TW200804365A - Selenophene compounds - Google Patents

Abstract

This invention relates to selenophene compounds of formula (I) shown below. Each variable in formula (I) is defined in the specification. These compounds can be used to treat cannabinoid-receptor mediated disorders.

Description

200804365 IX. Description of the invention: [Technical field to which the invention pertains] It can be used for the treatment of marijuana. This is a disease related to a selenophene compound receptor. [Prior Art] Cannabinoids extracted from cannabis have been used as therapeutic drugs for centuries. They are used for pain relief, muscle relaxation, appetite stimulation and anticonvulsant use. Recent studies have pointed to its efficacy in treating cancer and alleviating chronic 10 inflammatory diseases such as rheumatism and multiple sclerosis. The action of a = anesthetic is mediated by at least two cannabinoid receptors, CB1 and CB2 receptors, both of which are superfamilies of G protein-coupled receptors (GpcR). CB1 is mainly expressed in the brain to regulate the release of inhibitory transmitters, while receptors are mainly expressed in immune cells to regulate immune responses. For related information, see Chrono 15 et al., (1990) 346:561 and Mimro et al., (1993) 365:61. The CB1 receptor is characterized by a high amount of performance compared to other GPCRs. In the central nervous system, it is expressed in the cortex, hippocampus, basal nucleus, and cerebellum in high amounts, but exhibits low expression in the hypothalamus and ridge. 20 See Howlett et al., and ev (2002) 54:161. Its function can affect many neurological and psychological phenomena such as mood, appetite, vomiting control, memory, spatial coordination, muscle tone, and analgesia. See Goutopoulos et al., jP/mr and co/TTzer (2002) 95:103. In addition to the central nervous system, it is also expressed in many peripheral organs, such as: intestine, heart, 200804365 lung S, ovary, testis and peach. See, for example: Gaidgue et al·,

Eur J BioChem (1995) 232··54 44 CB2 steroids are 44% identical to the CB1 receptor, and 68% of them are identical in the transmembrane region. For related information, see Munr〇 et al., (1993) 5 365:61. Compared with the CB1 receptor, the high expression of the CB2 receptor is restricted to the spleen and the tonsils, but is low in the lungs, uterus, pancreas, bone marrow, and thymus. In immune cells, the CB2 receptor expressed by B cells is, and the second order is natural killer cells, monocytes, polymorphonuclear neutrophils (polymorphonuclear 10). Neutrophil), and T lymphocytes. For related information, see GalWgue et al., Ar (1995) 232:54. CB2 receptor activation has been shown to have analgesic effects on inflammation associated with degenerative diseases of the nervous system (such as Alzheimer's disease) and also plays a role in maintaining bone density and improving atherosclerosis. For related information, see Malan et al., Pdn (2001) 93:239; Benito et 15 al.? J Neurosci (2003) 23:11136; Ibrahim et al. 5 Proc Natl Acad Sci USA (2003) 100:10529; Idris Et al. 5 Nat Med V (2005) 11:774; and Steffens et al., (2005) 434:782. Recently, CB2 has been found to be expressed in nerve cells as well (Van Sickle et al., Science (2006) 310: 329), showing that CB2 also has a unique role in the central nervous system 20. SUMMARY OF THE INVENTION The present invention is based on the discovery that certain selenophene compounds have efficacy in treating cannabinoid receptor related diseases. In one aspect of the invention, the selenophene compound of the following formula (I) is characterized by: 6 200804365

^ a soil, L2 < 1Q Naa, CVCio alkynyl, 5 10 15 3 fully alkyl, cvc2Gif fluorenyl, Ci·^heterocyclic, c-heterocyclic, aryl, or heteroaryl; RUca . Silk, cvc1G dilute base, c2-c1G alkynyl group, C3_C2G cycloalkyl group, c3, cycloaliphatic group, Ci_C2. Heterocyclic alkyl, (4). Heterocyclic dilute, heteroaryl, dentate, ORa, C00Ra, 〇C(〇)Ra, C(9)Ra, c(Q)NRaRb 1 NRaRb, wherein each ^ and Rl/knife are independently hydrogen, Ci-CiG An alkyl group, a C3_C2G cycloalkyl group, a heterocyclic alkyl group, a aryl group, or a heteroaryl group; and each -H R5 and 1 are independently = wind, south, cvc10 filament, c2-Ci〇 dilute base, C2-Ci〇 Block base, C3_C2 oxime, C3-C2G cycloalkenyl, Cl-C2Q heterocycloalkyl, Ci_c ring, aryl, or heteroaryl. According to the above formula (I), the above-mentioned group of selenophene compounds is a group of I-substituted aryl groups (e.g., 2,4-dichlorophenyl). In these compounds, R2 may be C(0)NRaRb, C(0)Ra, or Ci-c2〇 heterocycloalkyl, NHC(0)NRcRd, NHC(S)NReRd, or NHC(〇)Rc Replace Cl%. An alkyl group, wherein Re and Rd are each independently hydrogen, CrCiG alkyl, cycloalkyl, C^Cao heterocycloalkyl, aryl, or heteroaryl. In one embodiment, R 2 may be C(0)NRaRb, wherein Ra is methyl, adamantane or cyclohexene substituted by 6·6-dimercaptobicyclo[311]heptyl eidimethylbicyclop.l.Uheptyi) Substituted ethyl, hexyl, decyl, cyclopentyl, cyclohexyl: cycloheptyl, pyridyl, morpholinyl, octahydrocyclopenta, or tetrahydronaphthyl; and Rb is hydrogen. In another embodiment, & can be c(〇)Ra, where 1 is 〇 ratio 7 20 200804365 pyridine, tetrahydroquinoline, decahydroquinoline, or via C(0)R or C(0) NRR, a substituted methyl group; R is an ethyl group, an isobutyl group, a u-pyrrolidyl group, or a pyridyl group optionally substituted with a methyl group, and R is an ethyl group or an isobutyl group. In another embodiment, R2 can be 1-mercaptoimidazolidinone, 1-cyclohexyl imidazolidinone, 1-phenylimidazolidinone, NHC(0)NReRd, NHC(S)NRcRd, or NHC ( 0) a Ci-Cio alkyl group substituted by Rc, wherein Re is propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl, and Rd is hydrogen.

10 15 20 The term "alkyl" refers to a saturated straight or branched hydrocarbon group such as _CH3 or -CH(CH3)2. The "alkenyl" branched hydrocarbon group ' is: -CH=CH-CH3. The term "alkynyl" refers to a straight or branched hydrocarbon group containing at least one bond, such as: _CeC_CH3. The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group such as cyclohexyl. The term "cycloalkenyl" refers to a non-aromatic cyclic hydrocarbon group containing at least one double bond, such as a hexenyl group. The term "heterocycloalkyl" refers to a saturated cyclic group having at least one ring hetero atom (e.g., nitrogen, oxygen or sulfur), such as 4-tetrahydropyranyl. The "heterocyclenyl"-term refers to a non-aromatic cyclic group having at least a ring heteroatom (e.g., nitrogen 'earth oxygen or sulfur) and at least one double bond, such as a pyranyl group. The term "aryl" refers to a hydrocarbon group having one aromatic ring. Aryl group: includes phenyl (Ph), phenylene, naphthyl, naphthylene, ketone, ketone, and non-base. "Heteroaryl" is a hydrocarbon group having one or more aromatic rings, and the aromatic ring contains at least one hetero atom, such as nitrogen, oxygen or sulfur. ). Examples of heterocyclic groups include fluorenyl and arylene.喃 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基8 200804365 Unless otherwise indicated, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl as described herein may include Substituted and unsubstituted groups. Substituted 5 groups which may be substituted for cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl include, but are not limited to, Ci-Cig alkyl, C2-C1 Galkenyl, c2_c1G alkynyl, C3_C2G%, C3-C2 indenyl, CVC2()heterocycloalkyl, CVC20 heterocycloalkenyl, alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy , anthracene, amine group, Cl_Cl() alkylamino group, C1_C2G dialkylamino group, arylamino group, diarylamine group, oxyalkyl group, halogen, thio group extension io), c "ci() sulphur group, aryl Sulfur-based, 10 alkylsulfonyl, arylsulf〇nyl, acylamino, aminoacyl, aminothioacyl, amidino, Guanidine, glutamic acid (Ureid), nitrile group, nitro group, sulfhydryl group, thiol group, acyloxy group, carboxyl group, and formic acid ester. On the other hand, it may be substituted for alkyl, The substituent of the dilute group or the 15 alkynyl group includes all of the above substituents other than the CrCw alkyl group. The cycloalkyl group, the cycloalkenyl group, the heterocycloalkyl group, the heterocycloalkenyl group, the aryl group, and the heteroaryl group may also be kappa. , fused to each other. In another In one aspect, the invention features a method of treating a cannabinoid receptor-related disorder, the method comprising administering an effective amount of one or more selenophene compounds of the above formula (1) 20 to a desired body. Sustain-related diseases are hair loss, obesity, metabolic syndrome (such as X syndrome), hyperlipidemia, type 2 diabetes, atherosclerosis, substance addiction (such as alcohol addiction and nicotine), depression, Motivation deficiency syndrome, learning or memory dysfunction, analgesia, hemorrhagic shock, local 9 200804365 L cirrhosis, erectile dysfunction, neuralgia, antiemetic, high intraocular pressure, stagnation, osteoporosis, cancer (eg Prostate cancer, lung cancer, breast cancer, head and neck cancer, neurodegenerative diseases (such as Alzheimer's disease or Parkinson's disease) or inflammatory diseases. In this paper, the term "treatment" refers to the administration of one or more selenophene compounds. I is infected with the above-mentioned diseases, symptoms of the disease, or the body of the disease-prone body of the disease, in order to achieve a therapeutic effect, for example: healing Relieve, alter, affect, ameliorate, or prevent the above diseases, the symptoms of, or predisposition. Further, the present invention relates to a pharmaceutical composition comprising an effective dose of at least one of the above ten selenophene compounds and a pharmaceutically acceptable carrier. The above selenophene compound comprises the compound itself, and salts, precursors, and solvates thereof which can be used. The salt, for example, can be formed between an anion and a positively charged group such as an amine group on the selenium. Suitable anions include: chloride, bromide, iodide, sulfate, nitrate, phosphate 15 ion, citrate, methanesulfonate, tdfluoroacetate, acetate, carnosate (malate), tosylate, tartrate, fumurate, glutamate, giucur〇nate, lactate, glutarate, and maleate. Similarly, salts can also form between the cation and the negatively charged group of the selenophene compound (e.g., an ester group). Suitable cations include nano ions, potassium ions, magnesium ions, calcium ions, and ammonium cations (e.g., tetramethylammonium ions). The porphin compound also includes a salt containing a quaternary nitrogen atom. Examples of prodrugs include esters or other pharmaceutically acceptable derivatives which, upon administration to a bulk, provide an active selenophene compound as described above. Solvate means the formation of a 200804365 complex of a phenanthrene compound and a pharmaceutically acceptable cross-section. Examples of solvents acceptable to t include water, ethanol, isopropanol, ethyl acetate, curric acid, and ethanolamine. * The invention also includes a composition for treating the above-mentioned diseases, 、, (7) 孓, or the above-mentioned selenophene compound; and using the composition to prepare the aforementioned treatment Used medicine. Details of various embodiments of the invention are disclosed below. Other features, objects, and advantages of the invention will be set forth in the description and claims. [Examples] The following are exemplary compounds of the present invention: iN.N〇 〇^C:

Cl Compound 1 ο

, Se <rcl Ο C1 Compound 2

Cl compound 3

Φτα

j:\ ci compound ^ compound 1 batch .Cl

Cl combined with W7

Cl compound 4

.Cl

Br Cl VIII compound 10 ο ◦ n h3c.

