, t, J=8. 1Hz) ; 7·76(1Η,d,J=8. 7Hz); 7. 81-7. 95(3H, m) ; 8·18-8·24(2Η,m) ; 8·53(1Η,d,J=6. 0Hz) ; 8·61(1Η, s); 10 9. 27(1H,s) ◦ IR(KBr)(cm-1): 3315, 1644, 1563, 1365, 1164, 624; MS(M++1) : 565. 35; melting point 229 ° C. Example 45: 1α,5α,6α-"6-(5-iso-4啾Aminocarbamoylamino)-3-(2,4-diylphenyl)sulfonyl-1-3-aza ring "3. 1. 01 hexane (Compound No. 45) was prepared by the same method as described in Example 39 from N-3-azabicyclo[3. 1. 0] 15 hex-6-yl-indole'-isoindoline-5-ylurea and 2,4-dichlorobenzenesulfonium chloride are used to prepare the present compound. 1H-NMR (DMSO-d6): δ 1. 7M. 79 (2H? m); 2. 39-2. 46(lH5 m); 3. 11(2H,m,J=9. 0Hz) ; 3·52(2Η,m,J=9. 0Hz) ; 6.84 (1Η, s); 7. 60 (1H, t, J = 7. 5Hz) ; 7·68(1Η,d,J=8. 1Hz); 7. 76(1H,d, J=7. 5Hz) ; 7·87(1Η,d,J=6. 0Hz) ; 7·92-8·02(2Η,m) ; 20 (1H, 20 d, J=7. 8Hz) ; 8·53(1Η,d,J=5. 7Hz); 8. 62 (1H, s); 9. 27(1H, s) ;. IR (KBr) (cm-1): 3315, 1643, 1572, 1552, 1164, 822, 631; MS (M++1): 477. 17; melting point 214 ° C. Example 46: lα. 5Q;. 6α-f6-(5-isoindolinylamine, a carboxy oxime group V3-[2-trifluoromethyl], thiol-1-azabicyclo" 1. 01 hexane (No. 46 compound 122 200813011) was prepared by the same method as described in Example 39 from N-3-azabicyclo[3. 1. 0] Hex-6-yl-indole-iso-ou-quinolin-5-ylurea and 2-trifluoromethylbenzene quinone chloride were prepared into the present compound. 5 ^-NMRC DMSO-^): 5 1. 80-1. 87 (2H? m); 2. 46-2. 60 (lH5 m); 3·30-3·46 (2Η, m); 3. 61(2H,m,J=9. 6Hz); 6. 83 (lH, s); 7. 60(lH, t, J=7. 8Hz); 7. 76(1H,d,J=7. 8Hz); 7·85-7·98(3Η, m); 8. 02-8. 12 (2H? m); 8. 20(1H5 d? J=7. 5Hz); 8. 53(1H9 d? J=5. 7Hz); 8. 62 (1H, s); 9. 27 (1H, s). IR (KBr) (;f m-1): 3374, 10 1651, 1552, 1308, 1170, 1118, 616; MS (M++1): 477. 25 ; melting point 193 ° C. Example 47: 1 α , 5α, 6α • Isoxalinylamine, a Carboxymethyl)_3_(γ2-fluorophenyl)-decyl)_3_Azabicyclo"3·1 ·〇1已烧(47 Process for the preparation of compound No. 15 by the same method as described in Example 39 from hydrazine-3-azabicyclo[3. 1. 0] hex-6-yl-Ν'-iso-σ Chalin _5_ base vein and 2-gas benzene qi qi are made into the present compound. 'H-NMRiDMSO-de): 5 1. 74-1. 83(2H5 m) ; 2. 33-2. 40(lH? m); 3·24·3·38(2Η,m) ; 3·56(2Η,m,J=9. 6Hz); 6·80(1Η, s); 7·42-7·64(3Η,m); 7·72-7·90(4Η,m) ; 8·19(1Η,d,J=8. 1Hz); 20 8. 53(1H,t,J=5. 7Hz); 8. 59 (1H, s); 9·27 (1Η, s). IR (KBr) (cm-1): 3318, 1686, 1644, 1474, 1338, 1163, 614; MS (M++1): 427. 47; melting point 193 to 195 ° C. Example 48: 1 a, 5a, 6a-"6-(5-isodecylamine, athranylamine, alkylaminol-3-azabicyclo)|~3·1·01 hexane (48th No. 123, 200813011 The process was carried out by the same method as described in Example 39 from N-3-azabicyclo[3. 1. 0] Hex-6-yl-N-iso-4-lin-5-ylurea and 2-gas benzene are used to prepare the present compound. iH, NMR (DMSO-d6): δ 1·78-1·86 (2Η, m); 2·42-2·49 (1Η, 5 m); 3·35-3·46 (2Η, m); 3·57 (2Η, d, J=9. 1Hz); 6·83(1Η, s); 7·55-7·65(2Η,m); 7·66-7·80(3Η,m) ; 7·87(1Η,d,J=6. 3Hz); 8. 00 (1H, d, J 2 8.1 Ηζ); 8. 21(1H,d,J=7. 2Hz) ; 8·53(1Η,d, J=5. 7 Hz); 8·62 (1Η, s); 9·28 (1Η, s). IR (KBr) (cm-1): 3295, 1645, 1580, 1569, 1345, 1157, 731, 621; MS (M++1): 10 443. 38; melting point 206 to 208 ° C. Example 49: 1 α,5α ,6α Isoporphyrin, amino-aminocarboxylamido)-3-(2-bromophenyl)-decyl 1-3-heterobicyclo "3丄01 hexane (No. 49) The compound was prepared by the same method as described in Example 39 from hydrazine-3-azabicyclo[3. 1. 0] 15 _6_ group is prepared by the use of '-isoporphyrin _5-based urea and 2-bromobenzene sulfonium oxime. iH-NMR (DMSO-d6): 5 1·78·1·87 (2Η, m); 46-2. 56 (1H9 m); 3. 38-3. 50(2H,d) ; 3·52-3·61(2Η,m) ; 6·83(1Η,s); 7·54-7·68(3Η,m) ; 7·72·7·80( 1Η,m) ; 7·82-7·92(2Η,m); 7·98·8·07(1Η,m) ; 8·16·8·24(1Η,m) ; 8·50-8· 57 (1Η, m); 20 8·61 (1Η, s); 28 (1H, s). IR (KBr) (cm. 1) : 3344, 1648, 1549, 1328, 1160, 613, 576; MS (M++1): 487. 33; melting point 204 to 206 ° C. Example __50: 1 α , 5α, 6α _ "6-(5-isoporphyrinylaminocarboxamide) - 3 彳 某 sulfonyl sulfonyl sulfonyl 1-3 - azabicycloindole.  1. 01 hexane (Compound No. 50) 124 200813011 The process was carried out in the same manner as described in Example 39 from N-3-azabicyclo[3·1·0]hex-6-yl-indole-isoquinoline. The compound is prepared by using 5-5-urea and benzenesulfonate. ^-NMRCDMSO-de): δ 1. 70-1. 78(2H? m) ; 2·36-2·44(1Η, 5 m) ; 3·09(2Η,m,J=6. 6Hz) ; 3·53(2Η,d,J=9. 3Hz) ; 6·78(1Η, s) ; 7·54-7·9〇(8Η,m) ; 15-8·24(1Η,m) ; 8·50·8·56(1Η,m); 8. 58(1H, s); 9·27(1Η, s) ; IR(KBr)(cm-1): 3367, 1655, 1552, 1330, 1308, 1168, 615; MS(M++1) : 409. 42; melting point 1841_186 ° C. Bromo-based sulfonyl 1-3-anthracene double ring "3. 1. Method for the preparation of 01 hexane (Compound No. 51) by the same method as described in Example 39, from 沁3_azabicyclo[3. 1. 0] hex-6-yl-N'- is different. set. Lin-5-carbazide and 4-indigenous benzene are used to prepare the present compound. 15 ^-NMRC DMSO-^): δ 1. 71-1. 79(2H? m) ; 2·39-2·46(1Η, m) ; 3·11(2Η,d,J=9. 0Hz) ; 3·53(2Η,d,J=9. 0Hz) ; 6·81(1Η, s) ; 7·60(1Η,t,J=8. 4Hz) ; 7·70-7·90(6Η,m) ; 8·91(1Η,d, J=7. 5Hz); 8. 54 (1H, s); 8. 61 (1H, s); 9. 28(1H, s); IR (KBi〇(cm-1): 3309, 1642, 1577, 1346, 1162, 741, 623; MS(M++1): 20 487. 43; melting point 227 to. A case 52: 1 α-_[6_(5_iso 4 oxanylamine, a certain carboxyamino group)_3_(4_ phenyl group) continued to be abbreviated with nitrogen. 1. 01 hexane ί No. 52 compound) oxime method by the same method as described in Example 39 but from Ν-3-azabicyclo[3丄0]hex 125 200813011 -6-yl·Ν'_isoporphyrin-5 - The base urea and 4-iodophenylsulfonium chloride are used to prepare the present compound. ^-NMRCDMSO-de): δ 1. 70-1. 78(2H?m); 2·39-2·46(1Η, m); 3·04-3·16(2Η,m); 46-3. 58(2H,m); 6·80(1Η,s); 7·55(2Η, d, J=7. 2Hz); 7. 50-7. 64 (lH? m); 7. 74-7. 81(1H? m); 5 7. 82-7·89 (1Η, m); 8. 05(1H,d,J=6. 6Hz); 8·14-8·24(1Η,m); 8·50·8·57(1Η,m) ; 59(1H,s) ; 9·27(1Η, s) ; IR(KBr)(cm"): 32996, 1645, 1569, 1580, 1345, 1109, 73 621 ; MS(M++1): 535 . 30; melting point 222 to 224 ° C. Example 53: 1 a , 6α-Ι~6-ί5-isoindolylaminocarboxylamido 10 decylphenyl)sulfonium hydrazine [~3丄〇1 hexane (Compound No. 53) The method was prepared by the same method as described in Example 39 from N_3_azabicyclo[3丄〇]hex-6-yl-fluorene'-iso-π-quinoline-5-ylurea and 4-mercaptobenzenesulfonium gas. Cost compound. lH-NMR (DMS0_d6): 5 1·64-1·76 (2Η, m); 2·32-2·46 (1Η, 15 m); 42 (3Η? s); 3. 00-3. 10(2Η? m); 3. 42-3. 54 (2Η5 m); 5. 70-5. 80 (1Η? m); 6. 79 (1Η? s); 7. 40-7. 90(6Η?m); 8·14-8·24(1Η,m); 8·53(1Η,d,J=5. 7Hz); 8·59(1Η, s); 9·27(1Η, s), IR(KBr)(cm. 1) : 3308, 1642, 1577, 1346, 1163, 11〇4, 741, 623 ′ MS (M++1): 423. 44; melting point 203 to 205 ° C. 20 1 case 54 · 1 α- "6-(5 · iso 4 phenylamine amine # 醯 醯 蒌 ) ) )) 1 rustic turtle double ring "3 · 1 · 〇 1? ϋ No. 54 servant ▲ compound The kf method was prepared in the same manner as described in Example 39 from N_3_azabicycloindole]hexyl-6-yl-N,-isoindolinyl-based urea and 4-methylbenzamide chloride. NMRCDMSO. d,): 5 1. 712-1. 84 (2H? m); 2. 32-2. 41(1Η? 126 200813011 m) ; 3·64-3·75(2Η,m) ; 3·98-4·08(2Η, m) ; 6·85(1Η,s); 7·39-7· 48(2Η,m) ; 7·56-7·69(3Η,m) ; 7·64-7·80(1Η,m); 7·84-7·91(1Η,m) ; 8·16- 7. 24(1Η,m) ; 8·50-8·55(1Η,m); 8·60(1Η,m) ; 9·28(1Η,s) ; MS(M++1) : 453. 52; IR (KBr) (cm 5 m_1): 3436, 3330, 3291, 1644, 1584, 1255, 830; melting point 230 to 233 °C. Example 55. 1〇;,5〇!,6(2-"6-(5-iso-linylamino-branched amine)-3-(4-1-phenylammonium)1-3-azabicyclo"3 . 1. 01 hexane (Compound No. 55) was prepared by the same method as described in Example 39 from N-3·azabicyclo[3. 1·0] 10 Ν-Ν'-isoindoline-5-ylurea and 4-chlorobenzhydrin chloride were prepared as a near-white solid. ^-NMRCDMSO-^): δ 1·79(2Η,m) ; 2·36(1Η,m); 3·43·3·50(2Η,t) ; 3·69(1Η,m) ; 3· 99-4·04 (1Η, d, J=12Hz); 6.94 (1Η, m); 7. 51(4H,s) ; 7·56-7·62(1Η,t,J=8. 1Hz); 15 7·74-7·76 (1Η, d, J=8. 1Hz) ; 7·89-7·91 (1Η, d, J=5. 1Hz); 8. 19-8. 21 (1H, d, J = 8. 1Hz) ; 8·51-8·52 (1Η, d, J=5. 4Hz); 8. 66 (1H, bs); 9. 26(1H,bs) ; IR(KBr)(cm-1) : 3435, 3292, 1627, 1225, 651 ; MS(M+-1) : 405. 26. Complex _ Example 56: 1α, 5 colors, 6α-『6-ί5-tomb Φ porphyrin amino-aminocarboxamide 20 benzothymidine) 1_3_ complex bismuth "3. 1. 01 P, alkane (3) compound 56) by the same method as described in Example 39 from N-3-azabicyclo[3. 1. 0] Hexyl-64_N'-isoporphyrin-5-ureaurea and 3-fluorobenzamide chloride are prepared as a near-white solid. lHeNMR (DMS0_d6): 5 1. 80(2H,m) ; 2·38(1Η,m); 127 200813011 3·41-3·51(2Η,t) ; 3·70(1Η,m) ; 3·99-4·03(1Η, d, J=11. 7Hz); 7·01(1Η,bs); 7·31(3Η,m) ; 7·49(1Η,t) ; 3·57_7·62(1Η, t, J=7. 8Hz) ; 7·74·7·76 (1Η, d, J=7. 2Hz) ; 7·90·7·91 (1Η, d, J=5. 1Hz); 8. 19(1H,d) ; 8·51-8·53(1Η,d,J=5. 1Hz); 8. 72 (1H, 5 bs); 9. 26(1H,bs); IR(KBr)(cm-1): 3434, 329b 1644, 1255, 652; MS(M++1) : 391. 33 〇 Example 57: phenylamino-aminocarboxylamido)-3-(2-linked 1-methylindenyl)1-upper AJ隹 double ring "3. 1. 0 hexane (Compound No. 57) was prepared by the same method as described in Example 39, from Ν3-azabicyclo[3. 1. 0] 10 -6 _ group-&gt;^'-isoporphyrinyl urea and hydrazine bromide are made into a compound such as a pale yellow solid. ^-NMRCDMSO-^): δ 1. 78-1. 84 (2H? m); 3. 11-3. 15(1H? m); 3. 44-3. 52 (3H9 m); 3. 91-3. 95 (1H? d5 J = 12Hz); 6. 86(1H, bs); 7. 38(2H,t) ; 7·45_7·49(1Η,t,J=6. 8Hz) ; 7·57_7·62 (1Η, t, 15 J=7. 7Hz) ·' 7·67-7·70 (1Η, d, J=7. 5Hz) ; 7·74-7·77 (1Η, d, J=8. 1Hz) ; 7·86-7·88 (1Η, t, J=6Hz); 8·20-8·23(1Η,d, J-7·5Ηζ) ' 8·52-8·54(1Η,d , J=6Hz) ; 8·60(1Η, s) ; 9·27(1Η, (4), IR(KBr)(cm_1) : 3366, 1619, 1547, 1236, 764 ; MS(M++1) : 451. 35 0 20 A_58 _ Iso 4 oxo amino-aminocarboxylidene double ring "3. 1. 01 Ρϋ篦 No. 58 compound) The same method as described in Example 39 was carried out from Ν3-azabicyclo[3. 1. 0] Hex-6-yl-indole-isoindole_5_urea and 2-fluorobenzamide were prepared as a compound of near-white solid spectrum. 128 200813011 ^-NMRCDMSO-^): δ 1. 78-1. 83 (2H? m); 2. 37(1H? m); 3·22(1Η,m); 3. 49-3. 53(2H,m) ; 3·95·3·99(1Η,d,J=12Hz); 85(1H,bs) ; 7·28-7·31(2Η,m) ; 7·40-7·42(1Η,t); 7·50·7·52(1Η,m) ; 7·57- 7·62 (1Η, t, J=7. 7Hz); 7. 75-7_77 (lH, 5 d, J=7_5Hz); 7·85_7·87 (1Η, d, J=5. 4Hz) ; 8·19·8·21 (1Η, d, J=6. 6Hz); 8·52-8·54 (1Η, d, J=6Hz); 8. 61 (1H, s); 9. 27(1H, bs) ; IR(KBr)(cm': 3379, 1625, 1546, 1219, 763; MS(M++1) : 391. 35. f Example 59: 1. . g. , 5a, 6 α-isoindolylaminocarboxylamido)_3-(2-10 I-benzylidene)1-3-azaindole "3丄〇1 hexane (compound No. 59) The method was the same as described in Example 39 and was obtained from Ν3-azabicyclo[3. 1. 〇] hexyl porphyrin-5-based urea and 2-gas benzoquinone are prepared as a light yellow solid. lH-NMR (DMS〇-d6): δ 1. 77-1. 84 (2H? m); 2. 25-2. 38(1Η? 15 m) ; 3·16(1Η,m) ; 3·51·3·68(2Η,m) ; 3·93(1Η,d) ; 6·87(1Η, brs) ; 7· 42-7·53(5Η,m) ; 7·75·7·87(2Η,m) ; 8·21(1Η,brs); 8·53-8·62(2Η,m) ; 9·27( 1Η, brs) ; IR(KBr)(cm': 3355, 162b 1549, 1237, 752; MS(M++1): 407. twenty three. : 1 _"6_(5_Isoprolinylaminocarboxamide oxime ^ 20 king cap styrene brewing base IL4A_heterobicyclo ring "3. 1. 己烷 箆 箆 箆 虢 虢 厶 厶 厶 厶 厶 厶 厶 厶 厶 厶 厶 Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν Ν _ _ Ν Ν _ _ _ _ _ _ _ _ _ _ _ _ _ Urea and 4-methylbenzhydrin chloride are prepared as a light yellow solid.