^C1

Br

Cl compound 8

H3P

Br compound 9 h3c 0

Br

Br into Se ^Gl Ό

Br compound 11\o ci

Br,

Rcl ci compound 12 ο

Cl compound 13

Cl compound 14

Cl compound 15

Cl compound 16 11 200804365

介’.9

H3c Cl compound 2 5 compound compound 27 compound ^28

An〇

Compound ^

C1 compound 31

Compound

Br compound ci compound framing C "39 compound 36 J〇 J〇 φτα compound 40 12 200804365

Compound 41 Compound 42

Compound 43

0

The compound of the above formulae 45 can be prepared by a synthetic method of a well-known technique. The manner in which the compounds 1-45 are made will be detailed in the following Examples 1-45. 5 Flowchart 1 below discloses a typical flow diagram for the synthesis of these exemplary compounds. In particular, first, a ketone-containing selenophene compound (for example, Compound A) can be subjected to a Claisen condensation reaction with an oxalate compound (for example, diethyl oxalate) in the presence of a lithium salt (Claisen condensation) Reaction) to form an ester group-containing 1,3-diketone compound (Example 10 such as Compound B). The 1,3-diketone compound can then be reacted with a hydrazine to form a hydrazine compound which can be subjected to intramolecular cyclization under reflux of acetic acid without further purification to form a pyrrazole containing an ester group. a compound (for example, compound C). The σ-specific thiol compound can be hydrolyzed to form a carboxyl group by addition, and the carboxyl group can be subsequently reacted with sulfinium chloride to form a ruthenium chloride group. The formed compound (e.g., compound D) can be reacted with an amine compound to form certain compounds of the invention (e.g., compounds 1-9). 13 200804365

Flow chart 1

R = H, CH3, or Br; Rl = H; R2 = flJS spin 1-in (piperidin-l-yl), cyclopentyl, morphine 4-yl (mQrpholin-4-yl), ring 3S, Piperidin-1-yl, cycloheptyl, cyclohexyl, cyclopentyl, or R1, R2 and N=piperidinyl group 10 The pyrazole compound of the above Scheme 1 can be modified by different types to obtain the present invention. Other compounds. For example, as shown in the following Scheme 2, the σ-rhodium compound can be reacted with iV bromosuccinimide (NBS) to form a bromine-containing compound at the 5th position of the porphin ring (for example, compound E). ). The compound can then be hydrolyzed in an alkali containing environment to form a carboxy 15 yl oxime which can then be reacted with sulfoxide to form a ruthenium halide. The formed compound (e.g., compound F) can be reacted with an amine compound to form certain compounds of the invention (e.g., compounds 10-27), or reacted with a keto compound to form certain other compounds of the invention (e.g., compound 34-3 8 ). 14 20 200804365

Flow chart 2

R = H, CH3, or Br; Ri = H; R2 = S pentyl, cyclodecyl, cycloheptyl, n-hexyl, n-decyl, piperidin-1-yl, tetrahydronaphthyl, eight Oxycyclopyrazine Ito (octahyjrocycbpentapyrrdyl), adamantyl, 2-cyclohexenylethyl, or 6,δ-dimethylbicyclo[3.1.1]heptanemethyl, or Hi, R2 and Ν=four Oxygen (tetrahydroisQquincjlinyl). + decaiiydrQquinDliyl, or piperazine-1-yl

B"犷 R=Br ; R3=flilrr-1-yl, diethylamine-piperidin-1-yl, diisobutylamine, or 3-methylacridin-1-yl

As shown in Scheme 3, a compound having a bromine group at the 5th position of the selenophene ring (for example, compound E) may also be substituted with another functional group (for example, an alkyl group, an alkenyl group or a heterocycloalkyl group) via a substitution reaction. Bromine group. The formed compound (e.g., compound G) can be reacted to form a compound containing a halogenated carboxyl group (e.g., compound H) by the same method as described above. It can then be reacted with an amine compound to form certain compounds of the invention (e.g., compounds 28-33). Flow chart 3

15 10 200804365 Alternatively, as shown in the following Scheme 4, the bromo group-containing compound at the 5th position of the selenophene ring can be reduced to form a hydroxyl group-containing compound (e.g., Compound I). The hydroxyl group can then be converted to a leaving group (e.g., by reaction with a sulfhydryl sulfonate). The formed compound (e.g., compound J) can be first reacted with sodium azide and then with triphenylphosphine to form an amine compound (e.g., compound K). The amine based compound can be reacted with an isocyanate or isothiocyanate to form certain compounds of the invention (e.g., compounds 39 and 42), or with cerium chloride to form certain other compounds of the invention (e.g., compounds 44 and 45). ). Flow chart 4

The porphin compound synthesized as described above can be purified by a suitable method, for example, column chromatography, south pressure liquid chromatography or recrystallization. Other selenophene compounds can be made using the appropriate starting materials via the synthetic procedures described above or by the methods of the art. The above methods may include additional steps before or after the steps described herein to add or remove suitable protecting groups to synthesize the selenophene compound. In addition, different synthetic steps can be carried out in other sequences or sequences to produce the desired compound. The synthetic chemical transformations used to synthesize the phenanthroline and the protective group methodology (protection and deprotection) are well known in the art. See: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989) TW Greene and PGM Wuts, Groups M Organic Synthesis, 2nd Ed., John Wiley and Sons (1991); L. 10 Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Reagents for Organic John Wiley and Sons (1995) and subsequent versions. As described herein; the δ cis compound may comprise a non-aromatic double bond and one or more than 15 asymmetric centers. Thus, it can be racemates (racemic mixtuRs), single mirror image isomers, individual non-image isomers, non-imagesome mixtures, and cis (Cis_) or trans-) isomers. . All isomers are considered. Also, a pharmaceutical composition comprising at least one effective amount of the above; an e-phenopeptide compound and a pharmaceutically acceptable carrier is also within the scope of the present invention. Further, the present invention encompasses a method of administering one or more effective doses of a porphin compound to the body of the disease described in the foregoing subject matter. "Effective dose" means a dose of an active selenophene compound which produces a therapeutic effect on the body of the drug. As is known to those skilled in the art, the effective dosage will vary depending on the type of disease being treated, 17 200804365, and the likely route of administration of the other treatments. 5 15 20 The composition of the compound can be administered by two or more kinds of the above-mentioned stone or sublingual. ",:: two oral, nasal, transrectal, local, pulse, intramuscular,: music" refers to subcutaneous, intraperitoneal, intravenous injection, intrathoracic injection, injection, main f pulse injection, joint fluid injection, Or other suitable drug delivery techniques. The intra-injection, intracranial m^ injectable composition may be a solution or suspended in a non-toxic intravenous injection diluent or solvent such as u-butanediol. The carrier and the solvent can be mannitol (_it♦ water, Ringer's solution ge...) or isotonic sodium chloride soluble fatty acid such as oleic acid (01eicAcid) and its glycerol derivative can also be: Second: the preparation, the oil acceptable for natural medicine is the type of polyoxyethylation. The oil ester solution long-chain alcohol diluent or dispersant, slow methyl fiber or two 'U = interface core _' such as Tween similar emulsifier, or used in general pharmaceutical manufacturing: the amount used for oral administration The substance may be any orally acceptable agent. The formula includes capsules, key tablets, emulsifiers and liquid suspensions, and dispersing agents. In the case of tablets, the carrier used in general is lactose or corn 18 200804365 starch. Lubricants such as magnesium stearate are also often added to it. In the case of oral capsule administration, effective diluents include lactose and dried corn starch. When orally administered as a liquid suspension or emulsifier, the active substance may be suspended or dissolved in an oily interface in combination with an emulsifier or suspending agent. If necessary, add a moderate amount of sweetener, flavor or color. Nasal gasifying sprays or inhalant compositions can be prepared according to known pharmaceutical dosage form techniques. For example, the composition can be prepared in physiological saline, p using benzyl alcohol or other suitable preservatives, an enhancer for enhancing bioavailability, fluorocarbons, and/or other techniques known 10 Solvent or dispersant. The composition of the package & or a plurality of active oxime compounds can also be administered in the form of a suppository for rectal administration. The carrier of the peony composition must be r acceptable, ie it must be compatible with the active principal component of the composition (more preferably, it has a stable active principal component of 15 1 ) and cannot be applied to the body being treated. cause some damages. One or more lysines can be used as a pharmaceutical excipient to deliver the active selenophene compound. Other carriers Examples include colloidal cerium oxide, magnesium stearate, cellulose, sodium lauryl sulfate and D&C Yellow #1〇. 2 〇Guanggang's selenophene compound can be initially screened for its efficacy in the treatment of the aforementioned diseases. 2 In vitro analysis was performed (see Example 46 below) and confirmed by an animal test. Other methods can also be obtained in a conventional manner. The following specific examples are to be construed as illustrative only, and are not intended to limit the scope of the disclosure. The omission, modification, derogation, and alteration of the formula of the present invention can be carried out by those skilled in the art without departing from the scope of the present invention. All published documents, which are not hereby incorporated by reference in their entirety, are hereby incorporated by reference.