'H-NMRC DMSO^): 5 1.78 (2H? m); 2.33 (4H?s); 3.48 (2H 129 200813011 m), 3.68 (1Η, m); 4·01·4·06 (1Η, d , J=12Hz) ; 6·84(1Η, s); 7·23-7·25(2Η,d,J=6.6Hz) ; 7·35·7·38(2Η,d,J=7.8Hz) 7·57·7·62 (1Η, t, J=7.8Hz); 7·74-7·77(1Η, d, J=7.5Hz); 7·85·7·87(1Η,d,J =5.7Hz) ; 8.18(1H,d) ; 8·51·8·53(1Η,d, 5 J=5.1Hz); 8.59(1H,s); 9·27(1Η,bs); IR(KBr ) (cm): 3292, 1643, 1255, 829, 641; MS (M++1): 387.21.例6: 丨6_(5_Isoporphyrinamine Aminoguanamine I methyl)benzhydryl 1-3.Azaindole "3.1.01 Hexane (Fence No. 61)) 10 By the same method as described in Example 39, from N_3-azabicyclo[3_1.0]hex-6-yl-indole-isoindoline-5-ylurea and 2-(trifluoromethyl)benzamide Chlorine is prepared as a white solid. 1H-NMR (DMSO-d6): δ 1.76-1.82 (2H?m); 2.35-2.40 (1?? m); 3·15-3·28 (2Η, m) ; 3·94(2Η,m) ; 6·89(1Η,bs); 15 7·65-7·76(7Η,m) ; 8·21(1Η,m) ; 8·53·8·63( 2Η,m) ; 9·29(1Η, bs) ; IR(KBr)(cm.1) : 3336, 1621, 1549, 1316, 754 ; MS(M++1) : 441.24. 1 case 62 : lα, 5π^6α·“6-(5·isoindolylaminocarbamoylamino)-3-(4-

Ul methyl benzamidine) l-3-azabiguanide: V1.01 hexane (compound No. 62) 20 was prepared by the same method as described in Example 39 from ν·3-azabicyclo ring [3.1.0] Hex-6-yl-indole'-isoindoline-5-ylurea and 4-(trifluoromethyl)benzhydrazide are used to prepare the present compound. ^-NMRC DMSO-^): δ 1.80 (2H? m); 2.40 (1H? m); 3.43 (1H? 130 200813011 m); 3·51-3·54 (1Η, d, J=l〇.2Hz) ; 3·68(1Η,m); 4·00-4·04(1Η, d,J=12.3Hz); 6·87(1Η,s) ; 7·57_7·61(1Η,t,J=7.2 Hz); 7·67-7·87(6Η,m); 8·19(1Η,m); 8·51-8·53(1Η,d,J=5.7Hz); 8.60(1H,s); 9.27 (1H, bs); IR (KBr) (cm): 3292, 1643, 5 1582, 1337, 641; MS (M++1): 441.24. Example 63: Ια,5 α,6 αisoindolinylaminocarboxylamido)-3-(4-bromobenzylindole-3-azindolebicycloindole·1·〇1 hexane (63th) Compound No.) by the same method as described in Example 39, from indole-3-azabicyclo[3.1.0]hex-6-yl-indole,-isoquinolin-5-ylurea and 4-bromo Methane gas was prepared into the compound. 10 1H-NMR (DMSO-d6): ^ 1.712-1.84 (2H5 m); 2.32-2.41 (1Η5 m); 3·64-3·75(2Η,m) ; 3·98 -4·08(2Η,m) ; 6·85(1Η,s); 7·39_7·48(2Η,m) ; 7·56-7·69(3Η,m) ; 7·64-7·80 (1Η,m); 7_84·7·91(1Η,m) ; 8.16·8_24(1Η,m) ; 8_50_8·55(1Η,m); 8·60(1Η,s) ; 9·28(1Η, MS (M++1): 453.52; IR (KBr) (cm 15 mil: 3436, 3330, 329, 1644, 1584, 1255, 830; melting point 230 to 233 〇 C. Example 64: 1 a . 5 a .6 a isoxalinylaminocarboxylamidobenzylcarbamate 1-3-azabicyclo P.1.01 hexane (compound No. 64) is prepared by the same method as described in Example 39 The present invention is prepared from N-3-azabicyclo[3.1.0]20hex-6-yl-indole-isoindoline-5-ylurea and benzyl bromide. IR (KBr): 3440, 2887, 1647, 1565, 1365, 1243, 1136, 1078, 995, 827, 748, 727 cm 1. ^-NMRPOOMHz, DMSO-d6): 51.54 (s, 2H), 2.37 (d, 2H, J = 7.8 Hz), 2.89 (s, lH), 2.98 (d, 2H, J = 8.7 Hz), 3.55 (s, 2H), 6.69 (s, 1H), 7.27-7.32 (m, 5H), 7.60 (t, 131 200813011 1H, J = 7.5 Hz ), 7.73 (d, 1H, J = 7.5 Hz), 7.86 (d, 1H, J = 5.4 Hz), 8.23 (d, 1H, J = 7.5 Hz), 8.52 (s, 2H), 9.25 (s, 1H) Melting point 184 to 186 〇C 0 Example 65: la,5 (a-6 a-"6-i5-isoindolylaminocarbamoylamino)-3-(4-5 succinyl)&gt; 3-Azabiguanium "3.1 01 Hexane (Compound No. 65) was prepared by the same method as described in Example 39 from N-3-azabicyclo[3.1.0]hex-6-yl·Ν' · Iso-4 Lin-5-urea and 4-chlorobenzyl bromide are made into the present compound. IR (KBr): 3355, 3302, 2907, 2795, 165, 1570, 1347, 1265, 1090, 828, 640 cm-1. h-NMROOOMHz, DMSO-d6): 51.55 (s, 10 2H), 2.38 (d, 2H, J = 8.1 Hz), 2.88 (s, 1H), 2.98 (d, 2H, J = 8.7 Hz), 3.55 ( s, 2H), 6.70 (s, 1H), 7.29 (d, 2H, J = 8.4 Hz), 7.32 (d, 2H, J = 8.1 Hz), 7.59 (t, 1H, J = 7.8 Hz), 7.74 ( d, 1H, J = 8.1 Hz), 7.87 (d, 1H, J = 6.0 Hz), 8.24 (d, 1H, J = 6.9 Hz), 8.52 (d, 2H, J = 6.0 Hz), 9.27 (s, 1H); melting point 186 to 188 °C. 15 Example 66: la,5 aa-"6-(5-isoquinolylaminocarbamoylamino)-3-(4-trifluorodecyl-based heterobicyclo[3.1.01 hexane (No. 66) The compound was prepared by the same method as described in Example 39 from hydrazine-3-azabicyclo[3.1.0]hex-6-yl-Ν'·isoindoline-5-ylurea and 4-(trifluoro) Methyl) benzyl bromide is prepared as the present compound. 20 IR (KBr): 3385, 3348, 2937, 1648, 1495, 1365, 1249, 1080, 995, 827, 748, 525 cm]. b-NMR pOOMHz, DMSO-d6) : 5 1.56(s, 2H), 2.41 (d, 2H, J = 8.4 Hz), 2.90 (s, 1H), 3.00 (d, 2H, J = 8.7 Hz), 3.66 (s, 2H), 6.70 (s , 1H), 7.49-7.73 (m, 6H), 7.78 (s, lH), 8.23 (s, lH), 8.53 (s, 2H), 9.26 (s, 1H); melting point 175 to 177 ° C. 132 200813011宭彻丨67—丄1 α-isoquine I-amine 1-3: UI double ring “3丄01 焓 γ γ Compound No. 67” 夕!^. Step 1: 1-phenyl-1Η-pyrrole-2, 5-dione production method Add aniline to a solution of butyl succinate (52 g 53.76 mmol) in benzene (100 ml) at room temperature and mix 2 to 3 J, day &quot;^.

10 The precipitated solid was filtered and dissolved in acetic anhydride (70 mL). Ethyl 35 sodium (6.6 g, 80.64 mmol) was added to the solution and heated at 8 to 9 ° C for 1 to 2 hours. The reaction mixture was cooled to room temperature and poured into ice water (7 mL). The precipitated solid was filtered, washed with water and dried to give a white solid product as a white solid; 1H-NMR (300 MHz, DMSO-d6): (57.19 (s 2H) 7.27-7.51 (m, 5H). Step 2: (lR,5S,6s)-6-nitro-3-phenyl-3-azabicyclo[3 j 〇] cadaveric-2,4-dione

Add bromonitrodecane (8.1 g, 57.8 mmol) to benzene 15-yl-1H_pyrrole_2,5-dione (5.0 g, 28.9 mmol) at -20 °C, Celite A mixture of diatomaceous earth (5 g) and molecular sieves (2.5 g) in N,N-dimethylformamide (50 ml). A carbonic acid clock (8 gram, 57.8 mmol) was added portionwise at -20 °C. The reaction mixture was filtered through a Celite bed. The filtrate was diluted with water (5 mL) and extracted with EtOAc EtOAc. The organic volume 20 was concentrated and purified by a hydrazine gel column using 10% ethyl acetate in petroleum ether to afford the product (7 mM); ih_NMr (3 〇〇 MHz, CDC13): (5 3.53 ( s, 2H); 4_82(s, 1H); 7.19-7.49(m, 5H) Step 3: (1〇;,5〇;,6〇〇-6-nitro-3-phenyl-3-nitrogen Heterobicyclo[3丄0]Heat-burning method 133 200813011 Add sodium borohydride (343 mg, 9.05 mmol) to (1α, 5 α,6 α )-6-shuji·3- at -2〇C Phenyl-3-azabicyclo[3"〇]hexanol 2,4-dione (7 gram, 3.013⁄4 mol) in tetrahydrofuran (3 mL), then at -30 After adding boron trifluoride-ether complex (128 g, 9 〇 5 mmol) via C, the reaction mixture was scrambled at room temperature for 24 hours. Add water at 0 to 5 °C. (100 ml) and the reaction of the reaction mixture was quenched. The organic material was extracted with ethyl acetate (3×50 ml). The organic volume was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product as crude white solid. (3〇〇mg). 10 H hire R (300MHz, DMSO-d6): δ 2.90(s, 2H) 3.28 (d, 2H, J = 9.9 Hz); 3.74 (s, 2H); 4.45 (S, lH); 6.54 (d, 2H, J = 8.1 Hz); 6.67 (t, 1H, J = 6.9 Hz); 7.16 (t, 2H, J = 7.8 Hz) Step 4 ·· 1 a,5 a,6a-[6-(Third)-butoxyaminemethanyl]_3_phenyl_3_ azabicyclo[ 3丄〇]Heteroic process 15 Hydrogenation of 1 α,5 α,6 α (1 winter nitro-3_phenyl-3_azabicyclo[3.1.0] in a Parr apparatus at 20 to 30 psi Hexane (3 〇〇 mg, ι·47 mmol), and Raney nickel (60 mg) and suspension in methanol, lapsed hours. The reaction mixture was filtered through Celite. Add b〇 Acetic anhydride (385 mg, 1.76 mmol) and triethylamine (5 ml) were added to the filtrate and stirred at room temperature for 20 hours for 2 hours. A stone was obtained by using 10% ethyl acetate in petroleum ether. The crude product obtained after the usual workup was purified by a gel column. Yield = 100 mg. iH-NMR (300 MHz, DMS0_d3): δ 1.45 (s, 9H); 1.83 (S, 2H); 2.43 (s, 1H); 3.26 (d, 2H, J = 8.4 Hz); 3.64 (d, 2H, J = 9.0 Hz); 4.72 (s, 1H); 6.54 (d, 2H, J = 7.2 Hz); 6.67 (brs, 1H), 7.20 (m, 2H). 134 200813011 Step 5: 1 a,5 a,6a-[6_(%isoindolinylaminocarbamoylamino-3-phenyl)S-azabicyclo[3J.0]hexane was added in 15% A solution of HC1 in ethyl acetate to 1 α,5 α,6 α _[6·(Third)-butoxyaminemethanyl]_3_phenyl-3-azabicyclo[31〇]hexane 5 (1 (9) Zucker '0.57473⁄4 mol) in a solution in ethyl acetate and stir for 3 to 4 hours. The residue obtained after removing the solvent was dissolved in dimethyl sulfoxide (ml), followed by hydrazine (0.5 ml) and 5-aminoisophthalocylidene amide (150 mg, 0.5747). Millions) and stirred at room temperature for 2 hours. Pour the reaction mixture onto cold water. The precipitated solid was filtered and immersed in methanol to give a pure product (30 mg) as white solid. IR (KBr): 3435, 3352, 2837, 1637, 1565, 1365, 1243, 1080, 995, 827, 748 cm]; iH-NMRQOOMHz, DMSO-d6): 51.90 (s, 2H); 3.22 (d, 3H) , J = 8.1 Hz); 3.60 (d, 2H, J = 9.3 Hz); 6.55-6.63 (m, 3H); 6.88 (s, 1H); 7.15 (t, 2H, J = 7.5 Hz); 7.60 (t , 15 1H, J = 8.1 Hz); 7.76 (d, 1H, J = 8.1 Hz); 7.89 (d, 1H, J = 5.4 Hz); 8.23 (d, 1H, J = 7.5 Hz); 8.54 (d, 1H, J = 6.0 Hz); 8.60 (s, 1H); 9.27 (s, 1H); melting point 225 to 227 °C. 1 case 68: N-"3-(3-trifluoromethyl ° than bit-2-yl) 1-3_氤 镂 ring "3丄〇1_氏二6-基-N-吴四琳- Process for the preparation of 5-based urea (compound No. 68) by adding 1,1-thiocarbonyldiimidazole to 1-isoindole_7-yl-3-{3-[3-(trifluoromethyl) at 〇 °C Pyridin-2-yl]-3-azabicyclo[3.1.