10 15 20 Example 1, Compound 1: 1·(2,4-Dichlorophenyl)(piperidin-1-yl&gt;5-2-yl)-1//-pyrazole-3-carboxamide Preparation (Shixiu at -780C, will dissolve in diethyl ether (13 mL) 1 (selenophene-2, yl) (3.2 g, 18.49 mmol, l-(selenophene-2-yl) ethanone)$ Liquor-soluble in diethyl ether (40 mL) of lithium bis(trimethylsilyl)amine (20.3 m]L 20.35 mmol, lithium bis (trimethylsilyl)amide) magnetically turbulent solution. Stir at the same temperature After 45 minutes, diethyl oxalate (3.0 mL, 22.19 mmol, diethyl oxalate) was added. The reaction mixture was returned to room temperature and stirred for additional 16 hours. The precipitate was then filtered and washed with diethyl ether. Drying in the state to obtain intermediate product 1 (a) (ie: ethyl 2,4-dioxo-4-(stone-phen-2-yl-butanone) salt, lithium salt of ethyl 2.4- dioxo_4_ (selenoehen_2- Yl_butanonte)) (3.5 g, 68%)) 0 The intermediate was dissolved in 40 mL of ethanol and magnetically stirred at room temperature with 2,4-dichlorophenylguanidine hydrochloride (2.9 g, 13.82 mmol). , 2.4- dichlorophenylhydrazine hydrochlorid). It was then incubated at room temperature for 20 hours. The formed precipitate was filtered and washed with ethyl acetate and diethyl ether. then dried in vacuo to give a pale yellow solid (4.0 g, 74%). This solid was dissolved in the wrong acid (30 mL) and heated under reflux for 24 hours. Then, the mixture was poured into ice water and extracted with ethyl acetate. The extract was washed sequentially with water, saturated 20 200804365 aqueous sodium hydrogencarbonate, and brine. The organic layer was separated, dried over anhydrous sodium sulfate and then filtered and evaporated, a) (ie · 1 - (2,4- &lt;One gas phenyl)-5_石西苯-2-yl-specific quinone 5 -3-carboxylic acid ethyl hydrazine, l_(2,4-dichlorophenyl)-5-selenophene-2-yl_li7 -pyrazole-3-carboxylic Acid ethyl ester, white solid (3. 0 g, 78%)). Potassium osmium oxide (813 mg, 14.) dissolved in decyl alcohol (7 mL). 48 mmol) of the solution was added to a stirred solution of the intermediate 11 (a) (3.0 g, 7.24 mmol) dissolved in methanol (15 mL). The mixture was heated under reflux for 3 hours. It was then cooled, poured into water and acidified with 10% aqueous hydrochloric acid. The precipitate is then filtered off, washed with water and dried under vacuum to give intermediate product 111 (a) (ie: 1-(2,4-diphenyl)-5--- ! than salivary-3-weilic acid, l-(254-dichlorophenyl)-5-selenophene-2-yl-lH-pyrazole-3-15 carboxylic acid, white solid (2. 6 g, 95%)) 中间 Intermediate product 111 (a) (100 mg, 0.) dissolved in toluene (5 mL). 25 mmol) and sulphur chloride (67·1 # L,0. The 92 mmol) solution was refluxed for 3 hours. The solvent was evaporated to dryness under reduced pressure. The residue was dissolved in toluene (5 mL), and the solvent was evaporated to dryness to give the crude product l-(2,4-dichloro-phenyl)_5_20 s.吼嗤-3-Resinated chlorine (100 mg, 96%, 1-(2,4-dichloro-phenyl)-5-selenophen-2-yl-li/-pyr azole-3-carboxylic chloride), pale solid. The above-mentioned formic acid chloride was dissolved in dichloromethane (5 mL) and added dropwise at 0 ° C to 1-aminopiperidine dissolved in dichloromethane (5 mL). 7 /zL, 0·39 mmol ) and triethylamine (56_5 //L, 0. 39 mmol) mixed 25 in solution. After stirring at room temperature for 3 hours, the reaction was quenched with water. The aqueous layer 21 200804365 will be separated and then extracted with dichloromethane (2 x 10 mL). The extract is washed with brine, dried over anhydrous sodium sulfate and filtered and evaporated to give a crude product, which is purified by flash chromatography on hexane/ethyl acetate (2:1). Solid Compound 1 (86 mg, 75%). 5 W-NMR (CDC13, ppm): 7. 96 (d, 1H), 7. 56 (s, 1H), 7. 46 (s, 2H), 7. 21-7. 12 (m, 3H), 6. 80 (d, 1H), 4. 43-4. 36 (m, 1H), 2. 10-2. 01 (m, 2H), 1. 74-1. 47 (m, 6H).  ES-MS (M+l): 469. 0.  Example 2, Compound 2: (l-(2,4-Dichlorophenyl)-5-(selenophen-2-yl)-1//-pyrazol-3-yl) (piperidine- Preparation of 1-yl)nonanone In addition to the final step, the crude product of formic acid chloride (100 mg, 0. The preparation of the remaining compound 2 was similar to that of the above Example 1 except that it was treated with a piperidine. 15 !H-NMR (CDC135 ppm): 7. 95 (d? 1H) 5 7. 55 (s, 1H) 3 7. 42-7. 33 (m, 2H), 7. 21-7. 12 (m, 3H), 6. 93 (d, 1H), 3. 87-3. 72 (m5 4H)? 1. 74-1. 46 (m5 6H).  ES-MS (M+l): 469. 0.  20 Example 3, Compound 3: Preparation of #-3⁄4-pentyl-1-(2,4-dichlorophenyl)-5-(code phen-2-yl)-1 ugly-pyrazole-3-decylamine In addition to the final step of the slow acid gas crude product (1 〇〇 mg, 0. 24 mmol) is cyclopentylamine (38. 0//L, 0. 39 mmol) and triethylamine (56. 5/zL, 0·39 mmol), the other compound 3 was prepared in a similar manner to that of the above-mentioned Example 1 25, whereby white solid compound 3 (90 mg, 83%) was obtained. 22 200804365 i-NMR (CDC13, ppm): 7. 96 (d, 1Η), 7·56 (s, 1Η), 7·46 (brs, 2H), 7. 21-7. 12 (m, 2H), 6. 80 (d5 1H), 4. 43-4. 36 (m, 1H), 2. 10-2. 02 (m, 2H), 1. 74_1. 47 (m, 6H).  ES-MS (M+23): 475. 9.  5 Example 4, Compound 4: Preparation of 1-(2,4-diphenyl)-iV-morpholine-5-(selenophene-2,yl)-1han-pyrazole-3-carboxamide In addition to the final step of the crude carboxylic acid chloride (100 mg, 0. 24 mmol) is #-胺基基琳 (iV&quot;aminomorpholine) (37. 9 // L,0·39 mmol) and three 10 ethylamine (56·5 # L,0. The procedure for the preparation of the remaining compound 4 was similar to that of the above Example 1, to obtain a white solid compound 4 (79 mg, 70%) °^-NMR (CDC13, ppm): 7. 98 (d, 1H), 7. 62 (brs, 1H), 7. 58 (d, 1H), 7. 44 (brs, 2H), 7. 22-7. 13 (m, 3H), 3. 87 (t, 2H), 15 2. 94 (t? 2H) ES-MS (M+l): 470. 9.  Example 5, Compound 5: Preparation of TV-cyclohexyl-l-(2,4-diphenyl)-5-(selenophen-2-yl)-1//-pyrazole-3-carboxamide 20 In addition to the final step of the crude carboxylic acid chloride (100 mg, 0. 24 mmol) is cyclohexylamine (44. 1//L, 0. 39 mmol) and triethylamine (56. The preparation of the remaining compound 5 was similar to that of the above Example 1 except that 5//L, 0-39 mmol), so that white solid compound 5 (89 mg, 80%) was obtained. iH-NMR (CDC13, ppm): 7. 96 (d, 1H), 7·56 (d, 1H), 25 7. 47-7. 40 (m, 2H), 7. 24-7. 09 (m, 3H), 6.74 (d, 1H), 3. 97-3. 91 23 200804365 (m, 1H), 2. 03-1. 99 (m, 2H), 1.77-1·62 (m, 4H), 1·47-1·05 (m, 4H).  ES-MS: 468. 0 (M+l) 5 490. 0 (M+23).  5 Example 6, Compound 6: l-(2,4-Dichlorophenyl)-4-mercaptopiperidin-1-yl)-5-(selenophen-2-ylpyrazole-3-carboxamide Preparation of the intermediate product 1 (b) (ethyl 3-mercapto-2) except for the substitution of 1 -(shixet-2-yl)propanoid , a salt of 4-dioxo-4-(selenophenen-2-yl-butanonte) (lithium salt of ethyl 3-methyl-2?4-dioxo-4-10 (selenoehen-2-yl-butanonte)) The preparation steps were similar to those of the intermediate product 1 (a) of the above Example 1, and the yield was 36%. Intermediate 11 (b) (1-(2,4-dichloro-phenyl)-4-indole 5--5-selenophen-2-yl-li/- σ than mouth _3_ vinegar vinegar (l_(2,4-dichloro-phenyl)-4-methyl -5-selenophen-2-yl-liir- Pyrazole-3-carboxylic acid ethyl 15 ester)) was prepared starting from intermediate product 1 (b) in a similar manner to the preparation of intermediate product 11 (a) of Example 1 above, in a yield of 50%. (b) (1_(2,4-dichlorophenyl)_4_indolyl-5-selenophen-2-yl-1J7- σ is more than stagnation -3- oxo acid (l_(2,4_dichloro_phenyl)-4 -metliyl_ 5-selenophen-2-yl-l/i-pyrazole-3-carboxylic acid)) by intermediate 20 product 11(b) The preparation method was similar to the preparation method of the intermediate product 11 (a) of the above Example 1, and the yield was 95%. The compound 6 was prepared from the intermediate product 111 (b) except 1-(2,4-di). Gas-phenyl)-4-methyl-5-selenophen-2-yl-1^-pyrazole-3-carboxylic acid chloride (100 mg, 0. Crude product of 24 mmol 5 1 -(2 ?4-dichloro-phenyl)-4-methyl-5-selenophen-2-yl- 24 200804365 l/i_pyrazole-3-carboxylic chloride) (1-(2) of non-Example 1 ,4-dichloro-phenyl)-5-porphin-2-yl-li/- σ than 嗤-3-wei acid gas, 1 -(2?4-dichloro-phenyl)-5-selenophen-2- Yl- Ι/ί-pyrazole-3 -carboxylic chloride) is bitten by 1-amino group (41. 0 pL, 0. The preparation steps were similar to those of the above Example 1 except that 38 mmol) and 5 triethylamine (54·3 μ, 0·38 mmol) were used to give a white solid compound 6 (75 mg, 65%). iH-NMR (CDC135 ppm): 8·05 (d, 1H), 7. 61 (brs, 1H), 7·48 (brs, 1H), 7·33 (brs, 2H), 7·23 (dd, 1H), 7. 09 (d, 1H), 10 2. 85-2. 84 (m, 4H), 2·47 (s, 3H), 1, 76-1. 25 (m,6H); ES-MS (M+23): 483. 0.  Example 7, Compound 7: Cycloheptyl-1-l-(2,4-dichlorophenyl)_4-methyl-5-(shisin-2-yl)· 1 /if·° 嗤-3 - Injuring of a brewing amine 15 In addition to the final step of the crude product of formic acid (100 mg, 0. 24 mmol) is cycloheptylamine (43. 4//L, 0. 38 mmol) and triethylamine (54. The procedure for the preparation of the other compound 7 was similar to that of the above Example 6 to give the compound 7 (86 mg, 73%) as a white solid. 20 iH-NMR (CDC13, ppm)·· 8. 05 (d, 1H), 7. 48 (brs, 1H), 7·34 (brs, 2H), 7·22 (dd, 1H), 7. 09 (d, 1H), 6. 88 (d, 1H), 4. 13-4. 11 (m, 1H), 2. 48 (s, 3H), 2. 06-1. 52 (m, 12H); ES-MS (M+23): 518.  25 200804365 Example 8, Compound 8: iV-cyclohexyl-l-(2,4-dichlorophenyl)-4-methyl-5-(stone)-pyrene-3-carboxamine Prepare a crude product of tarenic acid chloride in addition to the subsequent steps (1 〇〇mg, 0. 24 mmol) is cyclohexylamine (43. 5 #L,0. 38 mmol) and triethylamine (54. 3//L, 0. The procedure for the preparation of the other compound 8 was similar to that of the above Example 6 to give a white solid compound 8 (97 mg, 84%). ^-NMR (CDC13? ppm): 8. 04 (d, 1H), 7. 47 (brs, 1H), 7. 33 (brs, 2H), 7. 22 (brs, 1H), 7. 09 (brs, 1H), 6. 84 (d, 1H), 3. 95-3. 93 (m5 1H), 2·48 (s, 3H), 2·01-1·15 (m, 10H); 10 ES-MS (M+23): 503. 9.  Example 9, Preparation of compound 9: Cyclopentyl _; u(2,4-dichlorophenyl)_4_methyl_5-(shixiphen-2-yl ratio tr sit-3-carbamamine) In addition to the final step, the crude carboxylic acid chloride (1 〇〇 mg, 〇·24 mm 〇 1) is 15% pentylamine (37·6# L, 〇·38 mm〇i) and triethylamine (543# The preparation of the remaining compound 9 was similar to that of the above Example 6 to give a white solid compound 9 (9 2 mg, 82%). ^-NMR (CDC 135 ppm) : 8. 