〇]_hex-6_yl}_ thiourea (1.0 eq.), a stirred solution of triethylamine in anhydrous THF and stirred 3 〇 40 minutes. Then add a solution of isoindoline-5-amine (1.0 eq.) in anhydrous TfIF and stir for 8 to 1 hour. Purify by using the methanol and gas-mixed mixture as the dissolving agent 135 200813011. The solid residue obtained after removal of the solvent to give the product as a nearly pure white solid. W-NMRGOO MHz, DMSO-d6): 51.92-2.13 (m, 2H), 2.64 (s, 1H), 3.59 (d, 2H) , J = 10.5 Hz), 3.91-4.25 (m, 2H, J = 9.0 Hz), 6.85 (s, lH), 7.70 (m, 3H), 7.95 (d, 5 1H, J = 9.3 Hz), 8.09 ( d, 1H, J = 9.3 Hz), 8.33 (s, 1H), 8.52 (d, 1H, J = 5.7 Hz), 9.34 (s, 1H), 9.55 (s, 1H), 9.72 (s, 1H). IR (KBr) 3160, 2868, 1598, 1542, 1462, 1384, 1304, 1260, 1167, 1111 1092, 1018, 815, 759 cm _1 ; MS : [M+H]+ = 430.23 Melting point 191 to 192 ° C. 10 t Example 69 : 1 α,5α-丨6-(5•isoindolylamine Preparation of a certain amidino)-3-(3-pyridin-2-yl)1·3-azabicyclo "3·1.01 hexane (Compound No. 69) by stirring at room temperature 1 α,5 α ,6 α-[6-Amino-3-(3-apyridin-2-yl)]-3-azabicyclo[3·1·0]hexarene (intermediate 7) (1 mg, 〇 · 4651 millimoles) and a solution of phenyl-(5-aminoisoindoline-5-yl) carbamic acid phenyl ester (127 mg, 0.5116 15 mmol) in dimethyl hydrazine (5.0 mL) The reaction mixture was diluted with water (50 mL). EtOAc (EtOAc m. The residue obtained after removal of the solvent was purified by using a solution as a dissolving agent on a gel column to obtain 38 mg of product as a near-white solid. 20 IR (KBr): 3330, 2968, 1667, 1581, 1426, 1319 , 1237, 1042, 790 cm 1; h-NMRGOOMHz, CDC13): 5 1.90 (s, 2H), 2.62 (s, 1H), 3.62 (d, 2H, J = 9 .6 Hz), 4.29 (d, 2H, J = l 〇 .8 Hz), 6.73 (m, 1H), 7.65 (m, 2H), 7.90 (m, 1H), 8.08 (m, 2H), 8.47 (d, 1H, J=6.0 Hz), 9.23 (bs, 1H). The melting point is 245 to 247 〇C. (decomposition) 136 200813011 宜例70 : 1 αα , 6 α - "6-(5-isoporphyrinylaminocarboylamine v3-(5-methylacridinedi-2-ylindole-3diazepine) Preparation of 璟Β,ΐ·〇ΐhexane (Compound No. 7) by stirring at room temperature 1 α,5α,6α -[6-amino-3-(5-trifluoromethylpyridine 5-yl) ]_3_Azabicyclo[3丄〇]hexane (intermediate product 8) (100 mg, 0.4011 mmol) and N-(5-aminoisoindoline-5-yl)amino decanoate ( A solution of 127 mg (0.5116 mmol) in dimethyl acetonitrile (5 mL) was taken from EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removing solvent was purified by using a solution of 10 with 2.0% methanol in hexane as a solvent. For example, the product of a nearly pure white solid. IR (KBr): 3334, 297, 167, 1586, 1432, 132, 1245, 104, 793 cm-1; h-NMRpOOMHz, CDC13) J 1.95 (s, 2H), 2.40 ( s, 1H), 3.55 (d, 2H, J = 9.6 Hz), 3.82 (d, 2H, J = 10.8 Hz), 15 6.42 (bs , 1H), 6.62 (d, 1H, J = 8.7 Hz), 6.90 (s, 1H), 7.60 (m, 1H), 7.77 (m, 2H), 7.90 (s, 1H), 8.23 (m, 1H) , 8.39 (bs, 1H), 8.55 (d, 1H, J = 6.0 Hz), 8.62 (s, 1H), 9.27 (s, 1H). Melting point 195 to 197 ° C. (decomposition) Example 71:1〇 1,5〇;,6〇;-"6-(5-iso-n-linylamino) 8 basketsamino)-3-(3-20-trifluoromethylpyridin-2-yl)1-3-aza Double-loop "3.1.01 Hexane (Factor No. 71) is prepared by stirring 1 α,5 α,6α -[6-amino-3-(3-trifluoromethylpyridin-2-yl)] at room temperature 3-Azabicyclo[3丄0]hexane (intermediate product 9) (100 mg, 0.4011 mmol), N-(5-aminoisoquinolin-5-yl)carbamic acid phenyl ester (127 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removing the solvent by removing the solvent by using a solution of 2.0% methanol in a solvent as a dissolving agent to obtain 50 mg as near. Pure white The product of a color solid. IR (KBr): 297, 1669, 1578, 1428, 1325, 1249, 1033, 795 cm 1; h-NMR pOOMHz, CDC13): 5 1.87 (s, 2H), 2.38 (s, 1H), 3.61 (d, 2H) , J = 9.6 Hz), 3.96 (d, 2H, J = l 〇. 8 Hz), 6.86 (bs, 2H), 7.60 (t, 1H, J = 8.7 Hz), 7.70 (d, 1H, J = 7.8 Hz) ), 7.89 (d, 1H, 10 J = 5.7 Hz), 7.96 (d, 2H, J = 7.8 Hz), 8.24 (d, 1H, J = 6.3 Hz), 8.37 (bs, 1H), 8.54 (d, 1H, J = 6.0 Hz), 8.61 (s, 1H), 9.27 (s, 1H). The melting point is 201 to 203 ° C. λ Example 72 · 1 α-isoporphyrin 蚣 蚣 醯 醯 篡 V3-(3_ 气 methyl ring 1~3丄01 竿 72跋化15 compound) Method of stirring 1α , 5 α at room temperature , 6 a -[6-Amino-3-(2-chloro-5-trifluoromethyl ° °: 2_ base)]-3 rhythm bicyclo[3丄〇] hexane (intermediate product 1_〇mg , 0.40 moles of Ν-(5·aminoisoindolyl _5_yl) phenyl hydroxyacetate (127 mg, 0.5 U 6 mmol) in diterpene (5 〇 ml) solution The time-consuming 12 to 13 20 water-seeking (pen-liter) dilution reaction mixture was extracted with ethyl acetate (3). The combined layer was washed with water and dried over anhydrous Wei sodium. The solution was treated with 2.0% methanol in gas. After dissolving the solvent, the lyrium (4) is finely obtained as lion mg as near pure white solid. The refining point is 191 to ah, called: 2971, 1669, 1578, 138 200813011 1325, 1249, 1033, 795 cm 1 ; h-NMRpOOMHz, CDC13 ): (5 1.91 (s, 2H), 2.42 (s, lH), 3.80 (d, 2H, J = 9.6 Hz), 4.25 (d, 2H, J = 10.8 Hz), 6.88 (bs, 2H), 7.60 (t, 1H, J = 8.7 Hz), 7.77 (d, 1H, J = 7.8 Hz), 7.89 (d, 1H, J = 5.7 Hz), 7.99 (bs, 1H), 8.23 (d, 1H, 5 J) =6.3Hz), 8.41 (bs, lH), 8.54 (d, 1 H, J = 6.0 Hz), 8.61 (bs, 1H), 9.27 (s, 1H). [Ml] + 446. Example 73: 1α,5α·6α-"6_(5-iso-4-phenylaminocarbazide) Amino)-3-(3-Shoshyl hydrazin-2-yl) 1-3-indane bicyclic "3.1.01 Hexane (Compound No. 73) is prepared by stirring 1 α, 5 α at room temperature, 6 α -[6-Amino-3-(3-nitropyridine-2-10yl)]_3_azabicyclo[3.1.0]hexane (intermediate ιι) (ι 〇〇 mg, 0.45 mmol) a solution of phenyl N-(5-aminoisoindoline-5-yl)carbamate (127 mg, 0.51 mmol) in dimethyl hydrazine (5.0 mL), mp. The reaction mixture was diluted with water (50 mL), EtOAc (EtOAc m. The residue obtained after removing the solvent was purified by a hydrazine gel column to give 50 mg of product as a near-white solid. IR (KBr): 298, 1672, 1532, 1433, 1352, 1249, 1033, 795 cm 1 ; iH-NMR (300MHz, CDC13): (5 1.95 (s, 2H), 2.73 (s, 1H), 3.66 (d, 2H, J = 9.6 Hz), 4.31 (d, 2H, J = l 88 Hz), 5.50 (brs, 20 1H), 6.68 (m, 1H), 7_53 (t, 1H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.2 Hz), 7.79 (d, 1H, J=7_8Hz), 7.96 (brs, 1H), 8.08 (d, 1H, J=3.3Hz), 8.25 (d, 1H, J=7.5Hz), 8.47 (d, 1H, J=6.0Hz), 9.23 ( s, 1H). [M-l]+389. Melting point 162-164X:. Example 74: 1α,5α·6ηΜ6-(5-isoindolylamine, a carboxylamido)-3-(4- 139 200813011 house_three-butyl benzoyl ketone 3-indole bicyclic oxime 3.1. 01) method of preparation of 1:1 〇;, 5 〇;, 6 〇: -[6-(tris-butoxyaminomethyl fluorenyl)_3_(4_second phenyl fluorenyl)]- Process for the preparation of 3-azabicyclo[3.1.0]hexane 5 First from the addition of diethylamine and 4-tris-butylbenzhydryl chloride (98 mg, 〇5〇 mmol) to intermediate 12 (100) Mg, 〇·50 mmol) fully stirred in benzene. The reaction mixture is then heated to reflux for 7 to 8 hours. The reaction mixture was then cooled to room temperature, diluted with water (5 mL) andEtOAc. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The residue obtained after removing the solvent was purified via a hydrazine gel column using a solution of 1% methanol in chloroform as a solvent. 1H-NMR (300MHz, DMSO-d6): cn.32 (s, 9H), 5 1.44 (s, 9H), 1.60 (s, 2H), 2.61 (s, 1H), 3.42 (m, 2H), 3.78 (m, 2H), 6.19 (s, 1H), 7.45 (d, 2H, J = 8.1 Hz), 7.67 (d, 2H, 15 J = 8.4 Hz) 〇Step 2 · 1 a, 5 a, 6 a- [6-(5-isoindolylaminocarboxylamido)_3_(4_second-butylbenzylidene)]-3-azabicyclo[3丄〇]hexane is added by HCK5 .0 ml) saturated ethyl acetate 7 pan, 5 pan/pan_[6-(second-butoxycarbonyl_3_(4_t-butylbenzylidene))^_aza double 20 % seems to be 0 / hex (1 〇〇 mg, 〇 27 mmol) in a fully stirred solution in ethyl acetate and _ 5 to 6 hours. The residue obtained was treated with triethylamine (1·〇 ml) in dimethyl acetamide (10 ml), followed by the addition of bis(5-aminoisoindolyl) carbamic acid benzene. , Q•Mormo). It was then stirred at room temperature for 5 to 6 hours, diluted with water (5 liters) and extracted with ethyl acetate (3 χ 5 mL) 140 200813011. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the residue obtained after solvent removal was purified by using a 1% methanol in chloroform as a dissolving agent on a hydrazine gel column to give 100 mg as near-purity. The product of a white solid. IR (KBr): 2972, 1679, 1549, 1439, 1252, 1009, 835, 5 795 cm 1 ; 1 h-nmR (3 〇〇 MHz, DMSO-d6): δ 1.32 (s, 9H), 5 1.44 (s , 9H), 1.60 (s, 2H), 2.61 (s, 1H), 3.42 (m, 2H), 3.78 (m, 2H), 7.45 (d, 2H, J = 8.1 Hz), 7.67 (d, 2H, J = 8.4 Hz), 7.89 (d, 1H, J = 5.7 Hz), 7.99 (brs, 1H), 8.11 (d, 1H, J = 8.4 Hz), 8.23 (d, 1H, J = 6.3 Hz), 8.41 (bs, 1H), 8.54 (d, 1H, J = 6.0 Hz), 8.61 (s, 1H), 10 9.27 (s, 1H). [MM,: 427. Example 75: l-"3-(2,4-difluoro-p-yl-V3-indigobicyclo"3丄〇l FM-based]·3_(;2·-methyl_1-side gas-I·2- Process for the preparation of dihydroisotetralin-5-yl V-urea f compound No. 75) Step 1 : Multi-formation of 5-nitroisochromen-1-one 15 2-methyl-3_nitro group under tax mixing A solution of benzoic acid (5.08 g) in dry DMF (40 mL) eluting elute 1.62 g of the title compound (30° / ◦ yield). iH-NMR^CDCh, 300 MHz): 5 7·38-7·45 (ΑΒ q, J = 6.0 Hz and 9.9 Hz, 2H); 7.68 (t , 20 J = 7.5 Hz and 8.7 Hz, lH); 8.50 (d, J = 7.8 Hz, lH); 8.65 (d, J = 8.4 Hz, 1H). Step 2: 2-methyl-5-nitro- 2H-isoindol-1-one was prepared by refluxing a solution of 5-nitroisochromone 1-ketone (0.6 g) and methylamine (40%, 1 mL) in methanol (15 mL). After the solvent, the residue was extracted with EtOAc EtOAc EtOAc EtOAc EtOAc (EtOAc) 5--5-amino-2Η-isoindole Preparation of porphyrin ketone 2-methyl-5-nitro-2H-isoindolin-1-one containing palladium on carbon (0.25 g, 5 50% humidity) in a parr apparatus under 60 psi of hydrogen pressure A solution of 5 g) in methanol (20 ml) was subjected to a hydrogenation reaction. After the reaction was completed, it was filtered through celite, and the filtrate was evaporated to dryness to give 0.25 g of the title compound. DMSO-d6, 300 MHz): δ 3.46 (s, 3 Η); 5.65 (brs, 2H); 6.73 (d, J = 7.8 Hz, 1H); 6.84 (d, J = 7.8 Hz, 1H); 10 7.16 (t , J = 8.1 Hz, 1H); 7.33 (d, J = 7.2 Hz, 1H); 7.42 (d, J = 7.8 Hz, 1H). Step 4 ··· l-[3-(2,4-difluorobenzene) Benzyl-3-azabicyclo[3.1.0]hex-6-yl]winter (2-methyl-1-oxo-1,2-dihydroiso). Add phenyl chloroformate (1 equivalent) to a solution of 2-methyl-5-amino-2H-isoindoline 15-1-one (〇·25 g) in CH:2C12 (30 mL) The reaction mixture was stirred for 1 hour. The solution was then adsorbed onto a hydrazine gel and purified by column chromatography to give 0.1 g (2-methyl-1-yloxy-i,2-di Hydrogen isophthalene _5_yl)-amino benzoic acid benzene . This product was then added to 3_(2,4-difluorophenyl)-3-azabicyclo[3.1.0]hex-6-ylamine (0.067 g) and triethylamine 20 (0.5 mL) in DMS0 ( The reaction mixture was stirred in a solution of 5 ml) and allowed to stand at rt for 12 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Melting point: 205 to 210 ° C; IR (KBr, PCT-1): 3382, 3295, 1714, 1639, 1626, 1607, 1591, 1517, 1360, 142 200813011 1242, 1209, 1135, 1071, 948, 850 708; h-NMI^DMSCX, 300MHz): (5 1.80(s,2H); 2.59(s,1H); 3.22(d,J=8.7Hz,2H); 3.49(s,3H) ; 3.66(d , J = 1.8 Hz, 2H); 6.63 (d, J = 7.5 Hz, 1H); 6.74 (brs, 2H); 6.90 (br t, 1H); 7.10 (br t, 1H); 7.38 (br t, 1H); 5 7.51 (d, J = 7.2 Hz, 1H); 7.87 (d, J = 7.8 Hz, 1H); 8.08 (br d, 1H); 8.28 (br s, 1H). Example 76: Using 45 Calcium Screening of TRPV1 antagonists by absorption assays 10 TEPV1 receptor activation following inhibition of cellular uptake of capsaicin-induced radioactive calcium, which means calcium only via the cell membrane associated with the TRPV1 receptor Inhibition: Substance: Prepare a stock solution of capsaicin in ethanol and prepare the test compound in 1% DMSO. Dilute the stock solution to the appropriate final concentration in the assay buffer to maintain the final DMSO concentration at 0.1%. Between 0.55% and 15 0.25 microcurie/ml (pCi/ml) (4545Ca, ICN) final concentration of 4 5Ca. The assay buffer consisted of F-12 DMEM medium supplemented with 1.8 mM CaCl2 (final concentration) and 0.1% bovine serum albumin (BSA from SIGMA). The cleaning buffer was 0.1% BSA and 1.8. mM calcium supplemented with Tyrodes solution. Dissolved buffer containing 50 mM Tris-HCl (pH 7.5), 20 150 mM NaC Bu 1% Triton X-100, 0.5% deoxycholate and 0.1% sodium lauryl sulfate (SDS, SIGMA) Method: The assay was performed using a partially modified version as described by Toth et al. (see Toth A et al, Life Science 73 p 487-498, 2003) with 10% FBS (fetal) at 143 200813011 Bovine serum Hyclone), 1% penicillin-streptomycin solution, and 400 μg/ml G-418 F-12 DMEM medium (Dulbecco's modified Eagle's medium-GIBCO) Human TRPV1 expressive CHO cells. Cells were grown in 96# plates 48 hours prior to assay to obtain ~50,000 cells per day on the day of the experiment. The plates were incubated at 37 ° C in the presence of 5% CO 2 . The cells were then washed twice with 200 microliters of assay buffer and resuspended in 144 microliters of the same solution. The measurement was carried out at 30 ° C in a total volume of 200 μl. The test compound was added to the cells 10 minutes before the addition of capsaicin. The final concentration of capsaicin in this assay was 250 nM. After 5 minutes of treatment with the agonist, the drug was washed away and each well was washed 3 times with 3 liters of microliters of ice-cold wash buffer. The cells were lysed in 50 microliters of lysis buffer for 20 minutes. 40 microliters of cell lysate was mixed with 150 microliters of Microscint PS to allow the instrument to equilibrate. The radiation of the samples was measured in counts per minute (cpm) using a packard Bioscines 15 ToP Count. The 45Ca absorption value treated by the drug/vehicle/capsaicin was normalized to the base 45Ca value. The data is expressed as % inhibition of 45Ca uptake induced by the test compound relative to the maximum 45Ca absorption value induced only by capsaicin. The IC5 〇 value was calculated from the dose response 2〇 curve using the nonlinear regression analysis of the GraphPadPRISM software. The results are summarized in Tables 2 and 3 below: Table 2 Inhibition of compound number IC5〇(nM) at a concentration of 300 nM % 1 — L39~~~ 2 — 3.41 3 -- 8.44 4 122.9 69.01 144 200813011 5 -- 46.36 6 -- 5.53 7 71.12 99.98 8 117.2 95.99 9 146.1 98.83 10 -- 34.28 11 220.6 98.63 12 174.6 92.81 13 592.5 92.56 14 -- 44.93 15 — 34.53 16 202.9 70.58 17 194.8 84.21 18 160.4 95.62 19 -- 12.32 20 -- 15.45 21 29.6 95.73 22 126.6 82.51 23 297.9 66.65 24 -- 31.63 25 -- 28.05 26 33.1 95.27 27 193.8 62.36 28 -- 41.91 29 -- 44.23 30 77.98 64.21 31 114.0 72.07 32 305.8 58.66 33 297.9 59.37 34 140.9 78.96 35 30.58 -- 36 64.33 -- 37 46.8 -- 38 38.19 -- 39 -- 5.33 40 -- 33.45 41 -- 15.90 42 -- 16.06 43 -- 1.26 44 -- 15.47 45 -- 19.01 46 -- 12.01 47 -- 9.56 48 -- 1.65 49 -- 5.32 50 -- 25.26 51 -- 14.53 52 -- 10.52 53 -- 8.49 55 -- 3.77 56 -- 2.31 57 -- 13.76 58 -- 30.47 59 -- 21.02 145 200813011 60 -- 36.84 61 -- 5.79 62 -- 0.00 63 -- 11.05 64 -- 41.16 65 -- 32.46 6 6 — 30.36 67 -- 100.00 Table 3 Inhibition of compound number IC5〇(nM) at ΙμΜ concentration 7 71.21 99.98 9 146.1 98.83 11 220.6 98.63 12 174.6 92.81 13 592.5 92.56 64 -- 41.16 67 136.9 100.00 69 -- 94.63 70 -- 85.87 71 -- 100 72 -- 99.07 73 -- 1.22 L Simple description of the figure 3 5 (None) [Key component symbol description] (None) 146

Claims (1)

200813011 X. Patent application scope: 1.·, compound of general formula (I) a drug, a pharmaceutically acceptable salt thereof, an N-oxide thereof, an ester thereof, a catalyzed compound thereof, a tautomer thereof, a stereoisomer thereof or a polymorph thereof, wherein: X is hydrazine or s ; R1 is selected from 〇 wherein R 1 is attached to the main structure via any carbon atom in the ring, and may be optionally substituted with one or more R groups; R and R 6 are independently selected from the group consisting of hydrogen, nitro, and cyanide in each occurrence. Methyl, decyl, ethenyl, halogen, -OR7, -SR7, pendant oxy, thio, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted ring 147 200813011 alkenyl, substituted or unsubstituted ring Filament, substituted or unsubstituted aryl, substituted or unsubstituted ruthenium, substituted silk, disubstituted heterofilament, peak or unsubstituted base, substituted or not丝代之杂县, Nadaisi substituted heterocyclic group 5 counties, _C(〇)R7, -C(〇)〇-7, -C(0)NRV, -NR7R8, S(〇)mr, ^ (OLnrJrs, and a protecting group; R and R are independently selected from the group consisting of hydrogen, nitro, dentate, cyano OR, _SRa, pendant oxy, thio, substituted or unsubstituted alkyl. A substituted or unsubstituted alkenyl group, a substituted silk substituted by a 10th wire, a county or an unreacted cyclofilament, a substituted or unsubstituted % alkylalkyl group, a substituted or unsubstituted ring Alkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted heteroarylalkyl, substituted or unsubstituted 15 heterocyclic, substituted or unsubstituted heterocyclylalkyl, _C(〇)R, _C(〇)〇_Ra , c(〇)NRaRb 8 (〇) claw Ra, -S(〇)m_NRaRb, _NRaRb, and a protecting group, or RW, when directly bonded to the same nitrogen atom, are formed together with the nitrogen atom to which they are attached a substituted 3 to 7 membered saturated or unsaturated ring system ring which may include one or more heteroatoms selected from the group consisting of ruthenium, NRa and S; RlRb is independently selected from the group consisting of ruthenium and halogen at each occurrence. , nitro, cyano, decyl, ethane, oxime, thio, _c(〇&gt;Rc, -C(〇)〇-Rc ^ -C(〇)NRcRd . -S(0) m-Rc &gt; -S(0)m-NRcRd ^ -NRe Rd, -ORe, _SRd, protecting group, substituted or unsubstituted 148 200813011 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl a 5-substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic group, and Substituted or unsubstituted heteroarylalkyl; RlRd, when present, is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted saccharide, substituted or unsubstituted 1〇 substituted silk, substituted or unsubstituted cyclofilament, substituted or unsubstituted % alkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenyl Substituted, substituted or unsubstituted aryl, substituted or unsubstituted, substituted or unsubstituted Heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted 15-heterocyclic nucleus, substituted or unbranched nucleus and protecting group, or RlR, directly bonded to the same The nitrogen atom is bonded to the nitrogen atom to which they are attached to form a optionally substituted (1) saturated and unsaturated cyclocyclic ring, which may optionally include - or a plurality of heteroatoms selected from the group consisting of ruthenium, NRe or S. ; 0 Re at each time 立 is selected from hydrogen and substituted or unsubstituted alkyl; m is independently 〇, 1 or 2 in each occurrence; R2 and R3 are independently selected from hydrogen, thiol And Cm alkyl; and R4 and R5 are each independently selected from the group consisting of hydrogen, sulfonamide, and alkane 149 200813011, or when R4 and R5 are bonded to the same carbon atom, r1r5_ can form a pendant oxy group or Sulfur based. 2. A compound as claimed in claim 1, wherein R6 is not a substituted or unsubstituted pyrimidine. 5 3. A compound of claim 1 or 2 wherein R6 is not a substituted or unsubstituted tare base. 4. A compound according to any one of claims 3 to 3 wherein R1 is not a substituted or unsubstituted amine group. 5. A compound according to any one of claims 4 to 4, wherein R1 1 is a substituted or unsubstituted porphyrin, a substituted or unsubstituted porphyrinone, substituted or unsubstituted Isoporphyrin or substituted or unsubstituted iso-quinone. The compound of any one of claims 1 to 5, wherein R1 is a substituted or unsubstituted 15 porphyrin or isoindoline linked to a nitrogen at the 5th, 6th, 7th or 8th position. The compound of any one of claims 1 to 6, wherein R1 is a substituted or unsubstituted isoindoline attached to the nitrogen of the fifth position. 8. The compound of any one of claims 1 to 7 wherein R2, R3, R4 and R5 are hydrogen. The compound according to any one of claims 1 to 8, wherein the compound is further. The compound of any one of claims 1 to 9 wherein R6 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or not Substituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or 150 200813011 unsubstituted heteroaryl, substituted or unsubstituted An arylalkyl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclylalkyl group, C(0)R7, C(0)OR7 or S(0)mNR7R8. 11. A compound according to claim 10, wherein R6 is substituted or unsubstituted heteroaryl, C(0)R7, C(〇)〇R7 or S(0)mNR7R8. 12. A compound of the formula (la) 10 Or a prodrug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, an ester thereof, a solvate thereof, a tautomer thereof, a stereoisomer thereof or a polymorph thereof, wherein R2, R3, R4 and R5 is 氲; R6 is substituted by silk, H纟 recorded money unsubstituted = alkyl, modified silk substituted by the base or C〇〇R7; and R is substituted or unsubstituted aryl is 13· For example, the land of the 12th patent application. a pharmaceutically acceptable substance wherein the substituent is selected from the group consisting of methyl, isopropyl, tert-butyl, benzyl, methoxy, cyclopropylmethoxy, difluoromethoxy, tri-methoxy'&quot; Ethylamino, difluoroacetamido or formazan. 151 20 200813011 14. The compound of claim 12, wherein R6 is a substituted or unsubstituted aryl group. 15. The compound of any one of claims 14, wherein R6 is selected from the group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl , 5 2,4-diqi, 2,6-dioxa, 3,4-diphenyl, 3,5-diphenyl, 2,3,4-trifluorophenyl, 2 ,4,5·trifluorophenyl, 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-isopropyl Phenylphenyl, 4-isopropylphenyl, 4-tri-butylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 4·trifluoromethylphenyl, 2·Difluoromethoxyphenyl, 10 2-trifluoromethoxyphenyl, 2-fluoro-5-methylphenyl, 2-cyclopropylmethoxyphenyl, 2-fluoro-3-difluoro i methylphenyl, 2-difluoromethoxyphenyl, 2-fluoro-5-difluoromethylphenyl, 2-vapor-4-difluoromethoxyphenyl, and 2-fail-4-methyl Phenyl. 16. The compound of claim 12, wherein R6 is an aralkyl group. 17. The compound of claim 16, wherein R6 is selected from the group consisting of a benzyl group, a 15-4-gas group, and a 4-dimethyl group. 18. The compound of claim 12, wherein R6 is a heteroaryl group. 19. The compound of any one of claims 18, wherein R6 is selected from the group consisting of 3-(ethylamido)pyridin-2-yl, 3-(trifluoroethenylamino)pyridine-2- Base, 3-(carbophyllotoxyl) π than bit-2-yl, 3,5-dichloroindole 11 quinol-2-yl, 20 3-&gt; odor 17 to 11-but-2-yl, 5-dimethylmethyl 11 to 11-but-2-yl-3-gas 17 to 0--3-yl, 3-gas-5-diox π ratio 11-but-2-yl, 3-stone sigma σ ratio σ The quinol-2-yl, 3-dihydromethyl σ ratio is 11 -2-yl and 5- fluorenyl-0 to 1^_2-yl. 20. The compound of claim 12 or 13, wherein R6 is S〇2Ar 〇 152 200813011 21. The compound of claim 20, wherein R6 is selected from the group consisting of 4-pyrrolite, 4 -Two-gas methylbenzene dye base, 4-gas benzene continuous brewing base, 2-6-digas benzene brewing base, 2,6-digas benzene brewing base, 2,4-two&gt; Stuffed base, 2,4-dichlorobenzenesulfonyl, 2-trifluoromethylbenzenesulfonyl, 2-fluorobenzenesulfonyl, 5 2-chlorobenzenesulfonyl, 2-bromobenzenesulfonyl, benzene Sulfosyl, 4-bromobenzenesulfonyl, 4-iodobenzenesulfonyl or 4-methylbenzenesulfonyl. 22. The compound of claim 12, wherein R6 is -COAr. 23. The compound of claim 22, wherein R6 is selected from the group consisting of 4-bromobenzene 10 mercapto, 4-chlorobenzylidene, 3-fluorobenzhydryl, 2-bromobenzylidene , 2-fluorobenzhydryl, 2-chlorobenzylidene, 4-methylbenzhydryl, 2-trifluoromethylbenzhydryl, 4-trifluoromethylbenzhydryl, 4- Tertiary-butylbenzylidene and 4-benzylbenzimidyl. 24. A compound selected from the group consisting of: 15 1 α,5 α,6α -[6-(5-iso. quinalylamino-propionyl)-3-(3-ethylguanidinoylpyridine) -2-yl)]-3-azabicyclo[3.1.0]hexane, 1 ,5 ,6〇! -[6-(5-(iso-σ quinolinyl amidino)-3-( 3-difluoroacetamidopyridine 2 -yl)]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-isoindolylamine Carboxylamido)_3·(3-methyl 20 sulfonylaminopyridin-2-yl)]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6 -(5-iso-σ-quinolinyl-propionylamino)-3-(3-(3,5-dioxa)pyridin-2-yl)]-3-azabicyclo[3.1.0]hexane , 1 α,5 α,6α-[6-(5-isoindolinylaminocarbamoylamino)-3-(3-bromopyridine-2-yl)]-3-azabicyclo[3.1.0 ]Hexane, 153 200813011 1 ο;,5 (2,6〇! -[6-(5-isoindolyl-based amido)-3-(5-stone-succinyl-2-yl)]- 3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-isoindolylcarbamoylamino)-3-(2-fluorophenyl)] 3-Azabicyclo[3.1.0]hexane, 5 1 α,5 α,6α -[6-(5-isoindolylcarbamoylamino)-3-(4-fluorophenyl) ]-3- Heterobicyclo[3.1.0]hexane, 1 α,5 α,6α -[6-(5-isoindolylaminocarboxylamido)-3-(4-isopropylphenyl)]-3 -azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-isoindolylcarbamoylamino)-3-(2-methyl10-oxyphenyl) )]-3-azabicyclo[3.1.0]hexane, 1 α ,5 α,6α -[6-(5-isoindolylcarbamoylamino)-3-(4-third- Butylphenyl)]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6α -[6-(5-isoindolylcarbamoylamino)-3-(2 ,4-dimethylphenyl)]-3-azabicyclo[3.1.0]hexane, 15 1 α,5 α,6 α -[6-(5•iso. Kui 1 lysylamine-based Wei Amino)-3-(4-trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-isoindolyl Aminocarboxylamido)-3-((4-methoxy)phenyl)]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5 -isoindolylcarbocarboxamide 20 yl)-3-(3,4,5-trifluoro)phenyl]-3-azabicyclo[3·1·0]hexane, 1 λ, 5 ck, 6ύ! -[6-(5-iso-linylamino-branched amino)-3-(2-difluoromethoxy)phenyl]-3-azabicyclo[3.1.0]hexane, 1 α,5α,6α - [6-(5-Isoindolinylaminocarboxylamido)-3-(3,4-difluoro)phenyl]-3-azabicyclo[3.1.0]hexane, 154 200813011 1〇:, 5〇:,6〇!