05 (d5 1H) 5 7. 47 (brs5 1H), 7. 33 (brs, 2H), 7. 22 (d, 1H), 7. 09 (d, 1H), 6. 87 (d, 1H), 4. 38 20 (dtt, 1H), 2. 48 (s, 3H), 2. 07-1. 47 (m, 8H).  ES-MS (M+23): 490. 0.  Implementation y, compound 10: 5_(5_Mossin-2-yl) epoxide ring sulfhydryl small (2,4-dichlorophenyl)-4-methyl-If pyrazole _3_ decylamine preparation 26 200804365 The intermediate product 11(b) prepared in Example 6 (300 mg, 0. 70 mmol) dissolved in acetonitrile with magnetic stirring, and at a temperature of 〇 °c, a small amount of bismuth bromide (NBS, 85 mg, 0. 48 mmol) After stirring for 1 hour at 0 °C, force a saturated sodium sulfite solution. The solvent was evaporated and the product was extracted with ethyl acetate. 5 The product was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate, and brine. The organic layer was separated and dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> Such as: 4-mercapto-5·(5- &gt; stinky-shisin-2-yl)-1_(2,4-dichloro-phenyl)-1 ugly-pyrazole-3-furoate ethyl ester 10 (4-methyl-5-(5-bromo-selenophen-2-yl)-l-(254-dichloro-phenyl)-l/f-pyrazole-3-carboxylic acid ethyl ester), white solid (177 mg, 75%). A hydroxide clock (38·0 mg, 0.) dissolved in methanol (5 mL). 68 mmol) solution was added to intermediate product II (c) (177 mg, 0.) dissolved in methanol (5 mL). 34 mmol) 15 magnetically stirred solution. The mixture was heated under reflux for 3 hours. It was then cooled, poured into water and acidified with 10% aqueous hydrochloric acid. Next, the precipitate is filtered off, washed with water and dried under vacuum to give intermediate product 111 (c): 4-methyl-5-(5-bromo-selenophen-2-yl)-1-( 2,4-Dichlorophenyl)-1//- than 嗤-3-teric acid (4-methyl-5-(5-bromo-selenophen 20 -2-yl)-l - (254-dichlorophenyl)-li /-pyrazole-3-carboxylic acid, 155 mg, 95%), white solid. Intermediate III(c) (100 mg, 0. 20 mmol) and sulfoxide (51 · 0 // L, 0_70 mmol) were dissolved in toluene (5 mL) and refluxed for 3 h. Next, the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in toluene (5 mL), EtOAc (EtOAc) The above carboxylic acid chloride was dissolved in dichloromethane (5 mL) and added dropwise at 0QC to cyclopentylamine dissolved in 5 mL of dichloromethane. 7 // L,0. 32 mmol) and triethylamine (44. 6 /z L,0. 32 mmol) in the mixture. After stirring at room temperature for 5 hours, the reaction was quenched with water. The aqueous layer was separated and extracted with dichloromethane (2 x 10 mL). The extract was washed with brine and dried over anhydrous sodium sulfate and filtered and evaporated to give a crude product, which was purified by hexane/ethyl acetate (2:1). Solid compound 10 (87 mg, 80%). 10 ^-NMR (CDC13, ppm): 7. 50 (d, 1H), 7·38 (d, 1H), 7·38 (s, 1H), 7. 16 (d, 1H), 6. 87 (d, 1H), 6. 82 (d, 1H), 4·36 (dtt, 1H), 2·46 (s, 3H), 2. 09-2. 02 (m, 2H), 1. 73-1. 46 (m, 8H)· ES-MS (M+23): 567. 8.  15 Example 11, Compound 11: 5-(5-Bromoselenophen-2-yl)-l-(2,4-dichlorophenyl)-TV-(hexanitrozinc-distributed [c]pyridyl- 2 (1 ugly)-yl)-4 -mercapto-1 iY- ° than sputum -3 - sulphate preparation except for the final step of the crude product of formic acid (1 〇〇 mg, 0. 24 mmol) is a hexahydrocyclopenta-20 [c]pyrrol-2(lii)-amine hydrochloride, 52 mg, 0. 32 mmol) and triethylamine (72. 5# L,0. The procedure for the preparation of the remaining compound 11 was similar to that of the above-mentioned Example 10 to give the compound 11 (81 mg, 70%) as a white solid. ^H-NMR (CDC13? ppm): 7. 50 (d? 1H) 5 7. 47 (brs5 1H)5 25 7. 35 (d, 1H), 7. 33 (brs, 1H), 7. 15 (d, 1H), 6. 81 (d, 1H), 3. 25 28 200804365 (t, 2H), 2·66 (brs, 2H), 2. 49 (d, 2H), 2·45 (s, 3H), 1.66_1·49 (m, 6H).  ES-MS (M+l): 586. 8 5 Example 12, compound 12: 5, (5·bromoselenophen-2-ylcyclohexyl-l-(2,4-dichlorophenyl)-4-mercaptopyrazole-3-meramine Preparation of the crude product of the carboxylic acid gas except the final step (100 mg, 0. 20 mmol) is cyclohexylamine (36·5 /z L,0. 32 mmol) and triethylamine (44. 6 // L, 0. The procedure for the preparation of the other compound 12 was similar to that of the above-mentioned 10 Example 10, and finally the compound 12 (84 mg, 75%) obtained as a white solid: H-NMR (CDC 135 ppm): 7. 50 (d, 1H), 7. 38 (d5 1H), 7. 35 (d, 1H), 7. 35 (s, 1H), 7. 15 (d, 1H), 6. 81 (d, 1H), 6. 79 (brs, 1H), 3. 95-3. 88 (m5 1H), 2. 42 (s, 3H), 1. 99-1. 59 (m, 6H), 15 1. 45-1. 32 (m, 4H).  ES-MS (M+23): 581. 8 Example 13, the compound π: 5-(5_ selenophene-2•yl h#, dichlorophenyl)-4-methyl(piperidinyl)pyrazole_3_formamide was prepared except the last The crude carboxylic acid chloride (100 mg, 0 20 mm 〇l) in the step is 1-amino (tetra) (34. WL, 0. 32 and triethylamine (44 6仏 0. The 32-side treatment is carried out, and the remaining compounds (4) are prepared in the same manner as in the above-mentioned Example H), and finally a white solid is obtained _ (78 ,, 29 200804365 ^-NMR (CDC13? ppm): 7. 59 (brs5 1H)? 7. 51 (d5 1H), 7. 36 (d, 1H), 7. 34 (s, 1H), 7. 6 (d, 1H), 6. 81 (d, 1H), 2·84 (brs, 2H), 2. 45 (s, 3H), 1. 77-1. 24 (m, 8H) ES-MS (M+l): 562. 8.  5 Example 14, Compound 14: 4-bromo-5-(5-bromoselenophene-2-yl)-, cyclopentyl-1 -(2,4-dichlorophenyl)-li/-pyrazole- Preparation of 3-methanamine The intermediate product 11 (a) (500 mg, 1.20 mmol) was magnetically stirred in acetonitrile and a small amount of bromobutaneimine (NBS, 640 mg) was added at 0 °C. , 3. 6 10 mmol). It was stirred at room temperature for 48 hours. The precipitate formed is filtered off, washed with saturated sodium sulfate and cold water, and dried in vacuo to give an intermediate product 11 (d): 4-bromo-5-(5-bromo-selenophen-2-yl) )-1-(2,4-dioxa-phenyl)-1//-° ratio 4-bromo5-(5-bromo-selenophen -2-yl)-l-(254 -dichloro-phenyl)-li/-pyrazole-3-carboxylic acid ethyl ester) j 15 white solid (630 mg, 92%). Potassium hydroxide (117 mg, 2.) dissolved in methanol (5 mL). 10 mmol) of the solution was added to intermediate product II (d) (600 mg, 1.) in methanol (5 mL). 05 mmol) Magnetically stirred in solution. The mixture was heated under reflux for 3 hours. It was then cooled, poured into water and acidified with 10% aqueous hydrochloric acid. Next, the precipitate was filtered off over 2 Torr, washed with water and dried in vacuo to give Intermediate 111(d): 4-bromo-5-(5-bromo-selenophen-2-yl)-1 -(2,4-dichlorophenyl)-1//-σ than salivyl-3-weilic acid (4_bromo-5_(5-bromo-selenophen_ 2-yl)-l - (2 ?4-dichlorophenyl)-lii -pyrazole-3-carboxylic acid), white solid (542 mg, 95%). 30 200804365 The intermediate product 111(d) (100 mg, 0. 18 mmol) and sub-transported chlorine (46 j /z L,0. 63 mmol) was dissolved in toluene and refluxed for 3 hours. Then, the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in hydrazine (5 mL), and the solvent was evaporated to dryness to give the crude product 1-(2,4-di-phenyl)-4-bromo-5- _ 5 selenophen-2-yl-Iff-pyrazole-3-carboxylic acid gas (l-(254-dichloro-phenyl)-4-bromo-5-(5-bromo-selenophen-2-yl-li7-pyrazole -3-carboxylic chloride)), pale solid (98 mg, 95%). The above carboxylic acid chloride was dissolved in dioxane (5 mL) and added dropwise to 5 mL at 〇 ° C Di-methane methane cyclopentylamine (26. 7 // L,0. 27 10 mmol) and triethylamine (38. 6 // L,0. 27 mmol) in the mixture. After stirring at room temperature for 3 hours, the reaction was quenched with water. The aqueous layer was separated and then extracted with dichloromethane (2×10 mL). The extract was washed with brine and dried over anhydrous sodium sulfate and filtered and evaporated to give a crude product which was purified by flash chromatography on hexane/ethyl acetate (2:1). 15 Compound 14, white solid (86 mg, 83%). !H-NMR (CDC135 ppm): 7. 53 (d, 1H) 5 7. 40 (d5 1H) 3 7. 38 (s, 1H), 7. 15 (d, 1H), 6. 98 (d, 1H), 6. 77 (d, 1H), 4. 38 (dtt, 1H), 2. 10-2. 02 (m, 2H), 1. 72-1. 48 (m, 6H).  ES-MS (M+23): 631. 8.  20 Example 15, Compound 15: 4-bromo-5-(5-bromoselenophen-2-yl)-1-(2,4-diphenyl)-#-(piperidine-1-yl)_ Preparation of 1 仄pyrazole-3-decylamine The crude product of the carboxylic acid gas (100 mg, 0.17 mmol) except the final step was 1-aminopiperidine (29. 1/zL, 0. 27 mmol) and triethylamine (38. 6/z 25 L,0. The preparation of the remaining compound 15 was similar to that of the above-mentioned Example 31 200804365, Example 14, to give a white solid compound 15 (74 mg, 70%) ° iH-NMR (CDC13, ppm): 7. 54 (d, 2H), 7. 43-7. 36 (m, 2H), 7. 15 (d, 1H), 6. 98 (d5 1H), 2. 87 (t, 4H), 1. 77-1. 42 (m, 6H) 5 ES-MS (M+l): 624. 8.  Example 16: Compound 16: 4-bromo-5-(5-bromofluoren-2-yl)-iV-cyclohexyl-1-(2,4-dichlorophenyl)-1//-. ratio. Preparation of 3-methylamine: In addition to the final step of the crude carboxylic acid gas (100 mg, 〇·17 10 with cyclohexylamine (30. 9 41^,0. 27 111111〇1) and triethylamine (38. 6//1^,0. The preparation of the remaining compound 16 was similar to that of the above Example μ, so that a white solid compound 16 (85 mg, 80%) 〇 jH-NMR (CDC13, ppm) was obtained. 53 (d5 1H)? 7. 43 (d? 1H)? 7. 42 15 (S, 1H), 7*15 (d, 1H), 6 (d, 1H), 6. 70 (d, 1H), 3.97_3·94 (m, 1H), 2. 04-1. 98 (m, 2H), 1. 76-1. 15 (m, 8H).  ES-MS (M+l): 623. 7 Example 17, compound 17: 4-bromo-5-(5-bromo-selenophen-2-yl)-l-(2,4-dichlorobenzene 20-yl)- 尽 (丨, 2, 3, 4· Preparation of tetrahydronaphthalene·1_yl)-1//-pyrazole-3-decylamine The crude product of the carboxylic acid gas (100 mg, 〇·17 mmol) except the final step is 乂1,2,3,4- Tetrahydro-1·nylamine (38·9 &quot;l,0. 27 mmol) and triethylamine (3 8·6 // L, 0. The other compound 17 was prepared in the same manner as in the above Example 14 except that 27 mmol) was obtained, thus obtaining a white solid compound 32 200804365 17 (74 mg, 65%) 〇-NMR (CDC13, ppm): 7 . 50 (d, 1H), 7. 37 (d, iH) 7. 35 (s, 1H), 7. 26 (brs, 2H), 7. 18-7. 08 (m, 3H), 6. 98 (d, iH)’ 5. 39 (dt, 1H), 2. 82-2. 77 (m, 2H), 2. 17-1. 87 (m, 4H).  ’ 5 ES-MS (M+23): 693. 6.  Example 18, Compound 18: (4-Bromo-5-(5-bromoseleno-2-(yl))-1-(2,4-dichlorophenyl)-1 from thiazol-3-yl) 3,4-Dihydroisoquinoline_2(ι切_基)曱g同梦梦衣10 In addition to the final step, the crude carboxylic acid gas (100 mg, 〇·π mmol) is 1, 2, 3, 4·tetrahydroisoquinoline (38. 6 //L,0. 27 mmol) and triethylamine (38. 6 /zL,0. The other compound 18 preparation steps were similar to those of the above Example 14 except that 27 mmol) was treated, whereby white solidified human 18 (61 mg, 55%) was obtained. 15 !H-NMR (CDC13? ppm): 7. 55 (d5 1H), 7. 38 (d? 1H) 5 7. 35 (s, 1H), 7. 22-7. 16 (m, 5H), 7. 03 (d, 1H), 4. 95 (brs, 2H), 3. 85 (t, 2H), 2. 30-2. 94 (m, 2H)· ES-MS (M+23): 679. 7.  20 Example I9, compound 19: 4-bromo-5-(5-bromoselenophen-2-yl)-1-(2,4-dichlorophenyl)-dos(hexahydrocyclopenta[c]pyrrole Preparation of -2(li/)_yl)-1H-pyrazole-3-carboxamide In addition to the final step, the crude product of oxalate chloride (1 〇〇 mg, 〇17 mmol) is hexahydrocyclopentane _[c ] 吼 2 - (1 ugly) - amine hydrochloric acid (44. 0 mg, 0. 27 mmol) to 33 200804365 and triethylamine (62. 9 /zL,0. The procedure for the preparation of the remaining compound 19 was similar to that of the above Example 14 to give a white solid compound 19 (88 mg, 80%). H-NMR (CDC13, ppm): 7. 54 (d5 1H), 7. 39 (d,1H), 5 7·37 (S,1H),7·15 (d,1H),6·98 (d,1H), 3. 27 (t, 2H), 2. 65 (brs5 2H)3 2. 54 (d5 1H) 5 2. 52 (d5 1H) 5 1. 67. 1. 50 (m5 6H).  ES-MS (M+l): 650. 7.  Example 20, compound 20: 4-bromo-5-(5-bromoselenophen-2-yl)-1-(2,4-dioxabenzene-10-yl)_#-hexyl-lii-pyrazolium Preparation of the amine In addition to the final step, the crude carboxylic acid chloride (1 〇〇 mg, 〇 17 mm 〇 1) is hexylamine (35·9 /zL, 0. 27mmol) and triethylamine (38·6 #l, 〇. The other compound 2 oxime preparation steps were similar to those of the above Example 14 to obtain a white solid compound 2 〇 (88 mg, 15 80%) 〇h-NMI1 (CDC13, ppm): 7. 54 (d, 1H), 7. 40 (d, 1H), 7. 38 (s, 1H), 7. 16 (d, 1H), 6·98 (d, 1H), 6. 85 (t,1H) 3·41 (q,2H), 1. 63-1. 25 (m, 8H) 0. 87 (t,3H)_ ES-MS (M+l): 625. 9.  20 Example 21, compound 21: 4-bromo-5-(5-bromoselenophen-2-yl)-dos(2.cyclohexenylethyl)-1_(2,4-dichlorophenyl ratio _3_methanamine preparation except the final step of the crude carboxylic acid gas (1 〇〇 mg, 0. 17 mmol) is 2-cyclohexenylethylamine (15. 3 //L, 0. 11 mmol) and triethylamine (15. 7 25 # L,0. The preparation of the remaining compound 21 was similar to that of Example 14 of the above-mentioned 34 200804365, thus obtaining a white solid compound 21 (50 mg, 85%) ° W-NMR (CDC13, ppm): 7. 53 (d, 1H), 7. 42 (d, 1H), 7. 39 (s, 1H), 7. 16 (d, 1H), 6. 98 (d, 1H), 6. 86 (brs, 1H), 5. 49 (brs, 5 1H), 3'51 (q, 2H), 2. 22 (t, 2H), 1. 97- 1. 53 (m, 8H).  ES-MS (M+l): 649. 8.  κ细*Example 22, compound 22 · 4->gt; odor-5-(5-&gt; odorant phen-2-yl)-TV-cycloheptyl-1-(2,4-dichlorophenyl)_ Preparation of the product than the salino-3-carbamide 10 except for the final step of the crude carboxylic acid chloride (50 mg, 0. 07 mmol) is cycloheptylamine (12·4 // L, 0·11 mmol) and triethylamine (ΐ5·7 //L, 0. The procedure for the preparation of the other compound 22 was similar to that of the above Example 14 to give a white solid compound 22 (48 mg, 82%) 〇 15^-NMR (CDC13? ppm): 7. 50 (d5 1H) 5 7. 47 (brs5 1H)? 7·35 (d, 1H), 7. 33 (brs, 1H), 7. 15 (d5 1H), 6. 81 (d, 1H), 3. 25 (t, 2H), 2. 66 (brs, 2H), 2. 49 (d, 2H), 2. 45 (s, 3H), 1. 66-Γ 49 (m5 6H).  ES-MS (M+l): 637. 8.  20 Example 23, Compound 23: 4-bromo-5-(5.bromoselenophene-2-yl)-(2-adamantyl)-l-(2,4-diphenyl)-1/ /-°Compared to the preparation of salino-3-decylamine except for the final step of the crude carboxylic acid chloride (50 mg, 〇·〇7 mm〇i) is 1-adamantylethylamine (226 //L, O . Ll mmol) and triethylamine (157 # 25 L,0. The preparation of the remaining compound 23 was similar to that of the above-mentioned 35 200804365 Example 14 to give a white solid compound 23 (48 mg, 75%). iH-NMR (CDC13, ppm): 7. 53 (brs, 1H), 7. 41 (brs, 1H), 7. 40 (s, 1H), 7·15 (d, 1H), 6·98 (d, 1H), 6.74 (d, 1H), 3. 90 5 (dq, 1H), 1·98 (brs, 3H), 1. 75-1. 52 (m, 10H), 1. 11 (d, 3H).  Example 24, Compound 24: 4-bromo-5-(5-bromoselenophen-2-yl)-1-(2,4-dichlorophenyl)-, ((112!1, 511)_6,6 -Preparation of dimethylbicyclo[3丄1]heptan-2-yl)methyl)-Ifpyrazole-3-decylamine 10 except for the final step of the crude carboxylic acid chloride (50 mg, 0. 07 mmol) is ((1R,2R,5R)_6,6-dimethylbicyclo[3·1·1]heptan-2-yl)decylamine ((lR,2R,5R)-6,6 -dimethylbicyclo[3 · 1 · 1 ]heptan-2-yl)methanamine, 16. 1 # L,0· 11 mmol) and triethylamine (15. 7 // L,0. The preparation of the remaining compound 24 was similar to that of the above-mentioned Example 14 except that 11 mmol of the compound was obtained, and thus the white solid compound 24 (45 mg, 73%) was obtained. ^-NMR (CDC135 ppm): 7. 51 (d, 1H) 5 7. 37 (d? 1H), 7. 33 (s, 1H), 7. 12 (d, 1H), 6. 95 (d, 1H), 6. 84 (brs, 1H), 3. 50-3. 29 (m, 2H), 2. 35-2. 22 (m, 2H), 1. 93-1. 80 (m, 7H), 1. 16 (s, 3H), 1·〇3 (s, 3H).  20 ES-MS (M+l): 677. 8.  Example 25, Compound 25: (4-Bromo-5-(5-bromoselenophene-2-yl)-l-(2,4-dichlorophenyl)-pyrazol-3-yl) (octahydrogen) Preparation of isoquinoline-2(1//)•yl)methanone except the final step of the crude carboxylic acid gas (50 mg, 0. 07 mmol) is 25 with decahydroisoquinoline (15. 3 //L, 〇·11 mm〇i) and triethylamine (15. 7 //L, 36 200804365 O. UmmoD treatment of the remaining compound 25 preparation steps are similar to the method of the above example i 4, so that a white solid compound 2 5 (3 $ melon, 65%) 〇 ^H-NMRCCDCls, ppm) can be obtained: 50 (d}1H)5 7. 33-7. 31 (m52H)5 5 7. 13 (d, 1H), 6. 98 (d, 1H), 4. 79 (d, 1H), 4. 62 (d, 1H), 3. 92 (d, 1H)} 3. 76 (d 51H), 3. 08 (dt, 1H), 2. 76-2. 65 (m5 2H), 2. 35 (t, 1H), 1·70-0·95 (m, 8H) ES-MS (M+l): 663. 8.  10 Example 26, Compound 26: 4-bromo-5-(5-bromoselenophene-2-ylindenyl-l-(2,4-one gas-based ratio. Preparation of sit-araminide except for the final step The crude carboxylic acid chloride (5 〇 mg, 〇〇 7 mm 〇 1) is n-decylamine (49. 5 /zL,0. 27mmol) and triethylamine (38·6 #L, 〇. The procedure for the preparation of the remaining compound 26 was similar to that of the above Example 14 15 to give the white solid compound 26 (88 mg, 80%) 〇H-NMR (CDC13, ppm): 7. 53 (d, 1Η), 7. 40 (d, 1Η), 7·39 (s, 1H), 7·15 (d, 1H), 6. 98 (d, 1H), 6. 86 (t, 1H) 3. 41 (q, 2H), 1·60_1·25 (m, 8H) 0_86 (t, 3H).  20 ES-MS (M+l): 667. 9.  Example 27, Compound 27: 5-(5-bromoselenophen-2-yl)-indolecyclopentyl-l-(2,4-chlorophenyl)-1dan-吼11 sitting-3 _ brewing The preparation of the amine will be the intermediate product 11 (a) prepared in Example 1 (200 mg, 0. 48 mmol) 25 Stir in acetonitrile and add a small amount of bromobutaneimine at 0 °C. 200804365 (NBS, 85 mg, 〇·48 mmol). After stirring for 1 hour in 〇0C, a saturated sodium sulfite solution was added. The solvent was evaporated and extracted with ethyl acetate. The product was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was separated, dried over anhydrous sodium sulfate and filtered and evaporated tolulululululululululululululululu Namely: 5-(5-bromo-selenophen-2-yl)-1-(2,4-dichloro-phenyl)-177- 11 唆-3-carboxylate (5-(5_bromo_selenophen-2-) Yl)-l-(2,4-dichl〇ro肇phenyl)-l_if-pyrazole-3-carboxylic acid ethyl ester), white solid (177 mg, 75%). L〇 A hydroxide clock (19 mg, 0.) dissolved in decyl alcohol (5 mL). 68 mmol) solution was added to the intermediate product H(e) (170 mg, 0.) dissolved in decyl alcohol (5 mL). 34 mmol) magnetically stirred in solution. The mixture was heated to reflux for 3 hours. It was then cooled, poured into water and acidified with 10% aqueous hydrochloric acid. Next, the precipitate is filtered off, washed with water and dried under vacuum to give intermediate product 111(e), 15: 5-(5-bromo-selenophen-2-yl)-1-(2,4- Dichlorophenyl)-1/7-pyrazole-3-carboxylic acid (5-(5-bromo-selenophen-2-yl)-l-(2,4-dichlorophenyl)-l//-pyrazole-3- Carboxylic acid), white solid (147 mg, 92%). The intermediate product 111(e) (100 mg, 0. 21 mmol) and chlorine sulfite (67. 1 // L,0. 92 mmol) was dissolved in toluene (5 mL) and refluxed for 3 h. Next, the solvent was evaporated to dryness under reduced pressure. The residue was dissolved in EtOAc (5 mL). The above crude carboxylic acid gas was dissolved in dichloromethane (5 mL) and added dropwise to a cyclopentylamine dissolved in 5 mL of dichloromethane at 0Q. 7 //L,0. 32 mmol) and triethylamine (44·6 μL, 0. 32 mmol) mixture 25 medium. Stir at room temperature for 3 hours and terminate the reaction with water. The water layer was opened at 38 200804365 and then extracted with dichloromethane (2 x 10 mL). The extract was washed with brine and dried over anhydrous sodium sulfate. (85 mg, 80%). 5 ^-NMR (CDC13? ppm): 7. 58 (d5 1H)? 7. 44 (brs5 2H), 7. 13 (d, 1H), 7. 08 (s, 1H), 6. 90 (d, 1H), 4. 42-4. 35 (m, 1H), 2. 09-2. 01 (m, 2H), 1. 71-1. 46 (m, 6H).  ES-MS (M+l): 531. 8.  10 Example 28, Compound 28: Indolecyclohexyl-l-(2,4-diphenyl)-4-methyl-5-(5-methylselenophen-2-yl)-1 ugly-pyrazole The preparation of 3-methylformamide will contain compound 16 (50 mg, 0. 08 mmol), methyl zinc chloride, 24. 0 μ L, 0. 24 mmol), tetrakis(triphenylphosphino), bar (tetrakis-triphenylphosphinopallidum, 5 mg, 0. A solution of 004 15 mmol) and tetrahydrofuran (THF, 5 mL) was refluxed for 24 hours. Then, the solvent was evaporated under reduced pressure. The residue obtained was purified by flash chromatography on hexane/ethyl acetate (5:1) to afford compound 28 (23 mg, 60%) as pale solid. h-NMR (CDC13, ppm): 7·49 (d, 1H), 7. 34 (brs, 1H), 20 7. 38 (brs, 1H), 6. 87 (d, 1H), 6. 81 (brs, 1H), 6·80 (d, 1H), 2. 50 (s, 3H), 2·48 (s, 3H), 2. 00-1. 98 (m, 2H), 1. 77-1. 50 (m, 8H).  ES-MS (M+l): 496. 0.  25 Example 29, Compound 29: (E)-4-bromo-5-(5-(pent-1-enyl)selenophene-2- 39 200804365 yl)-l-(2,4-dichlorophenyl Preparation of -7/-(hexahydrocyclopenta[c]11 to 1 (7 each-2(li7)-yl)- 1 oxazole-3-carboxamide) will be prepared in accordance with Example 14. Intermediate product 11 (d) (1 〇〇 mg 0 · 17 mmol), pent-1-ene acid (pent-l_enylboronic acid, 23. 2 ma 5 0. 20 mmol), tetrakis(triphenylphosphine) triphenylphosphinopallidum, 10 mg, 0. 008 mmol), and carbonic acid planing (110 mg, 0. A solution of 34 mmol) of dimethyl ether (DME, 5 mL) was refluxed for 3 h. Next, the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on hexane/ethyl acetate (5:1) to give the intermediate product IV as a pale 10 solid, ie, 4-bromo-l-(2,4-dibenzene. Base: 戍-1-Lty base)-Shishen 2 base]_ 1 ϋΓ· 0 ratio σ sit _3-formic acid 酉 ( (4-bromo-1 -(254-dichlorophenyl)-5-[((E) -5-pent-l-enyl)-s elenophen-2-y 1] - li/-pyr azole-3-carboxylic acid ethyl ester), pale solid (65 mg, 70%). 