-[6-(5_isoindolyl-based amidoamino)-3-(2-a-5-methyl)phenyl]-3-azabicyclo[3.1. 0]hexane, 1 α , 5 α,6 α -[6-(5-iso-σ-quinolinyl-propionylamino)-3-(3-fluoro)phenyl]-3-azabicyclo[ 3.1.0] Hexane, 5 1 α,5 α ,6 α -[6-(5-isoindolyl)-indenylamino)-3-(3-fluoro)phenyl]-3-aza Bicyclo [3.1.0] hexane, 1 ύ!, 5 〇!, 6 ύ! -[6-(5-iso-indolyl amide amino)-3-(2,4-difluoro)phenyl ]-3-Azabicyclo[3·l·0]hexane, 1 α,5 ΰ:,6 α -[6-(5-isoindazylaminoguanidino)-3-(2, 6-10 Difluoro)phenyl]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-iso.奎 基 胺 胺 羧 ) -3 -3 -3 - (2-fluoro-3-trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6α -[ 6-(5·Isoindolinylaminocarboxylamido)-3-(2-trifluoromethoxy)phenyl]-3·azabicyclo[3.1.0]hexane, 15 1 α,5 α,6α -[6-(5-isoindolylaminocarboxylamido)-3-(2-trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -{6-(5-isoindolyl)-indenylamino-3-[2-fluoro-(5-trifluoromethyl)phenyl]}-3-aza Bicyclo[3·1·0]hexane, 1 α,5 α,6 α - {6-(5-isoindolylcarbamoylamino)-3-[2-fluoro 20 -(4_two Fluoromethoxy)phenyl]}-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-iso-4 °-linylamino-propylamino) -3-(2,3,4-trifluoro)phenyl]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-iso-allinylamine Resinylamino)-3-(2,4,6-trifluoro)phenyl]-3-azabicyclo[3.1.0]hexane, 155 200813011 1 α,5α,6α -[6-(5 -isoporphyrinylaminocarboxylamido)-3-(2,3-difluoro)phenyl]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[ 6-(5-isoporphyrin Aminocarboxylamido)-3-(2-fluoro-4-methylphenyl)phenyl]-3-azabicyclo[3.1.0]hexane, 5 1〇!,5(2,6(2) -[6-(5-iso-1? quinolinylamino)amino-3-(2-isopropyl)phenyl]-3-azabicyclo[3.1.0]hexane, 1 ,5fl :,6cj: -[6-(5-(iso-supplerylinylamino)-(3,5-difluorophenyl)l-3-azabicyclo[3.1.0]hexane , 1 α,5 α,6 α -[6-(5-iso-junylamino-propionamide 10-yl)_3-(2,4,5-trifluorophenyl)]-3-azabicyclo[ 3.1.0] Hexane, 1 ύ!,5 ΰ:,6ύ! -[6-(5-iso-quinuclidylamino-brown amine)-3-(2,4-difluorophenyl)] 3-Azabicyclo[3.1.0]hexane trifluoroacetate, 1 ΰ!,5 ο;,6ύ: -[6-(5-isoindolyl hydrazide s-amino)-3- (2,4-difluorophenyl)]_3-azabicyclo[3·l·0]hexane trifluoromethanesulfonate, 15 1 α,5 α,6 α -[6-(5-iso唆 基 胺 胺 醯 ) ) ) -3- -3- 3-(2,4-difluorophenyl)]-3-azabicyclo[3.1.0]hexane hydrochloride, 1 ο;, 5 ύ!,6 (2-[6-(5-(Iso-σ-Quinyl)-amino-propylamino)-3-(2,4-difluorophenyl)]-3-azabicyclo[3.1.0]hexanehexane sulfonate Acid salt, 1 α,5 α,6 α -[6-(5-iso喳 基 胺 胺 醯 ) ) ) -3- -3- ( ( ( ( ( ( ( ( ( ( ( 3 3 3 3 3 3 3 3 3 3 3 3 3 3 α α α α α α α α α α α α (5-isoindolinylcarbamoylamino)-3-[4-(trifluoromethyl)phenyl]sulfonyl-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-isoindolinylaminocarbamoylamino)-3-(4-fluorophenyl)sulfonyl]-3-azabicyclo[3.1.0]hexane, 156 200813011 1 α,5 α,6 α -[6·(5·iso 4: lysylamino ruthenium)_3-(2,6-dichlorophenyl)sulfonyl]-3-azabicyclo [3.1.0]hexane, 1 α,5 α,6 α -[6-(5-isoindolylaminocarbamoylamino)-3-(2,6-difluorophenyl)sulfonyl ]-3-Azabicyclo[3.1.0]hexane, 5 1 α ,5 α,6α -[6-(5-isoindolinylaminocarbamoylamino)-3-(2,4-dibromo Phenyl)sulfonyl]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 a -[6-(5-isoindolylaminocarbamoylamino)-3- (2,4-dichlorophenyl)sulfonyl]-3-azabicyclo[3.1.0]hexane, 1 a,5 a',6 a -[6=(5isoporphyrinylaminocarboxylate Amidino)-3-(2-tris10fluoromethylphenyl)sulfonyl]-3-azabicyclo[3.1.0]hexane, 1 λ,5 ο:,6 -[6-(5 -different. ° 林 胺 胺 竣 竣 胺 胺 胺 胺 胺 -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- -3- , , , , , , , , , , , , , -(5-isoindolylaminocarbamoylamino)-3-(2-chlorophenyl)sulfonyl]_3_azabicyclo[3.1.0]hexane, 15 1〇!, 5〇! ,6〇!-[6-(5-iso 17 quinolinylamino-branched amine)-3-(2-&gt;odor phenyl)sulfonyl]_3_azabicyclo[3.1.0] Alkane, 1 6K, 5 , 6〇! -[6-(5-isoindolequinylamino-branched amine)-3_(phenylsulfonyl)]-3-azabicyclo[3.1.0] Hexane, 1 ύ!,5 ύ!,6-[6-(5-iso-5 林 林 胺 胺 竣 竣 -3-)-3-(4-&gt; odor 20 phenyl) sulfonyl]-3 - azabicyclo[3.1.0]hexane, 1 ck, 5 ck, 6ck -[6-(5-isoindolylamine-branched amine)-3-(4-lycopene)sulfonate 3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5-isoindolinylaminocarbamoylamino)-3-(4-methyl Phenyl)sulfonyl]-3-azabicyclo[3.1.0]hexane, 157 200813011 1〇!,5〇!,6 61!-[6-(5-iso-linylamine-based amine ))-3-(4-'/odorobenzylidene)]-3-azabicyclo[3.1.0]hexane, 1 a,5 d,6 ο: -[6-(5-iso-line Aminoguanidine Amino)-3-(4-chlorobenzylidene)]-3-azabicyclo[3.1.0]hexane, 5 1α,5ύ!,6ύ!-[6-(5-iso-indolyl Amino-based arylamino)-3-(3-disindolyl)]-3-azabicyclo[3.1.0]hexane, 1 ύ!,5 ο;,6ύ! -[6-(5 - heterophilic °-based amine-based amide amino)-3-(2_ &gt; odorobenzyl)]-3-azabicyclo[3.1.0]hexane, 1 ύ!, 5 (2,6 [; -[6-(5-isoindolinylamino 竣S basket amine)-3-(2- gas 10 benzylidene)]-3-azabicyclo[3.1.0]hexane, 1 {3!,5〇!,6〇!-[6-(5-iso-linylamino 竣1-lanyl)-3-(2-phenanthryl)]-3-azabicyclo[ 3.1.0] Hexane, 1 α,5 α,6α -[6-(5-isoindolinylaminocarbamoylamino)-3-(4-methylbenzylidene)sulfonyl]- 3-Azabicyclo[3.1.0]hexane, ”15 ΐ6ϋ,56ϋ,6ύ!-[6-(5-isoindolylamine amide amino)-3_(2·difluoromethyl)benzene Methiol]-3-azabicyclo[3.1.0]hexane, 〇1 α,5 α,6 α -[6-(5-isoindolylcarbamoylamino)-3-(4 _三·fluoromethylbenzhydryl)]-3-azabicyclo[3.1.0]hexane, , 1 α,5 α,6 α -[6-(5-isoindolylaminocarbazide Amino)-3-( 4-bromo 20 benzylidene)]-3-azabicyclo[3.1.0]hexane, 1〇!,5〇!,6〇!-[6-(5-iso-linylamino decanoic acid Amino)-3-(4-pyrimidinyl)]-3-azabicyclo[3.1.0]hexane, 1 ύ!,5 (2,6〇! -[6-(5- Jun. Alkylamino-branched amine)-3-(4-carbobenzyl)]-3-azabicyclo[3.1.0]hexane, 158 200813011 1 α,5α,6α _[6-(5- Porphyrinylaminocarboxylamido)_3-(small tris.fluoromethylbenzyl)]-3-azabicyclo[3.1.0]hexane, 1 α,5 α,6 α -[6-(5 -isoporphyrinylaminocarboxylamido)-3-benzene, yl]-3-azabicyclo[3·1·〇]hexane, .5 Ν-[3-(3-fluoromethylpyridine_ 2_基)]冬氮杂双环[3·1·〇]-hex-6-yl-Ν-iso-0-quine-5-base, 1 α,5α,6α _[6-(5-isoindole Lolinylaminocarboxylamido)-3-(3-chloropyranyl-2-yl)]-3-azabicyclo[31〇]hexan, i 1 α,5α,6α-[6Η5-iso Porphyrinylaminocarboxylamido)-3-(5-tris10fluoromethylpyridin-2-yl)]-indole azabicyclo[3.1.0]hexane, 1 α,5 α,6 α - [6-(5-Isoindolinylaminocarboxylamido)_3_(3-a-5-··difluoromethylpyridyl)]-3-azabicyclo[3丄〇]hexane, . 1 α,5 α,6 α -[6 gas 5-isoindolinylaminocarboxylamido)·3-(3-chloro-5-trifluoromethylpyridin-2-yl)] azabicyclo[ 3丄〇]hexane, 15 1 α,5α,6α isoindolinylaminocarboxylamido)-3-(3-nitroguanidine) σ 啶 -2- -2-yl servative 3-azabicyclo[3.1.0] hexane, 1 α,5 α,6 α -[6_(5-isoindolylaminocarbamoylamino)_3_(4 _Third_butylbenzyl alcohol)]_3_azabicyclo[3·1〇]hexane, 2〇丨7々, 4·difluorophenyl)_3·azabicyclo[3.1.0] _6_yl]3-(2-methyl-small-oxydihydroisoindolyl-5-yl)urea, or a rigid drug thereof, a pharmaceutically acceptable salt thereof, an N-oxide thereof, a vinegar thereof, or a pharmaceutically acceptable salt thereof a compound, a tautomer thereof, a stereoisomer thereof or a polymorph thereof. 5. The pharmaceutically acceptable salt of any one of claims 1 to 24 wherein the salt is selected from the group consisting of the following inorganic acid addition salts: hydrochloride, sulfur 159 200813011 5 10 15 20 acid salt, Phosphate or benzoate; and the following organic acid addition salts: acetate, trifluoroacetate, oxalate, cis-butane, tri-m-acid, tartrate, citrate, A Fine acid salt, albino salt and cinnamic acid salt. 26. A pharmaceutical composition comprising - a compound as claimed in claim 3 and/or a pharmaceutically acceptable diluent, diluent or excipient. A method for preventing, ameliorating or treating a disease P premature or symptomatic by a vanilla extractor, which comprises administering a therapeutically effective amount to a patient in need of the therapy, such as A compound of any of the 26 items. 'Please turn to the method of item 27, where the disease, disorder or symptom of the vanilla extract, &quot; is a pain or inflammatory disease, disorder or symptom mediated by VR1. 