15 Compound 29 is prepared starting from intermediate IV, wherein the crude product of the tartrate chloride (50 mg, 0. 09 mmol) except for the last step is hexahydrocyclopenta-[c]pyrrole-2 (1 good)- Amine hydrochloride (23 mg, 0. 14 mmol) and triethylamine (32. 2 β L,0. The procedure for the preparation of the other compound 29 was similar to that of the above Example 14 to give a white solid compound 29 (40 20 mg, 72%) 〇 iH-NMR (CDC13, ppm): 7. 49 (d, 1H), 7·38_7·36 (m, 2H), 7. 08 (d, 1H), 6.84 (d, 1H), 6. 42 (d, 1H), 5·93 (dt, 1H), 3·31-3·26 (m, 2H), 2. 65-2. 56 (m, 4H), 2. 13- 1. 21 (m, 10H), 0. 90 (t5 3H).  40 25 200804365 Example 30, Compound 30: [4_Bromo-5-[5-((E)_2-cyclohexylvinylselenophen-2-yl]-l-(2,4-dichlorophenyl) Preparation of -1孖-pyrazol-3-yl]-piperidin-1-yl-fluorenone Compound 30 was prepared in a similar manner to the above Example 29, 5 but the pent-1-enylboronic acid was (5) -2_cyclohexylethyleneboronic acid ((E)-2-cyclohexylvinylboronic) instead of 〇^-NMR (CDC13, ppm): 7. 52 (s, 1H), 7. 39-7. 38 (m, 2H), 7. 11 (d, 1H), 6·87 (d, 1H), 6. 40 (d5 1H), 5. 91 (dd, 1H), 3.75 (brs, 2H), 3. 51 (brs, 2H), 1. 77-1. 07 (m, 6H).  10 Example 31, Compound 31·· 5-[5-(4-Chlorophenyl)-selenophen-2-yl]-indole-(2,4-chlorophenyl)-4-methyl-Ifpyrazole Preparation of 3-Carboxylic Cyclohexylamine Compound 31 was prepared in a similar manner to that of Example 29 above, but wherein the pent-1-iso-acid had to be 4-chlorophenylboronic acid 15 (4-chlorophenylboronic acid) )instead. ^-NMR (CDC13? ppm): 7. 50 (d? 1H) 5 7. 39^7. 28 (m3 7H)? 6. 82 (d, 1H), 3. 98-3. 91 (m, 1H), 2. 53 (s, 3H), 2. 02-1. 15 (m, 10H).  20 Example 32, Compound 32·· 4-Bromo-5-[5-((E)-2-cyclohexylethylene)-selenophen-2-yl]-1-(2,4-diphenyl) -1 Η-11 is prepared in a ratio of σ -3- carboxylic acid sigma -1-ylamine. Compound 31 is prepared in a similar manner to the above Example 29, but wherein pent-1-isoacid is required (5) -2-Cyclohexylethylene monoacid instead. iH-NMR (CDC13, ppm): 7. 55 (s5 1Η), 7. 52 (s, 1Η), 25 7·40-7·39 (m, 2H), 7·08 (d, 1H), 6·87 (d, 1H), 6. 40 (d, 1H), 41 200804365 5. 91 (dd, 1H), 2. 88 (t, 4H), 2. 07-0. 85 (m, 17H)· Example 33, Compound 33: 4-bromo-5·[5-((Ε)-2-cyclohexylvinyl)-selenophen-2-yl]-l-(2,4 -Preparation of dichlorophenylpyrazole-3-carboxylic acid hexylamine 5 Compound 33 was prepared in a similar manner to the above Example 29 except that pent-1-enylboronic acid was required to be (5)-2-cyclohexylethylene Replace with boric acid. h-NMR (CDC13, ppm): 7. 52 (d, 1Η), 7. 40-7. 39 (m, 2Η), 7. 09 (d, 1H), 6. 87 (d, 1H), 6. 40 (d, 1H), 5. 91 (dd, 1H), 3. 41 (q, 2H), 2. 07-1. 39 (m, 19H), 0. 88 (t, 3H).  10 Example 34, compound 34: 1-(4-bromo-5-(5-bromo-selenophen-2-yl)-l-(2,4-dichlorophenyl)-1 i/-σ -3-yl)-3-(°pyrazine-1 -yl)propanone-1,3·di S is prepared by dissolving in tetrahydrofuran (3 1111〇1·pyrrolidine) at -78 ° C. -1-yl-15 ethyl ketone (l-pyrrolidin-1-yl-ethanone, 21 mg5 0. The 18 mmol solution was added to a lithium bis(trimethylsilyl)amide, which was dissolved in tetrahydrogenethane (5 mL). 2 //L, 0·20 mmol) in the magnetically mixed solution. After stirring at the same temperature for 45 minutes, the crude product 1-(2,4-dichloro-phenyl) 4-bromo-5-(5-bromo 20-) obtained in the final step of the above Example 14 was added.西西吩-2-yl-li/-吼唆-3-weilic acid chloride (1-(2,4_(1丨(:111〇1*〇- phenyl)-4-bromo-5-(5-bromo -selenophen-2-yl-li/-pyrazole-3 -carboxylic chloride,100 mg,0. 17 mmol). After stirring at the same temperature for 30 minutes, the reaction was terminated with water. The aqueous layer was separated, and then extracted with ethyl acetate (2×10 mL). The extract was then washed with brine and dried over 25 anhydrous sodium sulfate. The mixture was concentrated to give a crude product to be hexane/acetic acid 42 200804365 ethyl ester (5 :1) Purification by flash column chromatography to obtain compound #34 (76 mg, 70%) of white solid. . ^-NMR (CDC13, ppm): 7. 54 (d5 1H) 5 7. 5〇 (d? 1H)? 7. 42-7. 39 (m, 2H), 7. 16 (d, 1H), 6·98 (d, 1H), 6. 05 (s ih) 5 4. 09 (s, 2H), 3. 58-3. 46 (m, 4H) 5 1. 99-1. 25 (m,4H)· ′ ES-MS (M+l): 737. 8.  Example 35, Compound 35: 3-(4-Bromo-5-(5.bromoselenophene-2-yl)+(2,4-dichlorophenylpyt-3-ylindole-diethyl_3 Preparation of ketone acrylamide 10 In addition to its crude product, chlorinated acid chloride (100 mg, 0.17 mmol) is lithium bis(trimethylsilyl)amide, 22 2 / / L, 0. 20 mmol) and diethyl-acetamide (A^iV-diethyl-acetamide, 21 mg, 0. The procedure for the preparation of the other compound 35 was similar to that of the above Example 34, so that a white solid compound 35 (81 mg, 75%) was obtained. 'H-NMR (CDC13&gt; ppm): 7. 54 (d? 1H)? 7. 50 (d5 1H) 5 7. 40-7. 39 (m, 2H), 7. 16 (d, 1H), 6. 97 (d, 1H), 6. 15 (s, ih), 4. 11 (s, 2H), 3, 45-3. 30 (m, 4H), 1. 25-1. 11 (m5 6H).  ES-MS (M+l): 639. 8.  20 Example 36, Compound 36: 1-(4-Bromo-5-(5-bromo-selenophen-2-yl)-l-(2,4-diphenylpyrazol-3-yl)-3- Preparation of (piperidin-1-yl)propane-1,3-dione except that its crude carboxylic acid gas (100 mg, 0.17 mmol) is lithium di(tridecyldecyl)amine (22·2) #L,0. 20 mmol) and 1-piperidin-1-yl-25 ethyl ketone (l_piperidin-l-yl-ethanone, 23 mg, 0. The procedure for the preparation of the remaining compound 36 was similar to that of the above-mentioned Example 34, whereby a white solid compound 36 (86 mg, 78%) was obtained. 'H-NMR (CDC135 ppm): 7. 54 (d5 1H) 5 7. 50 (d5 1H) 5 7. 42-7. 38 (m, 2H), 7·16 (d, 1H), 6. 98 (d, 1H), 6. 20 (s, 1H), 5 4. 16 (s5 2H)? 3. 60-3. 36 (m3 4H)? 1. 64-1. 23 (m5 6H).  ES-MS (M+l): 651. 8.  Example 37, Compound 37: 1-(4-Bromo-5-(5-bromoselenophen-2-yl)-l-(2,4-diphenyl)-177-pyrazol-3-yl) Preparation of -3-(3-methylpiperidine-indenyl)propane 4,^dione 1〇 except for its crude product (1〇〇mg, 〇17 mmol) Alkaloids 2 #L,0·20 mmol) and 1-(3-methyl-endaziridin-1-yl)-ethanone (l-(3-methyl-piperidin-i-yi)-ethanone, 26 mg, 〇 The preparation of the remaining compound 37 was similar to that of the above-mentioned 15 Example 34, so that a white solid compound 37 (81 mg, 72%) was obtained. H-NMR (CDC13, ppm): 7. 48 (brs, 1H), 7. 34 (brs, 2H), 7·1〇 (d, 1H), 6. 91(d,lH),6·14 (s,1H), 4. 37-4. 33 (m, 1H), 4. 10 (s, 1H), 3. 60-3. 50 (m, 1H), 2. 95-2. 21 (m, 2H), 1. 76-0. 79 2〇 (m, 8H).  Example 38, Compound 38: 3-(4-bromo-5. _(5•Bromoselenophene, anal two phenyl hydrazine sniffing winter base) &lt;Preparation of bis-isobutyl _3 ketopropanamide except for its crude carboxylic acid gas (1 〇〇 mg, Oi 7 mmol) is lithium bis(tri-25 fluorenyl) alkyl (22.2) // L, 0.20 mmol) and the following di-butyl-44 200804365 acetaminophen (A^iV-diisobutyl-acetamide, 32 mg, 0·18 mmol), the rest of the compound 38 preparation steps are the same as the above The procedure of Example 34 was similar to give a white solid compound 38 (94 mg, 80%). !H-NMR (CDC13, ppm): 7·44 (brs, 1H), 7.31 (brs, 2H), 5 7·09 (d, 1Η), 6.90 (d, 1H), 6.15 (brs, 1H), 4.05 (brs, 2H), 3.18-2.93 (m, 4H), 1.95-0.70 (m, 14H)· ES-MS (M+l): 695.8. Example 39, Compound 39: 1-((4-bromo -5-(5-bromoselenophen-2-yl)-bu(2,4-di- 10 chlorophenyl)-1 沁pyrazole-3-yl)methyl)-3-cyclohexylurea was prepared at 0 Lithium Hydrate (164 mg, 1.74 mmol) was added to a magnetically stirred solution of intermediate 11 (d) (500 mg, 0.87 mmol) dissolved in tetrahydrofuran (10 mL). Stir at the same temperature for 30 minutes and then terminate the reaction with water. The aqueous layer was separated and then extracted with ethyl acetate (2×10 mL). The extract was washed with brine, dried over anhydrous sodium sulfate and concentrated by filtration to give a crude product, which was dried in vacuo to give the intermediate product V as a white solid, (4-bromo-5-(5-bromosole) 2-yl)-1-(2,4-dichlorophenyl)-1//-pyrazol-3-yl)methanol ((4-bromo-5-(5-bromoselenophen-2-yl)-1 - (254-dichlorophenyl)-lii-pyrazol-3-yl)methanol, 438 mg, 95%) 〇20 Add triethylamine (127 //L, 0.89 mmol) to tetrahydroanthracene at 0 °C The intermediate product V (430 mg, 0.81 mmol) in m (10 mL) was magnetically mixed. Stir at the same temperature for 30 minutes and then add methanesulfonyl chloride (111 /zL, 0.97 mmol). It was then stirred at room temperature for 8 hours. The reaction was quenched with water and the aqueous layer was separated and extracted with ethyl acetate (2×10 mL). The extract was washed with brine and dried over anhydrous sodium sulfate s s s s s s s s s s s s s s s s s s s s s s s s Intermediate VI, 4-bromo-5-(5-bromo-selenophen-2-yl)-1-(2,4-dichloro-phenyl-r-but-3-ylmethyl ester of mercaptosulfonic acid (methanesulfonic acid 5 4-bromo-5-(5-bromo-selenophen-2-yl)-l-(2?4-dichloro-phenyl)-liir-pyrazol-3-ylmethyl ester 453 mg5 92%) ° ^- NMR (CDC13, ppm): 7.50 (d, 1H), 7.37 (d, 1H), 7.35 (s5 1H), 7.14 (d, 1H), 7.00 (d, 1H), 5.31 (s, 2H), 3.06 ( s, 3H)·,, sodium azide (96 mg, 1.48 mmol) was added to a magnetically stirred solution of intermediate VI (450 mg, 0.74 mmol) dissolved in dimethylformamide 10 (10 mL). The mixture was heated at 80 ° C for 3 hours, then cooled and quenched with water. The aqueous layer was separated and then extracted with ethyl acetate (2×10 mL). The extract was washed with brine and dried over anhydrous sodium sulfate. Concentrated by hydrazine to obtain a crude product, which was subjected to hexane/ethyl acetate (3:1). Purification by column flash chromatography to give intermediate VII, 3-azinomethyl-4-bromo-5-(5-bromo-selenophen-2-yl)-1-(2,4-) Dichloro-phenyl σ ratio. Sit (3- commit 1 (1〇11^111), 1-4-bromo-5-(5-bromo-selenophen-2-yl)-l-(2,4-dichloro -phenyl)-li/-pyrazole, 308 mg, 75%) 〇iH-NMR (CDCI3, ppm): 7.50 (d, 1H), 7.37 (d, 1H), 7.36 (s, 1H), 7.14 (d, 1H), 7·00 (d, 20 1H), 4.42 (s, 2H)· Triphenylphosphine (170 mg, 0.64 mmol) was added to tetrahydrogenate and water (10:1) The intermediate product VII (300 mg, 0.54 mmol) was stirred magnetically. After stirring at room temperature for 48 hours, it was extracted with ethyl acetate (2×10 mL). The extract was washed with brine and dried over anhydrous sodium sulfate Concentration by filtration afforded a crude product which was purified by flash chromatography eluting with EtOAc/EtOAc (4:1) -Bromo-selenophen-2-yl)-1-(2,4-dichloro-phenyl)-1 ugly-pyrazol-3-yl]-decylamine ([4-Bromo-5-(5- Bromo-selenophen-2-yl)-l-(2,4-dichloro-phenyl) -li/-pyrazol-3-yl]-methyl amine, 5 205 mg, 72%) ° Add cyclohexane isocyanate (14 pL, 0.10 mmol) to intermediate VIII in tetrahydrofuran (50 Mg, 0.09 mmol) in a magnetically stirred solution. After stirring at room temperature for 8 hours, the solvent was evaporated to dryness to give a crude product which was purified by flash chromatography on hexane/ethyl acetate (1:1). (41 mg, 70%). ^-NMR (CDC13, ppm)·· 7.50 (d,1H), 7.35 (d5 1H), 7 33 (s,1H), 7.13 (d,1H),6.96 (d,1H),4·42 (s , 2H), 1.87 Touch 0 '86 (m 10H). 3 ES-MS (M+l): 652.8. 15 Example 40, Compound 40: l-[l-(2,4-dichlorophenyl)- Preparation of 4-methyl-5_code phen-2-_2 carbazol-3-ylindenyl]-3 phenyl-urea In addition to its initial step, intermediate product 11(d) must be replaced by intermediate n(b) And the final step of the isogastric acid has been replaced by isocyanatotobenzene, and the other compounds 40 are prepared in the same manner as in the above Example 39, so that the compound 4 can be obtained. ^-NMR (CDC135 ppm): 8.01 (d5 1H)5 7.42 (brs5 1H) 7.36 (d,1H), 7.25-7.14 (m,6H),7.04 (d5 1H),6.97 (4 1H)' 6.09 (t , 1H), 4.49 (d, 2H), 2.17 (s, 3H). '25 ES-MS (M+l): 505.0; (M+23): 527.0. 200804365 Example 41, Compound 41: 1-( Preparation of (4-bromo-5-(5-bromo-selenophenyl)-indole-(2,4-dichlorophenyl)-1oxazol-3-yl)methyl)-3-propyl-urea Except that the final step of the isocyanate cyclohexane was replaced by propane cyanide, the other compound 41 preparation steps were similar to those of the above-mentioned embodiment, and thus Compound 41 was obtained. ^-NMR (CDC13, ppm): 7.52 (d,1H), 7.37 (d,1H), 7.35 (s,1H),7·15 (d,1H), 6.98 (d,1H), 5.01 (s, 1H),4·67 (s' 1H) 4.45 (d,2H),3.16-3.14 (m,2H),1.52-1.46 (m,'2H) 〇88 (t' Γ 3H)· ' , 10 ES- MS (M+l); 612.8; (M+23): 634.8. Example 42, Compound 42: 1-((4-bromo-5-(5-bromoselenophene-2-yl) Preparation of gas phenyl)-1 ugly-° than 嗤-3-yl) fluorenyl)-3-cyclohexyl thiourea In addition to the final step, the intermediate product VIII is isothiocyanatocyclo-hexane (isothiocyanatocyclo-hexane, The procedure for the preparation of the remaining compound 42 was similar to that of the above Example 39, whereby a white solid compound 42 (45 mg, 75%) was obtained. (CDC135 ppm): 7.52 (d? 1H)5 7.38^7.29 (m? 2H)? 7.14 (d,1H), 6.98 (d,1H),4·62 (s5 2H),1.94-1.65 (m,UH )·' 20 ES-MS (M+23): 690.8. 'Example 43, Compound 43: 1-[1-(2,4-Dichlorophenyl)_4_indolyl_54 s. In addition to the final step, the isocyanate ring p-alkane must be isothiocyanate. The other compound 43 was prepared in the same manner as in the above Example 4, except that the acid benzene was used instead of 25. Thus, Compound 43 was obtained. 48 200804365 h-NMR (CDC13, ppm): 8.03 (d, 1 Η), 7· 44 (d, ιΗ) 7.36-7.19 (m, 8H), 7.06 (d, 1H), 7.01 (brs, 1H), 4.90 (brs, 2H), 2.20 (s, 3H). ES-MS (M+23) ): 543.0. 5 Example 44, compound 44:, ((4-bromo-5-(5-bromo-selenophen-2-yldichlorophenyl)-1-polyoxazol-3-yl)methyl) ring Preparation of hexane decylamine Triethylamine (15 // L, 0.10 mmol) and cyclohexanecarbonyl chloride (18 //L, 〇·12 mmol) were added to dissolve 10 in dichloro Methane intermediate VIII (50 mg, 0.09 mmol) was magnetically stirred in the solution. After stirring continuously for 8 hours at room temperature, the reaction was terminated with water. The aqueous layer was separated and then extracted with dichloromethane (2×10 mL). The extract is then washed with brine and dried over anhydrous sodium sulfate, and concentrated to give a crude product, which is purified by flash chromatography on hexane/ethyl acetate (3:1) to give a white solid. Compound 44 (46 mg, 80%). iH-NMR (CDC13, ppm): 7.53 (d, 1H), 7.39 (d, 1H), 7.38 (s, 1H), 7.16 (d, 1H), 7.00 (d, 1H), 6.10 (brs, 1H) , 4.55 (d, I 2H), 2.16 (dt, 1H), 1.96-1.22 (m, 10H)· ES-MS (M+l): 637.8. 20 Example 45, Compound 45: iV_((4·Br Preparation of 5-(5-bromoselenophenan-2yl)_1-(2,4-dichlorophenylpyrazol-3-yl)methyl)cyclopentanecarbamide except for the intermediate VIII The preparation of the remaining compound 45 is similar to that of the above example 44, except that the amine (15 /z L, 0.10 mmol) and cyclopentanecarbonyl chloride (16 // L, 0.12 25 mmol) are treated. Compound 45 (41 mg, 49 200804365 73%) was obtained as a white solid. iH-NMR (CDC13, ppm): 7.49 (d, 1H), 7.35 (s, 1H), 7.34 (d, 1H), 7.12 (d,1H), 6.96 (d,1Η) 6·12 (brs,1H),4.52 (d 2H),2.58-2.53 (m,1H),1.90-1.50 (m,8H)· ? 5 ES- MS (M+l): 623.8. Example 46, in vitro assay The 45 test compounds of the invention were tested for receptor affinity I binding to CB1 and CB2 using an in vitro competitive radioligand receptor binding assay. The method of the present invention discriminates the binding ability by distinguishing the substitution ability of each compound for the radioligand of the receptor. A compound having a higher affinity for the receptor than the radioligand will replace the ligand with the receptor, and the radioligand is more Compounds with low or no affinity are not able to replace the ligand. Radiographic readings can be used for further receptor binding analysis and to help predict the drug activity of the test compound. 15 This test is based on male Sprague-Dawley rats. The brain and spleen extracts are used as CB1 and CB2 receptor sources. Male Sprague-Dawley rats weighing 175 to 200 g are used, and food and water are freely supplied for feeding under standard conditions. Cervical dislocation is used. The animals were sacrificed and the brain and spleen without cerebellum were removed. The brain and spleen tissues of the cut-off 20 were respectively placed in a Polytron hand-held homogenizer, and 10 volumes of ice-cold buffer A (50 mM) were added. Tris, 3 mM MgCl2, 2.5 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4, 10% sucrose) Of. The homogenate was centrifuged at 2000 x g for 4 minutes at 4 °C. The suspension was centrifuged at 43,000 xg and 4 ° C for 30 minutes. The final pellet was resuspended in buffer 50 200804365 solution A and stored at -80 °C. The protein concentration of the purified membrane was determined by the Bradford method mentioned in the manual of Bio-Rad Laboratories, Inc., Hercules, CA. In the receptor binding assay, 〇·2~8 pg membrane system was 0.75 nM 5 [3H]CP55,940 and test compound in culture buffer (50 mM Tris-HCl, 5 mM MgCl2, 1 mM EDTA, 0.3% BSA). Cultured in pH 7.4). Non-specific binding values were measured on CP55,940 with 1 μΜ. The mixture was placed in a Multiscreen microplate (Millipore, Billerica, MA) and incubated at 30 ° C for 1.5 hours. After the end of the incubation, the effect was terminated with a Manifold filtration system, 10 and rinsed four times with ice-cold wash buffer (50 mM Tris, pH 7.4, 0.25% BSA). The radiation value on the paper was measured by Topcount (Perkin Elmer Inc.). The concentration of the desired compound which inhibits 50% of [3H]CP55,940 binding is calculated to obtain an IC5 enthalpy. The efficacy of each test compound was tested using a DELFIA GTP· Binding Assay System (Perkin Elmer Inc., 15 Boston, ΜΑ). The DELFIA GTP-binding assay is a time-resolved fluorescence assay that activates G-protein coupled receptors by agonists, thereby allowing G-protein subunits to undergo GDP-GTP exchange. This method observes the activation of the agonist of the G protein by Eu-GTP. Activation of the CB1 receptor by CP55,940 results in 20 generations of GDP on the alpha subunit of the G protein. The GTP-Ga complex represents the activation form of the G protein. Eu-GTP (non-hydrolyzable GTP analog) can be used to quantify the activation of G protein (Peltonen et al. 5 Eur. J. Pharmacol. (1998) 355:275) ° Resuspension of HEK293 cell membrane expressing human CB1 in assay Buffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 100 // g/mL saponin, 51 200804365 5 mM MgCl2, 2 # M GDP, 0.5% BSA). An equal amount of sample (4 // g protein/well) was added to each well of AcroPlate (Pall Life Sciences, Ann Arbor, MI). After the test compound (different concentrations in 〇·1% DMSO) and CP55,940 (20 nM in assay buffer) were added, the assay plate was placed in the dark and shaken at 30 ° C for 60 minutes. to cultivate. Next, Eu-CiTP was added to each well, and the assay plate was placed in the dark, and cultured at 30 ° C for 35 minutes. Finally, the assay plate was washed four times with the wash solution provided by the assay system to terminate the effect. Fluorescence signals were measured using a Victor 2 multi-label reader to identify the binding amount of Eu-GTP. The IC5 enthalpy of each compound was obtained by a concentration curve of nonlinear regression (Prism; GraphPad, San Diego, CA) (i.e., inhibition of 50% of 〇卩55,940_activated Eu-GTP binding). In the CB1 receptor binding assay, all test compounds were found to have IC50 values less than 10/zM. In particular, 32 test compounds were found to have an IC5 〇 value of less than 1 // 于 in the CB1 receptor 15 binding assay. Among them, the IC5 enthalpy of the 15 test compounds was between 0.005 and 0.1 // Μ. In addition, IC5G values measured by all test compounds in the CB2 receptor binding assay ranged between 0.2 and 20/zM. The Eu-GTP binding assay can also serve as an indicator of the effect of the compound and the CB1 receptor, and the test results are in agreement with the above-mentioned CB1 radioligand receptor binding assay 20 test results. Other Embodiments All of the features disclosed in this specification can be combined in any manner. Features disclosed in this specification can be replaced by the same, equivalent, or similar purpose. Therefore, unless otherwise indicated, the features are merely examples of the general equivalent or similar features. And the present invention can be easily understood by those skilled in the art from the above description, and various changes and modifications can be made to the present invention without the invention. To suit a variety of uses and situations. Therefore, other specific embodiments are also within the scope of the present patent application. [Simple description of the diagram] None 10 [Description of main component symbols] None 53