29 = The method of claim 27 or 28, wherein the disease, disorder L symptom is selected from the group consisting of pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, postoperative pain, toothache, cancer pain, lack of Bloody myocardium = heartache 'migraine, pain caused, joint pain, neuropathy k, neuralgia, tri- and neuralgia, nerve damage, diabetic neuropathy: neurodegeneration, retinopathy, neuropathic skin disease, Stroke, bladder T allergy, urinary incontinence, chronic genital pain, gastrointestinal disease (such as colorectal irritation (IBS), gastroesophageal reflux disease (GERD), enteritis, ileitis, stomach _ duodenum, inflammatory bowel disease, cloning Symptoms, milky diarrhea, monthly inflammation (such as mumps), respiratory disorders (such as allergic and non-allergic nose) 160 2〇〇813〇u inflammation, asthma or chronic obstructive pulmonary disease), skin, eye or mucous membrane irritation, dermatitis, pruritus (such as uremia pruritus), rising body temperature, muscle cramps, vomiting, difficulty in movement, depression , Huntington's disease, memory deficiency, 5 _ sexual brain function, sclerosing muscular atrophy (ALS) H, Guan Langyan, osteoarthritis, diabetes, obesity, urticaria, actinic keratosis , horny acanthosis mni Ai, tinnitus, hyperesthesia, anxiety and benign prostate hypertrophy. A method of treating pain in a patient in need of such therapy, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 26 of the patent application. 31. The method of claim 3G wherein the pain is acute pain. 32. The method of claim 3G, wherein the (4) is chronic pain. 33. The method of claim 3, wherein the pain is post-operative pain. 34. A method of treating neuropathic pain in a patient in need of such therapy, comprising 15 administering to the patient a therapeutically effective amount of a compound as claimed in any one of claims ii to 26. 35. A method of treating urinary incontinence in a patient in need of such therapy, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-6 to 26. 2. A method of treating overactive bladder or benign prostate hypertrophy in a patient in need of the therapy, which comprises administering to the patient a therapeutically effective amount, such as any one of claims 1 to 26 of the patent application scope. compound of. 37. A method of treating ulcerative colitis in a patient in need of such therapy, comprising administering to the patient a therapeutically effective amount of a compound as claimed in any one of claims 161, 200813011 to 26. 38. A method of treating asthma in a patient in need of such therapy, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 26. A method of treating inflammation in a patient in need of such therapy, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 26. 40. - a compound of formula 26, R6 26 1〇 wherein R 4 and R 5 are hydrogen, and R 6 is selected from the group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-diphenyl, 2,4- Diphenyl, 2,6-diphenyl, 3,4-diphenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-tri Fluorophenyl, 15 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-isopropylphenyl , 4-isopropylphenyl, 4-tris-butylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-di Fluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2-fluoro-5-methylphenyl, 2-cyclopropylmethoxyphenyl, 2-ox-3-di-methylbenzene Base, 20 2-dimethoxyphenyl, 2-a-5-difluoromethylphenyl, 2-lac-4-pyrene 162 200813011 methoxyphenyl, 2-fluoro-4-methyl Phenyl, benzyl, 4-abenzyl, 4-trifluoromethyl, 4-chlorophenylsulfonyl, 4-trifluoromethylphenylsulfonyl, 4-fluorophenylsulfonyl , 2,6-dichlorophenylsulfonyl, 2,6-difluorophenylsulfonyl, 2,4-dibromophenylsulfonyl, 2,4-dichlorophenylsulfonyl-2 -3 5 fluoromethylphenylsulfonate Base, 2-fluorophenylsulfonyl, 2-oxophenylsulfonyl, 2-bromophenylsulfonyl, phenylsulfonyl, 4-bromophenylsulfonyl, 4-iodophenylsulfonate Sulfhydryl, 4-methylphenylsulfonyl, 4-bromobenzylidene, 4-chlorobenzhydryl, 3-fluorobenzhydryl, 2-bromobenzylidene, 2-fluorobenzamide Sulfhydryl, 2-chlorobenzhydryl, 4-methylphenylhydrazino, 2-trifluorodecylbenzoquinone 10 fluorenyl, 4-trifluoromethylphenylhydrazino, 4-benzylbenzyl Indenyl, 3-(ethionylamino)pyridin-2-yl, 3-(trifluoroethylamino)pyridin-2-yl, 3-(anthracene amine) 0-bite-2- Base, 3,5-dichloro, 3-&gt; odor-2-yl or 5- stone choline ratio. Set -2_ base. 41. A compound of formula 6a' PGHy Wherein R 4 and R 5 are hydrogen, and R 6 is selected from the group consisting of phenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl. , 2,6-difluorophenyl, 3,4-difluoro 20 phenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluorophenyl , 2,4,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2-methoxyphenyl, 4-methyl 163 200813011 oxyphenyl, 2-isopropylphenyl, 4 -isopropylphenyl, 4-tri-butylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-difluoroindole Oxyphenyl, 2-trifluoromethoxyphenyl, 2-fluoro-5-methylphenyl, 2-cyclopropylmethoxyphenyl, 2-fluoro-3-trifluoromethylphenyl, 5 2-difluoromethoxyphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-icon-4-difluoromethoxyphenyl, 2-fluoro-4-methylphenyl, benzyl , 4-a-benzyl, 4-trifluoromethyl, 4-chlorophenylsulfonyl, 4-trifluoromethylphenylsulfonyl, 4-fluorophenylsulfonyl, 2,6 -dichlorophenylsulfonyl, 2,6-difluorophenylsulfonyl, 2,4-dibromophenylsulfonyl, 2,4-dichlorophenylsulfonyl-2-trifluoro Methylphenylsulfonyl, 2-fluoro Sulfosyl, 2-chlorophenylsulfonyl, 2-bromophenylsulfonyl, phenylsulfonyl, 4-bromophenylsulfonyl, 4-iodophenylsulfonyl, 4-methyl Phenyl sulfonyl, 4-bromobenzylidene, 4-chlorobenzhydryl, 3-fluorobenzhydryl, 2-bromobenzylidene, 2-fluorobenzhydryl, 2-chloro Benzyl fluorenyl, 4-methylbenzhydryl, 2-trifluoromethylbenzyl 15-decyl, 4-trifluoromethylbenzhydryl, 4-benzylphenylhydrazino, 3-(B Hydrazinyl) σ than -2-yl, 3-(dihydroethylamino) 0 to 唆-2-yl, 3-(methyl sulphate) σ ratio 17-but-2-yl 3,5-dioxane 0 is 0-but-2-yl, 3-&gt; odor-2-yl or 5-cisyl-0 is 0-but-2-yl, and PG is an anthracene-protecting group. 20 42. If the compound of claim 7 is applied, 164 200813011 wherein R 4 and R 5 are hydrogen, and R 6 is selected from the group consisting of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluoro Phenyl, 2,6-difluorophenyl, 3,4-difluoro 5 phenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluoro Phenyl, 2,4,6-diphenylphenyl, 3,4,5-diphenylphenyl, 2-methyllacylphenyl, 4-methoxyphenyl, 2-isopropylphenyl, 4 -isopropylphenyl, 4-tri-butylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-dimethoxy Oxyphenyl, 2-dienyloxyphenyl, 2-dis-5-methyl-10-phenyl, 2-ylidepropylmethoxyphenyl, 2-nitro-3-dimethylbenzene , 2-difluoromethoxyphenyl, 2-fluoro-5-difluoromethylphenyl, 2-vapor-4-difluoromethoxyphenyl, 2-fluoro-4-methylphenyl, Benzyl, 4-a-benzyl, 4-trimethylmethyl, 4-phenylphenyl, 4-dimethylphenylphosphoryl, 4-fluorophenylsulfonyl, 2, 6-Dichlorophenylsulfonyl, 2,6-difluorophenylsulfonyl-15, 2,4-dibromophenylsulfonyl, 2,4-dichlorophenylsulfonyl-2-tri Fluoromethyl phenyl sulfonate , 2-fluorophenylsulfonyl, 2-phenylphenylsulfonyl, 2-bromophenylsulfonyl, phenylsulfonyl, 4-bromophenylsulfonyl, 4-iodophenylsulfonate Base, 4-methylphenylsulfonyl, 4-bromobenzylidene, 4-chlorobenzhydryl, 3-fluorobenzhydryl, 2-bromobenzylidene, 2-fluorobenzhydrazide 20 base, 2-chlorobenzhydryl, 4-methylbenzhydryl, 2-trifluoromethylbenzhydryl, 4-trifluoromethylbenzimidyl, 4-pyrimidinylbenzyl , 3-(ethenylamino)pyridin-2-yl, 3-(trifluoroethylhydrazino)pyridin-2-yl, 3-(methylsulfonylamino)pyridin-2-yl, 3, 5-Dichloropyridine-2-yl, 3-bromo-2-yl or 5-cisyl-0-but-2-yl-2-yl. 25 43. A method for the preparation of a compound according to claim 1 wherein R 3 165 200813011 is hydrazine and X is hydrazine, which comprises reacting a compound of formula 7 with a compound of formula 8a Wherein L is selected from the group consisting of i, aryloxy, alkoxy, imidazolyl, benzimidazolyl, tetrazolyl, benzotetrazolyl and amber quinone imine, and the reaction is carried out to form (I) a compound. 44. The method of claim 43, wherein the reaction is carried out in the presence of a base. 45. The method of claim 43 or 44, wherein the base is selected from the group consisting of triethylamine or. Than °. 10 46. A method for the preparation of a compound according to claim 1 wherein R 2 and R 3 are hydrogen, which comprises reacting a compound of formula 7 with a compound of formula 8b NHR3 X=C^NR] 8b A'rs R6 7 The reaction is carried out to form a compound of the formula (I). The method of claim 46, wherein the reaction is carried out in the presence of a base of 15. 48. The method of claim 46, wherein the base is selected from the group consisting of triethylamine and pyridine. 166 200813011 VII. Designated representative map: (1) The representative representative of the case is: (). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 4