Claims (1)

200804365, the scope of application for a patent of the compound of formula (I): R4R3 wherein, R) hydrogen: Cl-C 10 alkyl, C2-Cl° alkenyl, C 2 —Cl° alkynyl, c3-c 2 . = base = cycloalkenyl, Cl_C2. Heterocyclic alkyl, c-, aryl, or heteroaryl; hydrogen, CVC1 () alkyl, C2-c1() alkenyl, c2-c10, Γ Γ = yl, cvc20 cycloaliphatic, Cl -C20 heterocycloalkyl, W-yuan, 2, anthracene, heterocyclyl, _, 〇Ra, (10)Ra, 〇c(9)Ra (10) hui b, or b), wherein each Μ 独立 is independently 7, 10 , 匸 匸 匸 匸 环 环 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , C2-Cl()alkenyl, C2-"alkynyl, c3-c2^alkyl, C3_C2Gcycloalkenyl, heterocycloalkyl, 〇1&lt;20 heterocycloalkenyl, aryl, or heteroaryl. 2 The compound of claim 2, wherein Ri is a halogen-substituted aryl group. 3. The compound of claim 2, wherein the center is 20 2,4-dichlorophenyl. 4. A compound according to claim 3, wherein r2 is C(0)NRaRb, c(〇)Ra, or Ci_C2〇 heterocycloalkyl, NHC(〇)NReRd, 54 200804365 NHC( S) NRcRd, gamma c (〇) Rc replaced by c-heart group, its center and two: "stand for hydrogen, Cl_c' base Oh. Ring, GAO heterocycloalkyl, aryl, or heteroaryl. 5 10 15 5 5. The compound of claim 4, wherein the compound is C(〇)NRaRb, which is a τ group substituted by 6_6 dimethylbicyclo[m]heptyl, via a diamond or a cyclohexane Ethylenyl substituted ethyl, hexyl, decyl, cyclopentyl, cyclohexyl, cycloheptyl. ratio. A compound according to claim 5, wherein the compound is a compound 1, 3-17, 19_24, or a tetrahydronaphthyl group, and Rb is hydrogen. One of 26_29, and 31_33. 7. The compound of claim 4, wherein the compound is C(〇)Ra, which is 1 为, pyridyl, tetrahydroquinoline, decaquinium quinoline Or a methyl group substituted by c(〇)R or C(0)NRR'; wherein R is ethyl, isobutyl, pyrrolidinyl, or pyridyl optionally substituted with methyl, R is an ethyl group or an isobutyl group. The compound of claim 7, wherein the compound is one of the compounds 2, 18, 25, 30, and 34-38. The compound of claim 4, wherein R2 is 1-methylimidazolidinone, 1-cyclohexyl imidazolidinone, phenylphenylimidazolidinone, 20 NHC(〇)NRcRd, NHC(S) NRcRd, or NHC(0)Re substituted Cl-Cl oxime 'wherein Rc is propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl, And Rd is hydrogen. The compound of claim 9, wherein the compound is one of the compounds 39-45. 55 200804365 化合物. The compound of claim 1, wherein the compound is C(0)NRaRb, c ( 〇)Ra, or a Ci_Ci fluorene group substituted by Cl_C2G heterocycloalkyl, ΝΗ(::(〇)νκ^, NHC(S)NRcRd, or NHC(〇)Re, the generation and the Rd are each independently hydrogen, CVCw alkyl, (^-(^cycloalkyl, Ci_C2g heterocyclic 5-alkyl, aryl, or heteroaryl. 12. The compound of claim 11, wherein 2 is C(0) NRaRb, wherein Ra is a methyl group substituted with 6_6 dimethylbicyclo[311]heptyl, ethyl, hexyl, decyl, cyclopentyl, cyclohexyl, cycloheptyl, substituted with adamantyl or cyclohexene, a pyridyl group, a morpholinyl group, an octahydrocyclopentaazole, a 10 or a tetrahydronaphthyl group; and Rb is a hydrogen. 13 A compound according to claim 11 wherein C(0)Ra, Ra a methyl group substituted with π-bite, tetrahydroindenyl, decahydrolin, or c(〇) or C(0)NRR'; R is ethyl, isobutyl, pyrrolidinyl, or selected Acridine substituted with methyl And R, which is an ethyl group or an isobutyl group. The compound according to claim 11, wherein the rule 2 is 1-mercaptoimidazolidinone, K cyclohexyl imidazolidinone, phenyl Imidazoline _, NHC(0)NRcRd, NHC(S)NRcRd, or NHC(0)Re substituted CVC1() alkyl group' wherein Rc is propyl, cyclopropyl, butyl butyl, cyclopentyl, cyclohexyl , cycloheptyl, cyclooctyl, or phenyl; and Rd is hydrogen. 20 15. A method of treating a cannabinoid receptor-related disease comprising administering to a receptor an effective amount of a compound of formula (I): Among them, 56 200804365 wind, Cl-Cl. Burning base, C2-Ci. Alkenyl, CrCi. Block base, c3_c2, alkyl group, c3_c2q loop wire, Ci_C2. Heterocyclic alkyl, hydrazine. Heterocyclic, aryl or heteroaryl; R2 is hydrogen, CVC10, c2_Cig, C2_Ci〇, ring: cyclyl, cyclyl, Cl_c2. a heterocyclic alkyl group, a hetero group, a heteroaryl group, ", (10) a, c_a, oc (9) Ra C (9) fluorene b, or a paper Rb, wherein each oxime is independently a chlorine, a CVCiA group, a c3_c2 () cycloalkyl group, a Ci_c2 noisy group Cycloalkyl, aryl, aryl; and / ' 3 R4 5 and anti 6 are each independently hydrogen, halogen, Ci_Ci 〇 = 2 1 Ό dilute, C 2 _Cl () fast radical, c 3 - c 2 yf alkyl, C 3 C 2 C ring Alkenyl, ^2. Heterocyclic silk, Cl_C2. A hetero-based, aryl, or heteroaryl group. 16. The method as described in (4) (4), wherein Ri is a halogen-substituted aryl group. 15 20 α as described in claim 16 of the patent scope 2,4-dichlorophenyl. A. The method of claim 15, wherein Μ()RaRb C(0)Ra, or Ci_c2() heterocycle appearance, 丽^(9), NHC(8)NRelld, or NHC(〇)Re Ci_Ci. A burning group, wherein each of I and d is independently hydrogen, Ci_Ci. Burning base, c3_c2. Cycloalkyl, Ci_C2. Heterocyclic alkyl, aryl, or heteroaryl. 19. The method of claim 18, wherein ^ is C(9)NRaRb', wherein Ra is substituted by 6-6 dimethylbicyclo[3.i.heptyl substituted methyl, substituted with adamantyl or cyclohexene Ethyl, hexyl, decyl, cyclopentyl 57 200804365, cyclohexyl, cycloheptyl, π-bityl, morphinyl, octahydrocyclopentaquinol, or tetrahydronaphthyl; and Rb is hydrogen. 20. The method of claim 18, wherein 1 is C(0)Ra', wherein Ra is π-pyridyl, tetrahydroquinoline, decahydroquinoline, or c(〇)R 5 or C(0)NRR, substituted methyl; wherein R is ethyl, isobutyl, pyrrolidinyl, or pyridyl optionally substituted with fluorenyl, and R is ethyl or isobutyl. 1) The method of claim i, wherein R2 is 1-methylimidazolidinone, work-cyclohexyl imidazolidinone, phenylphenylimidazolidinone, NHC(0)NReRd, anaesthesia (8) NReRd Or NHC(9)R. Replace Cl%. And a phenyl group; wherein Rc is propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl; The method of claim 11, wherein the cannabinoid receptor-related disease is a hair loss, an obesity, a metabolic syndrome, a high: a month, a type 2 diabetes, an atherosclerosis Symptoms, substance addiction disorder, worry syndrome, motivation-deficient syndrome, learning f or memory dysfunction, analgesia, gram, ischemia, cirrhosis, erectile dysfunction, neuralgia, sexual disease, or inflammatory disease. Cancer, neurodegenerative The 22nd item of the sin receptor range is obesity, metabolic syndrome, neuralgia, or inflammatory disease. It is a disease of prostate cancer, lung cancer, breast cancer, or head and neck cancer. ...cancer 58 200804365 VII. Designated representative map: (1) Representative representative of the case: None. (2) A brief description of the symbol of the representative figure: None. 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Wherein Ri, R2, R3, R4, R5, and R6 are as defined in the specification. 4